MONDO:0002012

[PMID:35348993] [SUPPORT] Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. --- Explanation: Directly supports developmental delay risk in MMA.

[PMID:35348993] [SUPPORT] Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85 --- Explanation: Quantifies intellectual impairment severity by MMA subtype.


MONDO:0002012

[PMID:35348993] [SUPPORT] Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. --- Explanation: Supports cognitive difficulties as a key feature of MMA.


MONDO:0002012

[PMID:35348993] [SUPPORT] Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism associated with life-threatening acute metabolic decompensations and significant neuropsychological deficits. --- Explanation: Severe metabolic decompensation is associated with seizure risk and neurological injury.


MONDO:0002012


MONDO:0002012

[PMID:37243446] [SUPPORT] It is characterized by life-threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. --- Explanation: Directly identifies CKD as a characteristic complication of MMA.

[PMID:37169781] [SUPPORT] Chronic kidney disease (CKD) is a well-known long-term complication. --- Explanation: Confirms CKD as an established long-term complication.


MONDO:0002012

[PMID:38132258] [SUPPORT] Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) --- Explanation: Quantifies DCM as the predominant cardiac phenotype in OA patients including MMA.

[PMID:38132258] [SUPPORT] 35% in MMA with cardiomyopathy --- Explanation: Quantifies 5-year MACE rate in MMA patients with cardiomyopathy.


MONDO:0002012

[PMID:38132258] [SUPPORT] Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). --- Explanation: Directly reports acquired long QT syndrome in OA patients including MMA.


MONDO:0002012

[PMID:38271099] [SUPPORT] A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat --- Explanation: Directly identifies a novel lipodystrophy phenotype in MMA patients.


MONDO:0002012

[PMID:25205257] [INDIRECT EVIDENCE] [SUPPORT] Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). --- Explanation: Supports proximal enzyme/cofactor molecular defects as the initiating mechanism in MMA.


MONDO:0002012

[PMID:25205257] [INDIRECT EVIDENCE] [SUPPORT] Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). --- Explanation: Supports blocked methylmalonyl-CoA handling and downstream metabolite accumulation.

[PMID:38030482] [INDIRECT EVIDENCE] [PARTIAL] MMA is normally present at low levels in the body, but increased levels can come from different sources, such as vitamin B12 deficiency, genetic mutations in enzymes related to the propionate pathway --- Explanation: Opinion/review source providing supportive context for propionate-pathway genetic etiologies.


MONDO:0002012

[PMID:37078237] [INDIRECT EVIDENCE] [SUPPORT] While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. --- Explanation: Supports metabolite-driven mitochondrial dysfunction as central to pathophysiology.


MONDO:0002012

[PMID:37078237] [INDIRECT EVIDENCE] [SUPPORT] new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA --- Explanation: Directly supports hyperacylation/methylmalonylation and reduced sirtuin deacylation as key pathomechanism.


MONDO:0002012

[PMID:38760822] [INDIRECT EVIDENCE] [SUPPORT] Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. --- Explanation: Demonstrates lysosomal-autophagy dysfunction and pharmacological reversibility in MMA cellular models.


MONDO:0002012

[PMID:37169781] [INDIRECT EVIDENCE] [SUPPORT] Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission. --- Explanation: Directly demonstrates impaired mitophagy and fission shift in renal MMA cells.

[PMID:37169781] [INDIRECT EVIDENCE] [SUPPORT] Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells. --- Explanation: Supports compromised antioxidant defense in renal MMA cells.


MAXO:0000088

[PMID:25205257] [SUPPORT] Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. --- Explanation: Directly supports low-protein dietary therapy for MMA management.


MAXO:0000058

[PMID:25205257] [SUPPORT] Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. --- Explanation: Supports genotype-dependent cobalamin responsiveness in MMA management.

[PMID:39075538] [SUPPORT] NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12 --- Explanation: B12 responsiveness identified as a key factor in NBS-detected MMA outcomes.


MAXO:0000058

[PMID:25205257] [SUPPORT] Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. --- Explanation: Directly supports carnitine supplementation in MMA management.


MAXO:0000950

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia --- Explanation: Supports need for urgent supportive crisis management during acute decompensation.


MAXO:0010039

[PMID:33422927] [SUPPORT] Liver transplantation (LT) and combined liver and kidney transplantation (CLKT) have been proposed as enzyme replacement therapies for methylmalonic aciduria (MMA). --- Explanation: Directly supports transplantation as an established therapeutic strategy.

[PMID:33422927] [SUPPORT] The pooled estimate rates were 99.9% (95% CI 95.3-100.0) for patient survival, 98.5% (95% CI 91.5-100.0) for graft survival after LT/CLKT. --- Explanation: Quantifies favorable survival outcomes after transplantation.

[PMID:38132258] [SUPPORT] Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. --- Explanation: Supports liver transplantation for metabolic and cardiac stabilization.


MAXO:0000079

[PMID:25205257] [SUPPORT] MMA has an estimated incidence of ~ 1: 50,000 --- Explanation: Genetic etiology and defined inheritance pattern support the role of genetic counseling.


MAXO:0000058

[clinicaltrials:NCT04899310] [SUPPORT] This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency. --- Explanation: Directly supports active interventional testing of mRNA-3705 in MUT-deficient isolated MMA.

[clinicaltrials:NCT05295433] [SUPPORT] The primary objective of this study is to evaluate the long-term safety and clinical activity of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in other clinical studies of mRNA-3705. --- Explanation: Supports long-term extension evaluation of mRNA-3705 in the same MMA population.

[PMID:37243446] [SUPPORT] Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte-targeted genomic therapies. --- Explanation: Supports the rationale for hepatocyte-targeted therapies including mRNA replacement.

[PMID:37243446] [SUPPORT] A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA. --- Explanation: Supports biomarker-based clinical trial design for emerging MMA therapies.


hgnc:7526


hgnc:18871

[PMID:35348993] [SUPPORT] These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions. --- Explanation: Identifies cblA as a defined enzymatic subtype of MMA.


hgnc:19331

[PMID:37243446] [SUPPORT] Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut-type (N = 91), cblB-type (15), and cblA-type MMA (17) --- Explanation: Identifies cblB as a defined subtype with distinct severity profile.


MONDO:0005277

[PMID:37495957] [SUPPORT] In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. --- Explanation: Demonstrates that cortical spreading depression directly induces headache-related behaviors in animal models.

[PMID:39080518] [SUPPORT] We propose that neuronal stress induced by CSD or synaptic activity-energy mismatch may initiate a parenchymal inflammatory signaling cascade, transmitted to the meninges, thereby triggering lasting headaches characteristic of migraine, with or without aura. --- Explanation: Explains the mechanistic pathway from neuronal stress to the characteristic lasting headaches of migraine.


MONDO:0005277

[PMID:35322292] [SUPPORT] The coexistence of photophobia and headache is associated with the interactions between visual and pain pathway at retina, midbrain, thalamus, hypothalamus and visual cortex. --- Explanation: Describes the neuroanatomical basis for photophobia in migraine through visual-pain pathway interactions.


MONDO:0005277

[PMID:33305448] [SUPPORT] Higher amplitudes of BAEP waves in migraineurs and their relationship with the frequency of headache and HT suggest the sensitization of brainstem auditory neurons. --- Explanation: Demonstrates that phonophobia in migraine is associated with sensitization of brainstem auditory neurons, as evidenced by higher brainstem auditory evoked potential amplitudes.


MONDO:0005277

[PMID:39080518] [SUPPORT] After a single CSD, astrocytes respond by upregulating the transcription of proinflammatory enzymes and mediators, while microglia are involved in restoring neuronal structural integrity; however, repeated CSDs may prompt microglia to adopt a pro-inflammatory state. --- Explanation: Neuroinflammatory responses to CSD contribute to the full range of migraine symptoms including autonomic features like nausea through central nervous system activation.


MONDO:0005277

[PMID:39080518] [SUPPORT] PET studies utilizing inflammation markers have revealed meningeal inflammatory activity in patients experiencing migraine with aura, particularly over the occipital cortex generating visual auras. --- Explanation: Demonstrates that visual auras in migraine are associated with inflammatory activity localized to the occipital cortex, the brain region responsible for visual processing.


MONDO:0005277

[PMID:38619053] [SUPPORT] Vestibular migraine is an underdiagnosed migraine phenotype that shares the pathophysiological mechanisms of migraine, with growing interest in recent years. --- Explanation: Establishes vestibular migraine as a recognized migraine phenotype where vertigo is a prominent symptom.

[PMID:37889468] [SUPPORT] There is evidence of abnormal sensory processing and integration in VM patients. Calcitonin gene-related peptide (CGRP) has also been found to play a role in trigeminal and vestibular nucleus pathways. --- Explanation: Links vestibular symptoms to abnormal sensory processing and CGRP signaling in vestibular pathways.


MONDO:0005277

[PMID:37495957] [INDIRECT EVIDENCE] [SUPPORT] Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. --- Explanation: Establishes CSD as the neurophysiological basis of migraine aura and its role in activating trigeminal pain pathways.

[PMID:37495957] [INDIRECT EVIDENCE] [SUPPORT] In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. --- Explanation: Demonstrates that CSDs directly induce headache-related behaviors in animal models, supporting CSD's role in headache initiation.

[PMID:37495957] [INDIRECT EVIDENCE] [SUPPORT] Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release. --- Explanation: Shows that pannexin-1 channels mediate CSD-induced neuroinflammatory signaling and headache behaviors, identifying a key mechanism linking CSD to pain.

[PMID:39080518] [INDIRECT EVIDENCE] [SUPPORT] Neuronal pannexin-1 channels act as stress sensors, initiating the inflammatory signaling by inflammasome formation and high-mobility group box-1 release in response to transient perturbations such as cortical spreading depolarization (CSD) --- Explanation: Explains the molecular mechanism by which CSD triggers neuroinflammation through pannexin-1 channels and HMGB1 release.


MONDO:0005277

[PMID:37487740] [INDIRECT EVIDENCE] [SUPPORT] CSD is also thought to drive the headache phase in migraine by promoting the activation and mechanical sensitization of trigeminal primary afferent nociceptive neurons that innervate the cranial meninges. --- Explanation: Confirms that CSD drives trigeminovascular activation leading to headache phase in migraine.

