Neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD; OMIM:618356) is an ultra-rare autosomal recessive nodopathy caused by bi-allelic variants in NFASC, which encodes neurofascin, an L1-family immunoglobulin-superfamily cell adhesion molecule. Alternative splicing of NFASC gives a glial isoform (NF155), the myelin-side partner of the axonal contactin-1/CASPR1 complex at the paranodal axoglial junction, and neuronal isoforms (NF186 and NF140) that cluster voltage-gated sodium channels at the node of Ranvier and stabilise the axon initial segment. Most reported variants impair NF155, which disrupts the paranodal junction. Affected children present with neonatal or early-infantile hypotonia, severe global developmental delay, intellectual disability, absent or minimal speech, weakness with areflexia, and in many cases an early-onset demyelinating peripheral neuropathy with slow nerve conduction and loss of large myelinated fibres. Brain MRI shows cerebral white matter loss with corpus callosum and brainstem atrophy in the more severe cases, or cerebellar atrophy. A small number of families carry variants that spare NF155 but abolish full-length NF186 or reduce total neurofascin; their disease is dominated by a progressive cerebellar ataxia with milder cognitive involvement. Fewer than twenty affected individuals have been reported, and no disease-modifying treatment exists.
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Conditions with similar clinical presentations that must be differentiated from Neurodevelopmental Disorder with Central and Peripheral Motor Dysfunction:
name: Neurodevelopmental Disorder with Central and Peripheral Motor Dysfunction
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
synonyms:
- NEDCPMD
- NFASC-related neurodevelopmental disorder
- neurofascin deficiency
description: >-
Neurodevelopmental disorder with central and peripheral motor dysfunction
(NEDCPMD; OMIM:618356) is an ultra-rare autosomal recessive nodopathy caused
by bi-allelic variants in NFASC, which encodes neurofascin, an L1-family
immunoglobulin-superfamily cell adhesion molecule. Alternative splicing of
NFASC gives a glial isoform (NF155), the myelin-side partner of the axonal
contactin-1/CASPR1 complex at the paranodal axoglial junction, and neuronal
isoforms (NF186 and NF140) that cluster voltage-gated sodium channels at the
node of Ranvier and stabilise the axon initial segment. Most reported
variants impair NF155, which disrupts the paranodal junction. Affected
children present with neonatal or early-infantile hypotonia, severe global
developmental delay, intellectual disability, absent or minimal speech,
weakness with areflexia, and in many cases an early-onset demyelinating
peripheral neuropathy with slow nerve conduction and loss of large myelinated
fibres. Brain MRI shows cerebral white matter loss with corpus callosum and
brainstem atrophy in the more severe cases, or cerebellar atrophy. A small
number of families carry variants that spare NF155 but abolish full-length
NF186 or reduce total neurofascin; their disease is dominated by a
progressive cerebellar ataxia with milder cognitive involvement. Fewer than
twenty affected individuals have been reported, and no disease-modifying
treatment exists.
disease_term:
preferred_term: neurodevelopmental disorder with central and peripheral motor dysfunction
term:
id: MONDO:0032698
label: neurodevelopmental disorder with central and peripheral motor dysfunction
parents:
- Neurodevelopmental Disorder
- Peripheral Neuropathy
notes: >-
No GeneReviews chapter exists for this disorder; a PubMed search for NFASC or
neurofascin restricted to genereviews[book] returned no records (2026-10-15).
HPO has no term for auditory neuropathy spectrum disorder; an OLS search of
HP for "auditory neuropathy" returned no results (2026-10-15), so that
phenotype is bound to Hearing impairment with the specific finding carried in
preferred_term.
The two isoform-selective genotypes are recorded as has_subtypes rows rather
than separate entries: MONDO and OMIM treat the NFASC disease as one entity,
and the number of reported families (one or two per isoform class) is too
small to establish distinct first-line management.
has_subtypes:
- name: NF155-predominant
display_name: NF155 (glial isoform)-predominant NFASC disease
description: >-
Variants that abolish or destabilise the glial NF155 isoform, including the
NF155-specific nonsense variant p.Arg831Ter in the third fibronectin type
III repeat, the frameshift p.Pro939Ter, and missense variants in the
fibronectin type III repeats. Neuronal NF186 is preserved at the node. This
is the common presentation: neonatal hypotonia, severe developmental delay,
areflexia and demyelinating neuropathy with loss of the paranodal junction.
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variant creates a premature stop codon in 3 out of four NFASC human
transcripts and is predicted to specifically eliminate Nfasc155 leaving
neuronal Neurofascin intact.
explanation: >-
Defines the isoform-selective genotype: a variant that removes the glial
isoform and spares the neuronal one.
