MONDO:0021107

[PMID:25728441] [SUPPORT] Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. --- Explanation: Cataplexy is the defining feature that distinguishes Type 1 narcolepsy and is caused by hypocretin deficiency.


MONDO:0021107

[PMID:25728441] [SUPPORT] Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. --- Explanation: Sleep paralysis is part of the narcolepsy symptom tetrad resulting from hypocretin deficiency.


MONDO:0021107

[PMID:25728441] [SUPPORT] Narcolepsy with cataplexy is caused by hypocretin deficiency --- Explanation: Hypnagogic hallucinations are part of the classic narcolepsy tetrad resulting from REM sleep intrusion.


MONDO:0021107

[PMID:25728441] [SUPPORT] Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. --- Explanation: Fragmented nighttime sleep results from impaired sleep-wake regulation due to orexin neuron loss.


MONDO:0021107

[PMID:25728441] [INDIRECT EVIDENCE] [SUPPORT] Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. --- Explanation: Landmark review establishes hypocretin neuron loss as the cause of narcolepsy with cataplexy.


MONDO:0021107


MONDO:0021107

[PMID:25728441] [INDIRECT EVIDENCE] [SUPPORT] The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. --- Explanation: Genetic associations with HLA and TCR loci strongly support autoimmune etiology.

[PMID:32227223] [INDIRECT EVIDENCE] [SUPPORT] Narcolepsy type 1 is hypothesized to be an autoimmune disease targeting the hypocretin/orexin neurons in the hypothalamus. Ample genetic and epidemiological evidence points in the direction of a pathogenesis involving the immune system --- Explanation: Recent review summarizing that genetic and epidemiological evidence supports autoimmune pathogenesis.

[PMID:38077397] [INDIRECT EVIDENCE] [SUPPORT] NT1 is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. --- Explanation: Transcriptomic study confirms the immunological basis and T-cell involvement in narcolepsy pathogenesis.


MAXO:0000058

[PMID:22893778] [SUPPORT] Narcolepsy patients on SXB have significant reductions in cataplexy and daytime sleepiness. SXB is well tolerated in patients with narcolepsy, and most adverse events were mild to moderate in severity. --- Explanation: Systematic review and meta-analysis of 6 RCTs confirms efficacy for both cataplexy and sleepiness with acceptable safety.


MAXO:0000058

[PMID:20671626] [SUPPORT] In narcoleptic patients, modafinil in comparison with placebo is effective in the treatment of excessive daytime sleepiness, but not cataplexy. --- Explanation: Systematic review and meta-analysis of 9 RCTs confirms modafinil efficacy for excessive daytime sleepiness.


CHEBI:31859

[PMID:20671626] [INDIRECT EVIDENCE] [SUPPORT] In narcoleptic patients, modafinil in comparison with placebo is effective in the treatment of excessive daytime sleepiness, but not cataplexy. --- Explanation: Systematic review and meta-analysis of 9 RCTs confirms modafinil efficacy for excessive daytime sleepiness.


MAXO:0000058

[PMID:34935103] [SUPPORT] The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. --- Explanation: Analysis of randomized placebo-controlled trials demonstrates large effect sizes for pitolisant.


CHEBI:134709

[PMID:34935103] [INDIRECT EVIDENCE] [SUPPORT] The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. --- Explanation: Analysis of randomized placebo-controlled trials demonstrates large effect sizes for pitolisant.


MAXO:0000058

[PMID:30694576] [SUPPORT] Solriamfetol has the potential to be an important therapeutic option for the treatment of impaired wakefulness and excessive sleepiness in patients with narcolepsy. --- Explanation: Phase 3 RCT demonstrated significant improvements in MWT and ESS scores versus placebo.


NCIT:C152389

[PMID:30694576] [INDIRECT EVIDENCE] [SUPPORT] Solriamfetol has the potential to be an important therapeutic option for the treatment of impaired wakefulness and excessive sleepiness in patients with narcolepsy. --- Explanation: Phase 3 RCT demonstrated significant improvements in MWT and ESS scores versus placebo.


MAXO:0000058

[PMID:18830438] [SUPPORT] Modafinil has replaced methylphenidate and amphetamine as the first-line treatment of excessive daytime sleepiness (EDS) and sleep attacks --- Explanation: Confirms amphetamines were traditional first-line treatments for EDS before modafinil.


MAXO:0000058

[PMID:30837110] [SUPPORT] Venlafaxine demonstrated significantly greater improvements in MSL in the MWT (p < 0.01). --- Explanation: Prospective study of 148 patients showed significant improvement in cataplexy and sleepiness with antidepressants.


MAXO:0000077

[PMID:18830438] [SUPPORT] The management of narcolepsy is presently at a turning point. --- Explanation: Review discusses comprehensive narcolepsy management including behavioral approaches like scheduled naps.


HGNC.SYMBOL:HLA-DQB1*06:02

[PMID:32227223] [SUPPORT] Autoreactive T cells and autoantibodies have been detected in blood samples from patients --- Explanation: Detection of autoreactive T cells in narcolepsy patients supports the HLA-mediated autoimmune mechanism.


HGNC.SYMBOL:HCRT

[PMID:25728441] [SUPPORT] Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. --- Explanation: Demonstrates that loss of hypocretin gene function causes narcolepsy.


HGNC.SYMBOL:HCRTR2

[PMID:25728441] [SUPPORT] Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. --- Explanation: Confirms that hypocretin receptor mutations cause narcolepsy in animal models.


MONDO:0015459


MONDO:0015459

[PMID:25361008] [INDIRECT EVIDENCE] [SUPPORT] Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. --- Explanation: Demonstrates that EBV-driven LMP1 upregulates PD-L1 in NPC cell lines, establishing the mechanism of immune evasion via checkpoint ligand expression in EBV-associated nasopharyngeal carcinoma.

[PMID:25361008] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients. --- Explanation: Clinical evidence that PD-L1 expression correlates with worse outcomes in NPC patients, supporting the role of PD-L1-mediated immune evasion in disease progression.


MAXO:0000014


CHEBI:27899


MAXO:0000647


CHEBI:175901


MAXO:0000058


HGNC.SYMBOL:HLA-A


HGNC.SYMBOL:TP53


HGNC.SYMBOL:CDKN2A


HGNC.SYMBOL:NF-kB Pathway Alterations


NCBITaxon:10376

[PMID:41016806] [PARTIAL] In addition to its involvement in a wide range of malignancies such as lymphomas, nasopharyngeal carcinoma, and gastric cancer, recent evidence has shown its potential association with autoimmune diseases, positioning EBV as an interdisciplinary research model linking virology, oncology, and immunology. --- Explanation: Supports the association of EBV with nasopharyngeal carcinoma.


MONDO:0015459

[PMID:24733735] [SUPPORT] Nasopharyngeal squamous cell carcinoma (NPSCC) is uncommon in --- Explanation: Abstract identifies nasopharyngeal squamous cell carcinoma as an uncommon subtype.


MONDO:0018958

[PMID:38634969] [SUPPORT] Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking curative therapies. --- Explanation: Confirms muscle weakness as a cardinal feature of NEB-based nemaline myopathy.

[PMID:36714460] [SUPPORT] The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. --- Explanation: Documents generalized weakness across the spectrum of NEB-NM in a 33-patient cohort.


MONDO:0018958

[PMID:38500810] [SUPPORT] Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. --- Explanation: Case report demonstrating severe hypotonia as a presenting feature in neonatal NM.

[PMID:36661122] [SUPPORT] Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function. --- Explanation: Establishes hypotonia as a defining feature of nemaline myopathy.

[PMID:17272906] [SUPPORT] All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness. --- Explanation: Indian cohort confirming generalized hypotonia as a universal presenting feature in childhood-onset NM.


MONDO:0018958

[PMID:36714460] [SUPPORT] Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. --- Explanation: Identifies a novel facial/bulbar finding in NEB-NM patients associated with dysphagia.


MONDO:0018958

[PMID:36714460] [SUPPORT] 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. --- Explanation: Documents that 55% of NEB-NM patients required ventilatory support.

[PMID:36714460] [SUPPORT] Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. --- Explanation: Shows progressive respiratory involvement in NEB-NM patients over time.

[PMID:19208402] [SUPPORT] This case study reports a 60-year-old woman who presented with isolated type 2 respiratory failure secondary to bilateral hemidiaphragm weakness. --- Explanation: Documents that NM can present with isolated respiratory failure from diaphragm weakness, highlighting the importance of considering neuromuscular causes.


MONDO:0018958

[PMID:38500810] [SUPPORT] Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. --- Explanation: Documents feeding difficulties requiring gastrostomy in a neonate with NM.

[PMID:36714460] [SUPPORT] 32% of patients with NM-NEB used a G tube --- Explanation: Quantifies the frequency of gastrostomy tube use in NEB-NM patients.


