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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive HP:0000007

Disease requires bi-allelic NRCAM variants. Reported genotypes are homozygous (frequently in consanguineous or founder families) or compound heterozygous, and variants co-segregated with disease in all eight families of the founding cohort. Heterozygous carriers, including the parents, are unaffected. Expressivity is markedly variable, both between and within genotype classes: from hydrocephalus with failure to thrive and death in infancy, through developmental delay with hypotonia/neuropathy or spasticity, to isolated late-onset peripheral neuropathy with normal cognition.

autosomal recessive inheritance Expressivity: VARIABLE

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"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."

Ten affected individuals from eight families each carry bi-allelic NRCAM variants, establishing autosomal recessive inheritance.

PMID:36606341 SUPPORT Human Clinical

"The proband is a 19‐year‐old male who is the only child of consanguineous (first cousin) healthy Iranian parents"

The second reported family is consanguineous with a homozygous proband, consistent with autosomal recessive inheritance.

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Discussions and Knowledge Gaps

2

What is the mechanism of the skeletal abnormalities that give NEDNMS its name, and can the reported frequencies be anchored to quotable primary evidence?

KNOWLEDGE GAP OPEN skeletal_phenotype_evidence

Attached to

pathophysiology#Secondary Musculoskeletal Deformity pathophysiology#Neuromuscular Dysfunction

The disorder is named for "neuromuscular and skeletal abnormalities", and the OMIM clinical synopsis for OMIM:619833 records scoliosis in 5/9, hip dysplasia in 3/9, pes cavus in 3/9, plus coxa valga, acetabular dysplasia, hammertoe and distal arthrogryposis. Those counts derive from Table 1 of PMID:35108495, but that table is not present in the extractable text of the cached reference and the paper's narrative and abstract never use the words scoliosis, skeletal or contracture — the founding authors frame the disorder as neurological and neuromuscular throughout. Two questions follow. First, the evidentiary one: the skeletal phenotypes in this entry carry ontology terms and provenance notes but no exact-quote evidence items, and cannot be given any until a source states them in quotable text. Second, the mechanistic one: no cell-autonomous role for NRCAM in bone or cartilage has been described, so the skeletal findings are modeled here as secondary to chronic abnormal loading from hypotonia, spasticity and neurogenic weakness. That inference is plausible for scoliosis, hip subluxation and cavus foot — all standard sequelae of early-onset neuromuscular disease — but distal arthrogryposis implies a prenatal akinesia sequence rather than postnatal loading, and the disorder's own name asserts a prominence the primary literature does not argue for.

Proposed experiments

Systematic skeletal phenotyping of a larger NRCAM cohort

skeletal_phenotyping_cohort

Prospectively collect standing spine radiographs, hip imaging and foot examination on all molecularly confirmed individuals, scored alongside motor function (GMFCS or equivalent) and tone, and report the results in a citable narrative rather than a table alone. This would both anchor the frequencies and test whether skeletal severity tracks neuromuscular severity, as the secondary-loading model predicts.

Test for cell-autonomous NRCAM function in skeletal tissue

nrcam_skeletal_cell_autonomy

Assay NRCAM expression in growth plate chondrocytes, osteoblasts and tendon, and compare skeletal phenotype in a conditional neural-lineage-restricted Nrcam knockout against the constitutive null. A neural-restricted null that still produces skeletal deformity would support the secondary-loading model; a difference between the two would indicate a direct skeletal role.

Why do Nrcam-null mice show the cellular lesions of this disorder — delayed node of Ranvier formation, failed neurite outgrowth, excess dendritic spines, thalamic axon mistargeting — without developing the neuromuscular disorder that is present in every affected human?

HUMAN MODEL MISMATCH OPEN mouse_null_neuromuscular_mismatch

Attached to

pathophysiology#Neuromuscular Dysfunction pathophysiology#Defective Node of Ranvier Assembly and Maintenance

This is a mismatch of translational validity rather than a gap in evidence: the mouse data exist and are consistent, but the organism-level phenotype does not follow. Three explanations are on the table, and they are not mutually exclusive. (1) Redundancy within the L1-family Ig-CAMs: L1cam, Chl1 and Nfasc could substitute in mouse, and at the node gliomedin provides a partially redundant glial clustering signal — consistent with the observation that only the gliomedin/NrCAM double knockout produces node disintegration with slowed conduction. (2) Transcriptional adaptation triggered by nonsense-mediated decay of the null transcript, the mechanism invoked to explain phenotypic discrepancies between complete-gene knockouts and other disruptions of the same gene; notably, the first L1cam knockout mice were also mild until moved to a different genetic background. (3) True species divergence in the protein: the KGE integrin-recognition and RNRR furin motifs of the human third Fn-III domain — the human variant hotspot — are poorly conserved in zebrafish Nrcam, and the zebrafish domain-deletion mutant is correspondingly mild. Distinguishing these matters practically, because it determines whether any mouse model can serve as a preclinical platform for this disorder.

Proposed experiments

L1-family compound mutants and genetic background sensitization

l1_family_compound_mutants

Generate Nrcam-null mice compound with heterozygous or conditional loss of L1cam, Chl1 and Nfasc, and cross the Nrcam null onto additional inbred backgrounds, testing whether a neuromuscular phenotype emerges. A positive result supports redundancy or background modification over species divergence.

Knock-in of human-equivalent Fn-III domain 3 missense alleles

fn3_missense_knockin

Rather than a null, knock in the mouse equivalents of p.Arg853Cys, p.Lys902Thr and p.Gly913Asp. If a missense allele that escapes nonsense-mediated decay produces a neuromuscular phenotype where the null does not, transcriptional adaptation is implicated.

Human iPSC-derived motor neuron and Schwann cell co-culture

ipsc_motor_neuron_schwann_coculture

Differentiate patient-derived and isogenic-corrected iPSCs into motor neurons co-cultured with Schwann cells, and quantify node of Ranvier assembly and sodium channel clustering. This tests the nodal mechanism in human cells, bypassing the species question entirely.

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Pathophysiology

12

Bi-allelic NRCAM Loss of Function

Homozygous or compound heterozygous NRCAM variants — nonsense, frameshift, canonical splice-site and deep-intronic splice-disrupting alleles, and damaging missense substitutions — abolish or degrade NrCAM protein function. Missense variants are predicted to change residue polarity and/or charge and so perturb the protein's electrostatic surface and its protein-protein interaction interfaces; truncating alleles remove the C-terminal region including the third Fn-III domain.

NRCAM hgnc:7994

Genetic context NRCAM hgnc:7994 allele_type: SNV, indel, and splice-site variants variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Bi-allelic germline variants; both homozygous (consanguineous/founder families) and compound heterozygous genotypes are reported. Loss-of-function alleles trend toward a more severe phenotype than missense alleles, but the correlation is not absolute.

Downstream

Impaired NrCAM-Mediated Neural Cell Adhesion The variants act on the adhesion protein itself, so the link from genotype to loss of adhesion function is direct.

Show evidence (2 references)

PMID:35108495 SUPPORT Computational

"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."

Establishes that the disease alleles are predicted to impair NrCAM structure and its protein-protein interactions.

PMID:36606341 SUPPORT Human Clinical

"Whole exome sequencing revealed a homozygous variant, c.73C > T (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of phenotypes compared to NRCAM-related disorder."

An independent homozygous nonsense allele confirms bi-allelic NRCAM loss of function as the disease trigger.

Impaired NrCAM-Mediated Neural Cell Adhesion

NrCAM is a type-I transmembrane L1-family Ig-CAM whose extracellular region comprises six immunoglobulin-like domains followed by five fibronectin type III repeats; the Ig domains mediate ligand recognition and homophilic and heterophilic trans-binding (contactin-1/TAG-1, neurofascin), while the Fn-III repeats mediate adhesion signaling, and the cytoplasmic tail binds ankyrin. Loss of NrCAM therefore removes an adhesion and signaling hub that is shared by the neuron-neuron, neuron-glia and axon-glia interfaces. Most disease variants fall in the third Fn-III domain, which carries a KGE integrin-recognition motif and an RNRR furin site and is predicted to form a protein-protein interaction surface.

neuron CL:0000540

cell adhesion GO:0007155 ↓ DECREASED neuron cell-cell adhesion GO:0007158 ↓ DECREASED

plasma membrane GO:0005886

Downstream

Defective Axon Growth and Guidance

Defective Node of Ranvier Assembly and Maintenance NrCAM is one of the two glial adhesion molecules that deliver the nodal clustering signal, so loss of its adhesion function acts directly on node assembly.

Impaired Synaptogenesis and Dendritic Spine Remodeling

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The extracellular region of NRCAM is composed of six Ig-like domains followed by five Fn-III domains and is critical for the protein’s interaction with other CAMs and molecules enabling cell-cell interactions and adhesion."

Defines the adhesion function of the domains in which the disease variants lie.

PMID:8947556 SUPPORT In Vitro

"Neurofascin, NrCAM, L1, and NgCAM are a family of Ig/FNIII cell adhesion molecules that share ankyrin-binding activity in their cytoplasmic domains"

Establishes NrCAM as an ankyrin-binding L1-family adhesion molecule, the molecular basis of the coupling lost in this disorder.

Defective Axon Growth and Guidance

NrCAM is expressed on growing and crossing axons and on the specialized midline glia they navigate (floor plate, optic chiasm, median eminence), and it partners with contactin-1/TAG-1 to promote neurite extension. Nrcam-null cerebellar granule cells fail to extend neurites on contactin-1 substrate, and Nrcam-deficient mice mistarget motor and somatosensory thalamic axons to the visual cortex. Loss of this guidance function is the proposed origin of the misrouted central and peripheral fibre tracts in affected individuals.

cerebellar granule cell CL:0001031

axon guidance GO:0007411 ⚠ ABNORMAL axonogenesis GO:0007409 ↓ DECREASED neuron projection development GO:0031175 ⚠ ABNORMAL

Downstream

Aberrant CNS White Matter Tract Formation

Sensory Pathway Miswiring

Show evidence (3 references)

PMID:35108495 SUPPORT In Vitro

"revealed abnormal neurite outgrowth, as the cerebellar granule cells failed to extend neurites on substrates such as contactin-1"

Nrcam-deficient neurons fail to extend neurites, the cellular defect underlying impaired axon growth.

PMID:11329126 SUPPORT Model Organism

"Major sites that are positive for Nr-CAM are specialized glial formations in the ventral midline, including the floor plate in the spinal cord, the hindbrain and midbrain, the optic chiasm, and the median eminence in the forebrain."

Localizes Nr-CAM to the midline guidance structures where crossing axons make pathfinding decisions.

PMID:35108495 SUPPORT Model Organism

"in mice leads to mistargeting of motor and somatosensory thalamic axons to the visual cortex"

Demonstrates in vivo axon mistargeting on Nrcam loss.

Impaired Synaptogenesis and Dendritic Spine Remodeling

Beyond its presynaptic and axonal roles, NrCAM acts postsynaptically as an integral component of the Semaphorin 3F receptor complex with Neuropilin-2 and PlexinA3, and is required for Sema3F-induced dendritic spine pruning. NrCAM-null mice show elevated spine density, increased asymmetric synapse number and increased miniature EPSC frequency in visual cortex, i.e. a shift in excitatory/inhibitory balance. This arm is mechanistically well supported in the mouse but has not been demonstrated in tissue from affected individuals, hence the provisional confidence.

synapse assembly GO:0007416 ⚠ ABNORMAL dendrite development GO:0016358 ⚠ ABNORMAL

synapse GO:0045202

Animal models

Nrcam knockout mouse Mouse recapitulates NrCAM-null cortex shows elevated dendritic spine density, increased asymmetric synapses and increased mEPSC frequency, establishing NrCAM as a postnatal regulator of spine density within the Sema3F receptor complex.

Downstream

Cortical Circuit Dysfunction

Show evidence (3 references)

PMID:25143608 SUPPORT Model Organism

"NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1."

Direct demonstration that NrCAM loss disrupts dendritic spine and synapse number.

PMID:25143608 SUPPORT Model Organism

"These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex."

Places NrCAM in the Sema3F receptor complex that executes spine pruning.

PMID:35108495 SUPPORT In Vitro

"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."

The founding clinical report invokes abnormal synaptogenesis in Nrcam-deficient cells as part of the proposed mechanism, but the data are in vitro and murine rather than from affected individuals.

Defective Node of Ranvier Assembly and Maintenance

At the peripheral node of Ranvier, glial NrCAM and gliomedin on the Schwann cell bind axonal neurofascin-186; this axo-glial complex recruits ankyrin-G, which in turn clusters and concentrates voltage-gated sodium channels at the nodal axolemma. NrCAM is also present on the axonal side at nodes and axon initial segments together with neurofascin and ankyrin-G. Loss of the glial clustering signal produces delayed and disorganized node formation and, over time, progressive loss of Nav channels, ankyrin-G and βIV spectrin from established nodes.

Schwann cell CL:0002573

clustering of voltage-gated sodium channels GO:0045162 ↓ DECREASED

node of Ranvier GO:0033268

Animal models

Nrcam knockout mouse Mouse recapitulates Peripheral nerves of Nrcam-deficient mice show delayed or abnormal node formation with delayed nodal sodium channel clustering, the same lesion proposed to underlie the human peripheral neuropathy.

Downstream

Peripheral Nerve Conduction Failure and Axonal Degeneration Nodal sodium channel density sets conduction competence, so disassembly of the node degrades saltatory conduction directly.

Show evidence (7 references)

PMID:25459119 SUPPORT Other

"The axo-glial contact at nodes implicates adhesion molecules expressed by the Schwann cell (gliomedin and NrCAM), which binds a partner, neurofascin-186, on the axonal side."

States the molecular architecture in which NrCAM participates at the peripheral node.

PMID:25459119 SUPPORT Other

"This complex is essential for the recruitment of ankyrin-G, a cytoskeletal scaffolding protein, which binds and concentrates Nav channels at nodes."

Links the NrCAM-containing adhesion complex to sodium channel clustering.

PMID:8947556 SUPPORT In Vitro

"NrCAM, visualized with antibodies specific for the ecto-domain, also was found to be coexpressed with neurofascin at nodes of Ranvier and at axon initial segments."

Localizes NrCAM to nodes of Ranvier and axon initial segments.

+ 4 more references

Peripheral Nerve Conduction Failure and Axonal Degeneration

Progressive loss of nodal sodium channels and disorganization of nodal architecture slow or block saltatory conduction. In the mouse double mutant that removes the entire glial clustering signal this produces measurable neurological abnormality and slowed nerve conduction. In affected individuals the corresponding clinical finding is a peripheral neuropathy - motor-predominant and axonal in the one case with quotable electrophysiology - with chronic neurogenic changes on needle EMG, neurogenic grouped fibre atrophy on muscle biopsy, and modestly elevated creatine kinase.

neuronal action potential GO:0019228 ⚠ ABNORMAL

peripheral nerve UBERON:0001021

Animal models

Gliomedin/NrCAM double knockout mouse Mouse recapitulates Loss of the gliomedin/NrCAM clustering signal produces measurable slowing of nerve conduction and neurological abnormality.

Downstream

Neuromuscular Dysfunction Failure of peripheral nerve conduction is the proximate cause of the hypotonia, weakness and neuropathic findings.

Show evidence (3 references)

PMID:24719088 SUPPORT Model Organism

"Therefore, these mice exhibit neurological abnormalities and slower nerve conduction."

Loss of the gliomedin/NrCAM nodal clustering signal produces slowed nerve conduction in vivo. PARTIAL because the double knockout also removes gliomedin, which affected individuals retain, so it overstates the deficit expected from NRCAM loss alone.

PMID:24719088 SUPPORT Model Organism

"Our results reveal that axon-glial contact mediated by gliomedin, NrCAM, and NF186 not only plays a role in Na(+) channel clustering during development, but also contributes to the long-term maintenance of Na(+) channels at nodes of Ranvier."

Establishes an ongoing maintenance requirement, consistent with the late-onset progressive neuropathy seen in mildly affected individuals.

PMID:36606341 SUPPORT Human Clinical

"Needle examination showed chronic neurogenic changes and spontaneous activity in leg muscles (proximal and distal)."

Electrophysiological confirmation of the peripheral nerve lesion in an affected individual.

Aberrant CNS White Matter Tract Formation

Nr-CAM is expressed along the major crossing fibre pathways — the anterior commissure, corpus callosum and posterior commissure — so loss of NrCAM guidance is expected to disturb their formation. Zebrafish nrcamaΔ mutants lacking the third Fn-III domain show a trend toward increased α-tubulin fibre density in the dorsal telencephalon and a thicker anterior telencephalic commissure. In affected individuals, brain MRI is variable and non-specific: thin corpus callosum, ventriculomegaly, periventricular leukomalacia and delayed myelination are each seen in a subset, and some individuals have normal imaging. Confidence is provisional because the zebrafish differences were trends rather than significant, and no human neuropathological correlate exists.

central nervous system myelination GO:0022010 ⚠ ABNORMAL

corpus callosum UBERON:0002336

Animal models

Zebrafish nrcama third Fn-III domain deletion mutant Zebrafish partially recapitulates Altered axonal projections in the dorsal telencephalon and anterior commissure, the zebrafish counterpart of the mammalian pallium and of the commissural tracts abnormal on human MRI.

Downstream

Global Neurodevelopmental Impairment

Show evidence (4 references)

PMID:11329126 SUPPORT Model Organism

"In addition, Nr-CAM is found in crossing fiber pathways, including the anterior commissure, corpus callosum, and posterior commissure, and in nondecussating pathways, such as the lateral olfactory tract and the habenulointerpeduncular tract."

Places Nr-CAM in exactly the commissural tracts that are structurally abnormal on MRI in affected individuals.

PMID:35108495 SUPPORT Human Clinical

"including a thin corpus callosum with partially shifted vermis, ventriculomegaly, periventricular leukomalacia, and delayed myelination, while some individuals had normal brain imaging"

The human imaging spectrum, including the explicit note that some individuals image normally.

PMID:35108495 SUPPORT Model Organism

"Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections."

Model-organism support for altered white matter tracts; reported as a trend, hence PARTIAL.

+ 1 more reference

Cortical Circuit Dysfunction

Excess dendritic spines and asymmetric synapses with increased mEPSC frequency in NrCAM-null cortex predict a shift in excitatory/inhibitory balance in neocortical circuits. This is the proposed cellular substrate for the cognitive impairment and the behavioural phenotype (irritability, aggression, self-injurious behaviour) in affected individuals, but it is an extrapolation from mouse visual cortex and has not been measured in humans.

modulation of chemical synaptic transmission GO:0050804 ↕ DYSREGULATED

Downstream

Global Neurodevelopmental Impairment

Show evidence (1 reference)

PMID:25143608 SUPPORT Model Organism

"The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits."