[PMID:39080518] [INDIRECT EVIDENCE] [SUPPORT] Studies in rodents have demonstrated that sterile meningeal inflammation can stimulate and sensitize meningeal nociceptors, culminating in headaches. --- Explanation: Shows that meningeal inflammation activates and sensitizes trigeminal nociceptors, producing headache.

[PMID:39080518] [INDIRECT EVIDENCE] [SUPPORT] The parenchymal neuroinflammatory signaling involving neurons, astrocytes, and microglia, which eventually extends to the meninges, can link non-homeostatic perturbations in the insensate brain to pain-sensitive meninges. --- Explanation: Describes the pathway by which brain parenchymal inflammation extends to activate pain-sensitive meningeal structures and trigeminal afferents.


HGNC.SYMBOL:CACNA1A

[PMID:38508838] [SUPPORT] Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain --- Explanation: CACNA1A encodes a voltage-gated calcium channel involved in ion transport and neurotransmitter release, and is one of the established causative genes for familial hemiplegic migraine.


HGNC.SYMBOL:ATP1A2

[PMID:38508838] [SUPPORT] Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain --- Explanation: ATP1A2 encodes a Na+/K+-ATPase involved in ion transport, and is one of the established causative genes for familial hemiplegic migraine type 2.


HGNC.SYMBOL:SCN1A

[PMID:38508838] [SUPPORT] Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain --- Explanation: SCN1A encodes a voltage-gated sodium channel involved in ion transport, and is one of the established causative genes for familial hemiplegic migraine type 3.


HGNC.SYMBOL:TRPM8

[PMID:31873179] [SUPPORT] TRPM8 is highly expressed in migraine and pain neuronal circuitry, such as trigeminal and dorsal root ganglia --- Explanation: TRPM8 is expressed in pain-related neural circuitry and genetic variants near TRPM8 are associated with altered migraine risk.


HGNC.SYMBOL:LRP1

[PMID:21666692] [SUPPORT] rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. --- Explanation: GWAS of 5,122 migraineurs identified LRP1 SNP rs11172113 as genome-wide significant for migraine susceptibility.

[PMID:21666692] [SUPPORT] LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology. --- Explanation: LRP1's role in neuronal glutamate signaling provides mechanistic link to migraine.


MONDO:0012172

[PMID:31730477] [SUPPORT] Included studies suggested fewer heart and liver problems in screen-detected patients, but inconsistent results for mortality. --- Explanation: Supports cardiomyopathy as a significant MTP complication mitigated by early screening.

[PMID:34543737] [SUPPORT] Severe form is generally characterized by multiorgan involvement. --- Explanation: Cardiomyopathy is part of the multiorgan involvement in severe MTP deficiency.


MONDO:0012172

[PMID:35677112] [SUPPORT] many features including initial report of cardiomyopathy and hypoglycemia presented across a wide age spectrum. --- Explanation: Confirms hypoglycemia as a feature presenting across the age spectrum.

[PMID:24314034] [SUPPORT] hepatic form with recurrent hypoketotic hypoglycemia --- Explanation: Identifies hypoketotic hypoglycemia as a classical MTP/HADHB phenotype.


MONDO:0012172

[PMID:32253025] [SUPPORT] Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. --- Explanation: Characterizes peripheral neuropathy timing in adult MTP patients.

[PMID:35023662] [SUPPORT] Electroneuromyography (ENMG) analysis showed moderate symmetric distal sensorimotor and axonal neuropathy. --- Explanation: Confirms electrophysiological pattern of axonal neuropathy in MTP deficiency.


MONDO:0012172

[PMID:32253025] [SUPPORT] Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. --- Explanation: Characterizes rhabdomyolysis episodes occurring during childhood as the initial disease presentation in this cohort.


MONDO:0012172

[PMID:32253025] [SUPPORT] MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy. --- Explanation: Lists retinopathy among suggestive features of MTP deficiency.


MONDO:0012172

[PMID:31730477] [SUPPORT] Included studies suggested fewer heart and liver problems in screen-detected patients --- Explanation: Liver problems are significant enough to be a key outcome measure in MTP screening.


MONDO:0012172

[PMID:35023662] [SUPPORT] Signs and symptoms of MTPD may present during infancy or later in life; those that begin after infancy include hypotonia, muscle pain, rhabdomyolysis, and peripheral neuropathy. --- Explanation: Directly lists hypotonia as a presenting symptom of MTP deficiency.


MONDO:0012172

[PMID:28132977] [SUPPORT] He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood --- Explanation: Supports exercise-induced myopathy in MTP deficiency.


MONDO:0012172

[PMID:34543737] [SUPPORT] A notable feature of severe and intermediate form is respiratory failure. --- Explanation: Directly identifies respiratory failure as a notable feature of MTP deficiency.


MONDO:0012172

[PMID:34543737] [SUPPORT] Our case is a complete TFP deficiency patient dominated presented with hypoparathyroidism, neutropenia and nephrotic syndrome --- Explanation: Supports hypoparathyroidism as a reported atypical presentation.


MONDO:0012172

[PMID:29956646] [SUPPORT] Both had delayed motor development and slowly-progressing distal muscle weakness with areflexia and foot deformities. --- Explanation: Directly describes distal muscle weakness as a presenting feature.

[PMID:28132977] [SUPPORT] A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. --- Explanation: Confirms slowly progressive weakness in adult-onset MTP deficiency.


MONDO:0012172


MONDO:0012172

[PMID:34543737] [SUPPORT] The mortality of the present study is as high as 57.9%, which is linked with the onset age, phenotype, mutation type and muscular histology. --- Explanation: Confirms high mortality rate in MTP deficiency from multiple causes including metabolic crises.

[PMID:34878152] [SUPPORT] The two patients with MTPD experienced metabolic crises and died following an infectious disease. --- Explanation: Supports lethal metabolic crises in MTP deficiency.


MONDO:0012172

[PMID:34543737] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial trifunctional protein (TFP) deficiency is an autosomal recessive disorder that causes a clinical spectrum of diseases ranging from severe infantile cardiomyopathy to mild chronic progressive neuromyopathy --- Explanation: Supports proximal molecular dysfunction of TFP encoded by HADHA/HADHB.


MONDO:0012172

[PMID:34543737] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial trifunctional protein (TFP) deficiency is an autosomal recessive disorder that causes a clinical spectrum of diseases ranging from severe infantile cardiomyopathy to mild chronic progressive neuromyopathy --- Explanation: Supports impaired long-chain FAO and downstream tissue injury in MTP deficiency.


MONDO:0012172

[PMID:23065309] [INDIRECT EVIDENCE] [SUPPORT] 3 HTA and 3 HPA increased resting respiration and diminished the respiratory control and ADP/O ratios using glutamate/malate or succinate as substrates. --- Explanation: Confirms uncoupling effects of specific 3-hydroxy fatty acids on mitochondrial respiration.


MONDO:0012172

[PMID:34543737] [INDIRECT EVIDENCE] [SUPPORT] Neuromuscular system is more vulnerable involved. --- Explanation: Confirms neuromuscular system as the most commonly affected organ system.

[PMID:32253025] [INDIRECT EVIDENCE] [SUPPORT] Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy --- Explanation: Demonstrates sensory neuronopathy as a major adult neurological feature.


MAXO:0000088

[PMID:31730477] [SUPPORT] There is some evidence that dietary management following screen-detection might be associated with a lower incidence of some LCHAD and MTP deficiency-related complications. --- Explanation: Supports dietary management as the primary treatment modality.

[PMID:31730477] [SUPPORT] Without dietary management the conditions are life-threatening. --- Explanation: Emphasizes that dietary management is essential for survival.


MAXO:0000950

[PMID:35023662] [SUPPORT] acute relapsing episodes triggered by fasting or illnesses --- Explanation: Confirms fasting and illness as triggers for metabolic crises, supporting avoidance strategy.


MAXO:0000058


MAXO:0000058

[PMID:26109258] [SUPPORT] MTP is pharmacologically up-regulated by bezafibrate in human fibroblasts. --- Explanation: Confirms pharmacological upregulation of MTP by bezafibrate.


MAXO:0000124

[PMID:31730477] [SUPPORT] Included studies suggested fewer heart and liver problems in screen-detected patients, but inconsistent results for mortality. --- Explanation: Supports newborn screening benefit for reducing cardiac and hepatic complications.

[PMID:30682426] [SUPPORT] The mitigated phenotypes of this treatable disease were missed by the newborn screening, highlighting the importance of phenotype-based NGS analysis --- Explanation: Notes that milder MTP phenotypes may be missed by standard newborn screening.


MAXO:0000079

[PMID:28515471] [SUPPORT] Maternal hemolysis, elevated liver enzymes and low platelet count syndrome and acute fatty liver of pregnancy were noted in two and one mothers, respectively. --- Explanation: Maternal complications necessitate genetic counseling and pregnancy monitoring.

[PMID:34878152] [SUPPORT] Using amniotic fluid prenatal diagnostic testing, the unborn child was confirmed to carry only c.2107G>A (p.G703R). --- Explanation: Demonstrates availability and utility of prenatal diagnosis for MTP deficiency.


MAXO:0000950

[PMID:34878152] [SUPPORT] The two patients with MTPD experienced metabolic crises and died following an infectious disease. --- Explanation: Metabolic crises during infectious illness underscore need for aggressive crisis management.


MAXO:0000011

[PMID:29956646] [SUPPORT] Both had delayed motor development and slowly-progressing distal muscle weakness with areflexia and foot deformities. --- Explanation: Distal weakness and foot deformities support need for physical therapy and rehabilitation.


HGNC.SYMBOL:HADHA and HADHB variants causing MTP deficiency

[PMID:34543737] [SUPPORT] The type of mutation, rather than residual enzyme activity seem to be more related to the phenotype and prognosis. --- Explanation: Supports mutation type as a predictor of clinical phenotype.

