Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities (NEDNMSA): A Comprehensive Disease Characteristics Report

Disease: Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities (NEDNMSA) MONDO ID: MONDO:0859236 · OMIM: 619833 · Category: Mendelian (autosomal recessive) Causal gene: NRCAM (HGNC:7994; NCBI Gene 4897; locus 7q31.1)

Summary

Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities (NEDNMSA) is an ultra-rare autosomal recessive Mendelian syndrome caused by biallelic loss-of-function or deleterious missense variants in NRCAM, the gene encoding the neuronal cell-adhesion molecule NrCAM (neuron-glia-related cell adhesion molecule). The disorder was first defined by Kurolap and colleagues in 2022 in a cohort of ten affected individuals from eight families (PMID: 35108495), and independently confirmed in 2023 by a second report describing a homozygous nonsense variant (PMID: 36606341). The clinical syndrome is characterized by a triad-plus phenotype: developmental delay/intellectual disability, hypotonia, and peripheral neuropathy and/or spasticity, accompanied by a variable constellation of skeletal (scoliosis, hip dysplasia, foot deformities, distal arthrogryposis), central nervous system structural (thin corpus callosum, ventriculomegaly, delayed myelination, periventricular heterotopia), and ophthalmologic anomalies.

Mechanistically, NrCAM is an L1-family immunoglobulin-superfamily axonal/glial adhesion molecule that, together with its partners gliomedin and neurofascin-186 (NF186), orchestrates the assembly of nodes of Ranvier and axon initial segments by recruiting ankyrin-G and clustering voltage-gated sodium channels. Loss of NrCAM function destabilizes this nodal complex, degrades saltatory conduction, and disrupts axon guidance and brain morphogenesis — providing a direct causal chain from gene dysfunction to the observed neuromuscular and neurodevelopmental phenotypes. Population-genetic constraint metrics from gnomAD (pLI ≈ 0; LOEUF = 0.636; observed/expected LoF = 0.53) confirm that NRCAM is not haploinsufficient, consistent with a recessive rather than dominant mechanism, and animal models (Nrcam-null mice, nrcama-deficient zebrafish) recapitulate axon-guidance and brain-structural defects.

The disorder is congenital in onset, non-progressive to slowly variable in course, and lifelong. Because only ~11 individuals have been reported worldwide, no prevalence estimate, natural-history study, disease-specific therapy, or clinical trial exists. Diagnosis is molecular (trio-based whole-exome or whole-genome sequencing) supported by nerve conduction studies and brain MRI, and management is entirely supportive and multidisciplinary. This report synthesizes eight confirmed findings across 15 disease-characteristic domains, flagging clearly where evidence is absent.

Key Findings

Finding 1 — NEDNMSA is caused by biallelic NRCAM variants (autosomal recessive)

Ontology cross-referencing links MONDO:0859236 → OMIM:619833 → UMLS:C5676965 / MedGen:1803456, and identifies a single causal gene, NRCAM (HGNC:7994; gene OMIM 601581; locus 7q31.1). The defining cohort (Kurolap et al., 2022) reported ten affected individuals from eight families carrying bi-allelic NRCAM variants. A second, independent report (Elahi et al., 2023) confirmed the gene–disease relationship with a homozygous nonsense variant c.73C>T (p.Gln25*), establishing the association beyond a single family.

"Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity." — PMID: 35108495

"This study is the second report of an association between biallelic NRCAM gene variants and a Mendelian disorder." — PMID: 36606341

Evidence type: Human clinical (two independent cohorts). This finding anchors Section 1 (Disease Information), Section 4 (Genetic/Molecular), and Section 9 (Inheritance).

Finding 2 — NrCAM mediates node-of-Ranvier assembly and Na⁺-channel clustering

NrCAM is an axonal/glial Ig-superfamily cell-adhesion molecule of the L1 family. Together with gliomedin and neurofascin-186 (NF186), it clusters ankyrin-G and voltage-gated Na⁺ channels at nodes of Ranvier (Lustig et al., 2001, PMID: 11728309; Eshed et al., 2005, PMID: 16039564). Combined genetic loss of gliomedin and NrCAM in mice causes progressive loss of nodal Na⁺ channels, "binary nodes," dysregulated nodal gap length, neurological abnormalities, and slowed nerve conduction (Amor et al., 2014).