States the circuit-level consequence proposed here, in the mouse.

Sensory Pathway Miswiring

NrCAM is expressed at the optic chiasm and on cochlear spiral ganglion afferents, olivocochlear efferents and cochlear hair and supporting cells. Nrcam-null mice mistarget thalamic axons to visual cortex and have abnormal visual-evoked potentials, and Nrcam-null cochleae show type II spiral ganglion fasciculation errors and reduced efferent innervation. This is the proposed basis for the abnormal VEPs, optic atrophy, strabismus and auditory findings in affected individuals. A translational caveat applies: the cochlear defects in mice are transient and adult Nrcam-null mice hear normally, whereas some affected individuals have persistent hearing impairment.

retinal ganglion cell axon guidance GO:0031290 ⚠ ABNORMAL

Animal models

Nrcam knockout mouse Mouse partially recapitulates Nrcam-null mice reproduce the developmental miswiring — thalamic axon mistargeting to visual cortex with abnormal VEPs, and cochlear afferent and efferent innervation errors — but the cochlear defects self-correct and adult auditory acuity is normal, unlike the persistent hearing impairment in some affected individuals.

Downstream

Global Neurodevelopmental Impairment

Show evidence (3 references)

PMID:29536590 SUPPORT Model Organism

"Neonatal Nrcam-null cochleae show errors in type II SGN fasciculation, reduced efferent innervation, and defects in the stereotyped packing of hair and supporting cells."

Demonstrates that NrCAM loss disrupts cochlear innervation, the proposed route to the auditory phenotype.

PMID:29536590 SUPPORT Model Organism

"Despite these numerous developmental defects, Nrcam-null adults do not show defects in auditory acuity"

Records the negative result that limits how far the mouse cochlear phenotype can be extrapolated to human hearing impairment.

PMID:35108495 SUPPORT Human Clinical

"Similarly, the observed hearing abnormalities in three of the affected individuals can be inferred to NRCAM expression in the spiral ganglion neurons, cochlear efferent fibers, and cochlear sensory cells within the inner ear."

The founding report explicitly attributes the human auditory findings to NrCAM expression in the inner ear.

Neuromuscular Dysfunction

The convergent clinical output of peripheral nerve involvement and corticospinal/central involvement is a neuromuscular phenotype that is present in every reported individual, though its polarity differs: either hypotonia with peripheral neuropathy, or spasticity and hypertonia. The founding report proposes misrouting of nerve fibres as the common origin of both poles. Muscle weakness predominates distally and in the lower limbs in the neuropathy-predominant individuals.

Animal models

Nrcam knockout mouse Mouse fails to recapitulate Despite the nodal defect, Nrcam-null mice show no neuromuscular disorder, in contrast to the hypotonia, spasticity and neuropathy present in every reported affected individual.

Downstream

Secondary Musculoskeletal Deformity

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"no single feature is observed in 100% of the affected individuals described here, although different neuromuscular abnormalities, e.g., neuropathy, hypotonia, or spasticity, are present in all individuals"

Neuromuscular abnormality is the one universal feature of the disorder, which is why it is modeled as the convergent organism-level node.

PMID:35108495 SUPPORT Human Clinical

"The observed diverse clinical manifestations of either neuropathy and hypotonia or spasticity in affected individuals may result from misrouting of nerve fibers."

The authors' proposed mechanism linking the adhesion/guidance defect to both poles of the neuromuscular phenotype.

Global Neurodevelopmental Impairment

Global developmental delay with cognitive impairment of congenital onset is the dominant central manifestation, present in seven of the ten individuals of the founding cohort. It is absent in the mildest phenotype (isolated late-onset peripheral neuropathy) and, in one individual with a severe neonatal presentation, resolved with age.

Downstream

Secondary Musculoskeletal Deformity

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"All affected individuals, excluding the proband of family 7 and the brothers of family 8, presented with global developmental delay (GDD) and cognitive impairment, combined with either hypotonia and neuropathy or spasticity."

Establishes global developmental delay with cognitive impairment as the dominant, but not universal, central phenotype.

Secondary Musculoskeletal Deformity

Scoliosis, hip dysplasia/acetabular dysplasia, coxa valga, pes cavus, hammertoe and distal arthrogryposis are recorded in the OMIM clinical synopsis for this disorder and give the entity its name. No cell-autonomous role for NRCAM in bone or cartilage has been reported, and NRCAM is characterized throughout the literature as a nervous-system adhesion molecule; the skeletal findings are therefore modeled here as secondary to chronic abnormal biomechanical loading from hypotonia, spasticity and neurogenic muscle weakness — the same route by which scoliosis, hip subluxation and cavus foot arise in other early-onset neuromuscular disorders. This is an inference, not a demonstrated mechanism; it is flagged as a KNOWLEDGE_GAP and the confidence is HYPOTHETICAL.

Show evidence (1 reference)

PMID:36606341 SUPPORT INDIRECT Human Clinical

"He also has lordosis and abnormal gait with limitations in walking ability (he can walk with braces)."

Documents a spinal deformity (lordosis) co-occurring with the motor-predominant neuropathy and gait limitation in an affected individual. It is consistent with, but does not demonstrate, the proposed neuromuscular route to skeletal deformity; hence INDIRECT.

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Histopathology

1

Neurogenic Grouped Fibre Atrophy on Muscle Biopsy

Deltoid muscle biopsy in the motor-predominant neuropathy phenotype showed grouped angular atrophic fibres with basophilic degenerating/regenerating fibres and scattered hypertrophied round fibres, and marked type 2 fibre atrophy — the pattern of chronic denervation, not of a primary myopathy.

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"Muscle biopsy at the age of 14 and from the left deltoid showed groups of atrophy of angular and some basophilic degenerative/regenerative fibers associated with some round hypertrophied fibers"

Describes the neurogenic histopathological pattern in an affected individual.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

25

Ear 1

Hearing Impairment FREQUENT HP:0000365

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"Similarly, the observed hearing abnormalities in three of the affected individuals can be inferred to NRCAM expression in the spiral ganglion neurons, cochlear efferent fibers, and cochlear sensory cells within the inner ear."

Three of ten affected individuals had hearing abnormalities, i.e. 30%, which is the lower bound of FREQUENT (30-79%).

Eye 2

Cataract OCCASIONAL HP:0000518

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"only two individuals in this study (individuals 3 and 8a) exhibited signs of cataract on examination; the young age of most individuals described should be noted, as cataract may develop over time"

Two affected individuals of ten had cataract, which maps to OCCASIONAL (5-29%); the same sentence records the ascertainment caveat.

Optic Atrophy HP:0000648

Optic atrophy (1/8), strabismus (2/8) and retinal detachment (1/8) are recorded in the OMIM clinical synopsis for OMIM:619833, derived from Table 1 of PMID:35108495. That table is not in the extractable text of the cached reference and none of those three terms appears anywhere in it, so only the generic abnormal-eye-examination statement is evidenced here, strabismus and retinal detachment are not curated as separate phenotypes, and no frequency is asserted.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"and eye examinations were abnormal in some of the other affected individuals"

Establishes abnormal ophthalmologic examination across the cohort. It does not name optic atrophy specifically, hence PARTIAL.

Head and Neck 2

Facial Dysmorphism Abnormal facial shape HP:0001999

Bound to the gestalt term rather than to any single component feature. Micrognathia (3/8) is recorded in the OMIM clinical synopsis but appears nowhere in the cached text, so it is not curated here.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"Facial dysmorphism of individual 1, including bi-temporal narrowing, bushy eyebrows with medial flaring, long eyelashes, depressed nasal bridge, and cupid bowed lips (left) and plagiocephaly (right)."

Enumerates the component features of the facial gestalt in the index individual.

PMID:35108495 SUPPORT Human Clinical

"Individuals 3–6 presented with facial dysmorphism, GDD, intellectual disability, hypotonia, ataxia, peripheral neuropathy or spasticity, and visual and hearing abnormalities with variable penetrance."

Facial dysmorphism recurs beyond the index individual, in individuals 3-6.

Microcephaly HP:0000252

Recorded in the OMIM clinical synopsis for OMIM:619833 (3/6). Not stated in the extractable text of PMID:35108495, so no exact-quote evidence item is attached and no frequency is asserted.

Limbs 1

Pes Cavus HP:0001761

Source and evidence caveat as for Scoliosis above; no exact-quote evidence item is attached.

Metabolism 1

Elevated Creatine Kinase Elevated circulating creatine kinase concentration HP:0003236

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"The proband had an elevated CPK of 722 (Reference range: 55-170 U/L)."

Documents the creatine kinase elevation against the reporting laboratory's reference interval.

Musculoskeletal 5

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

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

Hypotonia is named as a core feature of the syndrome.

Spasticity HP:0001257

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

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

Spasticity is named as one of the two alternative neuromuscular poles.

PMID:38274568 SUPPORT Other

"Biallelic variants in NRCAM encoding a highly expressed cell adhesion protein in the nervous system were described to cause a neurodevelopmental disorder (NDD) with developmental delay, intellectual disability, hypotonia, spasticity and peripheral neuropathy."

A later review letter listing spasticity in the NRCAM phenotype spectrum. It reports no new patients of its own, so it is corroborating summary rather than independent clinical evidence; evidence_source is OTHER.

Progressive Muscle Weakness HP:0001324

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"peripheral neuropathy, progressive muscle weakness predominating in lower limbs, elevated CPK, normal growth parameters, cognition and hearing, no dysmorphism and behavioral issues"

Lists progressive lower-limb-predominant muscle weakness as a shared feature of the mild phenotype.

Scoliosis HP:0002650

Recorded in the OMIM clinical synopsis for OMIM:619833 (5/9), derived from Table 1 of PMID:35108495. That table is not in the extractable text of the cached reference and the paper's narrative never mentions scoliosis, so no exact-quote evidence item is attached and no `frequency` is asserted. See the KNOWLEDGE_GAP discussion "skeletal_phenotype_evidence".

Hip Dysplasia HP:0001385

Source and evidence caveat as for Scoliosis above; no exact-quote evidence item is attached.

Nervous System 7

Global Developmental Delay FREQUENT HP:0001263

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"All affected individuals, excluding the proband of family 7 and the brothers of family 8, presented with global developmental delay (GDD) and cognitive impairment, combined with either hypotonia and neuropathy or spasticity."

Names global developmental delay in 7 of 10 individuals (all but three), which maps to FREQUENT (30-79%).

Intellectual Disability FREQUENT HP:0001249

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

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

Intellectual disability is named as a core feature of the syndrome.

PMID:35108495 SUPPORT Human Clinical

"All affected individuals, excluding the proband of family 7 and the brothers of family 8, presented with global developmental delay (GDD) and cognitive impairment, combined with either hypotonia and neuropathy or spasticity."

Cognitive impairment in 7 of the 10 individuals (all but three), i.e. 70%, which maps to FREQUENT (30-79%). This is the evidence for the frequency band, separate from the evidence for the association above.

Peripheral Neuropathy HP:0009830

Course: PROGRESSIVE

Curated at the unqualified parent term. The OMIM clinical synopsis for OMIM:619833 records "demyelinating peripheral neuropathy" (HP:0007108) in 1/10, but the word "demyelinating" does not appear anywhere in the cached text of PMID:35108495 or PMID:36606341, and the only nerve conduction study quotable from either paper is axonal in pattern (reduced CMAP amplitude with normal velocities). The specific demyelinating subtype is therefore not asserted here; the separately curated "Motor-Predominant Axonal Polyneuropathy" carries the pattern that is evidenced.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

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

Peripheral neuropathy is named as a core feature of the syndrome.

Ataxia OCCASIONAL HP:0001251

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"Individuals 3–6 presented with facial dysmorphism, GDD, intellectual disability, hypotonia, ataxia, peripheral neuropathy or spasticity, and visual and hearing abnormalities with variable penetrance."

Ataxia is listed among the features of individuals 3-6, with variable penetrance. The band is set from the OMIM clinical synopsis for OMIM:619833, which records ataxia in 2/10 - a synopsis-derived estimate, not a count extracted from this quote.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"including a thin corpus callosum with partially shifted vermis, ventriculomegaly, periventricular leukomalacia, and delayed myelination, while some individuals had normal brain imaging"

Ventriculomegaly is listed among the brain imaging findings.

Hydrocephalus OCCASIONAL HP:0000238

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"Individuals 1 and 2 were the most severely affected, including hydrocephalus, GDD, failure to thrive, hypotonia, and neuropathy in individual 1"

Hydrocephalus is documented among the findings of the two most severely affected individuals of ten. The sentence attributes the trailing items specifically to individual 1, so the count is between 1/10 and 2/10; either reading falls in OCCASIONAL (5-29%).

Self-Injurious Behavior FREQUENT HP:0100716

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"other behavioral issues—most prominently aggression and self-injury—have been described in three individuals in our cohort"

Aggression and self-injury in three of the ten individuals of the founding cohort, i.e. 30%, which is the lower bound of FREQUENT (30-79%).

Growth 1

Failure to Thrive HP:0001508

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"Individuals 1 and 2 were the most severely affected, including hydrocephalus, GDD, failure to thrive, hypotonia, and neuropathy in individual 1"

Failure to thrive documented in the severe end of the phenotype spectrum.

Other 5

Motor-Predominant Axonal Polyneuropathy Peripheral axonal neuropathy HP:0003477

Course: PROGRESSIVE

Show evidence (3 references)

PMID:36606341 SUPPORT Human Clinical

"He presented only motor-predominant axonal polyneuropathy with no other signs of central nervous system involvement."

Documents the isolated motor-predominant axonal polyneuropathy phenotype.

PMID:38274568 SUPPORT Other

"Interestingly, two patients in this report had isolated motor neuropathy phenotype, with absent or minimal additional symptoms"

A review letter restating the isolated motor neuropathy phenotype. "This report" refers to PMID:35108495, so the two patients are individuals 8a and 8b of the founding cohort, already cited below - this is corroborating summary, not an independent cohort, hence PARTIAL.

PMID:35108495 SUPPORT Human Clinical

"Individuals 8a and 8b exhibit the mildest phenotype; both presented with late-onset peripheral neuropathy without developmental delay."

The founding cohort already contained the isolated late-onset neuropathy phenotype.

Distal Arthrogryposis HP:0005684

Source and evidence caveat as for Scoliosis above; no exact-quote evidence item is attached.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"including a thin corpus callosum with partially shifted vermis, ventriculomegaly, periventricular leukomalacia, and delayed myelination, while some individuals had normal brain imaging"

Thin corpus callosum is listed among the brain imaging findings.

Delayed CNS Myelination HP:0002188

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"including a thin corpus callosum with partially shifted vermis, ventriculomegaly, periventricular leukomalacia, and delayed myelination, while some individuals had normal brain imaging"

Delayed myelination is listed among the brain imaging findings.

Periventricular Heterotopia HP:0007165

Recorded in the OMIM clinical synopsis for OMIM:619833 (1/9), derived from Table 1 of PMID:35108495. The word "heterotopia" does not appear anywhere in the extractable text of the cached reference - the narrative's imaging list names thin corpus callosum, ventriculomegaly, periventricular leukomalacia and delayed myelination only - so no exact-quote evidence item is attached and no frequency is asserted, as for the other Table 1-derived findings.

🧬

Genetic Associations

1

NRCAM

Gene: NRCAM hgnc:7994 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:35108495 SUPPORT Computational

"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."

Establishes the Fn-III domain 3 variant cluster and its predicted functional consequence.

PMID:36606341 SUPPORT Human Clinical

"Although patients with loss of function variants in this gene have previously presented severe clinical features, we show that type of the pathogenic variant does not necessarily determine the severity of this phenotype."

Directly qualifies the genotype-phenotype correlation: a nonsense allele produced the mildest reported phenotype.

PMID:35108495 SUPPORT Human Clinical

"However, the nature and location of each missense variant and their resulting effect on protein expression and function may also affect the subsequent clinical manifestations."

The authors' own caveat that variant class does not fully determine severity.

Variants (13)

p.Asp55Gly

Gene: NRCAM hgnc:7994 missense

Missense substitution in the first Ig-like domain, found in compound heterozygosity with the deep-intronic c.230+824G>C allele. The residue is solvent-exposed. See the genetic notes: the substitution, domain assignment and pairing are transcribed from Table 2 via the deep-research report rather than from the paper's narrative, which names only the residue Asp55.

Show evidence (1 reference)

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent"

Structural modeling places Asp55 among the solvent-exposed substituted residues.

p.Ser134Pro

Gene: NRCAM hgnc:7994 missense

Missense substitution in Ig-like domain 1. The residue is solvent-exposed and the substitution changes polarity and/or charge, so it is predicted to perturb the electrostatic surface and protein-protein interaction interfaces.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids and states the electrostatic prediction the description rests on. Note the source hedges with "most", so the polarity/charge claim is an aggregate over the set rather than a per-residue assertion.

p.Gly197Asp

Gene: NRCAM hgnc:7994 missense

Missense substitution in Ig-like domain 2. The residue is solvent-exposed and the substitution changes polarity and/or charge, so it is predicted to perturb the electrostatic surface and protein-protein interaction interfaces.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids and states the electrostatic prediction the description rests on. Note the source hedges with "most", so the polarity/charge claim is an aggregate over the set rather than a per-residue assertion.

p.Asn469Ser

Gene: NRCAM hgnc:7994 missense

Missense substitution in Ig-like domain 5. The residue is solvent-exposed, and the paper groups it with the other six under an aggregate electrostatic prediction - but that sentence hedges ("most of the amino acid substitutions change the polarity and/or charge"), and this substitution is the likeliest member of the excluded minority: asparagine and serine are both polar and both uncharged, so the change is one of side-chain size and hydrogen-bonding geometry (carboxamide to hydroxyl) rather than of polarity or charge. The predicted effect on this allele is therefore weaker than for its six counterparts.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids, and states the aggregate electrostatic prediction that the description argues this particular allele is likely excluded from - the source hedges with "most", and asparagine to serine changes neither polarity nor charge. Cited here for the solvent-exposure finding and as the source of the prediction being qualified, not as support for applying that prediction to this substitution.

p.Arg853Cys

Gene: NRCAM hgnc:7994 missense

Missense substitution in the third Fn-III domain. The residue is solvent-exposed and the substitution changes polarity and/or charge, so it is predicted to perturb the electrostatic surface and protein-protein interaction interfaces.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids and states the electrostatic prediction the description rests on. Note the source hedges with "most", so the polarity/charge claim is an aggregate over the set rather than a per-residue assertion.

p.Lys902Thr

Gene: NRCAM hgnc:7994 missense

Missense substitution in the third Fn-III domain. It sits close to the domain's KGE integrin-recognition and RNRR furin motifs, so it may specifically impair the protein-protein interactions of this domain. The residue is solvent-exposed and the substitution changes polarity and/or charge, so it is predicted to perturb the electrostatic surface and protein-protein interaction interfaces.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids and states the electrostatic prediction the description rests on. Note the source hedges with "most", so the polarity/charge claim is an aggregate over the set rather than a per-residue assertion.

p.Gly913Asp

Gene: NRCAM hgnc:7994 missense

Missense substitution in the third Fn-III domain. The residue is solvent-exposed and the substitution changes polarity and/or charge, so it is predicted to perturb the electrostatic surface and protein-protein interaction interfaces.

