Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities

1. Disease Information

Overview: Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities (NEDNMS) is a rare, autosomal recessive Mendelian disorder caused by bi-allelic (homozygous or compound heterozygous) loss-of-function or damaging missense variants in NRCAM (Neuronal Cell Adhesion Molecule). It presents from infancy or early childhood with global developmental delay/intellectual disability, hypotonia and/or spasticity, peripheral neuropathy, skeletal anomalies, and dysmorphic facial features, with a highly variable severity spectrum ranging from early mortality to isolated adult-onset peripheral neuropathy without cognitive impairment. The disorder was first delineated in 2022 by Kurolap et al. in The American Journal of Human Genetics, describing 10 affected individuals from 8 families (PMID:35108495; PMC8948158).

Key identifiers: - OMIM: #619833 (NEDNMS); gene locus OMIM #601581 (NRCAM) - Gene: NRCAM (HGNC:7994), chromosome 7q31.1 - Suggested MONDO: disease should map to a MONDO term for OMIM 619833 (specific 7-digit MONDO CURIE not confirmed via direct lookup in this search session — verify via oak against sqlite:obo:mondo before curation, per dismech SOP) - Inheritance: Autosomal recessive - Synonyms: NEDNMS; NRCAM-related neurodevelopmental disorder; NRCAM deficiency

Evidence basis: Aggregated, disease-level cohort data derived from clinical genetics case series (exome sequencing cohorts) rather than large-scale EHR/registry data — this is a nano-rare disorder with fewer than 15 published cases to date across three case series.

2. Etiology

Primary cause: Bi-allelic pathogenic variants in NRCAM, encoding neuronal cell adhesion molecule (NrCAM), a member of the L1/neurofascin/NgCAM immunoglobulin-superfamily of cell adhesion molecules. Loss of functional NrCAM protein disrupts neuron-neuron adhesion, axon growth/guidance, node-of-Ranvier formation, and synaptogenesis (Kurolap et al., PMID:35108495).

Genetic risk factors: - Founder/recurrent variants have been reported in specific communities: the Amish population and Libyan Jewish population each contributed families with homozygous variants (Kurolap et al. 2022), consistent with founder-effect or consanguinity-driven homozygosity. - Reported variants cluster disproportionately in the third fibronectin type III (Fn-III) domain of NrCAM, which contains a putative RGD-equivalent integrin-binding motif (KGE, residues 934–936) and a furin protease recognition site (RNRR, residues 894–897) — suggesting this domain is functionally critical (PMC8948158). - A second, independent report (Elahi et al. 2023, Molecular Genetics & Genomic Medicine) identified a homozygous nonsense variant, c.73C>T (p.Gln25*), causing an isolated motor-predominant axonal polyneuropathy phenotype, expanding genetic and allelic heterogeneity.

Environmental risk factors: None established; this is a purely monogenic Mendelian disorder with no known environmental trigger or modifier reported in the literature reviewed.

Protective factors: None reported.

Gene-environment interactions: Not established for the Mendelian NEDNMS phenotype. (Note: common NRCAM SNPs, distinct from the rare bi-allelic disease-causing variants, have been separately associated with autism spectrum traits and substance-use/addiction vulnerability in population genetic-association studies — International Journal of Neuropsychopharmacology reports — but these are polygenic-susceptibility associations, not causal for NEDNMS, and should not be conflated with it.)

3. Phenotypes

Cohort of 10 patients (Kurolap et al. 2022) plus additional isolated-neuropathy cases (Elahi et al. 2023; Cortese/motor-neuronopathy cohort, PMC10808011) define the phenotypic spectrum:

Onset/course: Symptoms are apparent from infancy or early childhood in most cases; onset in the isolated-neuropathy phenocopies can be delayed to the second/third decade (Elahi et al. 2023; PMC10808011 motor-neuronopathy cohort reported onset "second decade of life" in some). Severity spans a continuum: most severe individuals died in infancy/early childhood (e.g., death at 21 months in one individual, with hydrocephalus, failure to thrive, and neuropathy); moderate cases show persistent intellectual disability, motor dysfunction and neuropathy/spasticity; a neonatally severe individual improved with age and had no intellectual disability by age 5; the mildest reported adults (ages 27–31) had isolated late-onset peripheral neuropathy with normal cognition.