- name: NF186-predominant
display_name: NF186 (neuronal isoform)-predominant NFASC disease
description: >-
Variants that abolish full-length neuronal NF186 (the exon 26 splice
acceptor variant c.3020-1G>A) or reduce total neurofascin through a
transmembrane-domain missense variant (p.Val1122Glu). The presentation is a
childhood-onset, progressive cerebellar ataxia with dysarthria, nystagmus
and weakness, normal or near-normal cognition in some individuals, and
normal or only mildly slowed nerve conduction.
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified a novel homozygous splice mutation (c.3020-1G > A) in
neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the
mutation resulted in inframe skipping of exon 26, with a deprived
expression of the full-length transcript that corresponds to NFASC
isoform NF186.
explanation: >-
Defines the neuronal-isoform genotype: selective loss of full-length
NF186.
inheritance:
- name: Autosomal recessive
description: >-
All reported individuals carry homozygous NFASC variants, mostly from
consanguineous or founder families; heterozygous parents are unaffected.
Expressivity varies with which isoform the variant affects, from a severe
infantile neurodevelopmental disorder with demyelinating neuropathy to a
childhood-onset ataxia with mild cognitive involvement.
inheritance_term:
preferred_term: autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
expressivity: VARIABLE
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who were found by exome or genome sequencing to carry one frameshift and
four different homozygous non-synonymous variants in NFASC
explanation: >-
The largest case series reports homozygous NFASC variants in all ten
affected individuals from six families.
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A family study using amplicon deep sequencing (ADS) and Sanger
sequencing confirmed the homozygosity for rs755160624 in the proband and
showed the heterozygous carrier status of her healthy parents
explanation: >-
Homozygous proband with healthy heterozygous parents, consistent with
autosomal recessive inheritance.
pathophysiology:
- name: Bi-allelic NFASC Loss of Function
description: >-
Homozygous NFASC variants (nonsense, frameshift, splice and missense)
remove or reduce one or more neurofascin isoforms. Which isoform is lost
depends on where the variant lies relative to the alternatively spliced
exons, and that determines which of the two downstream branches dominates.
biological_scale: MOLECULAR
genes:
- preferred_term: NFASC
term:
id: hgnc:29866
label: NFASC
molecular_functions:
- preferred_term: cell adhesion molecule binding
term:
id: GO:0050839
label: cell adhesion molecule binding
modifier: DECREASED
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:30850329
reference_title: "Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This mutation, affecting a highly conserved hydrophobic transmembrane
domain residue, led to significant loss of Neurofascin protein in the
iPSC-derived neurons of affected siblings.
explanation: >-
A homozygous missense variant reduces neurofascin protein in
patient-derived neurons, a loss-of-function mechanism.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Cell aggregation studies revealed a severely impaired
Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified
variants.
explanation: >-
Patient variants impair neurofascin binding to its adhesion partners
contactin-1 and CASPR1, which grounds the cell adhesion molecule binding
activity recorded as decreased on this node.
downstream:
- target: Loss of Glial Neurofascin-155
causal_link_type: DIRECT
- target: Loss of Neuronal Neurofascin-186
causal_link_type: DIRECT
- name: Loss of Glial Neurofascin-155
description: >-
Variants in the NF155-specific exons, or missense variants that destabilise
the protein, remove NF155 from the surface of myelinating Schwann cells and
oligodendrocytes. Several missense variants also abolish NF155 binding to
its axonal partners contactin-1 and CASPR1.
biological_scale: MOLECULAR
subtypes:
- NF155-predominant
cell_types:
- preferred_term: myelinating Schwann cell
term:
id: CL:0000218
label: myelinating Schwann cell
- preferred_term: oligodendrocyte
term:
id: CL:0000128
label: oligodendrocyte
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The selective absence of Nfasc155 and disruption of the paranodal junction
was confirmed by an immunofluorescent study of skin biopsies from the
patient versus control.
explanation: >-
Patient skin nerve fibres lack NF155 at the paranode.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Both p.P705T and p.P939Ter variants abolished the interaction between
Nfasc155 and CNTN1/CASPR1, indicating that these variants impact
Nfasc155 function
explanation: >-
Cell aggregation assays show patient variants abolish NF155 binding to
the contactin-1/CASPR1 complex.
downstream:
- target: Paranodal Axoglial Junction Disruption
causal_link_type: DIRECT
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hence, the loss of Caspr at the paranodes in the proband confirmed the
disruption of the axoglial complex as a result of the absence of
Nfasc155 in the proband
explanation: >-
Absence of NF155 leads to loss of its axonal partner CASPR1 from the
paranode, i.e. the junction fails to form.