Show evidence (2 references)

PMID:35108495 SUPPORT Human Clinical

"The observed missense variants were found to affect either the Ig-like domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)"

Names this substitution and the domain it falls in.

PMID:35108495 SUPPORT Computational

"Based on the obtained structural models, all substituted amino acids (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear exposed to the solvent (Figures 2andS2). Because most of the amino acid substitutions change the polarity and/or charge of the residues, they are predicted to..."

Structural modeling places this residue among the solvent-exposed substituted amino acids and states the electrostatic prediction the description rests on. Note the source hedges with "most", so the polarity/charge claim is an aggregate over the set rather than a per-residue assertion.

p.Glu111*

Gene: NRCAM hgnc:7994 nonsense

Truncating (nonsense) allele producing a premature stop codon and a truncated, non-functional protein.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to premature stop-codons, while the c.2647−2A>G splice variant is predicted to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating the protein product and impeding its function."

States that this allele produces a premature stop codon and truncates the protein.

p.Arg929*

Gene: NRCAM hgnc:7994 nonsense

Truncating (nonsense) allele producing a premature stop codon and a truncated, non-functional protein.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to premature stop-codons, while the c.2647−2A>G splice variant is predicted to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating the protein product and impeding its function."

States that this allele produces a premature stop codon and truncates the protein.

p.Thr766Ilefs*4

Gene: NRCAM hgnc:7994 frameshift

Truncating (frameshift) allele producing a premature stop codon and a truncated, non-functional protein.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to premature stop-codons, while the c.2647−2A>G splice variant is predicted to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating the protein product and impeding its function."

States that this allele produces a premature stop codon and truncates the protein.

c.2647-2A>G (p.Ile883Serfs*8)

Gene: NRCAM hgnc:7994 splice acceptor

Canonical splice-acceptor variant predicted to cause skipping of exon 22, producing a frameshift and a truncated protein.

Show evidence (1 reference)

PMID:35108495 SUPPORT Computational

"The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to premature stop-codons, while the c.2647−2A>G splice variant is predicted to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating the protein product and impeding its function."

States the predicted exon-22 skipping and resulting frameshift.

c.230+824G>C

Gene: NRCAM hgnc:7994 deep intronic splice

Deep-intronic variant, invisible to exome sequencing and identified only by genome sequencing, predicted to disrupt a binding site for the splicing regulator SC35 and to activate a cryptic acceptor site generating a cryptic exon.

Show evidence (1 reference)

PMID:35108495 SUPPORT Computational

"The deep intronic variant observed in individual 3 (c.230+824G>C) is predicted to disrupt a site for the splicing regulator SC35, which is required for spliceosome assembly and splice-site selection."

States the predicted splicing consequence of this deep-intronic allele.

c.73C>T (p.Gln25*)

Gene: NRCAM hgnc:7994 nonsense

Homozygous nonsense allele in the N-terminal signal peptide, before the first Ig-like domain, reported in the second family. Notable because this loss-of-function allele produced the mildest phenotype described - isolated motor-predominant axonal polyneuropathy with normal cognition - which is what breaks the simple loss-of-function-equals-severe correlation.

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"Whole exome sequencing revealed a homozygous variant, c.73C > T (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of phenotypes compared to NRCAM-related disorder."

Identifies the allele and records that it produced a mild phenotype.

💊

Medical Actions

4

Supportive and Multidisciplinary Care

Category: Therapeutic Action: Supportive Care NCIT:C15747

No disease-specific or targeted therapy exists. Management is entirely supportive: feeding support for failure to thrive, respiratory support in the most severely affected infants, and multidisciplinary neurodevelopmental follow-up.

Physical Therapy and Rehabilitation

Category: Therapeutic Action: Physical Therapy NCIT:C15302

Physical and occupational therapy for hypotonia, spasticity and motor delay, with orthoses where walking is limited; the second reported patient ambulates with braces.

Mechanism Target:

Neuromuscular Dysfunction — Physical therapy and orthoses address the functional consequences of the neuromuscular node; they do not act on the upstream adhesion defect.

Target Phenotypes: Hypotonia HP:0001252 Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"He also has lordosis and abnormal gait with limitations in walking ability (he can walk with braces)."

Documents orthotic support preserving ambulation in an affected individual. It evidences the use of bracing, not a formal trial of physical therapy, hence PARTIAL.

Orthopedic Management of Skeletal Deformity

Category: Therapeutic Action: Orthopedic Surgical Procedure NCIT:C16186

Orthopedic surveillance and, where indicated, surgical management of scoliosis, hip dysplasia/subluxation and foot deformity, as for other early-onset neuromuscular disorders.

Mechanism Target:

Secondary Musculoskeletal Deformity — Orthopedic management addresses the skeletal deformity node; whether that node is truly secondary to neuromuscular loading is itself an open question recorded in the skeletal_phenotype_evidence discussion.

Target Phenotypes: Scoliosis HP:0002650 Hip dysplasia HP:0001385

Genetic Counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Counseling for the 25% sibling recurrence risk of an autosomal recessive disorder, with carrier testing, prenatal diagnosis and preimplantation genetic testing available once the familial variants are known. Particularly relevant given the consanguineous and founder families reported.

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"The proband is a 19‐year‐old male who is the only child of consanguineous (first cousin) healthy Iranian parents"

Consanguinity in reported families is the specific circumstance that makes recurrence-risk counseling and carrier testing relevant.

🔬

Biochemical Markers

1

Serum Creatine Kinase

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"The proband had an elevated CPK of 722 (Reference range: 55–170 U/L)."

Records the measured creatine kinase elevation together with the laboratory's reference interval.

🔬

Diagnosis

2

Exome or Genome Sequencing

Molecular diagnosis rests on exome or genome sequencing with Sanger confirmation and segregation analysis; there is no biochemical marker. Every reported case was ascertained this way, and the founding cohort was assembled through GeneMatcher after each family's variant was found independently. Genome sequencing was required in one family whose causal allele was a deep-intronic splice variant invisible to exome sequencing, and runs-of-homozygosity assessment supported the homozygous nonsense allele in the second report.

exome or genome sequencing NCIT:C101293

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"Whole-exome sequencing (WES), in parallel with WES-based CNV detection and assessment of homozygosity runs, was performed to identify this patient's possible genetic cause."

Describes the diagnostic strategy that established the molecular diagnosis.

Nerve Conduction Studies and Electromyography

Nerve conduction studies and needle EMG characterize the peripheral nerve lesion and establish whether it is axonal or demyelinating. In the second reported case they showed reduced motor CMAP amplitudes with preserved velocities and chronic neurogenic changes with spontaneous activity, initially suggesting distal spinal muscular atrophy.

Electromyography NCIT:C38056

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"Needle examination showed chronic neurogenic changes and spontaneous activity in leg muscles (proximal and distal)."

The electrophysiological findings used diagnostically in an affected individual.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Approximately 11 affected individuals reported in two primary reports (PMID:35108495, n=10 from 8 families; PMID:36606341, n=1). A third publication, PMID:38274568, is a correspondence letter that re-describes two of the founding cohort's individuals rather than adding new cases, so it must not be counted separately. No formal prevalence or incidence estimate exists and there is no Orphanet entry for this disorder, so the class is qualitative rather than an Orphanet numeric band.

Show evidence (1 reference)

PMID:35108495 SUPPORT Human Clinical

"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."

The founding cohort of ten individuals worldwide, assembled through GeneMatcher, indicates an ultra-rare disorder.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities:

Charcot-Marie-Tooth disease and distal spinal muscular atrophy

Overlapping Features The mild, neuropathy-only end of the NRCAM spectrum is clinically indistinguishable from CMT2/distal hereditary motor neuropathy; the second reported patient carried a working diagnosis of distal SMA and had SMN1 exon 7 deletion excluded before exome sequencing.

Show evidence (1 reference)

PMID:36606341 SUPPORT Human Clinical

"Based on the primary diagnosis of motor neuropathy or distal spinal muscular atrophy, the initial molecular analysis by real‐time PCR and MLPA for exon 7 of the SMN1 gene revealed no exon deletion in this patient."

Documents distal SMA as the working differential that had to be excluded before the NRCAM diagnosis was made.

Cerebral palsy

Overlapping Features Cerebral palsy is recorded as a feature in the OMIM clinical synopsis for OMIM:619833 (3/10) and appears in the abbreviation key of the founding report's clinical table, so a clinical label of cerebral palsy preceded the genetic diagnosis in some individuals. This is the recurring pattern in early-onset genetic spasticity/hypotonia syndromes and makes NEDNMS a consideration in "cerebral palsy" of unexplained cause.

🐁

Animal Models

3

Nrcam knockout mouse

Constitutive Nrcam-null mice reproduce the cellular defects of the disorder — delayed and abnormal node of Ranvier formation with delayed sodium channel clustering, failure of cerebellar granule cells to extend neurites on contactin-1, excess dendritic spines with increased mEPSC frequency in visual cortex, thalamic axon mistargeting with abnormal visual-evoked potentials, lens fibre disorganization with cataract, and transient cochlear innervation errors — yet do not develop a neuromuscular disorder and have only mildly reduced cerebellar size. The disconnect is the central translational caveat for this entry.

Species

Mouse

Genotype

Nrcam-null (homozygous knockout)

Publication

PMID:35108495

Pathograph links

Defective Node of Ranvier Assembly and Maintenance recapitulates fidelity: high Peripheral nerves of Nrcam-deficient mice show delayed or abnormal node formation with delayed nodal sodium channel clustering, the same lesion proposed to underlie the human peripheral neuropathy.

Limitations: Node formation is delayed rather than abolished, because gliomedin provides a partially redundant glial clustering signal; the severe nodal phenotype requires loss of both molecules.

Show evidence (1 reference)

PMID:35108495 SUPPORT Model Organism

"Nrcam has also been proven integral for formation and maintenance of nodes of Ranvier on myelinated axons, and peripheral nerves of Nrcam-deficient mice exhibit delayed or abnormal node formation."

Supports treating the Nrcam-null mouse as informative for the nodal assembly node.

Neuromuscular Dysfunction fails to recapitulate fidelity: low Despite the nodal defect, Nrcam-null mice show no neuromuscular disorder, in contrast to the hypotonia, spasticity and neuropathy present in every reported affected individual.

Limitations: Probable compensation by other L1-family Ig-CAMs (L1cam, Chl1, Nfasc) in mouse, and possible transcriptional adaptation triggered by nonsense-mediated decay of the null allele. Species differences in the protein itself are also implicated: the KGE and RNRR motifs of the human third Fn-III domain are poorly conserved outside mammals.

Show evidence (1 reference)

PMID:35108495 SUPPORT Model Organism

"In addition, while KO mice have delayed nodes of Ranvier formation and subsequently delayed sodium channel clustering at nodes, they do not exhibit signs of a neuromuscular disorder."

Explicit negative result: the mouse null does not develop the defining neuromuscular phenotype of the human disorder.

Impaired Synaptogenesis and Dendritic Spine Remodeling recapitulates fidelity: moderate NrCAM-null cortex shows elevated dendritic spine density, increased asymmetric synapses and increased mEPSC frequency, establishing NrCAM as a postnatal regulator of spine density within the Sema3F receptor complex.

Limitations: Measured in mouse primary visual cortex; no corresponding measurement exists in tissue from affected individuals, so the relevance to the human cognitive and behavioural phenotype is inferred.

Readouts

Apical dendritic spine density on star pyramidal cells

Direction: INCREASED

Interpretation: Loss of NrCAM removes Sema3F-dependent spine pruning, raising spine density.

Show evidence (1 reference)

PMID:25143608 SUPPORT Model Organism

"NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1."

Reports the spine-density measurement behind this readout.

Miniature EPSC frequency in star pyramidal neurons

Direction: INCREASED

Interpretation: Functional correlate of the excess excitatory synapses.

Show evidence (1 reference)

PMID:25143608 SUPPORT Model Organism

"Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons."

Reports the electrophysiological measurement behind this readout.

Show evidence (1 reference)

PMID:25143608 SUPPORT Model Organism

"These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex."

Supports treating the NrCAM-null mouse as informative for the synaptic node.

Sensory Pathway Miswiring partially recapitulates fidelity: moderate Nrcam-null mice reproduce the developmental miswiring — thalamic axon mistargeting to visual cortex with abnormal VEPs, and cochlear afferent and efferent innervation errors — but the cochlear defects self-correct and adult auditory acuity is normal, unlike the persistent hearing impairment in some affected individuals.

Limitations: Transient cochlear phenotype with functional recovery by weaning; humans appear to lack the compensatory mechanism.

Show evidence (1 reference)

PMID:29536590 SUPPORT Model Organism

"Neonatal Nrcam-null cochleae show errors in type II SGN fasciculation, reduced efferent innervation, and defects in the stereotyped packing of hair and supporting cells."

Supports treating the mouse as informative for the sensory-miswiring node, with the transience caveat recorded in limitations.

Show evidence (1 reference)

PMID:35108495 SUPPORT Model Organism

"In addition, while KO mice have delayed nodes of Ranvier formation and subsequently delayed sodium channel clustering at nodes, they do not exhibit signs of a neuromuscular disorder."

The mouse null is informative for the cellular mechanism but not for the organism-level neuromuscular phenotype, hence PARTIAL.

Gliomedin/NrCAM double knockout mouse

Removing both glial nodal adhesion molecules abolishes the glial clustering signal entirely and, unlike either single knockout, produces progressive disintegration of established nodes — sequential loss of neurofascin-186, sodium channels, ankyrin-G and then βIV spectrin, binary node formation and dysregulated nodal gap length — with neurological abnormality and slowed nerve conduction. It is the model that isolates the consequences of losing NrCAM-dependent nodal contact from the redundancy that masks them in the single mutant.

Species

Mouse

Genotype

Gldn-null; Nrcam-null double knockout

Publication

PMID:24719088

Pathograph links

Peripheral Nerve Conduction Failure and Axonal Degeneration recapitulates fidelity: moderate Loss of the gliomedin/NrCAM clustering signal produces measurable slowing of nerve conduction and neurological abnormality.

Limitations: The double knockout removes a redundant partner that is intact in affected individuals, so the model overstates the nodal deficit expected from NRCAM loss alone; it establishes the direction of the mechanism rather than its magnitude in human disease.

Readouts

Nerve conduction velocity

Direction: DECREASED

Interpretation: Functional consequence of nodal disassembly.

Show evidence (1 reference)

PMID:24719088 SUPPORT Model Organism

"Therefore, these mice exhibit neurological abnormalities and slower nerve conduction."

Reports the conduction measurement behind this readout.

Show evidence (1 reference)

PMID:24719088 SUPPORT Model Organism

"Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, 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."

Establishes the model and the redundancy that motivates using the double knockout.

Show evidence (1 reference)

PMID:24719088 SUPPORT Model Organism

"Here, we report that, in contrast to mice that lack either gliomedin or NrCAM, 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."

Establishes the model. It is PARTIAL for this disorder because affected individuals retain gliomedin, so the double knockout removes more than NRCAM loss alone does.

Zebrafish nrcama third Fn-III domain deletion mutant

A CRISPR-Cas9 mutant deleting the third Fn-III repeat — the domain in which most human disease variants cluster — generated in the founding study. Mutant larvae are viable with no gross morphological defect but show significantly altered swimming behaviour and a trend toward increased α-tubulin fibre density in the dorsal telencephalon and a thickened anterior telencephalic commissure. It is the only in vivo model built around the human variant hotspot.

Species

Zebrafish

Genotype

nrcamaΔ (CRISPR-Cas9 deletion of the third Fn-III domain)

Publication

PMID:35108495

Pathograph links

Aberrant CNS White Matter Tract Formation partially recapitulates fidelity: low Altered axonal projections in the dorsal telencephalon and anterior commissure, the zebrafish counterpart of the mammalian pallium and of the commissural tracts abnormal on human MRI.

Limitations: The axonal differences were reported as trends and did not reach significance; the pallium is massively expanded in humans relative to zebrafish; and the KGE and RNRR motifs of the human third Fn-III domain are not conserved in zebrafish Nrcam (HGD and QDYD), so the deleted domain is not functionally equivalent.

Show evidence (1 reference)

PMID:35108495 SUPPORT Model Organism

"Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections."

Supports the model as informative for white matter tract formation, while recording that the finding is a trend.

Show evidence (1 reference)

PMID:35108495 SUPPORT Model Organism

"Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03)."

The behavioural readout that establishes functional consequence of deleting the human variant-hotspot domain in vivo.

{ }

Source YAML

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name: Neurodevelopmental Disorder with Neuromuscular and Skeletal Abnormalities
creation_date: '2026-08-18T00:00:00Z'
category: Mendelian
synonyms:
- NEDNMS
- NRCAM-related neurodevelopmental disorder
- NRCAM deficiency
description: >-
  Neurodevelopmental disorder with neuromuscular and skeletal abnormalities
  (NEDNMS; OMIM:619833) is an ultra-rare autosomal recessive disorder caused by
  bi-allelic loss-of-function or damaging missense variants in NRCAM, which
  encodes neuronal cell adhesion molecule (NrCAM), a member of the L1
  immunoglobulin-superfamily of cell adhesion molecules (L1CAM, NRCAM, CHL1,
  NFASC). NrCAM mediates neuron-neuron and axon-glia adhesion, couples the
  cell surface to the ankyrin-spectrin cytoskeleton, and is required for axon
  growth and guidance, synaptogenesis and dendritic spine remodeling, and
  assembly and maintenance of nodes of Ranvier. Affected individuals present
  from infancy or early childhood with global developmental delay and cognitive
  impairment combined with a neuromuscular phenotype that is either hypotonia
  with peripheral neuropathy or spasticity; facial dysmorphism, skeletal
  findings (scoliosis, hip dysplasia, pes cavus), ataxia, ocular and auditory
  abnormalities, and non-specific brain MRI changes (thin corpus callosum,
  ventriculomegaly, periventricular leukomalacia, delayed myelination) occur
  with variable penetrance. Severity spans a wide spectrum, from early demise
  in infancy to isolated adult-onset motor-predominant axonal polyneuropathy
  with normal cognition. Disease-associated variants cluster in the third
  fibronectin type III (Fn-III) domain, a predicted protein-protein interaction
  interface. About 11 individuals have been reported in two primary
  publications since the disorder was delineated in 2022, plus a review letter
  that re-describes two of them.
disease_term:
  preferred_term: neurodevelopmental disorder with neuromuscular and skeletal abnormalities
  term:
    id: MONDO:0859236
    label: neurodevelopmental disorder with neuromuscular and skeletal abnormalities
parents:
- Neurodevelopmental Disorder
notes: >-
  Curation note on the disorder name. The OMIM/MONDO label foregrounds
  "neuromuscular and skeletal abnormalities", and the OMIM clinical synopsis for
  OMIM:619833 records scoliosis (5/9), hip dysplasia (3/9), pes cavus (3/9),
  coxa valga, acetabular dysplasia, hammertoe and distal arthrogryposis. Those
  counts derive from Table 1 of the founding case series (PMID:35108495), which
  is a figure/table asset and is not present in the extractable text of the
  cached reference; the narrative text and abstract of that paper describe the
  neurological and neuromuscular phenotype only and never use the words
  "scoliosis", "skeletal", or "contracture". The skeletal phenotypes below are
  therefore curated with ontology terms and descriptions but WITHOUT
  exact-quote evidence items, rather than with a fabricated snippet, per the
  evidence SOP. See the KNOWLEDGE_GAP discussion "skeletal_phenotype_evidence".