MONDO:0018958

[PMID:36714460] [SUPPORT] Scoliosis and dysphagia were more common among patients who used VS. --- Explanation: Documents association of scoliosis with disease severity in NEB-NM.

[PMID:36714460] [SUPPORT] Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. --- Explanation: Demonstrates progressive scoliosis with increasing age in NEB-NM.


MONDO:0018958

[PMID:36703211] [SUPPORT] Acquired sporadic late onset nemaline myopathy (SLONM) and inherited nemaline myopathy (iNM) both feature accumulation of nemaline rods in muscle fibers. --- Explanation: Confirms nemaline rod accumulation as the defining feature across NM subtypes.

[PMID:9372751] [SUPPORT] A modified trichrome stain of the right biceps muscle revealed granular, basophilic, centrally located rods in the atrophic myofibers. Ultrastructurally, these myofibers contained osmiophilic rectangular structures with a latticelike appearance typical of nemaline myopathy. --- Explanation: Classic description of nemaline rod morphology on trichrome stain and electron microscopy.

[PMID:39691005] [SUPPORT] Modified Gomori trichrome staining revealed granular deposits in the myofibers. Ultrastructure examination showed numerous nemaline rods in the myofibers --- Explanation: Recent case confirming characteristic trichrome and ultrastructural appearance of nemaline rods.


MONDO:0018958

[PMID:39651462] [SUPPORT] Key patient-reported symptoms since childhood were muscle weakness (n = 23; 96%), slowness of movements (n = 23; 96%), and difficulties with running (n = 20; 83%). --- Explanation: Documents slowness of movements as a near-universal symptom in NEM6 patients.

[PMID:39651462] [SUPPORT] This might be related to delayed muscle relaxation. --- Explanation: Links the slowness of movements phenotype to the delayed muscle relaxation kinetics measured in NEM6 patients.


MONDO:0018958

[PMID:2804774] [SUPPORT] A 21-year-old female with nemaline myopathy and concomitant dysmorphism characteristic of elongated face, high arched palate, scoliosis and pes cavus is reported. --- Explanation: Documents high-arched palate as part of nemaline myopathy craniofacial phenotype.


MONDO:0018958

[PMID:38634969] [INDIRECT EVIDENCE] [SUPPORT] Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. --- Explanation: Establishes the role of nebulin in thin filament function and the consequence of its disruption.

[PMID:38376469] [INDIRECT EVIDENCE] [SUPPORT] Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3 --- Explanation: Confirms ACTA1-related NM is an actin-based thin filament disease with impaired muscle function.


MONDO:0018958


MONDO:0018958

[PMID:36703211] [INDIRECT EVIDENCE] [SUPPORT] In all iNM samples, nemaline rods were found in subsarcolemmal or central aggregates, whereas they were diffusely distributed within muscle fibers in most SLONM samples. --- Explanation: Documents the distinct distribution pattern of nemaline rods in inherited vs acquired forms.

[PMID:38500810] [INDIRECT EVIDENCE] [SUPPORT] Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion. --- Explanation: Confirms nemaline rods as a pathognomonic feature identified on muscle biopsy.

[PMID:31228046] [INDIRECT EVIDENCE] [SUPPORT] These rods or nemaline bodies are derived from Z lines (also known as Z discs or Z disks) and have a similar lattice structure and protein content. Their shape in patients with mutations in KLHL40 and LMOD3 is distinctive and can be useful for diagnosis. The number and distribution of nemaline bodies varies between fibres and different muscles but does not correlate with severity or prognosis. --- Explanation: Authoritative review establishing rod origin from Z-discs, gene-specific rod morphology, and lack of correlation between rod burden and clinical severity.

[PMID:35810298] [INDIRECT EVIDENCE] [SUPPORT] Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. --- Explanation: Documents intranuclear rods and cytoplasmic bodies as characteristic features of severe ACTA1-NM.

[PMID:17272906] [INDIRECT EVIDENCE] [SUPPORT] characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods. --- Explanation: Confirms alpha-actinin as a major component of nemaline rods demonstrated by immunostaining.


MONDO:0018958

[PMID:38634969] [INDIRECT EVIDENCE] [SUPPORT] We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a pathogenic duplication variant in nebulin that resulted in a four-copy gain in the triplicate region of NEB and a much larger nebulin protein and longer TFL. --- Explanation: Demonstrates that both shortened and elongated thin filaments from NEB variants impair force generation.

[PMID:38634969] [INDIRECT EVIDENCE] [SUPPORT] we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from pathogenic splicing variants. --- Explanation: Proposes that thin filament length dysregulation in both directions is a key disease mechanism.


MONDO:0018958

[PMID:38634969] [INDIRECT EVIDENCE] [SUPPORT] We observed a positive relation between the reduction in nebulin and a reduction in TFL, or reduction in tension (both maximal and submaximal tension). --- Explanation: Demonstrates reduced contractile tension in patient muscle fibers with pathogenic NEB variants.

[PMID:38376469] [INDIRECT EVIDENCE] [PARTIAL] Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. --- Explanation: Rescue of contractile capacity in ACTA1-NM model supports baseline sarcomeric tension deficits.


MONDO:0018958

[PMID:37432316] [INDIRECT EVIDENCE] [SUPPORT] Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40-deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. --- Explanation: Establishes that KLHL40 deficiency causes NM through disrupted ubiquitin-regulated vesicle trafficking.


MONDO:0018958

[PMID:35810298] [INDIRECT EVIDENCE] [SUPPORT] We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. --- Explanation: Identifies perinuclear space enlargement as a novel ultrastructural hallmark of severe ACTA1-NM.

[PMID:35810298] [INDIRECT EVIDENCE] [SUPPORT] In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. --- Explanation: Demonstrates disruption of nuclear envelope components in ACTA1-NM, linking actin mutations to nuclear biology.


MONDO:0018958

[PMID:36661122] [INDIRECT EVIDENCE] [SUPPORT] Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. --- Explanation: Identifies NRAP as a disease modifier in NEB-related NM with therapeutic targeting potential.


MAXO:0000506

[PMID:36714460] [SUPPORT] 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. --- Explanation: Documents that the majority of NEB-NM patients require ventilatory support.

[PMID:36714460] [SUPPORT] Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. --- Explanation: Supports longitudinal need for respiratory support as disease progresses.


MAXO:0000506

[PMID:36714460] [INDIRECT EVIDENCE] [SUPPORT] 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. --- Explanation: Documents that the majority of NEB-NM patients require ventilatory support.

[PMID:36714460] [INDIRECT EVIDENCE] [SUPPORT] Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. --- Explanation: Supports longitudinal need for respiratory support as disease progresses.


MAXO:0000011

[PMID:31228046] [SUPPORT] Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living. --- Explanation: Supports ongoing rehabilitative, mobility-preserving symptomatic care as standard management.


MAXO:0000011

[PMID:31228046] [INDIRECT EVIDENCE] [SUPPORT] Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living. --- Explanation: Supports ongoing rehabilitative, mobility-preserving symptomatic care as standard management.


MAXO:0000011


MAXO:0001346

[PMID:36714460] [SUPPORT] 32% of patients with NM-NEB used a G tube --- Explanation: Quantifies the need for gastrostomy in NEB-NM patients.

[PMID:38500810] [SUPPORT] Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. --- Explanation: Supports gastrostomy as a practical intervention for severe neonatal bulbar dysfunction.


MAXO:0001346

[PMID:36714460] [INDIRECT EVIDENCE] [SUPPORT] 32% of patients with NM-NEB used a G tube --- Explanation: Quantifies the need for gastrostomy in NEB-NM patients.

[PMID:38500810] [INDIRECT EVIDENCE] [SUPPORT] Here, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. --- Explanation: Supports gastrostomy as a practical intervention for severe neonatal bulbar dysfunction.


MAXO:0000477

[PMID:36714460] [SUPPORT] Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. --- Explanation: Progressive scoliosis supports need for structured orthopedic surveillance and intervention.

[PMID:31228046] [SUPPORT] Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living. --- Explanation: Supports symptom-directed orthopedic and mobility-preserving management as part of standard care.


MAXO:0000477

[PMID:36714460] [INDIRECT EVIDENCE] [SUPPORT] Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. --- Explanation: Progressive scoliosis supports need for structured orthopedic surveillance and intervention.

[PMID:31228046] [INDIRECT EVIDENCE] [SUPPORT] Animal models are advancing the understanding of the effects of various mutations in different genes and paving the way for the development of therapies, which at present only manage symptoms and are aimed at maintaining muscle strength, joint mobility, ambulation, respiration and independence in the activities of daily living. --- Explanation: Supports symptom-directed orthopedic and mobility-preserving management as part of standard care.


MAXO:0000079

[PMID:19208402] [SUPPORT] Unless appropriate tests are performed-including a muscle biopsy, if indicated-specific neuromuscular diseases are easily missed. This can lead to inappropriate counseling and treatment. --- Explanation: Highlights counseling consequences of diagnostic misclassification, supporting formal counseling in NM care pathways.