Quality of life impact: Not formally measured with standardized instruments (EQ-5D/SF-36) in the literature identified; qualitatively, severely affected individuals require gastrostomy feeding, tracheostomy/oxygen support, and have marked functional impairment; mildly affected adults function independently with isolated neuropathy.

4. Genetic/Molecular Information

Causal gene: NRCAM (HGNC:7994; OMIM 601581), chromosome 7q31.1, encoding a 1,275-amino-acid transmembrane protein with 6 Ig-like (V-set) domains and 5 fibronectin type III (Fn-III) repeats (UniProt Q92823).

Reported pathogenic variants (Kurolap et al. 2022, 8 families):

Plus: c.73C>T (p.Gln25*), homozygous, in an Iranian patient with isolated motor-predominant axonal polyneuropathy (Elahi et al. 2023).

Variant classification: Predominantly nonsense, frameshift, splice-site, and missense variants classified pathogenic/likely pathogenic per ACMG/AMP criteria in the original reports; formal aggregate ClinVar counts were not retrievable in this search session and should be queried directly at clinvar.ncbi.nlm.nih.gov before curation.

Genotype-phenotype correlation: Loss-of-function (nonsense/frameshift/splice) variants are associated with more severe phenotypes; missense variant effects are variant- and location-dependent. Variants cluster in the third Fn-III domain, implicated in protein-protein interaction interfaces (RGD-like integrin-binding motif, furin cleavage site).

Population allele frequency: NRCAM loss-of-function constraint metrics (pLI, o/e ratios) from gnomAD were not directly retrieved in this session; recommend querying gnomAD directly (gnomad.broadinstitute.org, gene NRCAM) prior to KB entry to populate case_fractions/constraint context.

Functional consequence: Loss of function (nonsense, frameshift, splice-disrupting) and hypomorphic/damaging missense — consistent with LOSS_OF_FUNCTION / PARTIAL_LOSS_OF_FUNCTION functional_impact_category values per dismech's GeneticContext slot guidance.

Epigenetic information: None reported specific to this disorder in the literature surveyed.

Chromosomal abnormalities: Not applicable — disease is caused by intragenic sequence variants, not large-scale chromosomal rearrangements.

Notable tangential molecular finding (not disease-causing for NEDNMS): A 2025 study (Cell Reports / bioRxiv, medRxiv preprint on TCGA analysis) describes an oncogenic NRCAM microexon-skipping splice isoform as a targetable cell-surface proteoform in high-grade gliomas — a distinct, non-Mendelian somatic phenomenon unrelated to the germline bi-allelic NEDNMS mechanism, included here only to flag it as an irrelevant hit if encountered during NEC preflight checks.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious triggers have been implicated in NEDNMS in the literature surveyed — consistent with its status as a purely monogenic, bi-allelic Mendelian disorder.

6. Mechanism / Pathophysiology

Molecular function of NrCAM: NrCAM is an L1-family immunoglobulin-superfamily cell adhesion molecule mediating homophilic trans-binding via its extracellular Ig-like and Fn-III domains, coupled intracellularly to the actin cytoskeleton via ankyrin and ERM (ezrin-radixin-moesin) proteins, and to PDZ-domain scaffolds (PSD-95, SAP102) at synapses.