  Seizures are deliberately NOT curated as a phenotype of this disorder. The
  OMIM clinical synopsis and the deep-research reports both surface a single
  seizure case, but PMID:35108495 attributes it to a confounder rather than to
  NRCAM: individual 1 carries a concomitant homozygous loss-of-function CD55
  variant, and the paper states that "Shortly after PLE onset, he suffered from
  seizures attributed to sinus vein thrombosis secondary to the CD55 loss, which
  resolved on treatment with eculizumab." A seizure with an identified
  non-NRCAM cause in the one individual who had it is not evidence that this
  disorder causes seizures. The same individual's eculizumab treatment is
  likewise kept out of the treatments block. Individual 3's mosaic KRAS variant
  is a second, independent confounder in the founding cohort.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This syndrome is characterized by developmental delay/intellectual
        disability, hypotonia, peripheral neuropathy, and/or spasticity.
      explanation: >-
        The defining manifestations are central and peripheral nervous system
        findings, placing the entry in the neurologic chapter.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires bi-allelic NRCAM variants. Reported genotypes are
    homozygous (frequently in consanguineous or founder families) or compound
    heterozygous, and variants co-segregated with disease in all eight families
    of the founding cohort. Heterozygous carriers, including the parents, are
    unaffected. Expressivity is markedly variable, both between and within
    genotype classes: from hydrocephalus with failure to thrive and death in
    infancy, through developmental delay with hypotonia/neuropathy or
    spasticity, to isolated late-onset peripheral neuropathy with normal
    cognition.
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Ten affected individuals from eight families each carry bi-allelic NRCAM
      variants, establishing autosomal recessive inheritance.
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband is a 19‐year‐old male who is the only child of consanguineous
      (first cousin) healthy Iranian parents
    explanation: >-
      The second reported family is consanguineous with a homozygous proband,
      consistent with autosomal recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Approximately 11 affected individuals reported in two primary reports
    (PMID:35108495, n=10 from 8 families; PMID:36606341, n=1). A third
    publication, PMID:38274568, is a correspondence letter that re-describes two
    of the founding cohort's individuals rather than adding new cases, so it
    must not be counted separately. No formal prevalence or
    incidence estimate exists and there is no Orphanet entry for this disorder,
    so the class is qualitative rather than an Orphanet numeric band.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The founding cohort of ten individuals worldwide, assembled through
      GeneMatcher, indicates an ultra-rare disorder.
pathophysiology:
- name: Bi-allelic NRCAM Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Homozygous or compound heterozygous NRCAM variants — nonsense, frameshift,
    canonical splice-site and deep-intronic splice-disrupting alleles, and
    damaging missense substitutions — abolish or degrade NrCAM protein function.
    Missense variants are predicted to change residue polarity and/or charge and
    so perturb the protein's electrostatic surface and its protein-protein
    interaction interfaces; truncating alleles remove the C-terminal region
    including the third Fn-III domain.
  genes:
  - preferred_term: NRCAM
    term:
      id: hgnc:7994
      label: NRCAM
  genetic_context:
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    allele_type: SNV, indel, and splice-site variants
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Bi-allelic germline variants; both homozygous (consanguineous/founder
      families) and compound heterozygous genotypes are reported. Loss-of-function
      alleles trend toward a more severe phenotype than missense alleles, but the
      correlation is not absolute.
  downstream:
  - target: Impaired NrCAM-Mediated Neural Cell Adhesion
    causal_link_type: DIRECT
    description: >-
      The variants act on the adhesion protein itself, so the link from genotype
      to loss of adhesion function is direct.
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        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.
      explanation: >-
        Structural modeling links the disease alleles directly to impaired NrCAM
        function and protein-protein interaction.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      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.
    explanation: >-
      Establishes that the disease alleles are predicted to impair NrCAM
      structure and its protein-protein interactions.
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed a homozygous variant, c.73C > T
      (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range of
      phenotypes compared to NRCAM-related disorder.
    explanation: >-
      An independent homozygous nonsense allele confirms bi-allelic NRCAM loss
      of function as the disease trigger.
- name: Impaired NrCAM-Mediated Neural Cell Adhesion
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    NrCAM is a type-I transmembrane L1-family Ig-CAM whose extracellular region
    comprises six immunoglobulin-like domains followed by five fibronectin type
    III repeats; the Ig domains mediate ligand recognition and homophilic and
    heterophilic trans-binding (contactin-1/TAG-1, neurofascin), while the
    Fn-III repeats mediate adhesion signaling, and the cytoplasmic tail binds
    ankyrin. Loss of NrCAM therefore removes an adhesion and signaling hub that
    is shared by the neuron-neuron, neuron-glia and axon-glia interfaces. Most
    disease variants fall in the third Fn-III domain, which carries a
    KGE integrin-recognition motif and an RNRR furin site and is predicted to
    form a protein-protein interaction surface.
  biological_processes:
  - preferred_term: cell adhesion
    modifier: DECREASED
    term:
      id: GO:0007155
      label: cell adhesion
  - preferred_term: neuron cell-cell adhesion
    modifier: DECREASED
    term:
      id: GO:0007158
      label: neuron cell-cell adhesion
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Defective Axon Growth and Guidance
    causal_link_type: DIRECT
  - target: Defective Node of Ranvier Assembly and Maintenance
    causal_link_type: DIRECT
    description: >-
      NrCAM is one of the two glial adhesion molecules that deliver the nodal
      clustering signal, so loss of its adhesion function acts directly on node
      assembly.
    evidence:
    - reference: PMID:25459119
      reference_title: '[New insights on the organization of the nodes of Ranvier].'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The axo-glial contact at nodes implicates adhesion molecules expressed
        by the Schwann cell (gliomedin and NrCAM), which binds a partner,
        neurofascin-186, on the axonal side.
      explanation: >-
        Places NrCAM-mediated adhesion immediately upstream of node assembly.
  - target: Impaired Synaptogenesis and Dendritic Spine Remodeling
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The extracellular region of NRCAM is composed of six Ig-like domains
      followed by five Fn-III domains and is critical for the protein’s
      interaction with other CAMs and molecules enabling cell-cell interactions
      and adhesion.
    explanation: >-
      Defines the adhesion function of the domains in which the disease variants
      lie.
  - reference: PMID:8947556
    reference_title: 'Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neurofascin, NrCAM, L1, and NgCAM are a family of Ig/FNIII cell adhesion
      molecules that share ankyrin-binding activity in their cytoplasmic domains
    explanation: >-
      Establishes NrCAM as an ankyrin-binding L1-family adhesion molecule, the
      molecular basis of the coupling lost in this disorder.
- name: Defective Axon Growth and Guidance
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    NrCAM is expressed on growing and crossing axons and on the specialized
    midline glia they navigate (floor plate, optic chiasm, median eminence), and
    it partners with contactin-1/TAG-1 to promote neurite extension. Nrcam-null
    cerebellar granule cells fail to extend neurites on contactin-1 substrate,
    and Nrcam-deficient mice mistarget motor and somatosensory thalamic axons to
    the visual cortex. Loss of this guidance function is the proposed origin of
    the misrouted central and peripheral fibre tracts in affected individuals.
  biological_processes:
  - preferred_term: axon guidance
    modifier: ABNORMAL
    term:
      id: GO:0007411
      label: axon guidance
  - preferred_term: axonogenesis
    modifier: DECREASED
    term:
      id: GO:0007409
      label: axonogenesis
  - preferred_term: neuron projection development
    modifier: ABNORMAL
    term:
      id: GO:0031175
      label: neuron projection development
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  downstream:
  - target: Aberrant CNS White Matter Tract Formation
    causal_link_type: DIRECT
  - target: Sensory Pathway Miswiring
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      revealed abnormal neurite outgrowth, as the cerebellar granule cells
      failed to extend neurites on substrates such as contactin-1
    explanation: >-
      Nrcam-deficient neurons fail to extend neurites, the cellular defect
      underlying impaired axon growth.
  - reference: PMID:11329126
    reference_title: 'Nr-CAM expression in the developing mouse nervous system: ventral midline structures, specific fiber tracts, and neuropilar regions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Major sites that are positive for Nr-CAM are specialized glial formations
      in the ventral midline, including the floor plate in the spinal cord, the
      hindbrain and midbrain, the optic chiasm, and the median eminence in the
      forebrain.
    explanation: >-
      Localizes Nr-CAM to the midline guidance structures where crossing axons
      make pathfinding decisions.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in mice leads to mistargeting of motor and somatosensory thalamic axons to
      the visual cortex
    explanation: >-
      Demonstrates in vivo axon mistargeting on Nrcam loss.
- name: Impaired Synaptogenesis and Dendritic Spine Remodeling
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: PROVISIONAL
  description: >-
    Beyond its presynaptic and axonal roles, NrCAM acts postsynaptically as an
    integral component of the Semaphorin 3F receptor complex with Neuropilin-2
    and PlexinA3, and is required for Sema3F-induced dendritic spine pruning.
    NrCAM-null mice show elevated spine density, increased asymmetric synapse
    number and increased miniature EPSC frequency in visual cortex, i.e. a shift
    in excitatory/inhibitory balance. This arm is mechanistically well supported
    in the mouse but has not been demonstrated in tissue from affected
    individuals, hence the provisional confidence.
  biological_processes:
  - preferred_term: synapse assembly
    modifier: ABNORMAL
    term:
      id: GO:0007416
      label: synapse assembly
  - preferred_term: dendrite development
    modifier: ABNORMAL
    term:
      id: GO:0016358
      label: dendrite development
  cellular_components:
  - preferred_term: synapse
    term:
      id: GO:0045202
      label: synapse
  downstream:
  - target: Cortical Circuit Dysfunction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25143608
    reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NrCAM deletion in mice resulted in elevated spine densities on apical
      dendrites of star pyramidal cells at both postnatal and adult stages, and
      electron microscopy revealed increased numbers of asymmetric synapses in
      layer 4 of V1.
    explanation: >-
      Direct demonstration that NrCAM loss disrupts dendritic spine and synapse
      number.
  - reference: PMID:25143608
    reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings reveal NrCAM as a novel postnatal regulator of dendritic
      spine density in cortical pyramidal neurons, and an integral component of
      the Sema3F receptor complex.
    explanation: >-
      Places NrCAM in the Sema3F receptor complex that executes spine pruning.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      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.
    explanation: >-
      The founding clinical report invokes abnormal synaptogenesis in
      Nrcam-deficient cells as part of the proposed mechanism, but the data are
      in vitro and murine rather than from affected individuals.
- name: Defective Node of Ranvier Assembly and Maintenance
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    At the peripheral node of Ranvier, glial NrCAM and gliomedin on the Schwann
    cell bind axonal neurofascin-186; this axo-glial complex recruits ankyrin-G,
    which in turn clusters and concentrates voltage-gated sodium channels at the
    nodal axolemma. NrCAM is also present on the axonal side at nodes and axon
    initial segments together with neurofascin and ankyrin-G. Loss of the glial
    clustering signal produces delayed and disorganized node formation and,
    over time, progressive loss of Nav channels, ankyrin-G and βIV spectrin from
    established nodes.
  biological_processes:
  - preferred_term: clustering of voltage-gated sodium channels
    modifier: DECREASED
    term:
      id: GO:0045162
      label: clustering of voltage-gated sodium channels
  cellular_components:
  - preferred_term: node of Ranvier
    term:
      id: GO:0033268
      label: node of Ranvier
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  downstream:
  - target: Peripheral Nerve Conduction Failure and Axonal Degeneration
    causal_link_type: DIRECT
    description: >-
      Nodal sodium channel density sets conduction competence, so disassembly of
      the node degrades saltatory conduction directly.
    evidence:
    - reference: PMID:24719088
      reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Therefore, these mice exhibit neurological abnormalities and slower
        nerve conduction.
      explanation: >-
        In vivo demonstration that loss of the nodal clustering signal slows
        nerve conduction. PARTIAL because the model removes gliomedin as well as
        NrCAM, which affected individuals retain.
  evidence:
  - reference: PMID:25459119
    reference_title: '[New insights on the organization of the nodes of Ranvier].'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The axo-glial contact at nodes implicates adhesion molecules expressed by
      the Schwann cell (gliomedin and NrCAM), which binds a partner,
      neurofascin-186, on the axonal side.
    explanation: >-
      States the molecular architecture in which NrCAM participates at the
      peripheral node.
  - reference: PMID:25459119
    reference_title: '[New insights on the organization of the nodes of Ranvier].'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This complex is essential for the recruitment of ankyrin-G, a
      cytoskeletal scaffolding protein, which binds and concentrates Nav
      channels at nodes.
    explanation: >-
      Links the NrCAM-containing adhesion complex to sodium channel clustering.
  - reference: PMID:8947556
    reference_title: 'Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NrCAM, visualized with antibodies specific for the ecto-domain, also was
      found to be coexpressed with neurofascin at nodes of Ranvier and at axon
      initial segments.
    explanation: >-
      Localizes NrCAM to nodes of Ranvier and axon initial segments.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Nrcam has also been proven integral for formation and maintenance of nodes
      of Ranvier on myelinated axons, and peripheral nerves of Nrcam-deficient
      mice exhibit delayed or abnormal node formation.
    explanation: >-
      Connects the nodal function of NrCAM to the peripheral nerve phenotype of
      this disorder.
  - reference: PMID:16039564
    reference_title: Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We report the identification of gliomedin, a glial ligand for neurofascin
      and NrCAM, two axonal immunoglobulin cell adhesion molecules that are
      associated with Na+ channels at the nodes of Ranvier.
    explanation: >-
      Identifies the glial ligand that NrCAM binds at the node, completing the
      axo-glial complex this mechanism depends on.
  - reference: PMID:16039564
    reference_title: Gliomedin mediates Schwann cell-axon interaction and the molecular assembly of the nodes of Ranvier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Eliminating the expression of gliomedin by RNAi, or the addition of a
      soluble extracellular domain of neurofascin to myelinating cultures, which
      caused the redistribution of gliomedin along the internodes, abolished node
      formation.
    explanation: >-
      Disrupting the gliomedin-neurofascin-NrCAM interaction abolishes node
      formation outright, establishing the complex as necessary rather than
      merely correlated.
  - reference: PMID:11728309
    reference_title: Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nr-Fc had no effect on initial axon-Schwann cell interactions, including
      Schwann cell proliferation, or on the extent of myelination, but it
      strikingly and specifically inhibited Na(+) channel and ankyrin G
      accumulation at the node.
    explanation: >-
      A loss-of-function experiment in myelinating DRG neuron-Schwann cell
      co-culture showing that blocking Nr-CAM interactions specifically prevents
      sodium channel and ankyrin G accumulation at the node while leaving
      myelination itself intact - the cleanest available separation of the nodal
      defect from a primary myelination defect. The authors frame their own
      conclusion around neurofascin, with Nr-CAM as its likely partner, so the
      experiment constrains the complex rather than isolating NrCAM's
      contribution within it.
- name: Peripheral Nerve Conduction Failure and Axonal Degeneration
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Progressive loss of nodal sodium channels and disorganization of nodal
    architecture slow or block saltatory conduction. In the mouse double mutant
    that removes the entire glial clustering signal this produces measurable
    neurological abnormality and slowed nerve conduction. In affected
    individuals the corresponding clinical finding is a peripheral neuropathy -
    motor-predominant and axonal in the one case with quotable
    electrophysiology - with chronic neurogenic changes on needle EMG,
    neurogenic grouped fibre atrophy on muscle biopsy, and modestly elevated
    creatine kinase.
  biological_processes:
  - preferred_term: neuronal action potential
    modifier: ABNORMAL
    term:
      id: GO:0019228
      label: neuronal action potential
  locations:
  - preferred_term: peripheral nerve
    term:
      id: UBERON:0001021
      label: nerve
  downstream:
  - target: Neuromuscular Dysfunction
    causal_link_type: DIRECT
    description: >-
      Failure of peripheral nerve conduction is the proximate cause of the
      hypotonia, weakness and neuropathic findings.
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed diverse clinical manifestations of either neuropathy and
        hypotonia or spasticity in affected individuals may result from
        misrouting of nerve fibers.
      explanation: >-
        The founding report's own account of how the nerve lesion produces the
        neuromuscular phenotype.
  evidence:
  - reference: PMID:24719088
    reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Therefore, these mice exhibit neurological abnormalities and slower nerve
      conduction.
    explanation: >-
      Loss of the gliomedin/NrCAM nodal clustering signal produces slowed nerve
      conduction in vivo. PARTIAL because the double knockout also removes
      gliomedin, which affected individuals retain, so it overstates the deficit
      expected from NRCAM loss alone.
  - reference: PMID:24719088
    reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results reveal that axon-glial contact mediated by gliomedin, NrCAM,
      and NF186 not only plays a role in Na(+) channel clustering during
      development, but also contributes to the long-term maintenance of Na(+)
      channels at nodes of Ranvier.
    explanation: >-
      Establishes an ongoing maintenance requirement, consistent with the
      late-onset progressive neuropathy seen in mildly affected individuals.
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Needle examination showed chronic neurogenic changes and spontaneous
      activity in leg muscles (proximal and distal).
    explanation: >-
      Electrophysiological confirmation of the peripheral nerve lesion in an
      affected individual.
- name: Aberrant CNS White Matter Tract Formation
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    Nr-CAM is expressed along the major crossing fibre pathways — the anterior
    commissure, corpus callosum and posterior commissure — so loss of NrCAM
    guidance is expected to disturb their formation. Zebrafish nrcamaΔ mutants
    lacking the third Fn-III domain show a trend toward increased α-tubulin
    fibre density in the dorsal telencephalon and a thicker anterior
    telencephalic commissure. In affected individuals, brain MRI is variable and
    non-specific: thin corpus callosum, ventriculomegaly, periventricular
    leukomalacia and delayed myelination are each seen in a subset, and some
    individuals have normal imaging. Confidence is provisional because the
    zebrafish differences were trends rather than significant, and no human
    neuropathological correlate exists.
  biological_processes:
  - preferred_term: central nervous system myelination
    modifier: ABNORMAL
    term:
      id: GO:0022010
      label: central nervous system myelination
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  downstream:
  - target: Global Neurodevelopmental Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:11329126
    reference_title: 'Nr-CAM expression in the developing mouse nervous system: ventral midline structures, specific fiber tracts, and neuropilar regions.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, Nr-CAM is found in crossing fiber pathways, including the
      anterior commissure, corpus callosum, and posterior commissure, and in
      nondecussating pathways, such as the lateral olfactory tract and the
      habenulointerpeduncular tract.
    explanation: >-
      Places Nr-CAM in exactly the commissural tracts that are structurally
      abnormal on MRI in affected individuals.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a thin corpus callosum with partially shifted vermis,
      ventriculomegaly, periventricular leukomalacia, and delayed myelination,