MAXO:0000058

[PMID:38376469] [SUPPORT] Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. --- Explanation: Demonstrates tirasemtiv efficacy in a mouse model of ACTA1-related NM.

[PMID:38376469] [SUPPORT] Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. --- Explanation: Shows improved respiratory efficiency with troponin activator treatment.


MAXO:0000058

[PMID:38376469] [INDIRECT EVIDENCE] [SUPPORT] Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. --- Explanation: Demonstrates tirasemtiv efficacy in a mouse model of ACTA1-related NM.

[PMID:38376469] [INDIRECT EVIDENCE] [SUPPORT] Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. --- Explanation: Shows improved respiratory efficiency with troponin activator treatment.


MAXO:0000058


MAXO:0000058

[PMID:38634969] [SUPPORT] OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin. --- Explanation: Ex vivo human muscle fiber data showing omecamtiv mecarbil increases force production in NEB-NM.


MAXO:0000058

[PMID:38634969] [INDIRECT EVIDENCE] [SUPPORT] OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87 to 318%, with the largest effects in patients with the lowest level of nebulin. --- Explanation: Ex vivo human muscle fiber data showing omecamtiv mecarbil increases force production in NEB-NM.


hgnc:7720

[PMID:36661122] [SUPPORT] Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients. --- Explanation: Establishes NEB as the most common causative gene in NM.

[PMID:38634969] [SUPPORT] Pathogenic variants in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness --- Explanation: Confirms NEB variants as causative for NEM2.

[PMID:31228046] [SUPPORT] The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. --- Explanation: Authoritative 2019 review confirming NEB and ACTA1 as the two most common causative genes.


hgnc:129

[PMID:38376469] [SUPPORT] Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. --- Explanation: Establishes ACTA1 as the second most common cause of NM.

[PMID:38500810] [SUPPORT] An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin. --- Explanation: Case report of a novel ACTA1 variant causing NM.

[PMID:35810298] [SUPPORT] ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. --- Explanation: Describes ACTA1 function and confirms its role in severe NM with characteristic intranuclear rods and perinuclear space abnormalities.

[PMID:35810298] [SUPPORT] we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. --- Explanation: Identifies compensatory cardiac alpha-actin expression as a potential modifier of ACTA1-NM severity.


hgnc:37227

[PMID:39651462] [SUPPORT] Nemaline myopathy type 6 (NEM6) is the most prevalent type of nemaline myopathy in the Netherlands. --- Explanation: Establishes KBTBD13-NEM6 as a significant form of NM.


hgnc:30372

[PMID:37432316] [SUPPORT] Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy --- Explanation: Confirms KLHL40 mutations as causative for severe congenital NM.


hgnc:12012

[PMID:27858751] [SUPPORT] Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1. --- Explanation: Directly supports TPM3 as a causative gene for NEM1 nemaline myopathy.


hgnc:12011

[PMID:23378224] [SUPPORT] We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. --- Explanation: Family-based human data support TPM2 as a causative gene in nemaline myopathy.


hgnc:11948

[PMID:29931346] [SUPPORT] We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT). --- Explanation: Cohort natural-history data establish pathogenic TNNT1 variants as causative in Amish nemaline myopathy.


hgnc:1875

[PMID:17160903] [SUPPORT] We report identification of a sixth gene, CFL2, encoding the actin-binding protein muscle cofilin-2, which is mutated in two siblings with congenital myopathy. --- Explanation: Human sibling data identify CFL2 as a causative gene for congenital nemaline myopathy.


hgnc:6649

[PMID:36893608] [SUPPORT] Nemaline myopathy (NEM) type 10, caused by biallelic mutations in LMOD3, is a severe congenital myopathy clinically characterized by generalized hypotonia and muscle weakness, respiratory insufficiency, joint contractures, and bulbar weakness. --- Explanation: Supports biallelic LMOD3 mutations as causative for NEM10.


hgnc:16905

[PMID:24268659] [SUPPORT] We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. --- Explanation: Whole-exome sequencing and follow-up cohort data support KLHL41 as a causative nemaline myopathy gene.


MONDO:0018958

[PMID:36661122] [SUPPORT] NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients. --- Explanation: Confirms that recessive NEB mutations are the most common cause of nemaline myopathy.


MONDO:0018958

[PMID:38376469] [SUPPORT] Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. --- Explanation: Supports ACTA1 as a significant genetic cause; ACTA1 mutations can be autosomal dominant.

[PMID:31228046] [SUPPORT] Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. --- Explanation: Authoritative review confirming de novo, dominant, and recessive inheritance patterns across NM genes.


MONDO:0019005

[PMID:17647025] [NO_EVIDENCE] Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions. --- Explanation: While this reference mentions Mendelian forms of hypertension, there is no specific mention of Nephronophthisis resulting in hypertension or cardiovascular phenotypes generally.

[PMID:20969579] [NO_EVIDENCE] A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. --- Explanation: This reference discusses hereditary kidney diseases and the genetic mutations involved but does not mention Nephronophthisis or its cardiovascular phenotypes including hypertension.

[PMID:12589180] [NO_EVIDENCE] Defective transduction of the dopamine receptor signal in the kidney... --- Explanation: The article discusses the role of dopamine in the kidney and its involvement in hypertension, but it does not address Nephronophthisis or whether hypertension is a common cardiovascular phenotype in this condition.

[PMID:23402468] [NO_EVIDENCE] Hypertension is the most common modifiable risk factor for cardiovascular disease. Antihypertensive treatment substantially reduces the risk of heart failure, stroke, and myocardial infarction. --- Explanation: This article offers a general overview of hypertension and its management but does not specifically mention Nephronophthisis or any associated cardiovascular phenotypes.

[PMID:16336577] [NO_EVIDENCE] Nephrosclerosis, benign nephrosclerosis, and hypertensive kidney disease are terms that clinicians use when renal damage is thought to be secondary to essential hypertension. --- Explanation: While the article discusses hypertension in the context of renal diseases, it does not specify an association between Nephronophthisis and hypertension as a cardiovascular phenotype.

[PMID:37910243] [NO_EVIDENCE] Hypertension is common in children with CAKUT and increases the risk of CKD. --- Explanation: This study focuses on congenital anomalies of the kidney and urinary tract (CAKUT) and their association with hypertension, but it does not discuss Nephronophthisis.


MONDO:0019005

[PMID:16966065] [SUPPORT] Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome)... --- Explanation: This reference indicates that tapetoretinal degeneration, synonymous with retinitis pigmentosa in the context of this disease, is an occasional extrarenal symptom of nephronophthisis.

[PMID:25161209] [SUPPORT] The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy...These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. --- Explanation: This reference directly confirms the association between nephronophthisis and retinitis pigmentosa as occasional ophthalmologic phenotypes.

[PMID:37644229] [SUPPORT] Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. --- Explanation: This indicates that ophthalmologic phenotypes, including retinal degeneration, are common in pediatric renal ciliopathies including nephronophthisis.


MONDO:0019005

[PMID:16966065] [PARTIAL] Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement. --- Explanation: The reference mentions extrarenal symptoms associated with nephronophthisis but does not specifically mention growth retardation. However, growth retardation could be inferred as a potential consequence of chronic kidney disease.

[PMID:30552565] [SUPPORT] Growth retardation is a major feature of chronic kidney disease (CKD) of onset in infants or children and is associated with increased morbidity and mortality. --- Explanation: This reference supports the statement that growth retardation is associated with chronic kidney disease, which can be a consequence of nephronophthisis.


MONDO:0019005

[PMID:16966065] [REFUTE] Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure. --- Explanation: Nephronophthisis is a type of chronic tubulo-interstitial nephritis and not an endocrine disorder. It primarily affects the kidneys and progresses to terminal renal failure, but it is not categorized as an endocrine disorder nor is it specifically associated with secondary hyperparathyroidism.


MONDO:0019005


MONDO:0019005

[PMID:19118152] [INDIRECT EVIDENCE] [SUPPORT] Nephronophthisis (NPHP), a recessive cystic kidney disease... Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. --- Explanation: The provided snippet indicates that mutations in NPHP genes affect mechanisms that disrupt cellular functions related to cilia, supporting the statement that these mutations lead to impaired cilia.

[PMID:34183231] [INDIRECT EVIDENCE] [SUPPORT] Mutations in genes encoding centriolar or ciliary proteins cause diseases collectively known as 'ciliopathies'. --- Explanation: This statement refers to how ciliary protein gene mutations cause related ciliopathies, aligning with impaired cilia as seen in Nephronophthisis.

[PMID:21113628] [INDIRECT EVIDENCE] [SUPPORT] Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies. --- Explanation: The excerpt affirms that ciliary dysfunction is fundamental to the development of various cystic kidney diseases, including Nephronophthisis, caused by mutations affecting cilia.