[PMID:28515471] [SUPPORT] This study suggests that the molecular and clinical aspects of Japanese patients with TFP deficiencies differ from those of Caucasian patients. --- Explanation: Demonstrates ethnic differences in MTP deficiency genetics and presentation.


MONDO:0005854

[PMID:16084319] [SUPPORT] Raynaud's phenomenon affects most patients who have mixed connective tissue disease (MCTD) and frequently represents the initial manifestation of the disease. --- Explanation: Raynaud phenomenon is nearly universal in MCTD and often the presenting symptom, reflecting the underlying systemic vasculopathy characterized by intimal fibrosis and vascular obliteration that links this cutaneous manifestation to visceral complications including pulmonary hypertension.


MONDO:0005854

[PMID:718271] [SUPPORT] Arthritis occurred in all 20 patients, being the presenting complaint in 11 patients. --- Explanation: This landmark 5-year longitudinal study demonstrated that arthritis is universal in MCTD, often as the presenting manifestation, with symmetric involvement of PIP, MCP, wrists, MTP joints and knees mimicking rheumatoid arthritis but with predominantly lymphocytic non-inflammatory effusions and good response to low-dose corticosteroids.


MONDO:0005854

[PMID:39876825] [PARTIAL] Eight patients had muscle weakness in the proximal extremities, and overall, six patients had atypical weakness in the face, neck, wrist, or fingers. --- Explanation: MCTD-associated myositis presents with both typical proximal muscle weakness and atypical distributions affecting axial and distal muscles, with muscle biopsy showing perivascular inflammatory infiltrates and muscle fiber necrosis, reflecting the heterogeneous nature of MCTD myopathy that may require intensive immunosuppressive therapy.


MONDO:0005854


MONDO:0005854

[PMID:31440254] [INDIRECT EVIDENCE] [PARTIAL] Mixed Connective Tissue Disease (MCTD) is a rare complex systemic autoimmune disease (SAD) characterized by the presence of increased levels of anti-U1 ribonucleoprotein autoantibodies and signs and symptoms that resemble other SADs such as systemic sclerosis (SSc), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). --- Explanation: This epigenome-wide study confirms anti-U1-RNP antibodies as the defining serological feature of MCTD, with pervasive hypomethylation at interferon-related genes (MX1, PARP9, DDX60, IFI44L) supporting the central role of this autoimmune response in disease pathogenesis.


MONDO:0005854

[PMID:38479808] [INDIRECT EVIDENCE] [PARTIAL] Among the MCTD patients, patients with the SLE immunophenotype had higher proportions of Th1 cells --- Explanation: Machine learning-based immunophenotyping revealed that MCTD patients with SLE-like features show significantly elevated Th1 cells (2.85% vs 1.33%, P=0.027) and plasmablasts, with enhanced interferon-alpha and interferon-gamma responses in central memory CD8+ T cells, demonstrating the central role of T cell-driven inflammation in disease heterogeneity.


MONDO:0005854

[PMID:16084319] [INDIRECT EVIDENCE] [SUPPORT] It is the cutaneous symptom of a systemic vasculopathy that is characterized by intimal fibrosis and blood vessel obliteration that frequently leads to visceral involvement, particularly pulmonary hypertension. --- Explanation: Raynaud phenomenon in MCTD reflects an underlying systemic vasculopathy with intimal fibrosis and vascular obliteration, providing the mechanistic link between endothelial dysfunction and pulmonary arterial hypertension development.

[PMID:37497727] [INDIRECT EVIDENCE] [PARTIAL] Pooled prevalence of PAH in MCTD patients was 12.53% [95% CI 8.30-18.48%] --- Explanation: This systematic review and meta-analysis of 983 MCTD patients establishes pulmonary arterial hypertension as a significant vascular complication, occurring in approximately 12.5% of patients, with mortality rates reaching up to 81.8% in affected individuals.


MONDO:0005854

[PMID:39876825] [INDIRECT EVIDENCE] [SUPPORT] In biopsied muscle specimens, common findings were mild myogenic change, increased necrotic and regenerating fibers, and inflammatory infiltrates predominating in the perivascular region. --- Explanation: This 2025 case series of nine MCTD myositis patients demonstrates the characteristic inflammatory myopathy with perivascular lymphocytic infiltration, muscle fiber necrosis and regeneration, and atypical weakness patterns affecting proximal and axial muscles, reflecting the heterogeneity of MCTD-associated muscle involvement.


MONDO:0005854

[PMID:31440254] [INDIRECT EVIDENCE] [SUPPORT] We observed a pervasive hypomethylation involving 170 genes enriched for immune-related function such as those involved in type I interferon signaling pathways or in negative regulation of viral genome replication. --- Explanation: The first epigenome-wide association study in MCTD revealed widespread DNA hypomethylation at interferon-related genes (MX1, PARP9, DDX60, IFI44L) with evidence that genetic variants at IRF7 and IFI44 may exert disease risk through DNA methylation changes, establishing type I interferon pathway activation as a central molecular mechanism shared with SLE and Sjogren syndrome.


HGNC.SYMBOL:HLA-DR4


MONDO:0002594

[PMID:36396927] [SUPPORT] Initially, there is a prodrome phase of a few days, which is followed by the appearance of rashes. The dermatological manifestations are in the form of an exanthematous rash, which transforms through a macular, papular, and vesicular phase and disappears after crusting in approximately 3 weeks. --- Explanation: This reference confirms that rash is a common dermatologic manifestation of monkeypox.

[PMID:36396927] [SUPPORT] Respiratory manifestations include nasal congestion and shortness of breath that may result in secondary bacterial infections. --- Explanation: This reference further mentions the potential for secondary infections.

[PMID:35904894] [SUPPORT] Pleomorphic skin lesions appear ranging from macules, papules, vesicles, pustules, some of which may appear umbilicated before crusting over. --- Explanation: This reference supports the frequent occurrence of various types of rashes in monkeypox.

[PMID:36223653] [SUPPORT] Our clinical evaluation identified skin lesions as the optimal diagnostic specimen source. --- Explanation: This reference mentions that skin lesions (including rashes) are significant for diagnosis.

[PMID:36729940] [SUPPORT] Primarily affecting the sexually active population, these cases present with mucocutaneous lesions mainly localized in perioral, genital, and anal areas. --- Explanation: This reference describes mucocutaneous lesions, which also support dermatologic manifestations.

[PMID:37403493] [SUPPORT] Monkeypox (MPX) characteristically presents as a fever with a vesiculopustular rash. --- Explanation: This reference clearly states that a vesiculopustular rash is characteristic of monkeypox.

[PMID:15660652] [SUPPORT] Initially, it presents with skin eruptions and fevers with diaphoresis and rigors. Clinically, the skin lesions progress from papules to vesiculopustules to resolving eschars. --- Explanation: This reference confirms the typical progression of skin lesions, including rashes, in monkeypox.


MONDO:0002594

[PMID:35924502] [SUPPORT] Monkeypox usually presents with a flu-like prodromal period (fever, headache, chills, sweating) associated or followed by the appearance of lymphadenopathy and a typical skin rash. --- Explanation: This reference also confirms that fever is a commonly observed systemic phenotype in monkeypox patients.


MONDO:0002594

[PMID:36396927] [SUPPORT] Other symptoms can include diarrhea, vomiting, myalgia, and backache. --- Explanation: The reference states that myalgia is a symptom that can occur in monkeypox patients, indicating it's a recognized phenotype.


MONDO:0002594


MONDO:0002594

[PMID:36554659] [SUPPORT] Monkeypox, a viral zoonosis caused by an Orthopoxvirus, is clinically characterized by fever, headache, lymphadenopathy, myalgia, rash and burdened by some complications that can be severe and life threatening. --- Explanation: This reference lists headache as a clinical characteristic of monkeypox, supporting the statement that headache is a frequent systemic symptom.

[PMID:37043648] [SUPPORT] Several neurological complications have been reported with MPX and its vaccines that include but not limited to headaches, myalgia, encephalitis, and coma. --- Explanation: This reference mentions headaches as one of the neurological complications associated with monkeypox, supporting the statement.


MONDO:0002594

[PMID:36396927] [NO_EVIDENCE] Other symptoms can include diarrhea, vomiting, myalgia, and backache. --- Explanation: The abstract does not mention fatigue as a frequent systemic symptom of monkeypox.

[PMID:36125794] [NO_EVIDENCE] known neurologic complications of monkeypox, which include headaches and mood disturbances, as well as rare presentations of encephalitis, transverse myelitis, and seizures. --- Explanation: The abstract does not mention fatigue as a frequent systemic symptom of monkeypox.

[PMID:36716982] [NO_EVIDENCE] The most common symptoms were fever (89%) and chest pain (100%). --- Explanation: The abstract does not mention fatigue as a frequent systemic symptom of monkeypox.

[PMID:36607751] [NO_EVIDENCE] monkeypox symptoms (fever, painful vesicular or pustular rash, and lymphadenopathy) are milder and fatalities are rare. --- Explanation: The abstract does not mention fatigue as a frequent systemic symptom of monkeypox.


MONDO:0002594

[PMID:36216412] [SUPPORT] Ophthalmic manifestations may include preseptal cellulitis, conjunctivitis and keratitis. --- Explanation: The reference mentions conjunctivitis as one of the ophthalmic manifestations of monkeypox.

[PMID:37405735] [SUPPORT] Mpox is an emerging zoonotic infection with potentially severe ocular and periocular consequences. --- Explanation: The reference discusses severe ocular consequences of monkeypox, implying various ophthalmic manifestations.

[PMID:36986374] [SUPPORT] The aim of this meta-analysis was to estimate the global prevalence of ophthalmic manifestations in mpox patients. --- Explanation: The reference indicates that ophthalmic manifestations, including conjunctivitis, are present in monkeypox patients.


MONDO:0002594

[PMID:37026012] [INDIRECT EVIDENCE] [SUPPORT] Once inoculated, the viruses multiply rapidly and spread into the bloodstream to cause viremia, which then affect multiple organs. --- Explanation: This snippet confirms that monkeypox virus multiplies at the site of entry and spreads into the bloodstream.