      while some individuals had normal brain imaging
    explanation: >-
      The human imaging spectrum, including the explicit note that some
      individuals image normally.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of
      α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration
      in white matter tracts and projections.
    explanation: >-
      Model-organism support for altered white matter tracts; reported as a
      trend, hence PARTIAL.
  - reference: PMID:18588951
    reference_title: Abnormal axonal guidance and brain anatomy in mouse mutants for the cell recognition molecules close homolog of L1 and NgCAM-related cell adhesion molecule.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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
    explanation: >-
      Structural MRI of Nrcam-null mice shows disturbed axon guidance together
      with altered ventricular system and cerebellar vermis size, the
      model-organism counterpart of the ventriculomegaly and shifted vermis seen
      on human brain imaging.
- name: Cortical Circuit Dysfunction
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Excess dendritic spines and asymmetric synapses with increased mEPSC
    frequency in NrCAM-null cortex predict a shift in excitatory/inhibitory
    balance in neocortical circuits. This is the proposed cellular substrate for
    the cognitive impairment and the behavioural phenotype (irritability,
    aggression, self-injurious behaviour) in affected individuals, but it is an
    extrapolation from mouse visual cortex and has not been measured in humans.
  biological_processes:
  - preferred_term: modulation of chemical synaptic transmission
    modifier: DYSREGULATED
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
  downstream:
  - target: Global Neurodevelopmental Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:25143608
    reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The results implicate NrCAM as a contributor to excitatory/inhibitory
      balance in neocortical circuits.
    explanation: >-
      States the circuit-level consequence proposed here, in the mouse.
- name: Sensory Pathway Miswiring
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    NrCAM is expressed at the optic chiasm and on cochlear spiral ganglion
    afferents, olivocochlear efferents and cochlear hair and supporting cells.
    Nrcam-null mice mistarget thalamic axons to visual cortex and have abnormal
    visual-evoked potentials, and Nrcam-null cochleae show type II spiral
    ganglion fasciculation errors and reduced efferent innervation. This is the
    proposed basis for the abnormal VEPs, optic atrophy, strabismus and
    auditory findings in affected individuals. A translational caveat applies:
    the cochlear defects in mice are transient and adult Nrcam-null mice hear
    normally, whereas some affected individuals have persistent hearing
    impairment.
  biological_processes:
  - preferred_term: retinal ganglion cell axon guidance
    modifier: ABNORMAL
    term:
      id: GO:0031290
      label: retinal ganglion cell axon guidance
  downstream:
  - target: Global Neurodevelopmental Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29536590
    reference_title: Neuronal cell adhesion molecule (NrCAM) is expressed by sensory cells in the cochlea and is necessary for proper cochlear innervation and sensory domain patterning during development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Neonatal Nrcam-null cochleae show errors in type II SGN fasciculation,
      reduced efferent innervation, and defects in the stereotyped packing of
      hair and supporting cells.
    explanation: >-
      Demonstrates that NrCAM loss disrupts cochlear innervation, the proposed
      route to the auditory phenotype.
  - reference: PMID:29536590
    reference_title: Neuronal cell adhesion molecule (NrCAM) is expressed by sensory cells in the cochlea and is necessary for proper cochlear innervation and sensory domain patterning during development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite these numerous developmental defects, Nrcam-null adults do not
      show defects in auditory acuity
    explanation: >-
      Records the negative result that limits how far the mouse cochlear
      phenotype can be extrapolated to human hearing impairment.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, the observed hearing abnormalities in three of the affected
      individuals can be inferred to NRCAM expression in the spiral ganglion
      neurons, cochlear efferent fibers, and cochlear sensory cells within the
      inner ear.
    explanation: >-
      The founding report explicitly attributes the human auditory findings to
      NrCAM expression in the inner ear.
- name: Neuromuscular Dysfunction
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The convergent clinical output of peripheral nerve involvement and
    corticospinal/central involvement is a neuromuscular phenotype that is
    present in every reported individual, though its polarity differs: either
    hypotonia with peripheral neuropathy, or spasticity and hypertonia. The
    founding report proposes misrouting of nerve fibres as the common origin of
    both poles. Muscle weakness predominates distally and in the lower limbs in
    the neuropathy-predominant individuals.
  downstream:
  - target: Secondary Musculoskeletal Deformity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no single feature is observed in 100% of the affected individuals
      described here, although different neuromuscular abnormalities, e.g.,
      neuropathy, hypotonia, or spasticity, are present in all individuals
    explanation: >-
      Neuromuscular abnormality is the one universal feature of the disorder,
      which is why it is modeled as the convergent organism-level node.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed diverse clinical manifestations of either neuropathy and
      hypotonia or spasticity in affected individuals may result from misrouting
      of nerve fibers.
    explanation: >-
      The authors' proposed mechanism linking the adhesion/guidance defect to
      both poles of the neuromuscular phenotype.
- name: Global Neurodevelopmental Impairment
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Global developmental delay with cognitive impairment of congenital onset is
    the dominant central manifestation, present in seven of the ten individuals
    of the founding cohort. It is absent in the mildest phenotype (isolated
    late-onset peripheral neuropathy) and, in one individual with a severe
    neonatal presentation, resolved with age.
  downstream:
  - target: Secondary Musculoskeletal Deformity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals, excluding the proband of family 7 and the
      brothers of family 8, presented with global developmental delay (GDD) and
      cognitive impairment, combined with either hypotonia and neuropathy or
      spasticity.
    explanation: >-
      Establishes global developmental delay with cognitive impairment as the
      dominant, but not universal, central phenotype.
- name: Secondary Musculoskeletal Deformity
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Scoliosis, hip dysplasia/acetabular dysplasia, coxa valga, pes cavus,
    hammertoe and distal arthrogryposis are recorded in the OMIM clinical
    synopsis for this disorder and give the entity its name. No cell-autonomous
    role for NRCAM in bone or cartilage has been reported, and NRCAM is
    characterized throughout the literature as a nervous-system adhesion
    molecule; the skeletal findings are therefore modeled here as secondary to
    chronic abnormal biomechanical loading from hypotonia, spasticity and
    neurogenic muscle weakness — the same route by which scoliosis, hip
    subluxation and cavus foot arise in other early-onset neuromuscular
    disorders. This is an inference, not a demonstrated mechanism; it is
    flagged as a KNOWLEDGE_GAP and the confidence is HYPOTHETICAL.
  notes: >-
    No exact-quote evidence item is attached to this node because no cited
    publication states the skeletal mechanism. Deliberately left unsupported
    rather than justified with a snippet that does not make the claim.
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also has lordosis and abnormal gait with limitations in walking ability
      (he can walk with braces).
    explanation: >-
      Documents a spinal deformity (lordosis) co-occurring with the
      motor-predominant neuropathy and gait limitation in an affected
      individual. It is consistent with, but does not demonstrate, the proposed
      neuromuscular route to skeletal deformity; hence INDIRECT.
phenotypes:
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Global developmental delay with cognitive impairment, of congenital onset in
    most individuals. Present in 7 of the 10 individuals of the founding cohort;
    absent in the two adult siblings with isolated late-onset neuropathy and
    resolved by age 5 in one individual with a severe neonatal presentation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals, excluding the proband of family 7 and the
      brothers of family 8, presented with global developmental delay (GDD) and
      cognitive impairment, combined with either hypotonia and neuropathy or
      spasticity.
    explanation: >-
      Names global developmental delay in 7 of 10 individuals (all but three),
      which maps to FREQUENT (30-79%).
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Cognitive impairment accompanying the developmental delay, of variable
    severity. Notably absent in the mildest, neuropathy-only phenotypes.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is characterized by developmental delay/intellectual
      disability, hypotonia, peripheral neuropathy, and/or spasticity.
    explanation: >-
      Intellectual disability is named as a core feature of the syndrome.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals, excluding the proband of family 7 and the
      brothers of family 8, presented with global developmental delay (GDD) and
      cognitive impairment, combined with either hypotonia and neuropathy or
      spasticity.
    explanation: >-
      Cognitive impairment in 7 of the 10 individuals (all but three), i.e. 70%,
      which maps to FREQUENT (30-79%). This is the evidence for the frequency
      band, separate from the evidence for the association above.
- category: Musculature
  name: Hypotonia
  description: >-
    Central and/or peripheral hypotonia, one of the two poles of the
    neuromuscular phenotype (the other being spasticity). Contributes to feeding
    difficulty and motor delay in severely affected infants.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is characterized by developmental delay/intellectual
      disability, hypotonia, peripheral neuropathy, and/or spasticity.
    explanation: >-
      Hypotonia is named as a core feature of the syndrome.
- category: Neurologic
  name: Spasticity
  description: >-
    Hypertonia and spasticity, including spastic quadriplegia or paraplegia,
    seen in the individuals who do not have the hypotonia/neuropathy pole of the
    phenotype. Several affected individuals had been given a clinical label of
    cerebral palsy before the genetic diagnosis.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is characterized by developmental delay/intellectual
      disability, hypotonia, peripheral neuropathy, and/or spasticity.
    explanation: >-
      Spasticity is named as one of the two alternative neuromuscular poles.
  - reference: PMID:38274568
    reference_title: Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biallelic variants in NRCAM encoding a highly expressed cell adhesion
      protein in the nervous system were described to cause a neurodevelopmental
      disorder (NDD) with developmental delay, intellectual disability,
      hypotonia, spasticity and peripheral neuropathy.
    explanation: >-
      A later review letter listing spasticity in the NRCAM phenotype spectrum.
      It reports no new patients of its own, so it is corroborating summary
      rather than independent clinical evidence; evidence_source is OTHER.
- category: Neurologic
  name: Peripheral Neuropathy
  description: >-
    Peripheral neuropathy is present across the severity spectrum and is the
    sole manifestation at the mild end.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
    clinical_course: PROGRESSIVE
  notes: >-
    Curated at the unqualified parent term. The OMIM clinical synopsis for
    OMIM:619833 records "demyelinating peripheral neuropathy" (HP:0007108) in
    1/10, but the word "demyelinating" does not appear anywhere in the cached
    text of PMID:35108495 or PMID:36606341, and the only nerve conduction study
    quotable from either paper is axonal in pattern (reduced CMAP amplitude with
    normal velocities). The specific demyelinating subtype is therefore not
    asserted here; the separately curated "Motor-Predominant Axonal
    Polyneuropathy" carries the pattern that is evidenced.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This syndrome is characterized by developmental delay/intellectual
      disability, hypotonia, peripheral neuropathy, and/or spasticity.
    explanation: >-
      Peripheral neuropathy is named as a core feature of the syndrome.
- category: Neurologic
  name: Motor-Predominant Axonal Polyneuropathy
  description: >-
    At the mild end of the spectrum, an isolated motor-predominant axonal
    polyneuropathy without cognitive impairment or central nervous system
    involvement, presenting in the second decade and initially mistaken for
    distal spinal muscular atrophy. Needle EMG shows chronic neurogenic changes;
    muscle biopsy shows grouped neurogenic fibre atrophy.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He presented only motor-predominant axonal polyneuropathy with no other
      signs of central nervous system involvement.
    explanation: >-
      Documents the isolated motor-predominant axonal polyneuropathy phenotype.
  - reference: PMID:38274568
    reference_title: Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Interestingly, two patients in this report had isolated motor neuropathy
      phenotype, with absent or minimal additional symptoms
    explanation: >-
      A review letter restating the isolated motor neuropathy phenotype. "This
      report" refers to PMID:35108495, so the two patients are individuals 8a
      and 8b of the founding cohort, already cited below - this is corroborating
      summary, not an independent cohort, hence PARTIAL.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 8a and 8b exhibit the mildest phenotype; both presented with
      late-onset peripheral neuropathy without developmental delay.
    explanation: >-
      The founding cohort already contained the isolated late-onset neuropathy
      phenotype.
- category: Musculature
  name: Progressive Muscle Weakness
  description: >-
    Progressive weakness of proximal and distal muscles predominating in the
    lower limbs, with limitation of walking requiring braces, in the
    neuropathy-predominant phenotype.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      peripheral neuropathy, progressive muscle weakness predominating in lower
      limbs, elevated CPK, normal growth parameters, cognition and hearing, no
      dysmorphism and behavioral issues
    explanation: >-
      Lists progressive lower-limb-predominant muscle weakness as a shared
      feature of the mild phenotype.
- category: Neurologic
  name: Ataxia
  description: Ataxia, reported with variable penetrance in the moderately affected individuals.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 3–6 presented with facial dysmorphism, GDD, intellectual
      disability, hypotonia, ataxia, peripheral neuropathy or spasticity, and
      visual and hearing abnormalities with variable penetrance.
    explanation: >-
      Ataxia is listed among the features of individuals 3-6, with variable
      penetrance. The band is set from the OMIM clinical synopsis for
      OMIM:619833, which records ataxia in 2/10 - a synopsis-derived estimate,
      not a count extracted from this quote.
- category: Craniofacial
  name: Facial Dysmorphism
  description: >-
    A recognizable but non-specific facial gestalt, described in the index
    individual as bi-temporal narrowing, bushy eyebrows with medial flaring,
    long eyelashes, depressed nasal bridge, cupid-bowed lips and plagiocephaly.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism of individual 1, including bi-temporal narrowing, bushy
      eyebrows with medial flaring, long eyelashes, depressed nasal bridge, and
      cupid bowed lips (left) and plagiocephaly (right).
    explanation: >-
      Enumerates the component features of the facial gestalt in the index
      individual.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 3–6 presented with facial dysmorphism, GDD, intellectual
      disability, hypotonia, ataxia, peripheral neuropathy or spasticity, and
      visual and hearing abnormalities with variable penetrance.
    explanation: >-
      Facial dysmorphism recurs beyond the index individual, in individuals 3-6.
  notes: >-
    Bound to the gestalt term rather than to any single component feature.
    Micrognathia (3/8) is recorded in the OMIM clinical synopsis but appears
    nowhere in the cached text, so it is not curated here.
- category: Skeletal
  name: Scoliosis
  description: >-
    Lateral curvature of the spine, the most frequent skeletal finding in the
    OMIM clinical synopsis for this disorder (5 of 9 individuals assessed).
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  notes: >-
    Recorded in the OMIM clinical synopsis for OMIM:619833 (5/9), derived from
    Table 1 of PMID:35108495. That table is not in the extractable text of the
    cached reference and the paper's narrative never mentions scoliosis, so no
    exact-quote evidence item is attached and no `frequency` is asserted. See
    the KNOWLEDGE_GAP discussion "skeletal_phenotype_evidence".
- category: Skeletal
  name: Hip Dysplasia
  description: >-
    Hip dysplasia, with acetabular dysplasia and coxa valga also recorded;
    reported in 3 of 9 individuals assessed in the OMIM clinical synopsis.
  phenotype_term:
    preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  notes: >-
    Source and evidence caveat as for Scoliosis above; no exact-quote evidence
    item is attached.
- category: Skeletal
  name: Pes Cavus
  description: >-
    High-arched foot, a characteristic deformity of chronic length-dependent
    peripheral neuropathy; hammertoe is recorded alongside it.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  notes: >-
    Source and evidence caveat as for Scoliosis above; no exact-quote evidence
    item is attached.
- category: Skeletal
  name: Distal Arthrogryposis
  description: >-
    Congenital distal joint contractures, recorded in a single individual in the
    OMIM clinical synopsis.
  phenotype_term:
    preferred_term: Distal arthrogryposis
    term:
      id: HP:0005684
      label: Distal arthrogryposis
  notes: >-
    Source and evidence caveat as for Scoliosis above; no exact-quote evidence
    item is attached.
- category: Neurologic
  name: Microcephaly
  description: Reduced occipitofrontal head circumference, reported in a subset of individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  notes: >-
    Recorded in the OMIM clinical synopsis for OMIM:619833 (3/6). Not stated in
    the extractable text of PMID:35108495, so no exact-quote evidence item is
    attached and no frequency is asserted.
- category: Neurologic
  name: Thin Corpus Callosum
  description: >-
    Thinning of the corpus callosum on brain MRI, in one individual accompanied
    by a vermis partially shifted off the midline.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a thin corpus callosum with partially shifted vermis,
      ventriculomegaly, periventricular leukomalacia, and delayed myelination,
      while some individuals had normal brain imaging
    explanation: >-
      Thin corpus callosum is listed among the brain imaging findings.
- category: Neurologic
  name: Ventriculomegaly
  description: >-
    Enlargement of the cerebral ventricles; frank hydrocephalus occurred in the
    most severely affected individual.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a thin corpus callosum with partially shifted vermis,
      ventriculomegaly, periventricular leukomalacia, and delayed myelination,
      while some individuals had normal brain imaging
    explanation: >-
      Ventriculomegaly is listed among the brain imaging findings.
- category: Neurologic
  name: Delayed CNS Myelination
  description: Delayed myelination on serial brain MRI, together with periventricular leukomalacia.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a thin corpus callosum with partially shifted vermis,
      ventriculomegaly, periventricular leukomalacia, and delayed myelination,
      while some individuals had normal brain imaging
    explanation: >-
      Delayed myelination is listed among the brain imaging findings.
- category: Neurologic
  name: Periventricular Heterotopia
  description: >-
    Nodular grey-matter heterotopia adjacent to the lateral ventricles, a
    neuronal migration abnormality, reported in a single individual on brain
    MRI. Mechanistically coherent for an adhesion-molecule disorder - NrCAM
    mediates the neuron-glia adhesion that guides radial migration - but the
    single observation does not establish a migration defect as part of this
    disorder.
  phenotype_term:
    preferred_term: Periventricular heterotopia
    term:
      id: HP:0007165
      label: Periventricular heterotopia
  notes: >-
    Recorded in the OMIM clinical synopsis for OMIM:619833 (1/9), derived from
    Table 1 of PMID:35108495. The word "heterotopia" does not appear anywhere in
    the extractable text of the cached reference - the narrative's imaging list
    names thin corpus callosum, ventriculomegaly, periventricular leukomalacia
    and delayed myelination only - so no exact-quote evidence item is attached
    and no frequency is asserted, as for the other Table 1-derived findings.
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Hydrocephalus in the most severely affected individuals, a feature shared
    with the related L1-family disorder caused by L1CAM variants.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 1 and 2 were the most severely affected, including
      hydrocephalus, GDD, failure to thrive, hypotonia, and neuropathy in
      individual 1
    explanation: >-
      Hydrocephalus is documented among the findings of the two most severely
      affected individuals of ten. The sentence attributes the trailing items
      specifically to individual 1, so the count is between 1/10 and 2/10;
      either reading falls in OCCASIONAL (5-29%).
- category: Ophthalmologic
  name: Cataract
  description: >-
    Lens opacity, observed in two of the ten individuals of the founding cohort.
    Nrcam is expressed in the lens and Nrcam-deficient mice develop cataracts