MONDO:0019005

[PMID:19186246] [INDIRECT EVIDENCE] [PARTIAL] Their importance for key developmental pathways such as Sonic Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal cilia, for example, is vital for breaking early embryonic symmetry, Shh signaling is important for tissue morphogenesis and successful Wnt signaling for organ growth and differentiation. When ciliary function is perturbed...brains form improperly. --- Explanation: This reference supports the idea that disrupted cilia function affects the Wnt and Hedgehog pathways, but it does not specify nephronophthisis directly.

[PMID:22206729] [INDIRECT EVIDENCE] [SUPPORT] Mutations of the ankyrin-repeat protein Inversin, a member of a diverse family of more than 12 proteins, cause nephronophthisis (NPH)...Most NPH gene products (NPHPs) localize to the cilium, and appear to control the transport of cargo protein to the cilium by forming functional networks. --- Explanation: This reference directly links nephronophthisis to defective cilia and mentions involvement in pathways like Wnt signaling.

[PMID:24162855] [INDIRECT EVIDENCE] [PARTIAL] The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function...one of the signaling pathways that requires the cilium for normal development is Wnt signaling. --- Explanation: This reference supports the involvement of the primary cilium in Wnt signaling but does not explicitly connect it to nephronophthisis.

[PMID:20544799] [INDIRECT EVIDENCE] [PARTIAL] mutation of proteins required for function of cilia often leads to impaired Shh signaling and to disruption of neural tube closure. --- Explanation: This reference supports the idea that ciliary dysfunction affects Hedgehog signaling but focuses on neural tube defects rather than nephronophthisis.

[PMID:35655331] [INDIRECT EVIDENCE] [SUPPORT] Ciliary dysfunction causes many human conditions termed ciliopathies...ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century...illustrates many core concepts of human genetics. --- Explanation: This reference supports the concept that defects in the primary cilia affect key signaling pathways, including the ones mentioned, in the context of nephronophthisis.


MONDO:0019005

[PMID:21071979] [INDIRECT EVIDENCE] [PARTIAL] Nephronophthisis is a recessive disorder of the kidney that is the leading cause of end-stage renal failure in children. Through positional cloning, many of the causative mutations have been mapped to genes involved in centrosome and cilia function. --- Explanation: The literature supports that nephronophthisis is related to ciliary dysfunction, but it does not explicitly mention polyuria and polydipsia as part of its pathophysiology.

[PMID:16186680] [INDIRECT EVIDENCE] [PARTIAL] Renal tubular disorders may affect multiple (e.g., Fanconi syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders. --- Explanation: The reference discusses renal tubular disorders, which can result in polyuria and electrolyte imbalance, but it does not explicitly link these to ciliary dysfunction in nephronophthisis.

[PMID:9790573] [INDIRECT EVIDENCE] [PARTIAL] Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts. --- Explanation: While the reference discusses fluid accumulation and cyst formation in polycystic kidney disease, it does not directly link these to nephronophthisis or explicitly mention polyuria.

[PMID:18312782] [INDIRECT EVIDENCE] [PARTIAL] Overlapping clinical entities including situs inversus, certain infertility disorders, as well as chronic respiratory infections have their roots in abnormal ciliary function. --- Explanation: This reference supports the involvement of ciliary dysfunction in various disorders but does not provide specific details on nephronophthisis and its pathophysiology related to polyuria and polydipsia.


MONDO:0019005

[PMID:35533128] [INDIRECT EVIDENCE] [SUPPORT] Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. --- Explanation: The diagnosis of nephronophthisis includes tubulointerstitial changes, which aligns with chronic tubular dysfunction and inflammation leading to interstitial fibrosis.

[PMID:31399984] [INDIRECT EVIDENCE] [PARTIAL] Renal interstitial lymphangiogenesis is found in patients with chronic kidney disease (CKD) and a series of animal models of renal fibrosis. --- Explanation: While the study focuses on lymphangiogenesis, it mentions renal interstitial fibrosis related to chronic kidney disease, of which nephronophthisis is a type.


MONDO:0019005

[PMID:16966065] [INDIRECT EVIDENCE] [PARTIAL] Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure. --- Explanation: The statement claims that abnormal cell proliferation and differentiation result in cyst formation in nephronophthisis, but the literature describes nephronophthisis as a chronic tubulo-interstitial nephritis without indicating cyst formation due to abnormal cell proliferation and differentiation as a characteristic pathophysiological mechanism. Instead, it mentions cortical microcysts in infantile forms but emphasizes interstitial fibrosis and tubular basement membrane changes.

[PMID:25575298] [INDIRECT EVIDENCE] [NO_EVIDENCE] Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia. --- Explanation: While this reference discusses abnormal cilia structure and function in cystic kidney diseases, it does not specifically address nephronophthisis or the mechanism of abnormal cell proliferation and differentiation leading to renal cyst formation in nephronophthisis.


MONDO:0019005

[PMID:35533128] [INDIRECT EVIDENCE] [PARTIAL] Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. --- Explanation: The literature supports the involvement of the liver and retina in nephronophthisis but does not mention the brain specifically in this context.

[PMID:32432520] [INDIRECT EVIDENCE] [PARTIAL] Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies. --- Explanation: The literature supports the involvement of the retina in Senior-Loken syndrome but does not mention the liver or brain specifically in this context.

[PMID:33306870] [INDIRECT EVIDENCE] [SUPPORT] Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. --- Explanation: The literature supports the involvement of the retina in Senior-Loken syndrome, which is a form of nephronophthisis.

[PMID:35655331] [INDIRECT EVIDENCE] [NO_EVIDENCE] The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. --- Explanation: This reference discusses the involvement of primary cilia in a broader sense but does not specify the extrarenal manifestations like those in Senior-Loken syndrome.


MAXO:0000601

[PMID:32906116] [SUPPORT] Nephronophthisis (NPHP) is an autosomal recessive disease manifesting as tubulointerstitial nephritis uniformly progressing to ESRD in approximately 5-10% patients in childhood. Living donor transplantation is the most beneficial mean of renal replacement therapy compared to other methods. --- Explanation: The abstract discusses that Nephronophthisis often leads to end-stage renal disease (ESRD) and mentions living donor transplantation as a beneficial renal replacement therapy option.

[PMID:15715116] [SUPPORT] Diabetes and ESRD receiving Renal Replacement Therapy (RRT)... The main choices of modalities are: 1) haemodialysis (HD), 2) Peritoneal dialysis (PD), 3) Kidney transplantation alone (KTA) or 4) simultaneous kidney and pancreas transplantation (SPKT). --- Explanation: Although this reference focuses on diabetic nephropathy, it supports the statement that renal replacement therapies for ESRD include dialysis and kidney transplantation.


MAXO:0000058

[PMID:36224286] [PARTIAL] Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD... therefore, one of the best strategies to slow the progression of CKD is to maintain the 'numbers' of these essential components necessary to preserve renal function. To this end, both the achievement of an optimal blood pressure and a maximum reduction in urinary protein excretion are essential. --- Explanation: This source suggests that managing blood pressure is essential in the context of CKD, which is related to nephron function. However, it does not explicitly mention Nephronophthisis, a specific type of nephropathy.

[PMID:30354828] [NO_EVIDENCE] Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes...evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. --- Explanation: This source provides comprehensive information on the evaluation and management of resistant hypertension but does not discuss Nephronophthisis specifically.


MAXO:0000950

[PMID:35533128] [SUPPORT] At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis. --- Explanation: There is no curative treatment for nephronophthisis, indicating that supportive care, including symptomatic treatment and monitoring, is currently applied to manage associated complications.


HGNC.SYMBOL:NPHP1

[PMID:15138899] [SUPPORT] Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone. --- Explanation: The NPHP1 gene deletion is associated with juvenile nephronophthisis, confirming the genetic link between NPHP1 and nephronophthisis.

[PMID:36990420] [SUPPORT] Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy. --- Explanation: This reference supports the genetic association of nephronophthisis with variants in several genes, highlighting NPHP1 among the genes associated with nephropathy.


HGNC.SYMBOL:NPHP3

[PMID:34212438] [SUPPORT] we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family.

[PMID:26184788] [SUPPORT] Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3.

[PMID:36990420] [SUPPORT] Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy.


HGNC.SYMBOL:NPHP4

[PMID:14750102] [SUPPORT] Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4. --- Explanation: The literature identifies NPHP4 as one of the genes responsible for different types of Nephronophthisis.

[PMID:34591160] [SUPPORT] Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4... contributes to end-stage renal disease in children and young adults. --- Explanation: The literature indicates that NPHP4 is associated with end-stage renal disease in Nephronophthisis, highlighting its pathogenic role.

[PMID:36990420] [SUPPORT] Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis... Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy. --- Explanation: The literature mentions that patients with NPHP4 variants develop nephropathy in the context of Nephronophthisis.


HGNC.SYMBOL:INVS

[PMID:14750102] [SUPPORT] Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4. --- Explanation: The literature identifies NPHP2 (INVS) as one of the genes responsible for different types of Nephronophthisis.