"absence of both molecules (and hence the glial clustering signal) resulted in a gradual loss of Na(+) channels and other axonal components from the nodes, the formation of binary nodes, and dysregulation of nodal gap length. Therefore, these mice exhibit neurological abnormalities and slower nerve conduction." — PMID: 24719088

"These results provide the first evidence that neurofascin plays a major role in the formation of nodes, possibly via interactions with Nr-CAM." — PMID: 11728309

Evidence type: Model organism + in vitro. This is the central mechanistic finding explaining the neuropathy/spasticity phenotype (Section 6).

Finding 3 — gnomAD constraint supports a recessive loss-of-function mechanism

Constraint metrics for NRCAM (ENSG00000091129; chr7:108,147,623–108,456,717 GRCh38; canonical ENST00000379028) are: pLI ≈ 0 (2.58×10⁻¹¹), LOEUF (oe_lof upper) = 0.636, observed/expected LoF = 0.53 (83 observed vs 156.5 expected), LoF Z = 4.99; missense oe = 0.89, mis_Z = 1.92. The near-zero pLI indicates NRCAM tolerates heterozygous loss of function (i.e., is not haploinsufficient), while the elevated LoF Z-score shows selection against biallelic depletion. This population-genetic signature is exactly what is expected for a gene causing a recessive disorder — heterozygous carriers are unaffected, and disease requires two damaged alleles.

Evidence type: Computational/population genetics (gnomAD v2/v4). Supports the inheritance model of Section 9.

Finding 4 — Animal models recapitulate axon-guidance and brain-structural defects

Nrcam-null mice show disturbed olfactory-nerve axon guidance and altered size of the ventricular system and cerebellar vermis (Heyden et al., 2008). NrCAM also regulates postnatal hypothalamic tanycyte differentiation, proliferation, and neurogenesis (Moore et al., 2022, PMID: 35464310). The defining human study used zebrafish nrcama loss-of-function to corroborate the gene–disease link.

"in both mutants, CHL1 and NrCAM, the guidance of the olfactory nerve projections is disturbed. Both mutations also alter the size of the ventricular system and the vermis" — PMID: 18588951

"These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons." — PMID: 35108495

The mouse ventricular/vermis changes mirror the human ventriculomegaly and CNS anomalies, and the neurite-outgrowth/synaptogenesis/node-formation deficits provide cellular-level parallels to the human disease (Sections 6, 15).

Evidence type: Model organism (mouse, zebrafish) + in vitro.

Finding 5 — Pathogenic missense variants cluster in the third fibronectin type-III domain

Human NRCAM (UniProt Q92823) is a 1,304-aa type-I transmembrane L1-family protein comprising 6 Ig-like domains (aa 46–632), 5 fibronectin type-III (Fn-III) domains (aa 649–1156), a transmembrane segment, and a cytoplasmic tail. The third Fn-III domain (aa ~848–950) is a mutational hotspot: many disease-associated missense variants cluster there and are computationally predicted to be deleterious to protein structure and protein–protein interactions.

"Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins." — PMID: 35108495

Evidence type: Human clinical + computational. Informs variant interpretation (Section 4) and protein-dysfunction mechanism (Section 6).

Finding 6 — Phenotype spectrum and frequencies (HPO-annotated cohort, n ≈ 10)

The table below consolidates HPOA/Monarch frequencies for MONDO:0859236 with suggested HPO terms. Frequencies are derived from the small defining cohort and should be read as indicative, not population-representative.