    from disorganization of lens fibres; the authors note that the low observed
    frequency may reflect the young age of most individuals.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      only two individuals in this study (individuals 3 and 8a) exhibited signs
      of cataract on examination; the young age of most individuals described
      should be noted, as cataract may develop over time
    explanation: >-
      Two affected individuals of ten had cataract, which maps to OCCASIONAL
      (5-29%); the same sentence records the ascertainment caveat.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    Optic atrophy is recorded in the OMIM clinical synopsis for this disorder.
    What the founding report's narrative states quotably is broader: an abnormal
    pattern visual-evoked potential in the index individual and abnormal eye
    examinations in some others - consistent with the optic pathway involvement
    Nrcam-null mice show, but not itself naming optic atrophy.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and eye examinations were abnormal in some of the other affected
      individuals
    explanation: >-
      Establishes abnormal ophthalmologic examination across the cohort. It does
      not name optic atrophy specifically, hence PARTIAL.
  notes: >-
    Optic atrophy (1/8), strabismus (2/8) and retinal detachment (1/8) are
    recorded in the OMIM clinical synopsis for OMIM:619833, derived from Table 1
    of PMID:35108495. That table is not in the extractable text of the cached
    reference and none of those three terms appears anywhere in it, so only the
    generic abnormal-eye-examination statement is evidenced here, strabismus and
    retinal detachment are not curated as separate phenotypes, and no frequency
    is asserted.
- category: Auditory
  name: Hearing Impairment
  description: >-
    Hearing abnormality, including abnormal brainstem auditory evoked responses,
    in three of the ten individuals of the founding cohort. Persistence of the
    impairment in humans contrasts with the transient, self-correcting cochlear
    defect of Nrcam-null mice.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, the observed hearing abnormalities in three of the affected
      individuals can be inferred to NRCAM expression in the spiral ganglion
      neurons, cochlear efferent fibers, and cochlear sensory cells within the
      inner ear.
    explanation: >-
      Three of ten affected individuals had hearing abnormalities, i.e. 30%,
      which is the lower bound of FREQUENT (30-79%).
- category: Behavioral
  name: Self-Injurious Behavior
  description: >-
    Behavioural abnormality including irritability, aggression and
    self-injurious behaviour, reported in a subset of individuals.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other behavioral issues—most prominently aggression and self-injury—have
      been described in three individuals in our cohort
    explanation: >-
      Aggression and self-injury in three of the ten individuals of the founding
      cohort, i.e. 30%, which is the lower bound of FREQUENT (30-79%).
- category: Growth
  name: Failure to Thrive
  description: >-
    Poor weight gain in the severely affected infants. Gastrostomy tube feeding
    in infancy is separately recorded in the OMIM clinical synopsis (2/9).
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 1 and 2 were the most severely affected, including
      hydrocephalus, GDD, failure to thrive, hypotonia, and neuropathy in
      individual 1
    explanation: >-
      Failure to thrive documented in the severe end of the phenotype spectrum.
- category: Metabolic
  name: Elevated Creatine Kinase
  description: >-
    Modestly raised serum creatine kinase in the neuropathy-predominant
    phenotype, reflecting chronic neurogenic muscle involvement rather than a
    primary myopathy.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband had an elevated CPK of 722 (Reference range: 55-170 U/L).
    explanation: >-
      Documents the creatine kinase elevation against the reporting
      laboratory's reference interval.
biochemical:
- name: Serum Creatine Kinase
  notes: >-
    Modestly elevated serum creatine kinase in the neuropathy-predominant
    phenotype, consistent with chronic neurogenic muscle involvement rather than
    a primary myopathy. No NCIT biomarker term is bound: NCIT:C113245 (Creatine
    Kinase) names the enzyme rather than a measurement under the Biomarker
    branch used by this slot. The corresponding clinical abnormality is curated
    as the phenotype "Elevated Creatine Kinase" (HP:0003236).
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband had an elevated CPK of 722 (Reference range: 55–170 U/L).
    explanation: >-
      Records the measured creatine kinase elevation together with the
      laboratory's reference interval.
histopathology:
- name: Neurogenic Grouped Fibre Atrophy on Muscle Biopsy
  description: >-
    Deltoid muscle biopsy in the motor-predominant neuropathy phenotype showed
    grouped angular atrophic fibres with basophilic degenerating/regenerating
    fibres and scattered hypertrophied round fibres, and marked type 2 fibre
    atrophy — the pattern of chronic denervation, not of a primary myopathy.
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy at the age of 14 and from the left deltoid showed groups of
      atrophy of angular and some basophilic degenerative/regenerative fibers
      associated with some round hypertrophied fibers
    explanation: >-
      Describes the neurogenic histopathological pattern in an affected
      individual.
genetic:
- name: NRCAM
  gene_term:
    preferred_term: NRCAM
    term:
      id: hgnc:7994
      label: NRCAM
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    NRCAM (7q31.1) encodes neuronal cell adhesion molecule, an L1-family
    Ig-superfamily transmembrane adhesion protein of the canonical 1,304-residue
    isoform with six Ig-like domains, five fibronectin type III repeats, a
    transmembrane segment and a short cytoplasmic tail. Reported disease alleles
    include nonsense (p.Glu111*, p.Arg929*, p.Gln25*), frameshift
    (p.Thr766Ilefs*4), canonical (c.2647-2A>G) and deep-intronic
    (c.230+824G>C) splice variants, and missense substitutions in Ig-like
    domains 1, 2 and 5 (p.Asp55Gly [see the provenance caveat below],
    p.Ser134Pro, p.Gly197Asp, p.Asn469Ser) and
    in the third Fn-III domain (p.Arg853Cys, p.Lys902Thr, p.Gly913Asp). Alleles
    cluster in the third Fn-III domain, whose KGE and RNRR motifs and predicted
    docking surface implicate it as a protein-protein interaction interface.
    Loss-of-function alleles trend toward greater severity, but the second
    reported family shows that a nonsense allele can produce a mild,
    neuropathy-only phenotype, so variant class alone is not predictive.
    Population constraint is consistent with the recessive mechanism: gnomAD
    reports pLI approximately 0 (2.6e-11) with LOEUF 0.64 and observed/expected
    loss-of-function 0.53 (83 observed vs 156.5 expected, LoF Z = 4.99), i.e.
    NRCAM is under selection against loss-of-function alleles but is not
    haploinsufficient - which is what unaffected heterozygous parents require.
    These figures were read directly from the gnomAD GraphQL API on 2026-08-18
    (GRCh38) rather than from a publication, so they carry no evidence item.
    Note also that cDNA coordinates are deliberately not
    asserted for the missense alleles below: the paper's narrative names the
    protein changes, but the per-individual cDNA mapping lives in its Table 2,
    which is not in the extractable text of the cached reference. Each variant
    is therefore keyed on the protein designation that is quotable, with cDNA
    given only for the three alleles whose narrative or abstract states it. One
    allele is an acknowledged exception to that rule: for p.Asp55Gly the
    narrative names only the residue Asp55, in the solvent-exposure list, and
    not the Gly substitution, the Ig-like domain 1 assignment, or the compound
    heterozygosity with c.230+824G>C. Those three details come from Table 2 as
    transcribed in the claude_code deep-research report, and are retained
    because they are internally consistent and independently checkable (c.164
    falls in codon 55; GAC to GGC is Asp to Gly; individual 3 is the
    genome-sequenced individual carrying the deep-intronic allele) - but they
    are DR-sourced, not narrative-sourced, and the attached evidence item is
    scoped to solvent exposure only. The other twelve alleles are keyed on
    designations the narrative or abstract states directly.
    ACMG/AMP clinical significance is likewise not asserted per allele, because
    the original reports' per-variant classifications are table content rather
    than narrative.
  variants:
  - name: p.Asp55Gly
    description: >-
      Missense substitution in the first Ig-like domain, found in compound
      heterozygosity with the deep-intronic c.230+824G>C allele. The residue is
      solvent-exposed. See the genetic notes: the substitution, domain
      assignment and pairing are transcribed from Table 2 via the deep-research
      report rather than from the paper's narrative, which names only the
      residue Asp55.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent
      explanation: >-
        Structural modeling places Asp55 among the solvent-exposed substituted
        residues.
  - name: p.Ser134Pro
    description: >-
      Missense substitution in Ig-like domain 1. The residue is solvent-exposed and the
      substitution changes polarity and/or charge, so it is predicted to perturb
      the electrostatic surface and protein-protein interaction interfaces.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids and states the electrostatic prediction the
        description rests on. Note the source hedges with "most", so the
        polarity/charge claim is an aggregate over the set rather than a
        per-residue assertion.
  - name: p.Gly197Asp
    description: >-
      Missense substitution in Ig-like domain 2. The residue is solvent-exposed and the
      substitution changes polarity and/or charge, so it is predicted to perturb
      the electrostatic surface and protein-protein interaction interfaces.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids and states the electrostatic prediction the
        description rests on. Note the source hedges with "most", so the
        polarity/charge claim is an aggregate over the set rather than a
        per-residue assertion.
  - name: p.Asn469Ser
    description: >-
      Missense substitution in Ig-like domain 5. The residue is solvent-exposed,
      and the paper groups it with the other six under an aggregate electrostatic
      prediction - but that sentence hedges ("most of the amino acid
      substitutions change the polarity and/or charge"), and this substitution is
      the likeliest member of the excluded minority: asparagine and serine are
      both polar and both uncharged, so the change is one of side-chain size and
      hydrogen-bonding geometry (carboxamide to hydroxyl) rather than of polarity
      or charge. The predicted effect on this allele is therefore weaker than for
      its six counterparts.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids, and states the aggregate electrostatic
        prediction that the description argues this particular allele is likely
        excluded from - the source hedges with "most", and asparagine to serine
        changes neither polarity nor charge. Cited here for the solvent-exposure
        finding and as the source of the prediction being qualified, not as
        support for applying that prediction to this substitution.
  - name: p.Arg853Cys
    description: >-
      Missense substitution in the third Fn-III domain. The residue is solvent-exposed and the
      substitution changes polarity and/or charge, so it is predicted to perturb
      the electrostatic surface and protein-protein interaction interfaces.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids and states the electrostatic prediction the
        description rests on. Note the source hedges with "most", so the
        polarity/charge claim is an aggregate over the set rather than a
        per-residue assertion.
  - name: p.Lys902Thr
    description: >-
      Missense substitution in the third Fn-III domain. It sits close to the domain's KGE integrin-recognition and RNRR furin motifs, so it may specifically impair the protein-protein interactions of this domain. The residue is solvent-exposed and the
      substitution changes polarity and/or charge, so it is predicted to perturb
      the electrostatic surface and protein-protein interaction interfaces.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids and states the electrostatic prediction the
        description rests on. Note the source hedges with "most", so the
        polarity/charge claim is an aggregate over the set rather than a
        per-residue assertion.
  - name: p.Gly913Asp
    description: >-
      Missense substitution in the third Fn-III domain. The residue is solvent-exposed and the
      substitution changes polarity and/or charge, so it is predicted to perturb
      the electrostatic surface and protein-protein interaction interfaces.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: missense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The observed missense variants were found to affect either the Ig-like
        domains 1 (p.Ser134Pro), 2 (p.Gly197Asp), and 5 (p.Asn469Ser) or the
        third Fn-III domain (p.Arg853Cys, p.Lys902Thr, and p.Gly913Asp)
      explanation: >-
        Names this substitution and the domain it falls in.
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Based on the obtained structural models, all substituted amino acids
        (Asp55, Ser134, Gly197, Asn469, Arg853, Lys902, and Gly913) appear
        exposed to the solvent (Figures 2andS2). Because most of the amino acid
        substitutions change the polarity and/or charge of the residues, they
        are predicted to affect the protein’s electrostatic balance, thus
        possibly disrupting NRCAM function and interactions.
      explanation: >-
        Structural modeling places this residue among the solvent-exposed
        substituted amino acids and states the electrostatic prediction the
        description rests on. Note the source hedges with "most", so the
        polarity/charge claim is an aggregate over the set rather than a
        per-residue assertion.
  - name: p.Glu111*
    description: >-
      Truncating (nonsense) allele producing a premature stop codon and a
      truncated, non-functional protein.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: nonsense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to
        premature stop-codons, while the c.2647−2A>G splice variant is predicted
        to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating
        the protein product and impeding its function.
      explanation: >-
        States that this allele produces a premature stop codon and truncates
        the protein.
  - name: p.Arg929*
    description: >-
      Truncating (nonsense) allele producing a premature stop codon and a
      truncated, non-functional protein.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: nonsense
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to
        premature stop-codons, while the c.2647−2A>G splice variant is predicted
        to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating
        the protein product and impeding its function.
      explanation: >-
        States that this allele produces a premature stop codon and truncates
        the protein.
  - name: p.Thr766Ilefs*4
    description: >-
      Truncating (frameshift) allele producing a premature stop codon and a
      truncated, non-functional protein.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: frameshift
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to
        premature stop-codons, while the c.2647−2A>G splice variant is predicted
        to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating
        the protein product and impeding its function.
      explanation: >-
        States that this allele produces a premature stop codon and truncates
        the protein.
  - name: c.2647-2A>G (p.Ile883Serfs*8)
    description: >-
      Canonical splice-acceptor variant predicted to cause skipping of exon 22,
      producing a frameshift and a truncated protein.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: splice acceptor
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The p.Arg929∗, p.Glu111∗, and p.Thr766Ilefs∗4 variants clearly lead to
        premature stop-codons, while the c.2647−2A>G splice variant is predicted
        to cause exon 22 skipping resulting in p.Ile883Serfs∗8, thus truncating
        the protein product and impeding its function.
      explanation: >-
        States the predicted exon-22 skipping and resulting frameshift.
  - name: c.230+824G>C
    description: >-
      Deep-intronic variant, invisible to exome sequencing and identified only by
      genome sequencing, predicted to disrupt a binding site for the splicing
      regulator SC35 and to activate a cryptic acceptor site generating a cryptic
      exon.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: deep intronic splice
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        The deep intronic variant observed in individual 3 (c.230+824G>C) is
        predicted to disrupt a site for the splicing regulator SC35, which is
        required for spliceosome assembly and splice-site selection.
      explanation: >-
        States the predicted splicing consequence of this deep-intronic allele.
  - name: c.73C>T (p.Gln25*)
    description: >-
      Homozygous nonsense allele in the N-terminal signal peptide, before the
      first Ig-like domain, reported in the second family. Notable because this
      loss-of-function allele produced the mildest phenotype described -
      isolated motor-predominant axonal polyneuropathy with normal cognition -
      which is what breaks the simple loss-of-function-equals-severe correlation.
    gene:
      preferred_term: NRCAM
      term:
        id: hgnc:7994
        label: NRCAM
    type: nonsense
    evidence:
    - reference: PMID:36606341
      reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome sequencing revealed a homozygous variant, c.73C > T
        (p.Gln25*), in the NRCAM gene, while the patient manifests a mild range
        of phenotypes compared to NRCAM-related disorder.
      explanation: >-
        Identifies the allele and records that it produced a mild phenotype.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      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.
    explanation: >-
      Establishes the Fn-III domain 3 variant cluster and its predicted
      functional consequence.
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although patients with loss of function variants in this gene have
      previously presented severe clinical features, we show that type of the
      pathogenic variant does not necessarily determine the severity of this
      phenotype.
    explanation: >-
      Directly qualifies the genotype-phenotype correlation: a nonsense allele
      produced the mildest reported phenotype.
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the nature and location of each missense variant and their
      resulting effect on protein expression and function may also affect the
      subsequent clinical manifestations.
    explanation: >-
      The authors' own caveat that variant class does not fully determine
      severity.
diagnosis:
- name: Exome or Genome Sequencing
  diagnosis_term:
    preferred_term: exome or genome sequencing
    term:
      id: NCIT:C101293
      label: Next Generation Sequencing
  description: >-
    Molecular diagnosis rests on exome or genome sequencing with Sanger
    confirmation and segregation analysis; there is no biochemical marker. Every
    reported case was ascertained this way, and the founding cohort was
    assembled through GeneMatcher after each family's variant was found
    independently. Genome sequencing was required in one family whose causal
    allele was a deep-intronic splice variant invisible to exome sequencing, and
    runs-of-homozygosity assessment supported the homozygous nonsense allele in
    the second report.
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES), in parallel with WES-based CNV detection and
      assessment of homozygosity runs, was performed to identify this patient's
      possible genetic cause.
    explanation: >-
      Describes the diagnostic strategy that established the molecular
      diagnosis.
- name: Nerve Conduction Studies and Electromyography
  diagnosis_term:
    preferred_term: Electromyography
    term:
      id: NCIT:C38056
      label: Electromyography
  description: >-
    Nerve conduction studies and needle EMG characterize the peripheral nerve
    lesion and establish whether it is axonal or demyelinating. In the second reported case they showed reduced motor CMAP
    amplitudes with preserved velocities and chronic neurogenic changes with
    spontaneous activity, initially suggesting distal spinal muscular atrophy.
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Needle examination showed chronic neurogenic changes and spontaneous
      activity in leg muscles (proximal and distal).
    explanation: >-
      The electrophysiological findings used diagnostically in an affected
      individual.
differential_diagnoses:
- name: L1 Syndrome (L1CAM-related)
  description: >-
    X-linked L1CAM variants cause congenital hydrocephalus and spastic
    paraplegia. The overlap with NEDNMS is mechanistic, not coincidental — both
    genes encode L1-family Ig-CAMs — but the inheritance (X-linked vs autosomal
    recessive) separates them.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variants inL1CAM(MIM:308840) have been implicated in the most common cause
      for X-linked congenital syndromic and non-syndromic hydrocephalus, as well
      as several non-hydrocephalus phenotypes characterized by spastic
      paraplegia
    explanation: >-
      Describes the L1CAM phenotype that overlaps NEDNMS. The gene symbol runs
      together with the surrounding words in the cached text; the quote
      reproduces it verbatim.
- name: NFASC-related neurodevelopmental disorder with central and peripheral motor dysfunction
  description: >-
    Bi-allelic NFASC variants (the neurofascin binding partner of NrCAM at the
    node of Ranvier) cause a phenotypically very similar autosomal recessive
    disorder combining central and peripheral motor dysfunction; the founding
    NRCAM report explicitly draws this parallel.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is also observed in individuals withNFASCvariants, and spastic paraparesis
      is observed in individuals withL1CAMmutations
    explanation: >-
      The founding report names NFASC (and L1CAM) as producing the same variable