[PMID:36990420] [SUPPORT] Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy. --- Explanation: The literature confirms INVS variants are associated with nephropathy in nephronophthisis.


HGNC.SYMBOL:NEK8

[PMID:36990420] [SUPPORT] Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy. --- Explanation: While this reference doesn't specifically mention NEK8, it establishes the context of genetic heterogeneity in nephronophthisis-related ciliopathies.


MONDO:0009735

[DOI:10.3390/genes14051080] [SUPPORT] It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. --- Explanation: This directly supports ichthyosis as a core clinical manifestation of NS.


MONDO:0009735

[PMID:41126693] [SUPPORT] Netherton syndrome (NTS) is a syndromic ichthyosis characterized by scaling, erythroderma, and proneness towards allergies and infections. --- Explanation: This explicitly reports erythroderma as a characteristic phenotype in NS.

[PMID:40299794] [SUPPORT] Physical examination showed generalized erythroderma and polycyclic and serpiginous erythematous plaques with double-edged scales at the margins. --- Explanation: This case report provides direct clinical evidence for erythroderma in NS.


MONDO:0009735

[DOI:10.3390/genes14051080] [SUPPORT] It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. --- Explanation: This supports hair-shaft abnormalities as a core component of the NS clinical triad.

[PMID:40299794] [SUPPORT] Trichoscopy of the scalp revealed a hair shaft abnormality, specifically trichorrhexis invaginata. --- Explanation: This provides direct clinical confirmation of characteristic bamboo-hair morphology in NS.


MONDO:0009735

[DOI:10.3390/genes14051080] [SUPPORT] We describe an NS patient, initially misdiagnosed with severe AD, who carried the heterozygous frameshift (null) mutation (NM_006846.4): c.957_960dup combined with homozygous rs2303067 in the SPINK5 gene. --- Explanation: This supports atopic-dermatitis-like presentations and diagnostic overlap in NS.

[PMID:40299794] [SUPPORT] The patient was previously diagnosed with atopic dermatitis and had been treated with systemic corticosteroids and omalizumab, without improvement. --- Explanation: This supports frequent diagnostic overlap and initial misclassification as severe atopic dermatitis.


MONDO:0009735

[clinicaltrials:NCT04244006] [SUPPORT] To date, there are no effective therapy for the management of Netherton Syndrome (NS) Patients use emollients with a limited efficacy on scaling and no efficacy on skin inflammation and pruritus. --- Explanation: Trial summary explicitly identifies pruritus as a persistent symptom and treatment target.

[PMID:40607310] [SUPPORT] He demonstrated substantial clinical benefits, with marked relief from pruritus resulting in better quality of life. --- Explanation: This supports that pruritus is a major and treatment-responsive symptomatic burden in NS.


MONDO:0009735

[PMID:41126693] [SUPPORT] Netherton syndrome (NTS) is a syndromic ichthyosis characterized by scaling, erythroderma, and proneness towards allergies and infections. --- Explanation: This supports recurrent infection susceptibility as part of the NS phenotype spectrum.

[PMID:40607310] [SUPPORT] The patient was treated with intravenous immunoglobulin due to frequent infections that required multiple hospital admissions. --- Explanation: This provides direct case-level evidence for recurrent severe infections in NS.


MONDO:0009735

[PMID:39931731] [SUPPORT] We observed that patients with variants or homozygous variants located in the 5' half of the gene were more likely to experience failure to thrive (P < 0.05). --- Explanation: This supports genotype-associated risk of failure to thrive in NS cohorts.

[PMID:38634098] [SUPPORT] We describe an 8-year-old boy with genetically proven NS treated with intravenous immunoglobulin for recurrent skin and systemic infections from infancy, growth retardation, and associated erythroderma. --- Explanation: This supports growth retardation/failure-to-thrive manifestations in pediatric NS.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] AbstractNetherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. --- Explanation: This supports SPINK5 loss of function as the initiating lesion in NS.

[PMID:40607310] [INDIRECT EVIDENCE] [SUPPORT] Netherton syndrome (NS) is a rare autosomal recessive genodermatosis caused by pathogenic mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, leading to impaired skin barrier function and immune dysregulation. --- Explanation: This supports pathogenic SPINK5 variants as the primary molecular driver in human NS.


MONDO:0009735


MONDO:0009735

[DOI:10.3390/genes14051080] [INDIRECT EVIDENCE] [SUPPORT] Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, resulting in a deficiency in its processed protein LEKTI. --- Explanation: This supports LEKTI deficiency as a distinct downstream molecular consequence of SPINK5 defects.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. --- Explanation: This supports increased protease activity as a central intermediary event in NS.

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] By comparing skin transcriptomes and proteomes, we uncover several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. --- Explanation: This directly supports KLK-driven IL-36 cytokine processing.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. --- Explanation: This supports protease-driven barrier/cornification pathology in NS.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. --- Explanation: This supports barrier dysfunction as a key pathophysiologic hub in NS.

[PMID:38025195] [INDIRECT EVIDENCE] [SUPPORT] Loss of LEKTI induces severe skin barrier defect. --- Explanation: This provides additional human case-level support for severe barrier disruption in NS.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] By comparing skin transcriptomes and proteomes, we uncover several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. --- Explanation: This defines the KLK-to-IL-36 activation step in the NS inflammatory cascade.

[DOI:10.3390/dermatopathology11030024] [INDIRECT EVIDENCE] [SUPPORT] Both cases demonstrated robust expression of IL-36. --- Explanation: This supports IL-36 pathway activation in NS patient skin biopsies.


MONDO:0009735

[PMID:41126693] [INDIRECT EVIDENCE] [SUPPORT] Netherton syndrome (NTS) is a syndromic ichthyosis characterized by scaling, erythroderma, and proneness towards allergies and infections. --- Explanation: This supports concurrent allergy-prone and infection-prone consequences of barrier failure.


MONDO:0009735

[DOI:10.1038/s42003-024-05780-y] [INDIRECT EVIDENCE] [SUPPORT] Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. --- Explanation: This supports IL-17/IL-36 axis overactivation as a core inflammatory driver in NS.

[DOI:10.3390/dermatopathology11030024] [INDIRECT EVIDENCE] [SUPPORT] Both cases demonstrated robust expression of IL-36. --- Explanation: This provides patient-level biopsy support for IL-36-driven inflammation.


MONDO:0009735

[DOI:10.3390/genes14051080] [INDIRECT EVIDENCE] [SUPPORT] It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. --- Explanation: This supports hair-shaft defects as a direct disease consequence within the SPINK5/LEKTI mechanism.


MAXO:0000950

[clinicaltrials:NCT04244006] [SUPPORT] To date, there are no effective therapy for the management of Netherton Syndrome (NS) Patients use emollients with a limited efficacy on scaling and no efficacy on skin inflammation and pruritus. --- Explanation: This trial summary supports current reliance on topical supportive care and its limitations.


MAXO:0001001

[clinicaltrials:NCT01545323] [SUPPORT] The investigators have used a disabled virus (vector) to carry a functional copy of the SPINK5 gene into skin stem cells. --- Explanation: This supports an ex vivo lentiviral SPINK5 gene-correction strategy in NS.

[clinicaltrials:NCT01545323] [SUPPORT] In this trial the investigators propose grafting of autologous epidermal sheets generated from genetically modified skin stem cells for the treatment of patients with Netherton Syndrome. --- Explanation: This supports autologous epidermal sheet grafting from genetically corrected skin stem cells as the investigational treatment approach.


MAXO:0000058

[PMID:40888388] [SUPPORT] This review provides a comprehensive overview of the current clinical landscape and future directions of biologics (e.g., dupilumab, secukinumab, ustekinumab) and small-molecule therapies (e.g., JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib) in the treatment of NS. --- Explanation: This supports use of cytokine-targeted and JAK-pathway therapies in severe NS.

[PMID:40888388] [PARTIAL] Though evidence remains limited to case reports and small series, preliminary data suggest that cytokine-targeted interventions-particularly those inhibiting IL-4, IL-13, IL-17, IL-36, and JAK pathways-may offer tangible clinical benefits. --- Explanation: This supports potential efficacy while acknowledging current evidence limits.

[PMID:40969297] [SUPPORT] Both patients had swift and enduring enhancement of skin lesions during the follow-up period. --- Explanation: This case series adds contemporary human evidence that biologic pathway targeting can improve NS skin disease.


NCIT:C162455

[PMID:40888388] [INDIRECT EVIDENCE] [SUPPORT] This review provides a comprehensive overview of the current clinical landscape and future directions of biologics (e.g., dupilumab, secukinumab, ustekinumab) and small-molecule therapies (e.g., JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib) in the treatment of NS. --- Explanation: This supports use of cytokine-targeted and JAK-pathway therapies in severe NS.