MONDO:0002594

[PMID:36253513] [INDIRECT EVIDENCE] [SUPPORT] We detected MPXV in interstitial cells and seminiferous tubules of testes as well as epididymal lumina, which are the sites of sperm production and maturation. --- Explanation: This reference mentions that the virus is found in specific tissues after initial replication, which supports the idea that it spreads systemically.


MAXO:0000950

[PMID:37403493] [SUPPORT] The clinical evaluation involves the assessment of the primary skin lesions, sites of involvement, distribution, number and size of lesions, and pattern of progression of the rash, along with the onset of the rash relative to the occurrence of fever and other systemic signs --- Explanation: The document emphasizes how supportive care is central to the management of symptoms, including fever.

[PMID:29231870] [SUPPORT] MPX patients could benefit from clinical support to mitigate the consequences of compromised skin and mucosa. This should include prevention and treatment of secondary bacterial infections (and other complications), ensuring adequate hydration and nutrition, and protecting vulnerable anatomical locations such as the eyes and genitals. --- Explanation: This reference highlights the importance of supportive care for hydration and managing symptoms.

[PMID:36342045] [SUPPORT] If individuals test positive for the monkeypox virus, self-isolation at home is recommended for most people with mild symptoms. If patients report severe symptoms, referral and admission to hospital will be needed, where further interventions such as antivirals may be administered. --- Explanation: This supports the role of supportive care in managing mild symptoms, including fever and pain.


MAXO:0000168

[PMID:36107794] [SUPPORT] Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. --- Explanation: The article supports the investigational use of tecovirimat (TPOXX) for treating Monkeypox under an investigational new drug protocol.

[PMID:36547989] [SUPPORT] Tecovirimat Treatment for Monkeypox Virus Keratouveitis. --- Explanation: The article specifically discusses the use of tecovirimat for treating a form of Monkeypox, indicating ongoing investigative use.

[PMID:36253931] [SUPPORT] Brincidofovir and tecovirimat were the most studied medications that got approval for smallpox treatment according to the Animal Rule. Due to the conserved virology among Orthopoxviruses, available medications might also be effective against monkeypox. --- Explanation: The text confirms that investigational treatments, particularly tecovirimat (TPOXX), are considered for treating Monkeypox.

[PMID:36470502] [SUPPORT] Tecovirimat was used in 61 individuals... Tecovirimat is the most used and has proven beneficial in several aggravating cases. --- Explanation: The article provides individual patient data on the use of tecovirimat as an investigational treatment for Monkeypox and summarizes its efficacy and safety.

[PMID:36851785] [SUPPORT] In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox --- Explanation: The article states that tecovirimat is effective at nanomolar quantities against Monkeypox, supporting its use as investigational therapy.

[PMID:36897017] [SUPPORT] The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. --- Explanation: The article mentions tecovirimat as one of the investigational treatments considered for monkeypox, supporting its use.


MAXO:0001017

[PMID:36104166] [PARTIAL] We report a case of monkeypox in the United States in a patient who had been vaccinated with ACAM2000 smallpox vaccine 8 years earlier. Despite his vaccination status, he still contracted disease. --- Explanation: This case indicates that the patient contracted monkeypox despite vaccination, suggesting limited or no cross-protection by the ACAM2000 vaccine.

[PMID:27768891] [PARTIAL] Monkeypox (MPXV) and cowpox (CPXV) are emerging agents that cause severe human infections on an intermittent basis, and variola virus (VARV) has potential for use as an agent of bioterror. Vaccinia immune globulin (VIG) has been used therapeutically to treat severe orthopoxvirus infections but is in short supply. --- Explanation: This reference mentions broader cross-protective immunity for orthopoxviruses, including monkeypox, suggesting a potential for cross-protection, though specifics about the smallpox vaccine's efficacy aren't detailed.

[PMID:35763248] [SUPPORT] Two vaccines are currently available, JYNNEOSTM (live, replication incompetent vaccinia virus) and ACAM2000® (live, replication competent vaccinia virus) --- Explanation: The presence of orthopoxvirus vaccines like ACAM2000 and JYNNEOS indicates their consideration in the context of monkeypox prevention, implying potential cross-protection.

[PMID:37087871] [SUPPORT] CONCLUSION: ACAM2000 and JYNNEOS vaccines have proven to be efficient in preventing Mpox even though variations exist in their modes of action and associated significant effects. --- Explanation: Both the ACAM2000 and JYNNEOS vaccines show efficacy in preventing monkeypox, supporting the statement regarding cross-protection.

[PMID:36274490] [SUPPORT] It has been observed that smallpox vaccines can be used to protect against MPX. The present article highlights the significant points and various issues for vaccines and vaccinations that should be considered related to MPX. --- Explanation: The use of smallpox vaccines for protection against monkeypox is explicitly mentioned, supporting the potential for cross-protection.


MAXO:0000168


MAXO:0000077

[PMID:36241815] [PARTIAL] Monkeypox is an infectious disease, characterised by a rash affecting the skin and soft tissues, including the oral cavity. --- Explanation: The literature mentions the importance of infection control in preventing the spread of monkeypox, particularly in dental settings.


HGNC.SYMBOL:Monkeypox Virus Genome

[PMID:12083817] [SUPPORT] Monkeypox virus (MPV) belongs to the orthopoxvirus genus of the family Poxviridae... The 196,858-bp MPV genome was analyzed with regard to structural features. --- Explanation: The reference confirms that the monkeypox virus belongs to the Orthopoxvirus genus and details the structural features of its DNA genome.

[PMID:38801573] [SUPPORT] The monkeypox virus is a part of the Poxviridae family, Orthopoxvirus genus, and is accountable for smallpox. --- Explanation: This reference reaffirms that the monkeypox virus belongs to the Orthopoxvirus genus and has a DNA-based genome.

[PMID:37611023] [SUPPORT] Monkeypox is a double-stranded DNA virus with an envelope and is a member of the Poxviridae family's Orthopoxvirus genus. --- Explanation: This reference confirms the genetic features and classification of the monkeypox virus as specified in the statement.


HGNC.SYMBOL:EGFR


HGNC.SYMBOL:STAT1


HGNC.SYMBOL:JAK2


HGNC.SYMBOL:IRF3


HGNC.SYMBOL:NFKB1


HGNC.SYMBOL:IL6


HGNC.SYMBOL:CXCL8


HGNC.SYMBOL:IFNG


NCBITaxon:10244

[PMID:36555584] [SUPPORT] Monkeypox infection is caused by a virus of the genus Orthopoxvirus, a member of the Poxviridae family. --- Explanation: This reference clearly states that monkeypox infection is caused by a virus from the genus Orthopoxvirus, which includes the monkeypox virus.

[PMID:38801568] [SUPPORT] Monkeypox (Mpox) is a zoonotic disease caused by a virus (monkeypox virus-MPV) belonging to the Poxviridae family. --- Explanation: The reference directly identifies the causative agent of monkeypox as the monkeypox virus.

[PMID:37507009] [SUPPORT] Monkeypox virus (MPXV) is an emerging zoonotic virus that has had on-going public health impacts in endemic regions of Central and West Africa for over a half-century. --- Explanation: This reference explicitly mentions monkeypox virus (MPXV) as the agent of monkeypox.

[PMID:18837778] [SUPPORT] Although monkeypox virus is less fatal and not as transmissible as variola virus, the causative agent of smallpox, there is concern that monkeypox virus could become a more efficient human pathogen. --- Explanation: This reference also points to 'monkeypox virus' as the causative agent of monkeypox.


MONDO:0007766

[PMID:36484746] [SUPPORT] Hyperostosis frontalis interna was first described in 1719 in association with obesity and hirsutism, forming Morgagni's syndrome. --- Explanation: Confirms hyperostosis frontalis interna as the defining feature of the syndrome, historically described from its first report.

[PMID:10407462] [SUPPORT] Hyperostosis frontalis interna (HFI) is manifested by the accretion of bone on the inner table of the frontal bone. --- Explanation: Defines HFI as bone accretion on the inner table of the frontal bone, consistent with the phenotype description.

[PMID:36484746] [SUPPORT] The anomaly exclusively involves the inner table and constantly spares the diploe and the external table. --- Explanation: Specifies that HFI exclusively affects the inner table, sparing the diploe and external table.


MONDO:0007766

[PMID:16909048] [SUPPORT] We report two 71-year-old female monozygotic twins presenting with advanced hyperostosis frontalis interna, obesity, shortness and cognitive impairment. --- Explanation: Obesity is documented as a core feature in this twin case report of MSM syndrome.

[PMID:27428347] [SUPPORT] During this hospital stay the presence of grade I obesity, hyperglycemia, hypertriglyceridemia and hyperuricemia was documented. --- Explanation: Obesity and metabolic disturbances documented in a clinical case of MSM syndrome.

[PMID:36452994] [SUPPORT] Morgagni-Stewart-Morel (MSM) syndrome is characterized by the thickening of the frontal bone of the skull (hyperostosis frontalis interna) obesity, neurological symptoms, and hypertrichosis. --- Explanation: Obesity is listed as a defining feature of MSM syndrome.


MONDO:0007766

[PMID:36452994] [SUPPORT] We present the case of a 76-year-old patient who complained of confusion, extreme irritability, and headache and was diagnosed with MSM based on examination, imaging, and test results. --- Explanation: Headache is documented as a presenting symptom in this case of MSM syndrome.

[PMID:23284007] [SUPPORT] A 75-year-old woman presented with severe frontal headache and a history of psychotic disorders. --- Explanation: Severe frontal headache was the presenting symptom in this case of full-penetrance MSM syndrome.


MONDO:0007766

[PMID:16909048] [SUPPORT] They both have suffered from generalized seizures since their early adulthood. --- Explanation: Both monozygotic twins with MSM syndrome had generalized seizures since early adulthood, supporting seizures as a feature of the syndrome.


MONDO:0007766

[PMID:16909048] [SUPPORT] We report two 71-year-old female monozygotic twins presenting with advanced hyperostosis frontalis interna, obesity, shortness and cognitive impairment. --- Explanation: Cognitive impairment is documented in both twins with MSM syndrome.