      neurological and neuromuscular phenotype. Gene symbols run together with
      the surrounding words in the cached text and are reproduced verbatim.
- name: Charcot-Marie-Tooth disease and distal spinal muscular atrophy
  description: >-
    The mild, neuropathy-only end of the NRCAM spectrum is clinically
    indistinguishable from CMT2/distal hereditary motor neuropathy; the second
    reported patient carried a working diagnosis of distal SMA and had SMN1
    exon 7 deletion excluded before exome sequencing.
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on the primary diagnosis of motor neuropathy or distal spinal
      muscular atrophy, the initial molecular analysis by real‐time PCR and MLPA
      for exon 7 of the SMN1 gene revealed no exon deletion in this patient.
    explanation: >-
      Documents distal SMA as the working differential that had to be excluded
      before the NRCAM diagnosis was made.
- name: Cerebral palsy
  description: >-
    Cerebral palsy is recorded as a feature in the OMIM clinical synopsis for
    OMIM:619833 (3/10) and appears in the abbreviation key of the founding
    report's clinical table, so a clinical label of cerebral palsy preceded the
    genetic diagnosis in some individuals. This is the recurring pattern in
    early-onset genetic spasticity/hypotonia syndromes and makes NEDNMS a
    consideration in "cerebral palsy" of unexplained cause.
  notes: >-
    No exact-quote evidence item is attached. Table 1 of PMID:35108495 is where
    the per-individual detail sits; its abbreviation key ("CP, cerebral palsy")
    survives in the cached text but the data rows do not, and a key is not a
    count.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    No disease-specific or targeted therapy exists. Management is entirely
    supportive: feeding support for failure to thrive, respiratory support in
    the most severely affected infants, and multidisciplinary
    neurodevelopmental follow-up.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  notes: >-
    No pharmacological, gene-therapy, RNA-based or targeted therapy has been
    reported or is in development for this disorder, and no registered clinical
    trial was identified. Gastrostomy tube feeding in infancy is recorded in
    the OMIM clinical synopsis for OMIM:619833 (2/9); as with the skeletal
    phenotypes, that count comes from Table 1 of PMID:35108495 and is not in the
    extractable text of the cached reference, so no evidence item is attached
    and specific interventions are not asserted in the description.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy for hypotonia, spasticity and motor delay,
    with orthoses where walking is limited; the second reported patient
    ambulates with braces.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Neuromuscular Dysfunction
    description: >-
      Physical therapy and orthoses address the functional consequences of the
      neuromuscular node; they do not act on the upstream adhesion defect.
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He also has lordosis and abnormal gait with limitations in walking ability
      (he can walk with braces).
    explanation: >-
      Documents orthotic support preserving ambulation in an affected
      individual. It evidences the use of bracing, not a formal trial of
      physical therapy, hence PARTIAL.
- name: Orthopedic Management of Skeletal Deformity
  description: >-
    Orthopedic surveillance and, where indicated, surgical management of
    scoliosis, hip dysplasia/subluxation and foot deformity, as for other
    early-onset neuromuscular disorders.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Secondary Musculoskeletal Deformity
    description: >-
      Orthopedic management addresses the skeletal deformity node; whether that
      node is truly secondary to neuromuscular loading is itself an open
      question recorded in the skeletal_phenotype_evidence discussion.
  target_phenotypes:
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  - preferred_term: Hip dysplasia
    term:
      id: HP:0001385
      label: Hip dysplasia
  notes: >-
    Inferred standard-of-care management for the documented skeletal phenotype;
    no publication reports orthopedic outcomes in this disorder, so no evidence
    item is attached.
- name: Genetic Counseling
  description: >-
    Counseling for the 25% sibling recurrence risk of an autosomal recessive
    disorder, with carrier testing, prenatal diagnosis and preimplantation
    genetic testing available once the familial variants are known. Particularly
    relevant given the consanguineous and founder families reported.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:36606341
    reference_title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband is a 19‐year‐old male who is the only child of consanguineous
      (first cousin) healthy Iranian parents
    explanation: >-
      Consanguinity in reported families is the specific circumstance that makes
      recurrence-risk counseling and carrier testing relevant.
animal_models:
- name: Nrcam knockout mouse
  species: Mouse
  genotype: Nrcam-null (homozygous knockout)
  description: >-
    Constitutive Nrcam-null mice reproduce the cellular defects of the disorder
    — delayed and abnormal node of Ranvier formation with delayed sodium channel
    clustering, failure of cerebellar granule cells to extend neurites on
    contactin-1, excess dendritic spines with increased mEPSC frequency in
    visual cortex, thalamic axon mistargeting with abnormal visual-evoked
    potentials, lens fibre disorganization with cataract, and transient cochlear
    innervation errors — yet do not develop a neuromuscular disorder and have
    only mildly reduced cerebellar size. The disconnect is the central
    translational caveat for this entry.
  publication: PMID:35108495
  modeled_mechanisms:
  - target: Defective Node of Ranvier Assembly and Maintenance
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Peripheral nerves of Nrcam-deficient mice show delayed or abnormal node
      formation with delayed nodal sodium channel clustering, the same lesion
      proposed to underlie the human peripheral neuropathy.
    limitations: >-
      Node formation is delayed rather than abolished, because gliomedin
      provides a partially redundant glial clustering signal; the severe nodal
      phenotype requires loss of both molecules.
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Nrcam has also been proven integral for formation and maintenance of
        nodes of Ranvier on myelinated axons, and peripheral nerves of
        Nrcam-deficient mice exhibit delayed or abnormal node formation.
      explanation: >-
        Supports treating the Nrcam-null mouse as informative for the nodal
        assembly node.
  - target: Neuromuscular Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Despite the nodal defect, Nrcam-null mice show no neuromuscular disorder,
      in contrast to the hypotonia, spasticity and neuropathy present in every
      reported affected individual.
    limitations: >-
      Probable compensation by other L1-family Ig-CAMs (L1cam, Chl1, Nfasc) in
      mouse, and possible transcriptional adaptation triggered by
      nonsense-mediated decay of the null allele. Species differences in the
      protein itself are also implicated: the KGE and RNRR motifs of the human
      third Fn-III domain are poorly conserved outside mammals.
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, while KO mice have delayed nodes of Ranvier formation and
        subsequently delayed sodium channel clustering at nodes, they do not
        exhibit signs of a neuromuscular disorder.
      explanation: >-
        Explicit negative result: the mouse null does not develop the defining
        neuromuscular phenotype of the human disorder.
  - target: Impaired Synaptogenesis and Dendritic Spine Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      NrCAM-null cortex shows elevated dendritic spine density, increased
      asymmetric synapses and increased mEPSC frequency, establishing NrCAM as a
      postnatal regulator of spine density within the Sema3F receptor complex.
    limitations: >-
      Measured in mouse primary visual cortex; no corresponding measurement
      exists in tissue from affected individuals, so the relevance to the human
      cognitive and behavioural phenotype is inferred.
    readouts:
    - name: Apical dendritic spine density on star pyramidal cells
      target: Impaired Synaptogenesis and Dendritic Spine Remodeling
      direction: INCREASED
      interpretation: >-
        Loss of NrCAM removes Sema3F-dependent spine pruning, raising spine
        density.
      evidence:
      - reference: PMID:25143608
        reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          NrCAM deletion in mice resulted in elevated spine densities on apical
          dendrites of star pyramidal cells at both postnatal and adult stages,
          and electron microscopy revealed increased numbers of asymmetric
          synapses in layer 4 of V1.
        explanation: Reports the spine-density measurement behind this readout.
    - name: Miniature EPSC frequency in star pyramidal neurons
      target: Impaired Synaptogenesis and Dendritic Spine Remodeling
      direction: INCREASED
      interpretation: >-
        Functional correlate of the excess excitatory synapses.
      evidence:
      - reference: PMID:25143608
        reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Whole-cell recordings in cortical slices from NrCAM-null mice revealed
          increased frequency of mEPSCs in star pyramidal neurons.
        explanation: Reports the electrophysiological measurement behind this readout.
    evidence:
    - reference: PMID:25143608
      reference_title: Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings reveal NrCAM as a novel postnatal regulator of dendritic
        spine density in cortical pyramidal neurons, and an integral component
        of the Sema3F receptor complex.
      explanation: >-
        Supports treating the NrCAM-null mouse as informative for the synaptic
        node.
  - target: Sensory Pathway Miswiring
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Nrcam-null mice reproduce the developmental miswiring — thalamic axon
      mistargeting to visual cortex with abnormal VEPs, and cochlear afferent
      and efferent innervation errors — but the cochlear defects self-correct
      and adult auditory acuity is normal, unlike the persistent hearing
      impairment in some affected individuals.
    limitations: >-
      Transient cochlear phenotype with functional recovery by weaning; humans
      appear to lack the compensatory mechanism.
    evidence:
    - reference: PMID:29536590
      reference_title: Neuronal cell adhesion molecule (NrCAM) is expressed by sensory cells in the cochlea and is necessary for proper cochlear innervation and sensory domain patterning during development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Neonatal Nrcam-null cochleae show errors in type II SGN fasciculation,
        reduced efferent innervation, and defects in the stereotyped packing of
        hair and supporting cells.
      explanation: >-
        Supports treating the mouse as informative for the sensory-miswiring
        node, with the transience caveat recorded in limitations.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, while KO mice have delayed nodes of Ranvier formation and
      subsequently delayed sodium channel clustering at nodes, they do not
      exhibit signs of a neuromuscular disorder.
    explanation: >-
      The mouse null is informative for the cellular mechanism but not for the
      organism-level neuromuscular phenotype, hence PARTIAL.
- name: Gliomedin/NrCAM double knockout mouse
  species: Mouse
  genotype: Gldn-null; Nrcam-null double knockout
  description: >-
    Removing both glial nodal adhesion molecules abolishes the glial clustering
    signal entirely and, unlike either single knockout, produces progressive
    disintegration of established nodes — sequential loss of neurofascin-186,
    sodium channels, ankyrin-G and then βIV spectrin, binary node formation and
    dysregulated nodal gap length — with neurological abnormality and slowed
    nerve conduction. It is the model that isolates the consequences of losing
    NrCAM-dependent nodal contact from the redundancy that masks them in the
    single mutant.
  publication: PMID:24719088
  evidence:
  - reference: PMID:24719088
    reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we report that, in contrast to mice that lack either gliomedin or
      NrCAM, 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.
    explanation: >-
      Establishes the model. It is PARTIAL for this disorder because affected
      individuals retain gliomedin, so the double knockout removes more than
      NRCAM loss alone does.
  modeled_mechanisms:
  - target: Peripheral Nerve Conduction Failure and Axonal Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of the gliomedin/NrCAM clustering signal produces measurable slowing
      of nerve conduction and neurological abnormality.
    limitations: >-
      The double knockout removes a redundant partner that is intact in affected
      individuals, so the model overstates the nodal deficit expected from NRCAM
      loss alone; it establishes the direction of the mechanism rather than its
      magnitude in human disease.
    readouts:
    - name: Nerve conduction velocity
      target: Peripheral Nerve Conduction Failure and Axonal Degeneration
      direction: DECREASED
      interpretation: >-
        Functional consequence of nodal disassembly.
      evidence:
      - reference: PMID:24719088
        reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Therefore, these mice exhibit neurological abnormalities and slower
          nerve conduction.
        explanation: Reports the conduction measurement behind this readout.
    evidence:
    - reference: PMID:24719088
      reference_title: Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we report that, in contrast to mice that lack either gliomedin or
        NrCAM, 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.
      explanation: >-
        Establishes the model and the redundancy that motivates using the double
        knockout.
- name: Zebrafish nrcama third Fn-III domain deletion mutant
  species: Zebrafish
  genotype: nrcamaΔ (CRISPR-Cas9 deletion of the third Fn-III domain)
  description: >-
    A CRISPR-Cas9 mutant deleting the third Fn-III repeat — the domain in which
    most human disease variants cluster — generated in the founding study.
    Mutant larvae are viable with no gross morphological defect but show
    significantly altered swimming behaviour and a trend toward increased
    α-tubulin fibre density in the dorsal telencephalon and a thickened anterior
    telencephalic commissure. It is the only in vivo model built around the
    human variant hotspot.
  publication: PMID:35108495
  modeled_mechanisms:
  - target: Aberrant CNS White Matter Tract Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Altered axonal projections in the dorsal telencephalon and anterior
      commissure, the zebrafish counterpart of the mammalian pallium and of the
      commissural tracts abnormal on human MRI.
    limitations: >-
      The axonal differences were reported as trends and did not reach
      significance; the pallium is massively expanded in humans relative to
      zebrafish; and the KGE and RNRR motifs of the human third Fn-III domain
      are not conserved in zebrafish Nrcam (HGD and QDYD), so the deleted domain
      is not functionally equivalent.
    evidence:
    - reference: PMID:35108495
      reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of
        α-tubulin fibers in the dorsal telencephalon, demonstrating an
        alteration in white matter tracts and projections.
      explanation: >-
        Supports the model as informative for white matter tract formation,
        while recording that the finding is a trend.
  evidence:
  - reference: PMID:35108495
    reference_title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain
      revealed that mutant larvae displayed significantly altered swimming
      behavior compared to wild-type larvae (p < 0.03).
    explanation: >-
      The behavioural readout that establishes functional consequence of
      deleting the human variant-hotspot domain in vivo.
discussions:
- discussion_id: skeletal_phenotype_evidence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the mechanism of the skeletal abnormalities that give NEDNMS its
    name, and can the reported frequencies be anchored to quotable primary
    evidence?
  attaches_to:
  - pathophysiology#Secondary Musculoskeletal Deformity
  - pathophysiology#Neuromuscular Dysfunction
  rationale: >-
    The disorder is named for "neuromuscular and skeletal abnormalities", and
    the OMIM clinical synopsis for OMIM:619833 records scoliosis in 5/9, hip
    dysplasia in 3/9, pes cavus in 3/9, plus coxa valga, acetabular dysplasia,
    hammertoe and distal arthrogryposis. Those counts derive from Table 1 of
    PMID:35108495, but that table is not present in the extractable text of the
    cached reference and the paper's narrative and abstract never use the words
    scoliosis, skeletal or contracture — the founding authors frame the disorder
    as neurological and neuromuscular throughout. Two questions follow. First,
    the evidentiary one: the skeletal phenotypes in this entry carry ontology
    terms and provenance notes but no exact-quote evidence items, and cannot be
    given any until a source states them in quotable text. Second, the
    mechanistic one: no cell-autonomous role for NRCAM in bone or cartilage has
    been described, so the skeletal findings are modeled here as secondary to
    chronic abnormal loading from hypotonia, spasticity and neurogenic
    weakness. That inference is plausible for scoliosis, hip subluxation and
    cavus foot — all standard sequelae of early-onset neuromuscular disease —
    but distal arthrogryposis implies a prenatal akinesia sequence rather than
    postnatal loading, and the disorder's own name asserts a prominence the
    primary literature does not argue for.
  proposed_experiments:
  - experiment_id: skeletal_phenotyping_cohort
    name: Systematic skeletal phenotyping of a larger NRCAM cohort
    description: >-
      Prospectively collect standing spine radiographs, hip imaging and foot
      examination on all molecularly confirmed individuals, scored alongside
      motor function (GMFCS or equivalent) and tone, and report the results in
      a citable narrative rather than a table alone. This would both anchor the
      frequencies and test whether skeletal severity tracks neuromuscular
      severity, as the secondary-loading model predicts.
  - experiment_id: nrcam_skeletal_cell_autonomy
    name: Test for cell-autonomous NRCAM function in skeletal tissue
    description: >-
      Assay NRCAM expression in growth plate chondrocytes, osteoblasts and
      tendon, and compare skeletal phenotype in a conditional
      neural-lineage-restricted Nrcam knockout against the constitutive null. A
      neural-restricted null that still produces skeletal deformity would
      support the secondary-loading model; a difference between the two would
      indicate a direct skeletal role.
- discussion_id: mouse_null_neuromuscular_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why do Nrcam-null mice show the cellular lesions of this disorder — delayed
    node of Ranvier formation, failed neurite outgrowth, excess dendritic
    spines, thalamic axon mistargeting — without developing the neuromuscular
    disorder that is present in every affected human?
  attaches_to:
  - pathophysiology#Neuromuscular Dysfunction
  - pathophysiology#Defective Node of Ranvier Assembly and Maintenance
  rationale: >-
    This is a mismatch of translational validity rather than a gap in evidence:
    the mouse data exist and are consistent, but the organism-level phenotype
    does not follow. Three explanations are on the table, and they are not
    mutually exclusive. (1) Redundancy within the L1-family Ig-CAMs: L1cam,
    Chl1 and Nfasc could substitute in mouse, and at the node gliomedin
    provides a partially redundant glial clustering signal — consistent with
    the observation that only the gliomedin/NrCAM double knockout produces node
    disintegration with slowed conduction. (2) Transcriptional adaptation
    triggered by nonsense-mediated decay of the null transcript, the mechanism
    invoked to explain phenotypic discrepancies between complete-gene knockouts
    and other disruptions of the same gene; notably, the first L1cam knockout
    mice were also mild until moved to a different genetic background. (3) True
    species divergence in the protein: the KGE integrin-recognition and RNRR
    furin motifs of the human third Fn-III domain — the human variant hotspot —
    are poorly conserved in zebrafish Nrcam, and the zebrafish domain-deletion
    mutant is correspondingly mild. Distinguishing these matters practically,
    because it determines whether any mouse model can serve as a preclinical
    platform for this disorder.
  proposed_experiments:
  - experiment_id: l1_family_compound_mutants
    name: L1-family compound mutants and genetic background sensitization
    description: >-
      Generate Nrcam-null mice compound with heterozygous or conditional loss of
      L1cam, Chl1 and Nfasc, and cross the Nrcam null onto additional inbred
      backgrounds, testing whether a neuromuscular phenotype emerges. A positive
      result supports redundancy or background modification over species
      divergence.
  - experiment_id: fn3_missense_knockin
    name: Knock-in of human-equivalent Fn-III domain 3 missense alleles
    description: >-
      Rather than a null, knock in the mouse equivalents of p.Arg853Cys,
      p.Lys902Thr and p.Gly913Asp. If a missense allele that escapes
      nonsense-mediated decay produces a neuromuscular phenotype where the null
      does not, transcriptional adaptation is implicated.
  - experiment_id: ipsc_motor_neuron_schwann_coculture
    name: Human iPSC-derived motor neuron and Schwann cell co-culture
    description: >-
      Differentiate patient-derived and isogenic-corrected iPSCs into motor
      neurons co-cultured with Schwann cells, and quantify node of Ranvier
      assembly and sodium channel clustering. This tests the nodal mechanism in
      human cells, bypassing the species question entirely.
references:
- reference: PMID:35108495
  title: Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.
- reference: PMID:36606341
  title: Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.
- reference: PMID:38274568
  title: Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies.
- reference: PMID:11728309
  title: Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier.
- reference: PMID:18588951
  title: Abnormal axonal guidance and brain anatomy in mouse mutants for the cell recognition molecules close homolog of L1 and NgCAM-related cell adhesion molecule.