Causal chain (proposed): 1. Bi-allelic NRCAM variant → loss/reduction of functional NrCAM protein or disruption of its Fn-III domain 3 interaction surface 2. → Impaired neuron-neuron and neuron-glia adhesion; disrupted axon growth/guidance signaling 3. → Abnormal synaptogenesis and defective neurite outgrowth (shown in Nrcam-deficient murine cerebellar granule cells) 4. → Impaired node-of-Ranvier formation/maintenance at the Schwann cell-axon interface (NrCAM + gliomedin establish the heminode that matures into the node), producing peripheral demyelinating neuropathy 5. → Thalamic axon mistargeting → abnormal visual-evoked potentials / optic atrophy 6. → Downstream: global developmental delay, hypotonia/spasticity, ataxia, and CNS structural anomalies (thin corpus callosum, delayed myelination, heterotopia) 7. Skeletal/musculoskeletal findings (scoliosis, hip dysplasia, contractures/arthrogryposis, pes cavus/planus) are likely secondary consequences of chronic hypotonia/neuropathy-driven altered biomechanical loading rather than a direct skeletal-lineage NRCAM defect (no primary bone/cartilage cell-autonomous mechanism reported).

Cellular processes involved: Axon guidance and outgrowth, cell adhesion, synaptogenesis, myelination/node-of-Ranvier assembly, actin cytoskeletal coupling.

Protein dysfunction: Predicted disruption of protein folding/surface electrostatics and protein-protein interaction interfaces by missense substitutions (SWISS-MODEL, ProSA-web, APBS electrostatics, ODA docking-area analyses in Kurolap et al. 2022); truncating variants predicted to produce loss of the Fn-III domain 3 region entirely.

Model-organism corroboration: CRISPR-generated zebrafish nrcama mutants (302-bp deletion of the third Fn-III domain) showed significantly increased swimming activity in darkness (p=0.03) versus wild-type, and trends toward increased α-tubulin-positive axonal fibers in the dorsal telencephalon and a thickened anterior telencephalic commissure — interpreted as altered axonal projections and abnormal activity-driven behavior, mechanistically consistent with the human phenotype (Kurolap et al. 2022).

Suggested GO terms: GO:0007155 (cell adhesion), GO:0007411 (axon guidance), GO:0031175 (neuron projection development), GO:0007416 (synapse assembly), GO:0031290 (retinal ganglion cell axon guidance), GO:1990138 (neuron projection extension involved in neuron projection guidance).

Suggested CL terms: CL:0000540 (neuron), CL:0000125 (glial cell), CL:0002573 (Schwann cell), CL:0000121 (cerebellar Purkinje cell) / cerebellar granule cell, CL:0000679 (glutamatergic neuron) as relevant to cortical circuits.

Cell types/tissues involved: Central and peripheral neurons, Schwann cells (myelinating peripheral glia), oligodendrocytes (CNS myelination), retinal ganglion cells/optic pathway neurons.

7. Anatomical Structures Affected

Organ/system level: Central nervous system (brain — cortex, corpus callosum, cerebellum, thalamus), peripheral nervous system (peripheral nerves), visual system (optic nerve, retina), auditory system, musculoskeletal system (spine, hips, feet), and secondarily the gastrointestinal system (failure to thrive/feeding difficulty).

Tissue/cell level: Peripheral nerve myelin and nodes of Ranvier; cerebellar granule neurons; corpus callosum white matter; optic nerve axons.

Subcellular level: Plasma membrane (NrCAM is a type-I transmembrane cell-surface glycoprotein), sites of axo-glial contact at nodes of Ranvier, synaptic membrane/postsynaptic density (PSD-95/SAP102 scaffold interactions). Suggested GO Cellular Component terms: GO:0033268 (node of Ranvier), GO:0043198 (dendritic shaft), GO:0045202 (synapse), GO:0005886 (plasma membrane).

Localization / UBERON suggestions: UBERON:0000955 (brain), UBERON:0001017 (central nervous system), UBERON:0000010 (peripheral nervous system), UBERON:0001851 (cortex), UBERON:0002336 (corpus callosum), UBERON:0002037 (cerebellum), UBERON:0000940 (optic nerve), UBERON:0001021 (nerve).

Lateralization: Findings are generally bilateral/symmetric (e.g., bilateral peripheral neuropathy, bilateral optic atrophy); not typically lateralized.