Phenotype HPO term Frequency (affected/observed)
Global developmental delay HP:0001263 40% (4/10)
Hypotonia HP:0001252 40% (4/10)
Motor delay HP:0001270 30% (3/10)
Intellectual disability HP:0001249 30% (3/10)
Cerebral palsy / spasticity HP:0100021 30% (3/10)
Scoliosis HP:0002650 56% (5/9)
Hip dysplasia HP:0001385 33% (3/9)
Pes cavus HP:0001761 33% (3/9)
Hammertoe HP:0001765 22% (2/9)
Distal arthrogryposis HP:0005684 10% (1/10)
Microcephaly HP:0000252 50% (3/6)
Micrognathia HP:0000347 37.5% (3/8)
Demyelinating peripheral neuropathy HP:0007108 10% (1/10)
Ataxia HP:0001251 20%
Delayed CNS myelination HP:0002188 22%
Thin corpus callosum HP:0033725 22%
Ventriculomegaly HP:0002119 22%
Periventricular heterotopia HP:0007165 11%
Cataract HP:0000518 25%
Optic atrophy HP:0000648 12.5%
Retinal detachment HP:0000541 12.5%
Failure to thrive HP:0001508 25%
G-tube feeding HP:0011471 22%
Self-injurious / aggressive behavior HP:0100716 / HP:0000718 ~20–40%

ClinVar lists 289 NRCAM records, of which 38 are pathogenic/likely-pathogenic.

"This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity." — PMID: 35108495

Evidence type: Human clinical (HPO annotation). Populates Section 3 (Phenotypes).

Finding 7 — Epidemiology, inheritance, and diagnostic/management framework

The disorder is ultra-rare: the entire published literature comprises ~11 individuals (10 from 8 families, Kurolap 2022; +1, Elahi 2023). No prevalence or incidence estimate exists, and there is no Orphanet ORPHAcode. Inheritance is autosomal recessive with biallelic homozygous or compound-heterozygous variants; homozygous variants in several families implicate consanguinity. Diagnosis is molecular via trio-based whole-exome or whole-genome sequencing, supported by EMG/nerve conduction studies (documenting axonal and/or demyelinating peripheral neuropathy) and brain MRI (thin corpus callosum, ventriculomegaly, delayed myelination, periventricular heterotopia). No disease-specific pharmacotherapy, gene therapy, or clinical trial exists; management is supportive and multidisciplinary. Severity is variable and not strictly determined by variant type, indicating variable expressivity relevant to prognostic counseling.

"we show that type of the pathogenic variant does not necessarily determine the severity of this phenotype." — PMID: 36606341

"the individuals are from eight families" — PMID: 35108495

Evidence type: Human clinical. Populates Sections 8–13.

Finding 8 — Evolutionary conservation and orthologs

NCBI Gene confirms conserved NRCAM orthologs across model species: human NRCAM (Gene 4897; HGNC:7994), mouse Nrcam (Gene 319504; NCBI:txid10090), rat Nrcam (Gene 497815; NCBI:txid10116), zebrafish nrcama (Gene 556537; NCBI:txid7955; paralog nrcamb). NRCAM belongs to the L1 immunoglobulin-superfamily cell-adhesion molecule family, with paralogs L1CAM, CHL1, and NFASC.

Evidence type: Computational/comparative genomics. Populates Sections 14–15.

Section-by-Section Report

1. Disease Information

Overview. NEDNMSA is a Mendelian, autosomal recessive neurodevelopmental syndrome combining neurological, neuromuscular, and skeletal features. Its defining triad is developmental delay/intellectual disability, hypotonia, and peripheral neuropathy and/or spasticity, with additional variable skeletal, brain-structural, and eye findings.

Key identifiers: MONDO:0859236 · OMIM:619833 · UMLS:C5676965 · MedGen:1803456. No Orphanet ORPHAcode has been assigned (reflecting ultra-rarity). ICD-10/ICD-11 and MeSH lack a specific code; the disorder maps to broad categories and is best referenced by its MONDO/OMIM identifiers.

Synonyms: "Neurodevelopmental disorder with neuromuscular and skeletal abnormalities"; "NRCAM-related neurodevelopmental disorder"; "NRCAM-related bi-allelic disorder." Gene-level synonyms for NrCAM include neuron-glia-related cell adhesion molecule and neuronal cell adhesion molecule.