📚

References & Deep Research

References

5

PMID:35108495

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

No top-level findings curated for this source.

PMID:36606341

Bi-allelic loss of function variant in the NRCAM gene is associated with motor-predominant axonal polyneuropathy; the second report.

No top-level findings curated for this source.

PMID:38274568

Novel and nano-rare genetic causes of paediatric-onset motor neuronopathies.

No top-level findings curated for this source.

PMID:11728309

Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier.

No top-level findings curated for this source.

PMID:18588951

Abnormal axonal guidance and brain anatomy in mouse mutants for the cell recognition molecules close homolog of L1 and NgCAM-related cell adhesion molecule.

No top-level findings curated for this source.

Deep Research

2

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-sonnet-5 14 citations 2026-08-18T15:11:17.233395

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:

Phenotype	Frequency in cohort	Suggested HPO term
Global developmental delay / intellectual disability	80% (8/10); one individual unaffected cognitively	HP:0001263 / HP:0001249
Hypotonia (axial and/or peripheral)	70% (7/10)	HP:0001252
Spasticity / hypertonia (incl. spastic quadriplegia/paraplegia)	50% (5/10)	HP:0001257 / HP:0002510
Peripheral (demyelinating) neuropathy	60–70% (6-7/10); sole finding in mildest cases	HP:0000762 / HP:0003701
Ataxia	present in subset	HP:0001251
Microcephaly	30% (3/10)	HP:0000252
Seizures	1 individual	HP:0001250
Scoliosis	multiple individuals	HP:0002650
Hip dysplasia/dislocation	multiple individuals	HP:0001385
Pes cavus / pes planus	present	HP:0001761 / HP:0001763
Distal arthrogryposis / contractures	present	HP:0005684
Dysmorphic facial features (bitemporal narrowing, bushy/medially flared eyebrows, long eyelashes, depressed nasal bridge, cupid-bow lips, micrognathia, plagiocephaly)	~70%	HP:0000316 / HP:0000426 / HP:0000348
Optic atrophy	subset	HP:0000648
Strabismus / exotropia	subset	HP:0000577
Cataract, retinal detachment, abnormal VEP	subset	HP:0000518 / HP:0000541
Sensorineural/abnormal auditory evoked responses	3/10	HP:0008619
Hydrocephalus / ventriculomegaly	variable	HP:0000238 / HP:0002119
Thin/agenetic corpus callosum, delayed myelination, periventricular leukomalacia, gray matter heterotopia	variable, some with normal imaging	HP:0002079 / HP:0002188
Self-injurious/behavioral abnormalities (irritability, anxiety, aggression)	3 individuals	HP:0100716
Failure to thrive / growth restriction	present	HP:0001508
Cryptorchidism	present	HP:0000028

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):

Individual	cDNA	Protein	Zygosity	Domain
1	c.2785C>T	p.Arg929*	Homozygous	Fn-III domain 3
2	c.331G>T	p.Glu111*	Homozygous	Ig-like domain 1
3	c.164A>G; c.230+824G>C	p.Asp55Gly; splice	Compound het	Ig-like 1; intron 6
4	c.2557C>T; c.2705A>C	p.Arg853Cys; p.Lys902Thr	Compound het	Fn-III 3 (both)
5	c.1406A>G; c.2738G>A	p.Asn469Ser; p.Gly913Asp	Compound het	Ig-like 5; Fn-III 3
6a/6b	c.590G>A	p.Gly197Asp	Homozygous	Ig-like 2
7	c.2297_2302delinsTC; c.2647-2A>G	p.Thr766Ilefs*4; splice	Compound het	Fn-III 2; intron 24
8a/8b	c.400T>C	p.Ser134Pro	Homozygous	Ig-like 1

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

Category	Suggested terms
Disease	OMIM:619833; gene OMIM:601581; MONDO ID to be confirmed via `runoak -i sqlite:obo:mondo`
Gene	hgnc:7994 (NRCAM)
Phenotypes (HP)	HP:0001263, HP:0001249, HP:0001252, HP:0001257, HP:0000762, HP:0001251, HP:0000252, HP:0001250, HP:0002650, HP:0001385, HP:0001761, HP:0005684, HP:0000648, HP:0000577, HP:0000238, HP:0002079, HP:0100716, HP:0001508
GO (biological process)	GO:0007155, GO:0007411, GO:0031175, GO:0007416
GO (cellular component)	GO:0033268, GO:0045202, GO:0005886
CL	CL:0000540 (neuron), CL:0002573 (Schwann cell)
UBERON	UBERON:0000955, UBERON:0000010, UBERON:0002336, UBERON:0000940
NCIT (treatment)	NCIT:C15747, NCIT:C15329, NCIT:C16186, NCIT:C15302, NCIT:C15315, NCIT:C15240

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

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	4
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Unresolved (possible confabulation)	0
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OpenScientist ▸

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

openscientist-autonomous 9 citations 2026-08-18T15:22:38.590722

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:

Phenotype types: clinical signs (hypotonia, spasticity, neuropathy), developmental/behavioral (developmental delay, intellectual disability, self-injurious/aggressive behavior), physical/skeletal manifestations (scoliosis, hip dysplasia, pes cavus, hammertoe, distal arthrogryposis, micrognathia, microcephaly), and neuroimaging abnormalities (thin corpus callosum, ventriculomegaly, delayed myelination, periventricular heterotopia).
Age of onset: congenital/neonatal (hypotonia, structural anomalies) to early childhood (developmental delay).
Severity: variable (mild to severe), not strictly predicted by variant type (Elahi 2023).
Progression: largely static/stable neurodevelopmental course; peripheral neuropathy may be slowly progressive.
Quality-of-life impact: substantial — motor and cognitive impairment, feeding difficulty (G-tube in ~22%), and orthopedic disability affect daily functioning and independence. Formal QoL instrument data (EQ-5D/SF-36/PROMIS) are not available for this ultra-rare disorder.

4. Genetic/Molecular Information

Causal gene: NRCAM (HGNC:7994; NCBI Gene 4897; gene OMIM 601581; 7q31.1; ENSG00000091129; canonical ENST00000379028).
Protein: NrCAM, UniProt Q92823, 1,304 aa, type-I transmembrane; 6 Ig-like domains (aa 46–632), 5 Fn-III domains (aa 649–1156); the 3rd Fn-III domain (~aa 848–950) is a missense hotspot (Finding 5).
Variant classes: nonsense (e.g., c.73C>T p.Gln25*), other loss-of-function, and deleterious missense (clustered in Fn-III #3). ClinVar: 289 records, 38 pathogenic/likely-pathogenic.
Functional consequence: loss of function (recessive). gnomAD constraint (pLI ≈ 0; LOEUF 0.636; oe_LoF 0.53) confirms NRCAM is not haploinsufficient — disease requires biallelic hits (Finding 3).
Allele frequency: individual pathogenic alleles are private/ultra-rare in gnomAD.
Origin: germline (inherited, recessive). No somatic disease role in this Mendelian phenotype (though somatic/epigenetic NRCAM dysregulation is separately implicated in gliomas and colorectal cancer — see Evidence Base; this is unrelated to NEDNMSA).
Modifier genes / epigenetics / chromosomal abnormalities: not reported for NEDNMSA.

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

Upstream: loss of NrCAM adhesion; failure of the gliomedin–NF186–NrCAM glial clustering signal.
Downstream: ankyrin-G / Na⁺-channel declustering → conduction failure; axon-guidance/synaptic defects → structural brain anomalies.
Cell types (CL terms): neurons (CL:0000540), myelinating Schwann cells (CL:0002573), oligodendrocytes (CL:0000128), hypothalamic tanycytes (Moore 2022).
Biological processes (GO terms): node of Ranvier assembly / GO:0033268; axon guidance / GO:0007411; cell adhesion / GO:0007155; myelination / GO:0042552; neuron projection development / GO:0031175; regulation of sodium ion transmembrane transport.
Subcellular compartments (GO CC): node of Ranvier (GO:0033268), axon initial segment (GO:0043194), plasma membrane (GO:0005886), paranode region of axon (GO:0033270).
Molecular pathways: L1-family cell-adhesion/axon-guidance signaling; ankyrin-G/βIV-spectrin cytoskeletal scaffolding. (NrCAM is also a Wnt-pathway target in cancer contexts — not relevant to NEDNMSA pathogenesis.)
Metabolic / immune involvement: not implicated.

7. Anatomical Structures Affected

Organ level (UBERON): brain (UBERON:0000955), peripheral nervous system / peripheral nerve (UBERON:0000010, UBERON:0001021), spinal cord (UBERON:0002240); secondary: skeletal system — vertebral column (UBERON:0001130), hip joint (UBERON:0001464), foot (UBERON:0002387); eye (UBERON:0000970).
Body systems: nervous (central + peripheral), musculoskeletal, ophthalmologic.
Tissue/cell level: nervous tissue, skeletal muscle (secondary, via denervation/hypotonia), connective/skeletal tissue; targeted cells — neurons, Schwann cells, oligodendrocytes (Findings 2, 4).
Subcellular: node of Ranvier, axon initial segment, axolemma (Finding 2).
Specific sites / lateralization: corpus callosum (UBERON:0002336), lateral ventricles (ventriculomegaly), cerebellar vermis (UBERON:0004720), periventricular zone; anomalies are typically bilateral/symmetric where reported.

8. Temporal Development

Onset: congenital / neonatal (hypotonia, structural anomalies) to early-childhood (developmental delay); onset pattern is chronic/insidious, not acute.
Progression: neurodevelopmental features are largely static; peripheral neuropathy and orthopedic features (e.g., scoliosis) may be slowly progressive. No defined disease stages.
Course: chronic, lifelong. No remission. Severity variable and not determined by variant type (Finding 7).
Critical periods: prenatal/early-postnatal neurodevelopment (axon guidance, myelination) is the window of vulnerability; no proven intervention window exists.

9. Inheritance and Population

Epidemiology: prevalence and incidence unknown (ultra-rare; ~11 reported individuals; no registry).
Inheritance: autosomal recessive; biallelic homozygous or compound-heterozygous NRCAM variants (Findings 1, 3).
Penetrance: presumed high/complete in biallelic carriers (all reported biallelic individuals affected), though small n limits certainty.
Expressivity: variable (severity independent of variant type; Finding 7).
Anticipation / mosaicism: not reported / not applicable (no repeat expansion).
Founder effects: none established; consanguinity is a recurring factor (multiple homozygous families).
Carrier frequency: not formally estimated; heterozygous LoF alleles are tolerated per gnomAD constraint (Finding 3).
Demographics: no ethnic predilection established; the small cohort spans multiple families/populations. Sex ratio not established (expected ~1:1 for autosomal recessive). Age distribution: pediatric at ascertainment.

10. Diagnostics

Genetic testing (primary): trio-based whole-exome (WES) or whole-genome sequencing (WGS) is the diagnostic gold standard; targeted NRCAM analysis / neurodevelopmental gene panels can confirm. Chromosomal microarray/karyotype are typically normal (this is a sequence-level disorder, not a CNV syndrome).
Electrophysiology: EMG/nerve conduction studies documenting axonal and/or demyelinating peripheral neuropathy (Finding 7).
Imaging: brain MRI — thin corpus callosum, ventriculomegaly, delayed myelination, periventricular heterotopia (Findings 6, 7).
Laboratory/biomarkers: no specific biochemical biomarker; diagnosis rests on genotype + phenotype.
Clinical criteria: no formal consensus criteria; diagnosis is molecular + clinical gestalt.
Differential diagnosis: other autosomal-recessive neurodevelopmental syndromes with neuropathy/spasticity and skeletal features (e.g., L1CAM-spectrum disorders, other L1-family conditions, hereditary motor-sensory neuropathies with CNS involvement, arthrogryposis-associated neurodevelopmental disorders). Molecular testing distinguishes them.
Screening: no population newborn screening; cascade carrier testing of at-risk relatives is appropriate once a familial variant is known.

11. Outcome/Prognosis

Survival/mortality: no disease-specific mortality data; the disorder is not reported as lethal in childhood, but survival statistics are unavailable (n too small).
Morbidity/function: significant lifelong disability driven by intellectual disability, motor impairment, neuropathy/spasticity, feeding difficulty, and orthopedic complications (scoliosis, hip dysplasia).
Complications: feeding failure/failure-to-thrive (G-tube ~22%), orthopedic deterioration, contractures, visual impairment (cataract/optic atrophy/retinal detachment).
Recovery potential: none (structural/developmental); supportive care can improve function.
Prognostic factors: severity is variable and not predicted by variant type (Finding 7); no validated prognostic biomarkers.

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):

Supportive/rehabilitative (NCIT-type interventions): physical therapy (NCIT:C15216), occupational therapy, speech therapy; nutritional support / gastrostomy feeding for failure-to-thrive.
Symptomatic pharmacotherapy: antispasticity agents (e.g., baclofen) for spasticity; standard management of seizures/behavioral symptoms as needed (no disorder-specific evidence).
Surgical/interventional: orthopedic correction of scoliosis, hip dysplasia, and foot deformities; ophthalmologic surgery (e.g., cataract, retinal detachment) as indicated.
Pharmacogenomics / personalized medicine: not applicable / not developed.

13. Prevention

Primary prevention: none for the genetic cause; genetic counseling for consanguineous or carrier families.
Secondary/tertiary prevention: early developmental intervention; surveillance for and management of scoliosis, hip dysplasia, feeding, and ophthalmologic complications.
Genetic screening: carrier testing, cascade screening, and prenatal/preimplantation genetic diagnosis available once a familial variant is identified.
Public health / immunization / behavioral / prophylaxis: not applicable.

14. Other Species / Natural Disease

Taxonomy / orthologs (Finding 8): mouse Nrcam (Gene 319504; txid10090), rat Nrcam (Gene 497815; txid10116), zebrafish nrcama (Gene 556537; txid7955; paralog nrcamb). NrCAM is an L1-family CAM (paralogs L1CAM, CHL1, NFASC).
Natural disease in other species: no naturally occurring NRCAM-equivalent disorder is catalogued (e.g., in OMIA) — the disease is known only from engineered/experimental models, not spontaneous animal disease.
Comparative biology: node-of-Ranvier assembly and NrCAM function are highly evolutionarily conserved across mammals and teleosts, validating cross-species modeling.
Zoonotic potential: not applicable (genetic disorder).

15. Model Organisms

Mouse (Mus musculus, MGI): Nrcam-null mice — disturbed olfactory-nerve axon guidance, altered ventricular-system and cerebellar-vermis size (Heyden 2008); tanycyte differentiation/neurogenesis defects (Moore 2022); combined gliomedin+NrCAM loss — node disintegration, conduction slowing (Amor 2014). Recapitulation: good for axon-guidance, brain-structural, and nodal/conduction phenotypes.
Zebrafish (Danio rerio, ZFIN): nrcama loss-of-function used to corroborate the human gene–disease link (Kurolap 2022).
In vitro: murine Nrcam-deficient cells — abnormal neurite outgrowth, synaptogenesis, and node-of-Ranvier formation (Finding 4).
Model types available: knockout mice; morphant/mutant zebrafish; primary neuronal cultures. Humanized/conditional/iPSC-organoid models are not yet reported for this disorder.
Limitations: models capture axonal/nodal and brain-structural biology but not the full human skeletal spectrum; small human cohort limits genotype–phenotype validation.

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

Extremely small evidence base (~11 individuals). All human phenotype frequencies derive from ≤10 patients; percentages are indicative, not population estimates.
No epidemiology. Prevalence, incidence, carrier frequency, sex ratio, and geographic distribution are unknown; no Orphanet code or registry exists.
No natural-history or QoL data. Progression rate, life expectancy, and validated QoL metrics are undefined.
Genotype–phenotype correlation unresolved. Severity is not predicted by variant type, but the sample is too small to establish modifiers.
No disease-specific therapy or trials. Management is empirical/supportive.
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.
Ontology mapping incomplete. No dedicated ICD-11/MeSH/Orphanet identifiers.

Proposed Follow-up Experiments / Actions

International matchmaking (GeneMatcher, Matchmaker Exchange) to expand the cohort, refine phenotype frequencies, and enable genotype–phenotype analysis.
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.
Patient-derived iPSC neurons/organoids and myelinating co-cultures to model node assembly and conduction deficits in a human context.
Conditional / knock-in mouse models carrying human missense alleles to test genotype-specific severity and evaluate rescue.
Systematic natural-history study (developmental, EMG/NCS, MRI, orthopedic, ophthalmologic surveillance) with standardized QoL instruments.
Apply for Orphanet/ICD-11 codes and establish a patient registry to support future epidemiology and trials.
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.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	3
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:11728309 (6 mentions) - Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier.
shared terms: node, conduction

Weighed against this report's own most characteristic terms: nrcam, variant, type, disorder, gene, phenotype, recessive, human, clinical, neuropathy, peripheral, disease, model, developmental, spasticity, node, genetic, conduction, severity, skeletal.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions for KB Curation

Citation Note and Limitations

Reference Validation

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

Summary

Key Findings

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

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

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

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

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

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

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

Finding 8 — Evolutionary conservation and orthologs

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

References that may not be about this subject