[PMID:27428347] [SUPPORT] A 74 years old female with a history of exposure to wood smoke, vitiligo, type 2 diabetes mellitus, hypertension and cognitive impairment who enters the hospital by malaise, dizziness, anxiety, confusion, disorientation and difficulty walking. --- Explanation: Cognitive impairment is part of the clinical presentation in this case of MSM syndrome.


MONDO:0007766

[PMID:25382447] [SUPPORT] In 1928 Stewart and in 1930 Morel added neuropsychiatric symptoms, e.g. depression and dementia, which led to the definition of the Morgagni-Stewart-Morel Syndrome (MSM). --- Explanation: Depression is one of the classic neuropsychiatric features that helped define MSM syndrome.

[PMID:16909048] [SUPPORT] Moreover, the patients showed some additional conditions only occurring in one individual or the other such as migraine, marked recurrent depressive disorder or polyarthrosis. --- Explanation: Recurrent depressive disorder documented in one of the monozygotic twins with MSM syndrome.


MONDO:0007766

[PMID:36484746] [SUPPORT] Hyperostosis frontalis interna was first described in 1719 in association with obesity and hirsutism, forming Morgagni's syndrome. --- Explanation: Hirsutism was one of the original features described by Morgagni in 1719 alongside HFI and obesity.

[PMID:36452994] [SUPPORT] Morgagni-Stewart-Morel (MSM) syndrome is characterized by the thickening of the frontal bone of the skull (hyperostosis frontalis interna) obesity, neurological symptoms, and hypertrichosis. --- Explanation: Hypertrichosis (hirsutism) is listed as a defining feature of MSM syndrome.


MONDO:0007766

[PMID:27428347] [SUPPORT] A 74 years old female with a history of exposure to wood smoke, vitiligo, type 2 diabetes mellitus, hypertension and cognitive impairment who enters the hospital by malaise, dizziness, anxiety, confusion, disorientation and difficulty walking. --- Explanation: Dizziness documented as part of the clinical presentation in a case of MSM syndrome.


MONDO:0007766

[PMID:2349162] [SUPPORT] Acromegalic patients with hyperprolactinaemia also expressed HFI in a higher proportion of individuals than the control group (P = 0.0001). --- Explanation: Hyperprolactinemia is strongly associated with HFI, and amenorrhea is a well-established consequence of hyperprolactinemia.


MONDO:0007766

[PMID:2349162] [SUPPORT] The cause of HFI remains unknown but appears to be strongly associated with acromegaly, particularly in the presence of co-existent hyperprolactinaemia. --- Explanation: Hyperprolactinemia is strongly associated with HFI. Galactorrhea is a direct clinical manifestation of hyperprolactinemia.


MONDO:0007766

[PMID:27428347] [SUPPORT] A 74 years old female with a history of exposure to wood smoke, vitiligo, type 2 diabetes mellitus, hypertension and cognitive impairment who enters the hospital by malaise, dizziness, anxiety, confusion, disorientation and difficulty walking. --- Explanation: Type 2 diabetes mellitus is documented as a comorbidity in this MSM syndrome case report.

[PMID:27428347] [SUPPORT] During this hospital stay the presence of grade I obesity, hyperglycemia, hypertriglyceridemia and hyperuricemia was documented. --- Explanation: Hyperglycemia and metabolic disturbances are documented features of MSM syndrome.

[PMID:23284007] [SUPPORT] Metabolic and endocrine dysfunctions should be interpreted not only as isolated components of the syndrome, but also as the reason behind its pathogenesis. --- Explanation: Metabolic dysfunctions including glucose dysregulation are considered integral components of MSM syndrome.


MONDO:0007766


MONDO:0007766

[PMID:10407462] [INDIRECT EVIDENCE] [SUPPORT] It is most commonly found among females and is believed to be associated with prolonged estrogen stimulation --- Explanation: Establishes the estrogen hypothesis for HFI pathogenesis based on a large-scale anthropological study of over 1,700 skulls.

[PMID:10407462] [INDIRECT EVIDENCE] [SUPPORT] While its magnitude of manifestation and frequency are much higher in females, HFI is not a purely female phenomenon. Males with hormonal disturbances such as atrophic testis were found to manifest HFI type D. --- Explanation: The association of HFI with hormonal disturbances in males further supports the endocrine-mediated pathogenesis hypothesis.

[PMID:36217295] [INDIRECT EVIDENCE] [SUPPORT] It is most often found in women after menopause. It is also associated with hormonal imbalance, being overweight, history of headaches, and neurocognitive degenerative conditions. Female gender, advanced age, extended estrogen stimulation, and elevated leptin levels may also play a role. --- Explanation: Summarizes the leading etiological theories including estrogen, leptin, and hormonal imbalance for HFI development.

[PMID:36223065] [INDIRECT EVIDENCE] [PARTIAL] Although the frequency of HFI is 22% in patients with acromegaly, neither excess GH nor hyperprolactinemia plays a role in its etiopathogenesis. Various genetic or epigenetic factors may contribute to its etiology. --- Explanation: While HFI is more frequent in acromegaly, this study found no direct role for GH excess or hyperprolactinemia, suggesting genetic/epigenetic factors instead.

[PMID:23284007] [INDIRECT EVIDENCE] [SUPPORT] Endocrine or nutritional disorders may have led to an altered bone metabolism with frontal bone apposition. --- Explanation: Supports the concept that endocrine and metabolic dysfunction drives altered bone metabolism leading to frontal hyperostosis.


MONDO:0007766

[PMID:27428347] [INDIRECT EVIDENCE] [SUPPORT] In she were performed imaging of the skull where was observed the presence of extensive hyperostosis frontalis interna, cortical atrophy and a left thalamic lacunar infarction. --- Explanation: Imaging findings demonstrate the association between HFI and cortical atrophy in a patient with MSM syndrome.

[PMID:25382447] [INDIRECT EVIDENCE] [SUPPORT] In 1928 Stewart and in 1930 Morel added neuropsychiatric symptoms, e.g. depression and dementia, which led to the definition of the Morgagni-Stewart-Morel Syndrome (MSM). --- Explanation: Establishes the historical association between HFI and neuropsychiatric symptoms including depression and dementia as core features of MSM.

[PMID:23284007] [INDIRECT EVIDENCE] [SUPPORT] the severity of our patient's neurological and psychiatric symptoms correlates well with the severity of her hyperostosis frontalis interna and the cortical atrophy. --- Explanation: Demonstrates dose-response relationship between HFI severity and neuropsychiatric symptom severity, supporting mechanical compression.


MONDO:0007766

[PMID:2349162] [INDIRECT EVIDENCE] [SUPPORT] Acromegalic patients with hyperprolactinaemia also expressed HFI in a higher proportion of individuals than the control group (P = 0.0001). --- Explanation: Demonstrates a highly significant association between hyperprolactinemia and HFI in acromegalic patients.

[PMID:2349162] [INDIRECT EVIDENCE] [SUPPORT] The cause of HFI remains unknown but appears to be strongly associated with acromegaly, particularly in the presence of co-existent hyperprolactinaemia. --- Explanation: Supports the association between HFI and hyperprolactinemia as a contributing pathway in MSM syndrome.

[PMID:36223065] [INDIRECT EVIDENCE] [PARTIAL] There was no difference between the HFI positive and negative acromegalic patients in basal GH, IGF-1, and PRL levels, IGF-1 index, diagnosis lag time, and insulin resistance. --- Explanation: A more recent study found no difference in prolactin levels between HFI-positive and HFI-negative acromegalic patients, suggesting the relationship may be indirect.


MONDO:0007766

[PMID:36217295] [INDIRECT EVIDENCE] [SUPPORT] It is most often found in women after menopause. It is also associated with hormonal imbalance, being overweight, history of headaches, and neurocognitive degenerative conditions. --- Explanation: Establishes the association between HFI and headaches in affected individuals, supporting the increased ICP hypothesis.

[PMID:27428347] [INDIRECT EVIDENCE] [SUPPORT] In she were performed imaging of the skull where was observed the presence of extensive hyperostosis frontalis interna, cortical atrophy and a left thalamic lacunar infarction. --- Explanation: The imaging findings of cortical atrophy in conjunction with extensive HFI support the hypothesis of increased intracranial pressure effects.


MAXO:0000058

[PMID:23284007] [SUPPORT] A 75-year-old woman presented with severe frontal headache and a history of psychotic disorders. --- Explanation: Severe frontal headache is a prominent presenting symptom in MSM syndrome requiring pharmacological management.

[PMID:36452994] [SUPPORT] We present the case of a 76-year-old patient who complained of confusion, extreme irritability, and headache and was diagnosed with MSM based on examination, imaging, and test results. --- Explanation: Headache is documented as a presenting complaint requiring symptomatic treatment in MSM.


MAXO:0000058

[PMID:16909048] [SUPPORT] They both have suffered from generalized seizures since their early adulthood. --- Explanation: Generalized seizures from early adulthood in MSM patients require ongoing antiepileptic management.


MAXO:0000950

[PMID:41229651] [SUPPORT] A multidisciplinary approach targeting the neurological, endocrine, and respiratory components led to progressive clinical improvement and a favourable recovery. --- Explanation: Multidisciplinary management targeting multiple organ systems led to favorable outcomes in an acute MSM case.

[PMID:41229651] [SUPPORT] Multidisciplinary collaboration is crucial in managing complex cases of Morgagni-Stewart-Morel syndrome, especially in acute settings where diagnosis is challenging. --- Explanation: Authors emphasize the importance of multidisciplinary collaboration for MSM syndrome management.


MAXO:0000079

[PMID:16909048] [SUPPORT] The symptoms common to both twins appear to correspond to the Morgagni-Stewart-Morel syndrome and indicate a genetic basis of this disorder as these features occur in genetically identical patients. --- Explanation: Evidence for a genetic basis supports the recommendation for genetic counseling in affected families.


HGNC.SYMBOL:Familial hyperostosis frontalis interna

[PMID:16909048] [SUPPORT] The symptoms common to both twins appear to correspond to the Morgagni-Stewart-Morel syndrome and indicate a genetic basis of this disorder as these features occur in genetically identical patients. --- Explanation: Identical phenotype in monozygotic twins provides strong evidence for a genetic basis of MSM syndrome.