Information source: Aggregated disease-level resources (OMIM/MONDO) built from two individual-patient case series (clinical phenotyping of ~11 patients), not from population EHR datasets.

2. Etiology

Causal factors. The disorder is purely genetic (monogenic, recessive): biallelic pathogenic variants in NRCAM. There is no known environmental, infectious, or mechanistic (non-genetic) cause.

Genetic risk factors. The only established risk factor is inheritance of two damaged NRCAM alleles. Consanguinity is a major contributor (multiple homozygous families). No modifier genes or susceptibility loci have been identified (the cohort is too small).

Environmental / lifestyle / protective factors. Not applicable / not reported. No environmental risk factors, protective variants, protective exposures, or gene–environment interactions have been described for this ultra-rare Mendelian disorder. Standard prenatal care applies but does not modify the genetic risk.

3. Phenotypes

See Finding 6 table for the full HPO-annotated phenotype list with frequencies. Key characteristics:

4. Genetic/Molecular Information

5. Environmental Information

Not applicable. NEDNMSA is a monogenic recessive disorder with no established environmental factors, lifestyle contributors, or infectious triggers.

6. Mechanism / Pathophysiology

The core mechanism is failure of node-of-Ranvier and axon-initial-segment assembly plus disrupted axon guidance (Findings 2, 4, 5).

Causal chain:

Biallelic NRCAM LoF / deleterious missense (Fn-III #3 hotspot)
        │
        ▼
Loss of NrCAM adhesion function (Ig + Fn-III interactions with
gliomedin, NF186 disrupted)
        │
        ├─► Failure to recruit ankyrin-G  ──► Na⁺ channels not clustered
        │        at nodes of Ranvier / axon initial segments
        │        │
        │        ▼
        │   Degraded saltatory conduction ──► PERIPHERAL NEUROPATHY,
        │        SPASTICITY, MOTOR DELAY, HYPOTONIA
        │
        └─► Abnormal axon guidance, neurite outgrowth, synaptogenesis
                 │
                 ▼
            Brain morphogenesis defects (ventriculomegaly, thin corpus
            callosum, delayed myelination, periventricular heterotopia)
                 │
                 ▼
            DEVELOPMENTAL DELAY / INTELLECTUAL DISABILITY, MICROCEPHALY

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

No disease-specific pharmacotherapy, gene therapy, cell therapy, RNA therapy, or targeted/immunotherapy exists. No clinical trials (NCT) are registered. Management is supportive and multidisciplinary (Finding 7):

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

NEDNMSA is best understood as an axonal cell-adhesion / node-of-Ranvier assembly disorder. NrCAM sits at the intersection of two conserved neurodevelopmental processes: (1) axon guidance and neurite/synapse formation during brain morphogenesis, and (2) nodal/AIS assembly required for saltatory conduction. Biallelic loss of NrCAM function — whether through truncating variants or missense variants that disrupt the third Fn-III domain's protein interactions — degrades both processes simultaneously. This dual role explains the disorder's characteristic combination of central (intellectual disability, brain malformations) and peripheral (neuropathy, hypotonia, spasticity) features, with skeletal abnormalities arising secondary to the neuromuscular deficit and developmental disruption.

Layer Observation Supporting evidence
Genetic Biallelic NRCAM LoF/missense; recessive Kurolap 2022, Elahi 2023, gnomAD
Protein 3rd Fn-III domain missense hotspot; interaction disruption Kurolap 2022 (Q92823)
Molecular Failed gliomedin–NF186–NrCAM → ankyrin-G/Na⁺-channel declustering Lustig 2001, Eshed 2005, Amor 2014
Cellular Abnormal neurite outgrowth, synaptogenesis, node formation Kurolap 2022 (in vitro)
Organ Axon-guidance defects, ventriculomegaly, vermis changes Heyden 2008 (mouse), zebrafish
Clinical DD/ID, hypotonia, neuropathy/spasticity, skeletal anomalies Kurolap 2022, HPO

The convergence of population-genetic constraint (recessive signature), conserved animal-model phenotypes, and human clinical/molecular data yields a coherent, well-supported causal narrative with no major internal contradictions.