8. Temporal Development

Onset: Most cases present from infancy or early childhood (congenital-to-early-childhood onset); a subset of loss-of-function homozygotes present later, in the second-to-third decade, with an isolated motor-predominant polyneuropathy phenotype only.

Onset pattern: Insidious/developmental for the classic multisystem phenotype; can be subacute in the milder isolated-neuropathy phenocopy.

Progression: Highly variable — ranges from a static/non-progressive developmental delay pattern in some, to a progressive/severe course leading to early mortality in others (death at 21 months reported in the most severe case), to an improving trajectory in at least one neonatally severe individual who lost the intellectual disability component by age 5. The isolated-neuropathy phenotype in older, mildly affected adults (ages 27–31) appears slowly progressive or stable.

Disease course pattern: Chronic; not episodic or relapsing-remitting based on available reports.

Critical periods: Neurodevelopmental window (infancy-early childhood) appears to be the period of greatest phenotypic expressivity for the CNS component; no established treatment window identified.

9. Inheritance and Population

Epidemiology: NEDNMS is an ultra-rare disorder; only ~13 patients have been reported in the peer-reviewed literature across three publications (Kurolap et al. 2022, n=10; Elahi et al. 2023, n=1; motor-neuronopathy cohort n≥2 with isolated neuropathy phenotype). No formal prevalence or incidence estimate exists; classify as prevalence_class NOT_YET_DOCUMENTED or ULTRA_RARE pending Orphanet assignment.

Inheritance pattern: Autosomal recessive (bi-allelic — homozygous or compound heterozygous).

Penetrance: Appears complete for at least some phenotypic manifestation, though expressivity is markedly variable (from lethal multisystem disease to isolated late-onset neuropathy).

Expressivity: Highly variable, both between and within genotype classes; genotype-phenotype correlation trends toward LOF variants = more severe, but is not absolute.

Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for NEDNMS.

Founder effects: Suggested by recurrent homozygous variants in the Amish and Libyan Jewish communities in the original cohort (Kurolap et al. 2022), consistent with population-specific founder alleles, though formal founder-haplotype analysis was not confirmed in the sources reviewed.

Consanguinity: Implied as a contributing factor given the preponderance of homozygous (rather than compound heterozygous) genotypes in several families.

Population demographics: Reported affected families span diverse ancestries — Muslim Arab, European, Chinese, Amish, Libyan Jewish, Turkish, and Iranian — indicating a pan-ethnic distribution rather than restriction to a single population.

Sex ratio: Not clearly skewed in the reported cohort (mixed male/female cases, including sibling pairs 6a/6b and 8a/8b).

10. Diagnostics

Genetic testing (primary diagnostic modality): Whole exome sequencing (WES) is the modality used in all reported cases, with Sanger confirmation and segregation analysis; WES-based CNV detection and runs-of-homozygosity assessment were used to detect the homozygous nonsense variant in the Elahi et al. 2023 case. Gene panel testing for hereditary spastic paraplegia / peripheral neuropathy / intellectual disability may include NRCAM (it is listed on the Genomics England PanelApp "Childhood onset hereditary spastic paraplegia" panel).

Clinical/laboratory tests: No specific biomarker or lab test exists; diagnosis relies on WES/WGS plus supportive clinical, neuroimaging, and electrophysiologic findings: - Nerve conduction studies — demonstrating demyelinating peripheral neuropathy - Brain MRI — variable findings (thin/agenetic corpus callosum, delayed myelination, periventricular leukomalacia, ventriculomegaly/hydrocephalus, gray matter heterotopia; can also be normal) - Visual evoked potentials — abnormal, consistent with optic pathway involvement - Brainstem auditory evoked responses — abnormal in a subset (3/10) - Skeletal radiographs — for scoliosis, hip dysplasia, contractures

Differential diagnosis: Other genetic causes of the combined developmental delay + hypotonia/spasticity + peripheral neuropathy phenotype — e.g., other L1CAM-family disorders (L1CAM syndrome/X-linked hydrocephalus), Charcot-Marie-Tooth disease subtypes, other hereditary spastic paraplegias, and other syndromic intellectual disability disorders with skeletal involvement should be excluded by targeted or exome-wide testing given phenotypic overlap.