[PMID:36223065] [SUPPORT] Various genetic or epigenetic factors may contribute to its etiology. --- Explanation: Supports the hypothesis that genetic or epigenetic factors underlie HFI susceptibility.


ECTO:9000010

[PMID:10407462] [SUPPORT] It is most commonly found among females and is believed to be associated with prolonged estrogen stimulation --- Explanation: Large-scale anthropological study supports prolonged estrogen stimulation as a contributing factor to HFI development.

[PMID:10407462] [SUPPORT] HFI is associated with age insofar as it is much less frequent in females under 40 years of age. --- Explanation: Age-related increase in HFI frequency is consistent with cumulative estrogen exposure as a risk factor.

[PMID:36217295] [SUPPORT] Female gender, advanced age, extended estrogen stimulation, and elevated leptin levels may also play a role. --- Explanation: Identifies extended estrogen stimulation as a potential contributing factor for HFI development.


MONDO:0007766

[PMID:16909048] [SUPPORT] We report two 71-year-old female monozygotic twins presenting with advanced hyperostosis frontalis interna, obesity, shortness and cognitive impairment. They both have suffered from generalized seizures since their early adulthood. --- Explanation: Monozygotic twin concordance for MSM syndrome features strongly supports a genetic basis for the disorder.

[PMID:16909048] [SUPPORT] The symptoms common to both twins appear to correspond to the Morgagni-Stewart-Morel syndrome and indicate a genetic basis of this disorder as these features occur in genetically identical patients. --- Explanation: The authors explicitly conclude that the concordance in monozygotic twins indicates a genetic basis for MSM syndrome.


MONDO:0007766

[PMID:36223065] [PARTIAL] The frequency of HFI was higher in acromegalic patients than in the controls (22%, 0%, and 2.2%, respectively). --- Explanation: HFI is significantly more frequent in patients with GH excess (acromegaly), though the study found no direct causal role for GH in HFI etiopathogenesis.

[PMID:2349162] [SUPPORT] There was a higher prevalence of HFI in the skull X-rays of the acromegalic cohort (P = 0.0002) when compared to the control group. --- Explanation: Highly significant association between acromegaly (GH excess) and HFI prevalence.


MONDO:0007766

[PMID:2349162] [SUPPORT] Acromegalic patients with hyperprolactinaemia also expressed HFI in a higher proportion of individuals than the control group (P = 0.0001). --- Explanation: Highly significant association between hyperprolactinemia and HFI in acromegalic patients.

[PMID:36223065] [PARTIAL] There was no difference between the HFI positive and negative acromegalic patients in basal GH, IGF-1, and PRL levels, IGF-1 index, diagnosis lag time, and insulin resistance. --- Explanation: While hyperprolactinemia has been historically associated with MSM, this study found no difference in prolactin levels between HFI-positive and HFI-negative acromegalic patients.


MONDO:0019249

[PMID:32780955] [SUPPORT] A prominent clinical manifestation of MPS-IH is dysostosis multiplex, a constellation of skeletal abnormalities --- Explanation: Confirms dysostosis multiplex as a prominent skeletal manifestation of MPS.


MONDO:0019249

[PMID:25624320] [SUPPORT] Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood --- Explanation: Multisystem morbidity in MPS I-H includes growth failure contributing to short stature.


MONDO:0019249

[PMID:35216110] [SUPPORT] progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure --- Explanation: Musculoskeletal abnormalities from GAG storage include progressive joint stiffness and contractures.


MONDO:0019249


MONDO:0019249

[PMID:30442189] [SUPPORT] ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume --- Explanation: Hepatosplenomegaly is a recognized MPS feature that responds to ERT, confirming organ enlargement from GAG storage.


MONDO:0019249

[PMID:30442189] [SUPPORT] cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue --- Explanation: Corneal and ocular involvement in MPS is poorly responsive to ERT due to limited tissue penetration.


MONDO:0019249

[PMID:30442189] [SUPPORT] ERT in the present formulations also does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by ERT --- Explanation: CNS involvement causing intellectual disability is a major challenge as ERT cannot cross the blood-brain barrier.

[PMID:35216110] [SUPPORT] in others, to cognitive decline, which is still a challenge for current therapies --- Explanation: Cognitive decline is a characteristic feature that remains a therapeutic challenge in MPS.

[PMID:25624320] [SUPPORT] Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant --- Explanation: Cognitive decline is a major concern in MPS I-H; early HCT can preserve cognitive function.


MONDO:0019249

[PMID:35216110] [INDIRECT EVIDENCE] [SUPPORT] Mucopolysaccharidoses are rare paediatric lysosomal storage disorders, characterised by accumulation of glycosaminoglycans within lysosomes --- Explanation: Confirms MPS as lysosomal storage disorders with GAG accumulation.

[PMID:35216110] [INDIRECT EVIDENCE] [SUPPORT] caused by deficiencies in lysosomal enzymes involved in degradation of these molecules --- Explanation: Confirms enzyme deficiency as the underlying cause of GAG accumulation.

[PMID:32780955] [INDIRECT EVIDENCE] [SUPPORT] Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of α-L-iduronidase, and consequent accumulation of dermatan and heparan sulfates --- Explanation: Specific example of enzyme deficiency (alpha-L-iduronidase) causing GAG accumulation in MPS I.


MONDO:0019249

[PMID:35216110] [INDIRECT EVIDENCE] [SUPPORT] We propose a model whereby progressive accumulation of glycosaminoglycans elicits an innate immune response, initiated by the Toll-like receptor 4 pathway --- Explanation: Proposes TLR4-mediated innate immune activation by accumulated GAGs as key secondary mechanism.

[PMID:35216110] [INDIRECT EVIDENCE] [SUPPORT] While TNF-α is mostly associated with bone and joint disease in mucopolysaccharidoses, increasing evidence implicates IL-1 as a main effector of innate immunity in the central nervous system --- Explanation: Distinguishes inflammatory mediators: TNF-alpha drives skeletal disease, IL-1 drives CNS inflammation.

[PMID:35216110] [INDIRECT EVIDENCE] [SUPPORT] progressive build-up of sugars may lead to musculoskeletal abnormalities and multi-organ failure, and in others, to cognitive decline --- Explanation: GAG accumulation leads to progressive multisystem damage including musculoskeletal and cognitive decline.


HGNC.SYMBOL:MPS I (IDUA Mutations)

[PMID:32780955] [SUPPORT] caused by deficiency of α-L-iduronidase, and consequent accumulation of dermatan and heparan sulfates --- Explanation: Confirms alpha-L-iduronidase deficiency as the cause of MPS I with dermatan and heparan sulfate accumulation.

[PMID:32780955] [SUPPORT] Severity of the disease ranges from mild (Scheie) to moderate (Hurler-Scheie) to severe (Hurler or MPS-IH) --- Explanation: Confirms the clinical severity spectrum of MPS I from Scheie to Hurler.


HGNC.SYMBOL:MPS II (IDS Mutations)

[PMID:30442189] [SUPPORT] This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline --- Explanation: Confirms MPS II has severe forms with cognitive decline.


HGNC.SYMBOL:MPS IV (GALNS/GLB1 Mutations)


MONDO:0011274

[PMID:26740388] [SUPPORT] Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis) --- Explanation: The largest natural history study of Muenke syndrome confirmed that craniosynostosis is the predominant feature, present in 85% of affected individuals.

[PMID:9042914] [SUPPORT] coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene --- Explanation: The original paper defining the syndrome identified coronal synostosis as the primary cranial manifestation caused by the FGFR3 P250R mutation.


MONDO:0011274


MONDO:0011274

[PMID:26740388] [SUPPORT] Hearing loss was identified in 70.8% --- Explanation: The international multicenter study documented hearing loss in over 70% of individuals with Muenke syndrome, confirming it as a major clinical feature.

[PMID:18818193] [SUPPORT] The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss --- Explanation: This study characterized the hearing loss in Muenke syndrome as predominantly low-frequency sensorineural in nature, with incomplete penetrance in the human cohort.

[PMID:18000976] [SUPPORT] a majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss --- Explanation: This study established low-frequency sensorineural hearing loss as a characteristic and previously underrecognized feature of Muenke syndrome.


MONDO:0011274

[PMID:9042914] [SUPPORT] some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases --- Explanation: The original description of Muenke syndrome documented brachydactyly and other hand/foot abnormalities as part of the phenotypic spectrum.


MONDO:0011274

[PMID:9042914] [SUPPORT] some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions --- Explanation: Carpal and tarsal fusions were identified as radiographic features in the original description of Muenke syndrome.


MONDO:0011274

[PMID:26740388] [SUPPORT] developmental delay in 66.3%, intellectual disability in 35.6% --- Explanation: The multicenter natural history study documented developmental delay in two-thirds of patients and intellectual disability in about one-third, indicating variable cognitive involvement.

[PMID:9042914] [SUPPORT] developmental delay was seen in a minority --- Explanation: The original description noted developmental delay as a feature in some patients, though it was less common than the skeletal manifestations.


MONDO:0011274

[PMID:10696568] [INDIRECT EVIDENCE] [SUPPORT] Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. --- Explanation: This review explains that FGFR3 mutations cause varying degrees of constitutive receptor activation, which underlies the pathophysiology of Muenke syndrome and related FGFR3 disorders.


MAXO:0000004


HGNC.SYMBOL:FGFR3 P250R Mutation

[PMID:9042914] [SUPPORT] Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. --- Explanation: This is the original paper defining Muenke syndrome, demonstrating that the P250R mutation in FGFR3 is the causative mutation in all cases of this craniosynostosis syndrome.


MONDO:0019754

[PMID:30181172] [SUPPORT] Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. --- Explanation: Multicentric lymph node enlargement is the defining feature of MCD.


MONDO:0019754

[PMID:29157612] [SUPPORT] TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). --- Explanation: Fever is a defining feature of the TAFRO subtype and is common across all MCD subtypes.