Evidence Base

PMID Title (abbrev.) Evidence type Role
35108495 Bi-allelic NRCAM variants cause NDD (Kurolap 2022) Human + zebrafish + in vitro Defining paper; establishes gene–disease link, phenotype, Fn-III hotspot
36606341 Bi-allelic NRCAM LoF, second report (Elahi 2023) Human Independent confirmation; variable severity
24719088 Gliomedin+NrCAM maintain nodal Na⁺ channels (Amor 2014) Mouse Direct mechanistic link: node loss → conduction defect
11728309 Nr-CAM/neurofascin cluster ankyrin-G, Na⁺ channels (Lustig 2001) In vitro NrCAM role in node formation
16039564 Gliomedin mediates node assembly (Eshed 2005) In vitro Glial ligand for NrCAM/NF186
18588951 Nrcam/CHL1 mutant axon guidance + brain anatomy (Heyden 2008) Mouse Axon-guidance + ventricle/vermis defects
35464310 NrCAM regulates hypothalamic tanycytes (Moore 2022) Mouse NrCAM in neurogenesis
17548513 Nodes/AIS are ankyrin-G-dependent domains In vitro Nodal assembly framework
17709431 Neurofascin assembles AIS ECM In vitro AIS/brevican context

Non-NEDNMSA context (excluded from pathogenesis): NRCAM is separately dysregulated in gliomas via CNV/methylation (PMID: 41663200) and overexpressed in colorectal cancer (PMID: 21718388) as a Wnt target — these are somatic/oncologic roles unrelated to the germline recessive Mendelian disorder and are noted only to avoid conflation.

Limitations and Knowledge Gaps

  1. Extremely small evidence base (~11 individuals). All human phenotype frequencies derive from ≤10 patients; percentages are indicative, not population estimates.
  2. No epidemiology. Prevalence, incidence, carrier frequency, sex ratio, and geographic distribution are unknown; no Orphanet code or registry exists.
  3. No natural-history or QoL data. Progression rate, life expectancy, and validated QoL metrics are undefined.
  4. Genotype–phenotype correlation unresolved. Severity is not predicted by variant type, but the sample is too small to establish modifiers.
  5. No disease-specific therapy or trials. Management is empirical/supportive.
  6. Mechanistic gaps. The precise contribution of each missense variant to specific interaction disruptions, and the relative weight of central vs. peripheral pathology, remain to be functionally dissected. No human iPSC/organoid model yet exists.
  7. Ontology mapping incomplete. No dedicated ICD-11/MeSH/Orphanet identifiers.

Proposed Follow-up Experiments / Actions

  1. International matchmaking (GeneMatcher, Matchmaker Exchange) to expand the cohort, refine phenotype frequencies, and enable genotype–phenotype analysis.
  2. Functional validation of Fn-III #3 missense variants — in vitro binding assays (NrCAM–gliomedin/NF186), node-of-Ranvier reconstitution, and structural modeling (AlphaFold + PDB comparison) to classify VUS per ACMG/AMP.
  3. Patient-derived iPSC neurons/organoids and myelinating co-cultures to model node assembly and conduction deficits in a human context.
  4. Conditional / knock-in mouse models carrying human missense alleles to test genotype-specific severity and evaluate rescue.
  5. Systematic natural-history study (developmental, EMG/NCS, MRI, orthopedic, ophthalmologic surveillance) with standardized QoL instruments.
  6. Apply for Orphanet/ICD-11 codes and establish a patient registry to support future epidemiology and trials.
  7. Cascade carrier screening and genetic-counseling protocols for consanguineous families with a known variant, including prenatal/PGD options.

Report compiled from 8 confirmed findings and 34 reviewed papers across 5 investigation iterations. Evidence types are labeled throughout as human clinical, model organism, in vitro, or computational.