[PMID:40888388] [INDIRECT EVIDENCE] [PARTIAL] Though evidence remains limited to case reports and small series, preliminary data suggest that cytokine-targeted interventions-particularly those inhibiting IL-4, IL-13, IL-17, IL-36, and JAK pathways-may offer tangible clinical benefits. --- Explanation: This supports potential efficacy while acknowledging current evidence limits.

[PMID:40969297] [INDIRECT EVIDENCE] [SUPPORT] Both patients had swift and enduring enhancement of skin lesions during the follow-up period. --- Explanation: This case series adds contemporary human evidence that biologic pathway targeting can improve NS skin disease.


NCIT:C152315


NCIT:C166985


MAXO:0000058

[PMID:35464459] [SUPPORT] Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. --- Explanation: This supports observed skin benefit in aggregated case-based treatment evidence.

[PMID:38634098] [SUPPORT] Under this therapy, his skin status, infectious exacerbations, and quality of life all improved. --- Explanation: This provides additional pediatric case-level support for IVIG-centered systemic therapy.


NCIT:C162455

[PMID:35464459] [INDIRECT EVIDENCE] [SUPPORT] Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. --- Explanation: This supports observed skin benefit in aggregated case-based treatment evidence.

[PMID:38634098] [INDIRECT EVIDENCE] [SUPPORT] Under this therapy, his skin status, infectious exacerbations, and quality of life all improved. --- Explanation: This provides additional pediatric case-level support for IVIG-centered systemic therapy.


MAXO:0000058

[PMID:38634098] [SUPPORT] KEY CLINICAL MESSAGE: High-dose intravenous immunoglobulin exhibits great potential in the treatment of Netherton syndrome. --- Explanation: This explicitly supports IVIG as a promising strategy in pediatric NS.

[PMID:40607310] [SUPPORT] The patient was treated with intravenous immunoglobulin due to frequent infections that required multiple hospital admissions. --- Explanation: This supports IVIG use in infection-prone NS with severe recurrent admissions.


MAXO:0000058

[PMID:40607310] [SUPPORT] When he was 6 years old, dupilumab was added to reduce skin inflammation and improve skin barrier function before food reintroduction. --- Explanation: This supports dupilumab targeting inflammatory and barrier manifestations in pediatric NS.

[PMID:40969297] [SUPPORT] The child received treatment with dupilumab, while the 19-year-old woman alternated between using dupilumab and secukinumab. --- Explanation: This supports real-world use of dupilumab across pediatric and young-adult NS cases.

[PMID:35327681] [SUPPORT] Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. --- Explanation: This adds additional case-level evidence for dupilumab benefit on pruritus and inflammatory skin burden.


NCIT:C162455

[PMID:40607310] [INDIRECT EVIDENCE] [SUPPORT] When he was 6 years old, dupilumab was added to reduce skin inflammation and improve skin barrier function before food reintroduction. --- Explanation: This supports dupilumab targeting inflammatory and barrier manifestations in pediatric NS.

[PMID:40969297] [INDIRECT EVIDENCE] [SUPPORT] The child received treatment with dupilumab, while the 19-year-old woman alternated between using dupilumab and secukinumab. --- Explanation: This supports real-world use of dupilumab across pediatric and young-adult NS cases.

[PMID:35327681] [INDIRECT EVIDENCE] [SUPPORT] Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. --- Explanation: This adds additional case-level evidence for dupilumab benefit on pruritus and inflammatory skin burden.


MAXO:0000058

[PMID:40299794] [SUPPORT] After 2 injections, the patient's condition markedly improved and the effect after the last injection was maintained for 4-5 months. --- Explanation: This supports clinically meaningful short-term and sustained response to secukinumab in refractory NS.

[PMID:40969297] [SUPPORT] The child received treatment with dupilumab, while the 19-year-old woman alternated between using dupilumab and secukinumab. --- Explanation: This supports secukinumab use as part of targeted biologic treatment strategies in NS.


NCIT:C152315

[PMID:40299794] [INDIRECT EVIDENCE] [SUPPORT] After 2 injections, the patient's condition markedly improved and the effect after the last injection was maintained for 4-5 months. --- Explanation: This supports clinically meaningful short-term and sustained response to secukinumab in refractory NS.

[PMID:40969297] [INDIRECT EVIDENCE] [SUPPORT] The child received treatment with dupilumab, while the 19-year-old woman alternated between using dupilumab and secukinumab. --- Explanation: This supports secukinumab use as part of targeted biologic treatment strategies in NS.


MAXO:0000058

[PMID:40159127] [SUPPORT] Following six months of Abrocitinib therapy, the patient exhibited marked improvement in skin rash and overall disease severity. --- Explanation: This supports JAK1 inhibition as a promising targeted option in NS.


NCIT:C166985

[PMID:40159127] [INDIRECT EVIDENCE] [SUPPORT] Following six months of Abrocitinib therapy, the patient exhibited marked improvement in skin rash and overall disease severity. --- Explanation: This supports JAK1 inhibition as a promising targeted option in NS.


MAXO:0000058

[clinicaltrials:NCT07151508] [SUPPORT] In this study, we describe our experience with secukinumab (IL-17A inhibitor) and dupilumab (IL-4/IL-13 inhibitor) treatment of a group of pediatric patients with severe Neterton syndrome. --- Explanation: This supports real-world investigational use of combination biologic therapy in severe pediatric NS.


NCIT:C152315

[clinicaltrials:NCT07151508] [INDIRECT EVIDENCE] [SUPPORT] In this study, we describe our experience with secukinumab (IL-17A inhibitor) and dupilumab (IL-4/IL-13 inhibitor) treatment of a group of pediatric patients with severe Neterton syndrome. --- Explanation: This supports real-world investigational use of combination biologic therapy in severe pediatric NS.


NCIT:C162455


hgnc:15464

[DOI:10.3390/genes14051080] [SUPPORT] Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, resulting in a deficiency in its processed protein LEKTI. --- Explanation: This directly supports SPINK5 as the causal gene and links genotype to LEKTI deficiency.

[PMID:27905021] [SUPPORT] The identification of SPINK5, which encodes for the serine protease inhibitor LEKTI, as the gene responsible for Netherton syndrome, enabled the search for causative mutations in Netherton syndrome patients and families. --- Explanation: This supports SPINK5 as the established disease gene and highlights genotype-phenotype analysis in affected families.

[PMID:39931731] [SUPPORT] Among 162 patients, we identified 324 allele variants, comprising 75 different mutations. --- Explanation: This supports broad allelic heterogeneity and the need for comprehensive SPINK5 variant interpretation.

[PMID:40159127] [SUPPORT] Genetic analysis revealed that the patient harbored compound heterozygous mutations in the SPINK5 gene, including a missense mutation in exon 26 (c.2475G > T, p.Trp825Cys). --- Explanation: This supports ongoing expansion of pathogenic SPINK5 variant classes, including missense alleles.

[PMID:40969297] [SUPPORT] Subsequently, genetic testing identified a defective SPINK5 gene, leading to a diagnosis of NS. --- Explanation: This provides additional contemporary clinical evidence of SPINK5 defects as the diagnostic molecular basis of NS.

[PMID:36159989] [SUPPORT] We identified a novel frameshift mutation c.2474_2475del (p.Glu825Glyfs*2) in the SPINK5 gene. --- Explanation: This adds evidence that novel SPINK5 pathogenic variants continue to be identified in NS.


MONDO:0009735

[PMID:27905021] [SUPPORT] Netherton syndrome (OMIM #256500) is a rare but severe autosomal recessive form of ichthyosis that affects the skin, hair, and immune system. --- Explanation: This review explicitly states the autosomal recessive inheritance mode for Netherton syndrome.


MONDO:0005072


MONDO:0005072

[PMID:41560679] [INDIRECT EVIDENCE] [SUPPORT] Neuroblastoma (NB) is a pediatric solid tumor originating from neural crest cells (NCCs), which are precursors of the sympathetic nervous system. --- Explanation: This abstract states neuroblastoma originates from neural crest cells, supporting the developmental origin described.

[PMID:32296467] [INDIRECT EVIDENCE] [SUPPORT] Neuroblastoma is a clinically heterogenous pediatric cancer of the sympathetic nervous system that originates from neural crest cells. --- Explanation: Supports neural crest origin and clinical heterogeneity of neuroblastoma.


MAXO:0000647


CHEBI:27899


CHEBI:4911


CHEBI:4026


MAXO:0000004


MAXO:0000747


MAXO:0000014


MAXO:0001002


MAXO:0000058


CHEBI:6067


HGNC.SYMBOL:MYCN Amplification


HGNC.SYMBOL:ALK Mutations


HGNC.SYMBOL:Segmental Chromosomal Aberrations


MONDO:0005072

[PMID:10985139] [SUPPORT] Neuroblastoma is a malignant tumor of neural crest origin that may arise --- Explanation: Abstract describes neuroblastoma as a malignant tumor of neural crest origin.