MONDO:0019754

[PMID:25042199] [SUPPORT] The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). --- Explanation: Night sweats listed as a common symptom in MCD patients in the siltuximab trial.


MONDO:0019754


MONDO:0019754

[PMID:25042199] [SUPPORT] The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). --- Explanation: Fatigue listed as one of the most common symptoms in the siltuximab clinical trial.


MONDO:0019754

[PMID:25042199] [SUPPORT] The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). --- Explanation: Anemia is a common hematologic manifestation in MCD patients.


MONDO:0019754

[PMID:29157612] [SUPPORT] Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS). --- Explanation: Thrombocytopenia is a characteristic feature of iMCD-TAFRO.


MONDO:0019754

[PMID:29157612] [SUPPORT] Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome --- Explanation: Severe anasarca is a hallmark of iMCD-TAFRO.


MONDO:0019754

[PMID:25042199] [INDIRECT EVIDENCE] [SUPPORT] Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. --- Explanation: The pivotal siltuximab trial establishes IL-6 dysregulation as the central driver of MCD.

[PMID:24622327] [INDIRECT EVIDENCE] [SUPPORT] Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. --- Explanation: Confirms IL-6 hypercytokinemia as the central pathogenic mechanism in MCD.

[PMID:24622327] [INDIRECT EVIDENCE] [SUPPORT] We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. --- Explanation: Proposes three candidate processes that may drive IL-6 hypersecretion in idiopathic MCD.


MONDO:0019754

[PMID:24622327] [INDIRECT EVIDENCE] [PARTIAL] Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. --- Explanation: Describes the systemic effects of hypercytokinemia including organ impairment, consistent with VEGF-driven vascular pathology.


MAXO:0000058

[PMID:25042199] [SUPPORT] Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). --- Explanation: Pivotal randomized controlled trial demonstrating siltuximab efficacy in iMCD.

[PMID:25042199] [SUPPORT] Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. --- Explanation: Trial conclusion establishing siltuximab as a key treatment for MCD.


MAXO:0000058

[PMID:30181172] [SUPPORT] The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. --- Explanation: International consensus guidelines recommend tocilizumab as alternative first-line therapy for iMCD.


MAXO:0000058

[PMID:21778341] [SUPPORT] Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD. --- Explanation: Multicenter retrospective study demonstrating improved outcomes with rituximab in HIV-associated MCD.

[PMID:37288720] [SUPPORT] Rituximab has revolutionized the treatment of Kaposi sarcoma-associated herpesvirus/human herpesvirus 8-associated multicentric Castleman disease (HHV8+ MCD), converting a rapidly fatal illness into a relapsing disease. --- Explanation: Confirms rituximab as transformative therapy for HHV-8+ MCD.

[PMID:37288720] [SUPPORT] Ninety-five patients (70 HIV+ and 25 HIV-) achieved complete remission (CR) after rituximab-based therapy. --- Explanation: Demonstrates high complete remission rates with rituximab-based therapy across both HIV+ and HIV- HHV8+ MCD patients.


MAXO:0000647

[PMID:30181172] [SUPPORT] In the most severe cases, adjuvant combination chemotherapy is recommended. --- Explanation: International consensus guidelines recommend chemotherapy for severe refractory iMCD.


MONDO:0009282

[PMID:38951975] [SUPPORT] All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. --- Explanation: All 14 MADD patients in the Malaysian cohort showed proximal limb weakness.

[PMID:37217231] [SUPPORT] The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. --- Explanation: Myopathy is listed among the common clinical manifestations.


MONDO:0009282

[PMID:37217231] [SUPPORT] Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. --- Explanation: Metabolic acidosis is a major presenting feature in MADD.


MONDO:0009282

[PMID:37217231] [SUPPORT] Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. --- Explanation: Non-ketotic hypoglycemia is listed as a major presenting feature.


MONDO:0009282

[PMID:38951975] [SUPPORT] All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. --- Explanation: All patients in the Malaysian MADD cohort had elevated CK.


MONDO:0009282

[PMID:37217231] [SUPPORT] The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. --- Explanation: Exercise intolerance is a recognized clinical manifestation of MADD.


MONDO:0009282

[PMID:37217231] [SUPPORT] The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. --- Explanation: Cardiomyopathy is listed among variable MADD manifestations.


MONDO:0009282

[PMID:17584774] [SUPPORT] All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms --- Explanation: Encephalopathy was a presenting feature in the Olsen et al. MADD cohort.

[PMID:37217231] [SUPPORT] This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation. --- Explanation: Case report of hyperammonemic encephalopathy as MADD presentation.


MONDO:0009282

[PMID:37217231] [SUPPORT] Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. --- Explanation: Hyperammonemia is a recognized acute presentation in MADD.


MONDO:0009282

[PMID:39455656] [SUPPORT] Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. --- Explanation: Rhabdomyolysis is recognized among the phenotypic spectrum of MADD.


MONDO:0009282

[PMID:38951975] [PARTIAL] Three patients experienced a metabolic crisis at their presentation. --- Explanation: Metabolic crises in severe MADD can include respiratory compromise, though this snippet describes metabolic crisis broadly without specifying respiratory involvement.


MONDO:0009282

[PMID:37217231] [PARTIAL] The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. --- Explanation: Hepatomegaly is well-recognized in severe MADD, though not explicitly listed in this particular abstract.


MONDO:0009282

[PMID:39455656] [SUPPORT] Various phenotypes, including episodic weakness or rhabdomyolysis, exercise intolerance, and peripheral neuropathy, have been reported in both muscular and neuronal contexts. --- Explanation: Peripheral neuropathy is part of the MADD phenotypic spectrum.


MONDO:0009282

[PMID:17584774] [SUPPORT] several had previously suffered cyclical vomiting. --- Explanation: Cyclical vomiting occurred as a prodromal symptom in MADD patients.


MONDO:0009282

[PMID:17584774] [PARTIAL] All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms --- Explanation: Muscle weakness is a presenting feature of MADD. Neonatal forms typically include hypotonia, though this abstract describes muscle weakness in riboflavin-responsive patients rather than the neonatal presentation specifically.


MONDO:0009282

[PMID:17584774] [INDIRECT EVIDENCE] [SUPPORT] Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). --- Explanation: Supports ETF/ETFDH molecular dysfunction as the initiating defect in MADD.


MONDO:0009282

[PMID:17584774] [INDIRECT EVIDENCE] [SUPPORT] Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). --- Explanation: Supports downstream multi-pathway catabolic disruption from ETF system failure.


MONDO:0009282


MONDO:0009282

[PMID:38243131] [INDIRECT EVIDENCE] [SUPPORT] We identify a complex (comprising ETFDH, CIII and the Q-biosynthesis regulator COQ2) that directs electrons from lipid substrates to the respiratory chain, thereby reducing electron leaks and reactive oxygen species production. --- Explanation: Identifies the ETFDH-CIII-COQ2 metabolon supporting OXPHOS efficiency.


MONDO:0009282

[PMID:39455656] [INDIRECT EVIDENCE] [SUPPORT] Our cellular models of MADD exhibit neurite growth defects and excessive apoptosis. --- Explanation: Demonstrates apoptosis and neurite pathology in ETFDH mutation cellular models.


MONDO:0009282

[PMID:38365830] [INDIRECT EVIDENCE] [SUPPORT] Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common lipid storage myopathy. --- Explanation: Establishes late-onset MADD as the most common lipid storage myopathy.

[PMID:38951975] [INDIRECT EVIDENCE] [SUPPORT] Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). --- Explanation: Confirms MADD causes lipid storage myopathy in a clinical cohort.


MAXO:0000058

[PMID:17584774] [SUPPORT] Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. --- Explanation: Landmark demonstration of riboflavin responsiveness in MADD with ETFDH mutations.

[PMID:38951975] [SUPPORT] All of the patients responded well to riboflavin therapy. --- Explanation: All 14 patients in the Malaysian cohort responded to riboflavin.

[PMID:39092677] [SUPPORT] All 9 patients responded to riboflavin treatment with normalization of creatine kinase and muscle biopsy findings, and in 8 patients the clinical symptoms clearly improved. --- Explanation: Riboflavin effective in both genetic and sertraline-associated MADD.


MAXO:0000058

[PMID:39455656] [SUPPORT] Subsequent treatment of the mutant cells with coenzyme Q10 downregulated activated protein expression and mitigated neurite growth defects. --- Explanation: Demonstrates CoQ10 rescue of apoptosis and neurite defects in ETFDH mutant cells.

[PMID:39950184] [SUPPORT] After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. --- Explanation: CoQ10 used as part of successful combination therapy in late-onset MADD.


MAXO:0000058

[PMID:39950184] [SUPPORT] After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. --- Explanation: Levocarnitine used as part of successful treatment regimen in late-onset MADD.


MAXO:0000088

[PMID:37217231] [SUPPORT] MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation. --- Explanation: Appropriate nutrition and decompensation prevention are core management elements.

[PMID:39950184] [SUPPORT] After 1 month of dietary intervention and daily diet supplements (riboflavin 400 mg TID, levocarnitine 1 g TID, Q10 150 mg qD in two doses), the patient had almost recovered to his habitual level. --- Explanation: Dietary intervention was part of the successful treatment approach.


MAXO:0000950

[PMID:37217231] [SUPPORT] This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation. --- Explanation: Acute metabolic crisis in MADD required intubation and intensive supportive care.


MAXO:0000124

[PMID:39273584] [SUPPORT] Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs. --- Explanation: TMS-based newborn screening can identify MADD cases.


MAXO:0000079

[PMID:38221620] [SUPPORT] The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population. --- Explanation: Genetic characterization supports genetic counseling and patient-specific management.

[PMID:39273584] [SUPPORT] Despite significant advancements in sequencing techniques, many patients remain undiagnosed, impacting their access to clinical care and genetic counseling. --- Explanation: Highlights the importance of genetic counseling for MADD families.


MAXO:0000058

[PMID:39092677] [SUPPORT] Our findings strongly suggest that sertraline may induce an acquired form of MADD in some patients. Importantly, riboflavin treatment seems to be similarly effective as in genetic MADD, but discontinuation of sertraline is reasonably warranted. --- Explanation: Identifies sertraline as a potential trigger for acquired MADD and recommends discontinuation.