Screening: No newborn screening or population carrier-screening program exists given the disorder's recent delineation (2022) and extreme rarity.

11. Outcome/Prognosis

Survival/mortality: Highly variable; the most severely affected reported individual died at 21 months of age with hydrocephalus, failure to thrive, and neuropathy. No formal survival statistics exist given the small case count.

Morbidity/function: Severely affected individuals require gastrostomy feeding and, in some cases, tracheostomy/supplemental oxygen; the mildest reported adults (ages 27–31) have normal cognition with isolated peripheral neuropathy and are functionally independent.

Complications: Hydrocephalus, failure to thrive, self-injurious behavior, seizures (rare), scoliosis/hip dysplasia requiring orthopedic management.

Recovery potential: At least one neonatally severely affected individual showed improvement with age, losing the intellectual disability component by age 5 — suggesting some plasticity/reversibility is possible in a subset of cases, though this is based on a single reported observation and should not be generalized.

Prognostic factors: Variant type (LOF vs. missense) and domain location appear to correlate loosely with severity; the mildest phenotype (isolated adult-onset neuropathy) has so far only been associated with specific homozygous LOF or missense genotypes in outlier families, so genotype alone is an imperfect predictor.

12. Treatment

There is no disease-specific or targeted therapy for NEDNMS; management reported in the literature is entirely supportive/symptomatic:

• Supportive care: Gastrostomy tube feeding for failure to thrive; supplemental oxygen; tracheostomy (reported as reversible in some cases) — NCIT:C15747 (Supportive Care)
• Orthopedic/surgical management: For scoliosis and hip dysplasia/dislocation — NCIT:C15329 (Surgical Procedure) / NCIT:C16186 (Orthopedic Surgical Procedure)
• Physical/rehabilitative therapy: For hypotonia/spasticity and motor delay (inferred standard-of-care management, not explicitly detailed in source abstracts) — NCIT:C15302 (Physical Therapy) / NCIT:C15315 (Rehabilitation)
• Genetic counseling: Recommended given autosomal recessive inheritance and reported consanguinity/founder patterns — NCIT:C15240 (Genetic Counseling)
• Incidental/unrelated treatment note: One individual (Individual 1 in Kurolap et al. 2022) received eculizumab for seizures secondary to thrombosis attributed to an unrelated co-occurring CD55 deficiency — this is not an NRCAM-targeted therapy and should not be curated as a NEDNMS treatment.
• Experimental/investigational: No registered clinical trials (ClinicalTrials.gov / WHO ICTRP) for NRCAM-related NEDNMS were identified in this search.

No pharmacogenomic, gene-therapy, RNA-based, or targeted-molecular therapy has been reported or is in development specifically for NEDNMS as of this search.

13. Prevention

No primary, secondary, or tertiary prevention strategies are established beyond standard genetic counseling for carrier parents (especially in consanguineous unions or founder populations such as the Amish and Libyan Jewish communities identified in the literature) regarding the 25% recurrence risk in future pregnancies under autosomal recessive inheritance, and the theoretical availability of carrier screening / prenatal diagnosis / preimplantation genetic testing once a familial variant is known. No population-level screening program, vaccine, or prophylactic medication applies.

14. Other Species / Natural Disease

No spontaneously occurring NRCAM-deficient disease has been reported in companion animals or wildlife (no OMIA entry identified in this search). All non-human data derive from engineered laboratory models (see Section 15).

Orthologous gene: Nrcam is conserved in mouse (MGI), zebrafish (nrcama/nrcamb paralogs, ZFIN), and other vertebrates as a core L1-family cell adhesion molecule.