MONDO:0018975

[PMID:9874851] [SUPPORT] The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). --- Explanation: Review identifies cafe-au-lait spots as a cardinal feature of NF1.


MONDO:0018975

[PMID:9874851] [SUPPORT] The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). --- Explanation: Review identifies cutaneous neurofibromas as a cardinal feature of NF1.


MONDO:0018975

[PMID:33395032] [PARTIAL] Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. --- Explanation: Review confirms plexiform neurofibromas are a significant clinical problem in NF1 amenable to MEK inhibitor therapy.


MONDO:0018975

[PMID:9874851] [SUPPORT] The cardinal features of the disorder are cafe au lait spots, axillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). --- Explanation: Review identifies Lisch nodules (iris hamartomas) as a cardinal feature of NF1.


MONDO:0018975

[PMID:9874851] [SUPPORT] Common complications include learning disability, scoliosis, and optic gliomas. --- Explanation: Review identifies optic gliomas as a common complication of NF1.


MONDO:0018975

[PMID:32234870] [SUPPORT] Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs). --- Explanation: Review confirms approximately 10% of peripheral nerve sheath tumors in NF1 undergo malignant transformation to MPNST.


MONDO:0018975

[PMID:9874851] [SUPPORT] Common complications include learning disability, scoliosis, and optic gliomas. --- Explanation: Review identifies scoliosis as a common complication of NF1.


MONDO:0018975

[PMID:9874851] [SUPPORT] Common complications include learning disability, scoliosis, and optic gliomas. --- Explanation: Review identifies learning disability as a common complication of NF1.


MONDO:0018975


MAXO:0000058

[PMID:33395032] [SUPPORT] The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. --- Explanation: SPRINT trial demonstrated selumetinib efficacy in plexiform neurofibromas leading to FDA approval for pediatric NF1 patients.


MAXO:0000004


MAXO:0000126

[PMID:9874851] [SUPPORT] The mainstay of care for patients with NF1 is anticipatory guidance, and the early detection and symptomatic treatment of disease complications. --- Explanation: Review emphasizes surveillance and early detection as the foundation of NF1 management.


MAXO:0000079

[PMID:9874851] [SUPPORT] Counseling of patients and their families should provide a realistic overview of possible disease complications, while emphasizing that most individuals with NF1 lead healthy and productive lives. --- Explanation: Review discusses the importance of genetic counseling for NF1 families, addressing both disease complications and positive prognosis.


HGNC.SYMBOL:NF1


MONDO:0019100

[PMID:38819039] [SUPPORT] Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction. --- Explanation: Visual loss is explicitly described as a consequence of NMOSD.


MONDO:0019100

[PMID:38819039] [SUPPORT] Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction. --- Explanation: Motor dysfunction in NMOSD manifests clinically as weakness.


MONDO:0019100

[PMID:21368286] [SUPPORT] Aquaporin-4 (AQP4) autoimmunity targets this region, resulting in intractable nausea associated with vomiting or hiccups in NMO. --- Explanation: The abstract links NMO area postrema involvement with intractable nausea and vomiting.


MONDO:0019100

[PMID:35454180] [INDIRECT EVIDENCE] [SUPPORT] In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. --- Explanation: The abstract describes AQP4-IgG binding and complement-mediated astrocyte disruption.


MONDO:0019100


MONDO:0019100

[PMID:35454180] [INDIRECT EVIDENCE] [SUPPORT] Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. --- Explanation: The abstract notes complement-independent cytotoxicity and AQP4 endocytosis in NMOSD.


MAXO:0000058

[PMID:33741809] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists eculizumab as an approved maintenance therapy for NMOSD.


NCIT:C48386

[PMID:33741809] [INDIRECT EVIDENCE] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists eculizumab as an approved maintenance therapy for NMOSD.


MAXO:0000058

[PMID:33741809] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists inebilizumab as an approved maintenance therapy for NMOSD.


NCIT:C88283

[PMID:33741809] [INDIRECT EVIDENCE] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists inebilizumab as an approved maintenance therapy for NMOSD.


MAXO:0000058

[PMID:33741809] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists satralizumab as an approved maintenance therapy for NMOSD.


NCIT:C152307

[PMID:33741809] [INDIRECT EVIDENCE] [SUPPORT] Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD. --- Explanation: The abstract lists satralizumab as an approved maintenance therapy for NMOSD.


MONDO:0019100

[PMID:26092914] [SUPPORT] The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. --- Explanation: International diagnostic criteria identify optic nerve involvement as a core clinical characteristic of NMOSD.


MONDO:0019100

[PMID:26092914] [SUPPORT] The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema --- Explanation: Spinal cord involvement (transverse myelitis) is a core diagnostic criterion.


MONDO:0019100

[PMID:26092914] [SUPPORT] The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema --- Explanation: Area postrema syndrome is recognized as a core clinical feature of NMOSD.


MONDO:0019100

[PMID:35454180] [INDIRECT EVIDENCE] [SUPPORT] In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. --- Explanation: This review confirms that NMO-IgG binds AQP4 on astrocyte end-feet and causes complement-dependent astrocyte destruction.


MONDO:0019100

[PMID:31050279] [INDIRECT EVIDENCE] [SUPPORT] At least two thirds of cases are associated with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. --- Explanation: The PREVENT trial confirms that NMOSD involves complement-mediated CNS damage.


MAXO:0000058


MAXO:0000058

[PMID:31050279] [SUPPORT] Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group --- Explanation: The PREVENT trial demonstrated 94% reduction in relapse risk with eculizumab in AQP4-IgG-positive NMOSD.

[PMID:32266705] [SUPPORT] The terminal complement protein (C5) inhibitor eculizumab (Soliris) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive --- Explanation: Review confirms eculizumab as first approved targeted therapy for NMOSD.


NCIT:C48386

[PMID:31050279] [INDIRECT EVIDENCE] [SUPPORT] Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group --- Explanation: The PREVENT trial demonstrated 94% reduction in relapse risk with eculizumab in AQP4-IgG-positive NMOSD.

[PMID:32266705] [INDIRECT EVIDENCE] [SUPPORT] The terminal complement protein (C5) inhibitor eculizumab (Soliris) is the first agent to be specifically approved in the EU, USA, Canada and Japan for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are aquaporin-4 water channel autoantibody (AQP4-IgG) seropositive --- Explanation: Review confirms eculizumab as first approved targeted therapy for NMOSD.


MAXO:0000058

[PMID:31495497] [SUPPORT] 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo --- Explanation: The N-MOmentum trial demonstrated 73% reduction in attack risk with inebilizumab treatment.

[PMID:36070074] [SUPPORT] Inebilizumab (Uplizna) is a recently approved monoclonal antibody for use in adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody seropositive. --- Explanation: Review confirms regulatory approval of inebilizumab for NMOSD.


NCIT:C88283

[PMID:31495497] [INDIRECT EVIDENCE] [SUPPORT] 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo --- Explanation: The N-MOmentum trial demonstrated 73% reduction in attack risk with inebilizumab treatment.

[PMID:36070074] [INDIRECT EVIDENCE] [SUPPORT] Inebilizumab (Uplizna) is a recently approved monoclonal antibody for use in adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody seropositive. --- Explanation: Review confirms regulatory approval of inebilizumab for NMOSD.


MAXO:0000058

[PMID:36933107] [SUPPORT] Satralizumab (Enspryng) is a monoclonal antibody that blocks the interleukin-6 (IL-6) receptor and is approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in patients who are aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive. --- Explanation: Review confirms satralizumab mechanism and approval for NMOSD.


NCIT:C152307

[PMID:36933107] [INDIRECT EVIDENCE] [SUPPORT] Satralizumab (Enspryng) is a monoclonal antibody that blocks the interleukin-6 (IL-6) receptor and is approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in patients who are aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive. --- Explanation: Review confirms satralizumab mechanism and approval for NMOSD.


HGNC.SYMBOL:HLA-DRB1*03:01

[PMID:33420337] [SUPPORT] Neuromyelitis Optica patients have 2.46 more chances of having the DRB1*03 allelic group than controls. Ethnicity can influence genetic susceptibility. The main HLA association with Neuromyelitis Optica was the DRB1*03:01 allele in Western populations and with the DPB1*05:01 allele in Asia. --- Explanation: Meta-analysis confirms HLA-DRB1*03:01 as the primary genetic risk factor for NMO in Western populations, distinct from MS associations.


MONDO:0016295

[PMID:35628533] [SUPPORT] Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. --- Explanation: This review directly identifies progressive vision loss as a common NCL symptom.


MONDO:0016295

[PMID:35628533] [SUPPORT] Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. --- Explanation: The abstract identifies progressive mental deterioration as a common NCL manifestation, supporting progressive cognitive impairment.


MONDO:0016295

[PMID:35628533] [SUPPORT] Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. --- Explanation: This review directly lists epileptic seizures among the common symptoms of NCL.