[PMID:39092677] [SUPPORT] Remarkably, all 7 patients without disease-causing mutations were treated with sertraline. In some cases, a deterioration of symptoms closely followed dose increase, and discontinuation resulted in an improved acylcarnitine profile. --- Explanation: Dose-response relationship and improvement with sertraline discontinuation.


HGNC.SYMBOL:ETFDH variants (most common cause)

[PMID:17584774] [SUPPORT] All patients had mutations in the gene for ETF:QO. --- Explanation: Landmark paper establishing ETFDH as a major cause of riboflavin-responsive MADD.


HGNC.SYMBOL:ETFA and ETFB variants


HGNC.SYMBOL:FLAD1 variants (MADD-like phenotype)

[PMID:38228875] [SUPPORT] Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features. --- Explanation: Comparative study demonstrating FLAD1 as a MADD-like disease gene.


MONDO:0019003

[PMID:21862994] [SUPPORT] MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. --- Explanation: Review confirms MTC is the hallmark of MEN2 with genotype-phenotype correlations determining clinical presentation and aggressiveness.


MONDO:0019003


MAXO:0000004

[PMID:21862994] [SUPPORT] Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. --- Explanation: Review confirms prophylactic thyroidectomy as curative treatment for MEN2 with excellent outcomes when performed early based on genotype.


MAXO:0000058


NCIT:C134987


MAXO:0000126


MAXO:0000079


HGNC.SYMBOL:RET

[PMID:11786689] [SUPPORT] The gene causing all three MEN2 variants is located on chromosome 10cen-10q11.2, and is the c-ret proto-oncogene which encodes a tyrosine kinase receptor with cadherin-like and cysteine-rich extracellular domains, and a tyrosine kinase intracellular domain. Specific mutations of c-ret have been identified for each of the three MEN2 variants. --- Explanation: Review confirms RET proto-oncogene as the gene responsible for all MEN2 variants with specific mutations identified for each clinical variant.


MONDO:0971174

[PMID:39669623] [SUPPORT] Optic atrophy, movement disorder, and developmental delay were frequent findings.
 --- Explanation: Optic atrophy identified as one of the most frequent findings in the natural history study.


MONDO:0971174


MONDO:0971174

[PMID:37046037] [SUPPORT] The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%)
 --- Explanation: Systematic review documenting 43% frequency of ataxia.


MONDO:0971174

[PMID:39669623] [SUPPORT] Optic atrophy, movement disorder, and developmental delay were frequent findings.
 --- Explanation: Developmental delay identified as a frequent finding in natural history study.


MONDO:0971174

[PMID:37481223] [SUPPORT] Retinal dystrophy with attenuated retinal vessels appearing as white lines was observed in this cohort, and the FFA images revealed that retinal vascular occlusion could be a distinct clinical characteristic
 --- Explanation: Documents retinal dystrophy with characteristic vascular findings.


MONDO:0971174

[PMID:39669623] [SUPPORT] Optic atrophy, movement disorder, and developmental delay were frequent findings.
 --- Explanation: Movement disorder identified as frequent in natural history study.


MONDO:0971174

[DOI:10.1172/jci.insight.179071] [SUPPORT] FDXR variants cause adrenal insufficiency and atypical sexual development
 --- Explanation: Pignatti et al. 2024 document adrenal insufficiency and DSD phenotypes in severe FDXR-related mitochondriopathy, linking FDXR to steroidogenic P450 enzyme dysfunction.


MONDO:0971174

[PMID:29040572] [INDIRECT EVIDENCE] [SUPPORT] In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS).
 --- Explanation: Fibroblast assays demonstrating impaired electron transfer and mitochondrial dysfunction from FDXR mutations.


MONDO:0971174

[PMID:32995353] [INDIRECT EVIDENCE] [SUPPORT] The deficiencies of complex I in the brain, heart, and muscle tissues of the FdxrR389Q/R389Q mutants were all significantly recovered after the AAV treatment
 --- Explanation: Demonstrates that Fdxr mutation causes mitochondrial complex deficiencies that can be reversed with gene therapy.


MONDO:0971174

[PMID:32995353] [INDIRECT EVIDENCE] [SUPPORT] the FdxrR389Q/R389Q mutants re-acquired iron homeostasis in heart and muscle after AAV treatment
 --- Explanation: Demonstrates mitochondrial iron overload in Fdxr mutant mice that is reversed by gene therapy.


MONDO:0971174

[DOI:10.1038/s41420-025-02840-y] [INDIRECT EVIDENCE] [SUPPORT] We demonstrated increased lipid peroxidation in the inner mitochondrial and plasma membranes, resulting in susceptibility to ferroptosis. Closer examination revealed that disruption of the NRF2 pathway and its target gene SLC7A11 appear to play important roles in this pathogenic process.
 --- Explanation: Mouse model and cell studies demonstrate ferroptosis as a novel pathogenic mechanism in FDXR-related disease via NRF2/SLC7A11 disruption.


MONDO:0971174

[PMID:30250212] [INDIRECT EVIDENCE] [SUPPORT] we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy
 --- Explanation: Describes neurodegeneration in FDXR patients with brain autopsy findings and mouse model showing Fluoro-Jade C positivity.


MONDO:0971174

[PMID:30250212] [INDIRECT EVIDENCE] [SUPPORT] we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy
 --- Explanation: Documents neuroinflammation with astrogliosis in FDXR patient brain autopsy and increased GFAP in mouse model.


MONDO:0971174

[PMID:37481223] [INDIRECT EVIDENCE] [SUPPORT] all patients presented with retinal dystrophy, and electroretinogram showed severely impaired cone and rod functions in their first decades
 --- Explanation: Documents retinal dystrophy and vascular abnormalities in FDXR patients.


MONDO:0971174

[PMID:37046037] [INDIRECT EVIDENCE] [SUPPORT] The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%)
 --- Explanation: Systematic review documenting frequency of peripheral neuropathy and ataxia in FDXR patients.


MAXO:0000950


MAXO:0000058


MAXO:0000004


MAXO:0000088


MAXO:0001001

[PMID:32995353] [SUPPORT] AAV-Fdxr treatment reversed almost all the symptoms of the mutants (Fdxr R389Q/R389Q). This therapy also improved the electronic conductivity of the sciatic nerves, prevented optic atrophy, improved mobility, and restored mitochondrial complex function.
 --- Explanation: First demonstration of AAV gene therapy efficacy in Fdxr mutant mice.


MAXO:0000058

[DOI:10.1038/s41420-025-02840-y] [SUPPORT] administration of the NRF2 activator omaveloxolone, which was recently approved by the FDA for treatment of Friedreich's ataxia, helps mitigate the pathogenesis
 --- Explanation: Preclinical evidence for omaveloxolone as an NRF2-activating therapeutic strategy in FDXR-related disease.


MAXO:0000079

[PMID:39669623] [SUPPORT] consideration of a new approach for population carrier screening and development of therapeutics for affected individuals is needed.
 --- Explanation: Recommends carrier screening in Mexican population based on high carrier frequency.


MAXO:0000011


MAXO:0001017


HGNC.SYMBOL:Autosomal Recessive FDXR Deficiency


MONDO:0009693

[PMID:34201396] [SUPPORT] Patients with MM usually present with hypercalcemia, anemia, renal damage, increased risk for infections, and pathological fracture secondary to osteolytic bone destruction --- Explanation: Anemia is listed as a common presenting feature of multiple myeloma.


MONDO:0009693

[PMID:34201396] [SUPPORT] Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. --- Explanation: Bone pain is listed as a frequent skeletal-related event complicating osteolytic lesions in 80% of myeloma patients.


MONDO:0009693

[PMID:34201396] [SUPPORT] Osteolytic lesions are seen in 80% of patients with MM --- Explanation: Osteolytic lesions are present in 80% of myeloma patients at diagnosis.


MONDO:0009693

[PMID:34201396] [SUPPORT] Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. --- Explanation: Pathological fractures are a frequent complication of myeloma bone disease.


MONDO:0009693

[PMID:25439696] [SUPPORT] existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). --- Explanation: Renal failure is a defining CRAB feature per IMWG diagnostic criteria.


MONDO:0009693

[PMID:25439696] [SUPPORT] existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). --- Explanation: Hypercalcemia is a defining CRAB feature per IMWG diagnostic criteria.


MONDO:0009693

[PMID:34201396] [SUPPORT] Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. --- Explanation: Immunoparesis directly leads to increased infection risk in myeloma patients.


MONDO:0009693

[PMID:18753647] [SUPPORT] Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. --- Explanation: The VISTA trial documents peripheral neuropathy as a known adverse event of bortezomib-based treatment in myeloma.


MONDO:0009693

[PMID:34201396] [SUPPORT] Patients with MM usually present with hypercalcemia, anemia, renal damage, increased risk for infections, and pathological fracture secondary to osteolytic bone destruction --- Explanation: Anemia and renal damage, both presenting features of myeloma, are primary contributors to fatigue in myeloma patients.


MONDO:0009693

[PMID:34201396] [INDIRECT EVIDENCE] [SUPPORT] Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). --- Explanation: Mukkamalla et al. review confirms MM as a neoplastic clonal proliferation of plasma cells producing monoclonal proteins.


MONDO:0009693


MONDO:0009693

[PMID:25439696] [INDIRECT EVIDENCE] [SUPPORT] This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). --- Explanation: The IMWG diagnostic criteria define myeloma partly through detection of monoclonal protein, confirming its central role in pathophysiology.


MONDO:0009693

[PMID:34201396] [INDIRECT EVIDENCE] [SUPPORT] Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG, MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast stimulation, differentiation, and maturation, whereas osteoblast inhibitory factors such as the Wnt/DKK1 pathway, secreted frizzle related protein-2, and runt-related transcription factor 2 inhibit osteoblast differentiation and formation leading to decreased bone formation. --- Explanation: Comprehensive review details the molecular mechanisms of myeloma bone disease including RANKL/OPG imbalance and DKK1-mediated osteoblast inhibition.