15. Model Organisms

Mouse (Nrcam⁻/⁻ knockout): - No overt gross neuromuscular phenotype or obvious motor-behavior deficits at baseline. - Delayed node-of-Ranvier formation and occasional "split nodes" in adult peripheral nerve, consistent with NrCAM's role (with gliomedin) in heminode-to-node maturation at the Schwann cell-axon interface. - Behaviorally: impaired context-dependent fear conditioning; male Nrcam knockout mice display autism-related behaviors — impaired sociability, cognitive rigidity, and repetitive behavior. - Nrcam-deficient cerebellar granule cells show abnormal neurite outgrowth and defective synaptogenesis (cited in Kurolap et al. 2022). - Thalamic axon mistargeting has been linked to abnormal visual-evoked potentials in Nrcam-deficient mice, mechanistically mirroring the human optic-pathway findings.

Zebrafish (CRISPR nrcama third-Fn-III-domain deletion mutant, generated in Kurolap et al. 2022): - 302-bp deletion removing the third Fn-III domain (the same domain where most human disease variants cluster). - Significantly increased swimming activity in darkness versus wild-type (p=0.03). - Trend toward increased α-tubulin-positive axonal fiber density in the dorsal telencephalon and a thickened anterior telencephalic commissure. - Interpreted as recapitulating altered axonal projection patterning and abnormal activity-driven behavior, providing in vivo functional support for pathogenicity of Fn-III domain 3 variants.

Model limitations: The mouse knockout does not reproduce the severe multisystem human phenotype (developmental delay, spasticity, skeletal anomalies) despite recapitulating the peripheral nodal and some behavioral/synaptic phenotypes — a translational gap worth flagging as a HUMAN_MODEL_MISMATCH in any dismech curation of this entry, since basal mouse motor function is preserved despite null Nrcam, unlike the human hypotonia/spasticity phenotype.

Applications: Both models support the causal role of NRCAM loss-of-function in axon guidance/adhesion defects, nodal architecture, and behavioral abnormalities, and specifically implicate the Fn-III domain 3 region as functionally critical, consistent with human variant clustering.

Summary of Key Ontology Term Suggestions for KB Curation

Citation Note and Limitations

All primary clinical/molecular detail above derives from three peer-reviewed sources: Kurolap A, et al. (2022), Am J Hum Genet, PMID:35108495 (PMCID: PMC8948158) — the founding case series; Elahi Z, et al. (2023), Mol Genet Genomic Med, "Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report"; and the pediatric-onset motor neuronopathy cohort paper (PMCID: PMC10808011) referencing additional isolated-neuropathy NRCAM cases. Direct PubMed/OMIM full-text fetches were blocked (HTTP 403) during this session; all figures and quotes above were relayed through search-engine-summarized excerpts of the cited PMC full texts rather than a first-hand read of the primary HTML — before committing any of these snippets as dismech evidence items, curators must independently fetch and cache each PMID via just fetch-reference, and run just count-verified-snippets / just validate-terms to confirm exact-quote and ontology-term accuracy, per the project's anti-hallucination SOP. Prevalence, gnomAD constraint metrics, and a confirmed MONDO CURIE were not resolved in this session and require direct database queries prior to KB entry.

Sources: - Entry - #619833 - NEURODEVELOPMENTAL DISORDER WITH NEUROMUSCULAR AND SKELETAL ABNORMALITIES; NEDNMS - OMIM - Clinical Synopsis - #619833 - OMIM - NEURONAL CELL ADHESION MOLECULE; NRCAM - OMIM #601581 - Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity - PubMed (PMID:35108495) - PMC8948158 - full text - Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report - Elahi et al. 2023, Molecular Genetics & Genomic Medicine - Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies - PMC10808011 - NRCAM Gene - GeneCards - Neuronal cell adhesion molecule - UniProt Q92823 - The role of NrCAM in neural development and disorders—Beyond a simple glue in the brain - ScienceDirect - Gene: NRCAM (Childhood onset hereditary spastic paraplegia) - Genomics England PanelApp - Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism - IJNP - NRCAM variant defined by microexon skipping is a targetable cell surface proteoform in high-grade gliomas - Cell Reports - Mondo Disease Ontology - Monarch Initiative

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