MONDO:0016295

[PMID:35628533] [PARTIAL] Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. --- Explanation: Although the review does not use the phrase developmental regression directly, progressive mental and motor deterioration in a childhood-onset neurodegenerative disorder partially supports loss of acquired developmental function.


MONDO:0016295

[PMID:35359645] [INDIRECT EVIDENCE] [SUPPORT] These are genetic diseases associated with the formation of toxic endo-lysosomal storage. --- Explanation: This review identifies toxic endo-lysosomal storage as a core mechanistic feature of childhood NCL.


MONDO:0016295


MONDO:0016295

[PMID:37022340] [INDIRECT EVIDENCE] [SUPPORT] Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. --- Explanation: This review places CLN proteins in a shared endomembrane network that regulates multiple intracellular processes relevant to NCL pathogenesis.

[PMID:37022340] [INDIRECT EVIDENCE] [SUPPORT] A growing body of literature supports the networking of CLN genes and proteins within cells, which aligns with the broadly similar cellular and clinical manifestations among the different subtypes of NCL. --- Explanation: This supports convergent intracellular CLN protein dysfunction as an explanation for shared manifestations across NCL subtypes.


MONDO:0016295

[PMID:35359645] [INDIRECT EVIDENCE] [SUPPORT] We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. --- Explanation: This review identifies autophagy as a central cellular pathology mechanism in childhood NCL.


MONDO:0016295

[PMID:35359645] [INDIRECT EVIDENCE] [SUPPORT] We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. --- Explanation: This review identifies apoptosis as a core mechanistic component of NCL cellular pathology.


MONDO:0016295

[PMID:37022340] [INDIRECT EVIDENCE] [SUPPORT] In humans, mutations in CLN genes cause a devastating form of neurodegeneration called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. --- Explanation: This review directly identifies NCL as a devastating form of neurodegeneration.


MAXO:0000933

[PMID:31884868] [SUPPORT] Treatment with intracerebroventricular cerliponase alfa resulted in slower decline of motor and language functions compared with natural history controls. --- Explanation: This review summarizes clinical evidence that cerliponase alfa slows functional decline in CLN2 disease.

[PMID:31884868] [SUPPORT] Cerliponase alfa is the first therapy for neuronal ceroid lipofuscinosis type 2 that targets the disease etiology. --- Explanation: This identifies cerliponase alfa as an etiologically targeted treatment for the CLN2 subtype of NCL.


MAXO:0000950

[PMID:35359645] [SUPPORT] Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions. --- Explanation: This review makes clear that supportive and symptomatic care remains the main intervention for most NCL forms.


HGNC.SYMBOL:CLN Genes

[PMID:35628533] [SUPPORT] To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. --- Explanation: This review summarizes the marked genetic heterogeneity of NCL across multiple causative CLN loci.


MONDO:0018982

[PMID:20525256] [SUPPORT] The most characteristic sign is vertical supranuclear gaze palsy. --- Explanation: Vanier review identifies VSGP as the single most characteristic sign of NPC.


MONDO:0018982

[PMID:20525256] [SUPPORT] The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. --- Explanation: Cerebellar ataxia is listed as one of the main neurological manifestations.


MONDO:0018982

[PMID:20525256] [SUPPORT] The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. --- Explanation: Dysarthria is a core neurological feature of NPC.


MONDO:0018982

[PMID:20525256] [SUPPORT] The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. --- Explanation: Vanier review lists dysphagia as a core neurological feature of NPC.

[PMID:20301473] [SUPPORT] Death from aspiration pneumonia usually occurs in the late second or third decade. --- Explanation: GeneReviews confirms aspiration pneumonia from dysphagia as a major cause of death.


MONDO:0018982

[PMID:20525256] [SUPPORT] The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. --- Explanation: Progressive dementia is a core neurological feature of NPC.


MONDO:0018982

[PMID:20525256] [SUPPORT] Cataplexy, seizures and dystonia are other common features. --- Explanation: Dystonia is identified as a common neurological feature of NPC.


MONDO:0018982

[PMID:22572546] [SUPPORT] Epileptic seizures are also common in affected patients. --- Explanation: Patterson et al. guideline update confirms seizures are common in NPC.


MONDO:0018982

[PMID:22572546] [SUPPORT] Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy. --- Explanation: Patterson et al. guideline identifies gelastic cataplexy as a characteristic NPC manifestation.


MONDO:0018982

[PMID:20301473] [SUPPORT] The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. --- Explanation: GeneReviews confirms hepatosplenomegaly as a presenting feature in perinatal/infantile NPC.


MONDO:0018982

[PMID:20301473] [SUPPORT] The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. --- Explanation: Cholestatic jaundice is a key early visceral manifestation of NPC.


MONDO:0018982

[PMID:22572546] [SUPPORT] an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations. --- Explanation: Patterson guidelines confirm psychiatric manifestations as a presentation in adult-onset NPC.

[PMID:20525256] [SUPPORT] ataxia not unfrequently following initial psychiatric disturbances (adult form). --- Explanation: Vanier review identifies psychiatric disturbances as a common initial presentation in adult-onset NPC.


MONDO:0018982

[PMID:39502943] [SUPPORT] Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. --- Explanation: NFT pathology is a confirmed shared neuropathological feature of NPC.


MONDO:0018982

[PMID:33445799] [INDIRECT EVIDENCE] [SUPPORT] Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). --- Explanation: This review directly identifies NPC1 and NPC2 as the proteins required for lysosomal cholesterol egress.

[PMID:9211849] [INDIRECT EVIDENCE] [SUPPORT] Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. --- Explanation: NPC1 cDNA rescues the cholesterol trafficking defect in patient fibroblasts.


MONDO:0018982


MONDO:0018982

[PMID:9211849] [INDIRECT EVIDENCE] [SUPPORT] Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. --- Explanation: The landmark NPC1 paper establishes lysosomal cholesterol accumulation as a defining disease abnormality.


MONDO:0018982

[PMID:20525256] [INDIRECT EVIDENCE] [SUPPORT] NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. --- Explanation: Vanier review confirms that gangliosides rather than cholesterol are the predominant storage material in the NPC brain.

[PMID:15078881] [INDIRECT EVIDENCE] [SUPPORT] High pressure liquid chromatography and mass spectrometric analysis of NPC1(-/-) mouse brain revealed large increases in GSL. --- Explanation: Mass spectrometry of NPC1-null mouse brain confirms glycosphingolipid accumulation.


MONDO:0018982

[PMID:28803710] [INDIRECT EVIDENCE] [SUPPORT] In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. --- Explanation: Animal model data confirms that Purkinje cell loss is a central feature of NPC1 pathology that can be delayed with cyclodextrin treatment.


MONDO:0018982

[PMID:18953351] [INDIRECT EVIDENCE] [SUPPORT] Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. --- Explanation: Lloyd-Evans et al. demonstrate that sphingosine accumulation in lysosomes is the initiating event driving secondary lipid storage in NPC.


MONDO:0018982

[PMID:18953351] [INDIRECT EVIDENCE] [SUPPORT] NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. --- Explanation: Lysosomal calcium stores are significantly reduced in NPC1-mutant cells, linking calcium dysregulation to lipid storage.


MONDO:0018982

[PMID:26014711] [INDIRECT EVIDENCE] [SUPPORT] Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes. --- Explanation: This review supports defective cellular autophagy as a secondary pathophysiologic mechanism in NPC downstream of the core cholesterol trafficking defect.


MONDO:0018982

[PMID:39502943] [INDIRECT EVIDENCE] [SUPPORT] plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset --- Explanation: Elevated p-tau217 in NPC patients demonstrates active tau pathology paralleling Alzheimer-like neurodegeneration.

[PMID:39502943] [INDIRECT EVIDENCE] [SUPPORT] Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. --- Explanation: Confirms shared NFT pathology between NPC and Alzheimer disease.


MAXO:0000058

[PMID:20525256] [SUPPORT] A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. --- Explanation: Vanier review confirms miglustat authorization for NPC neurological manifestations.


MAXO:0000058

[PMID:28803710] [SUPPORT] Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. --- Explanation: Phase 1-2 trial demonstrates intrathecal HPbCD slows neurological progression in NPC1.


MAXO:0000058

[PMID:20301473] [SUPPORT] Treatment for the neurologic manifestations of NPC can include miglustat (approved in several countries but not currently FDA approved for standalone treatment of NPC), arimoclomol (approved for use in combination with miglustat), and levacetylleucine (standalone treatment approved by FDA). --- Explanation: GeneReviews confirms FDA approval of levacetylleucine as standalone therapy for NPC.


MAXO:0000058

[PMID:20301473] [SUPPORT] Treatment for the neurologic manifestations of NPC can include miglustat (approved in several countries but not currently FDA approved for standalone treatment of NPC), arimoclomol (approved for use in combination with miglustat), and levacetylleucine (standalone treatment approved by FDA). --- Explanation: GeneReviews confirms arimoclomol is approved for NPC in combination with miglustat.