- name: Paranodal Axoglial Junction Disruption
description: >-
Without NF155 the septate-like junction that anchors the myelin loops to
the axon on either side of the node does not assemble; CASPR1 and
contactin-1 are lost from the paranode. The junction is needed to segregate
nodal sodium channels from juxtaparanodal potassium channels and to support
myelin attachment and the migration of myelinating processes along the
axon.
biological_scale: CELLULAR
biological_processes:
- preferred_term: paranodal junction assembly
term:
id: GO:0030913
label: paranodal junction assembly
modifier: DECREASED
cellular_components:
- preferred_term: paranodal junction
term:
id: GO:0033010
label: paranodal junction
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CASPR1 immunoreactivity was completely absent in the paranodal regions
explanation: >-
Skin biopsy of a patient homozygous for the NF155-abolishing frameshift
shows complete loss of paranodal CASPR1.
- reference: PMID:16337912
reference_title: "Neurofascins are required to establish axonal domains for saltatory conduction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Transgenic expression of Nfasc155 in the myelinating glia of Nfasc-/-
nerves rescues the axoglial adhesion complex by recruiting the axonal
proteins Caspr and Contactin to the paranodes.
explanation: >-
In mice, glial NF155 is necessary and sufficient to recruit CASPR1 and
contactin to the paranode.
downstream:
- target: Peripheral Myelinated Fibre Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There was, however, a severe alteration of the paranode as showed by
the complete absence of the CASPR1, the physiological ligand of
Nfasc155, and a severe effect on myelination and/or maintenance of
myelin and survival of large fibres, which appears to be
length-dependent.
explanation: >-
Paranodal disruption accompanies a length-dependent loss of large
myelinated fibres in patient skin nerves.
- reference: PMID:19185024
reference_title: "Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the absence of glial Nfasc(NF155), paranodal axoglial junctions fail
to form, axonal domains fail to segregate, and myelinated axons undergo
degeneration.
explanation: >-
Glia-specific NF155 knockout mice show that loss of the paranodal
junction is followed by degeneration of myelinated axons.
- target: Impaired Saltatory Conduction
causal_link_type: DIRECT
evidence:
- reference: PMID:19185024
reference_title: "Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Electrophysiological measurements of peripheral nerves from
Nfasc(NF155) mutants revealed dramatic reductions in nerve conduction
velocities.
explanation: >-
Loss of the glial isoform alone is enough to slow peripheral nerve
conduction in mice.
- target: Central White Matter Loss
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:18573915
reference_title: "Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, the Nfasc155 adhesion complex has an additional function in
promoting the migration of myelinating processes along CNS axons.
explanation: >-
In the mouse CNS the NF155 adhesion complex is needed for oligodendrocyte
myelinating processes to extend along axons, a plausible route from
paranodal failure to central white matter loss.
- name: Loss of Neuronal Neurofascin-186
description: >-
Variants that remove full-length NF186 (or reduce total neurofascin) deplete
the neuronal isoform that anchors the nodal complex and the axon initial
segment through ankyrin-G.
biological_scale: MOLECULAR
subtypes:
- NF186-predominant
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identified a novel homozygous splice mutation (c.3020-1G > A) in
neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the
mutation resulted in inframe skipping of exon 26, with a deprived
expression of the full-length transcript that corresponds to NFASC
isoform NF186.
explanation: >-
Patient cells lack the full-length NF186 transcript.
downstream:
- target: Impaired Sodium Channel Clustering
causal_link_type: DIRECT
evidence:
- reference: PMID:16337912
reference_title: "Neurofascins are required to establish axonal domains for saltatory conduction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, in the absence of Nfasc186, sodium channels remain diffusely
distributed along the axon.
explanation: >-
In mice lacking neuronal neurofascin, sodium channels fail to cluster at
the node even when the paranode is rescued.
- target: Impaired Neurite Outgrowth
causal_link_type: DIRECT
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In early neurogenesis, differentiating cells with selective depletion of
the NF186 isoform showed significantly reduced neurite outgrowth as well
as fewer emerging neurites.
explanation: >-
Patient iPSC-derived neurons lacking NF186 extend fewer and shorter
neurites.
- name: Impaired Sodium Channel Clustering
description: >-
Loss of NF186 impairs clustering and stabilisation of voltage-gated sodium
channels at nodes of Ranvier and the axon initial segment, and patient
neurons show altered sodium channel opening thresholds.
biological_scale: CELLULAR
biological_processes:
- preferred_term: clustering of voltage-gated sodium channels
term:
id: GO:0045162
label: clustering of voltage-gated sodium channels
modifier: DECREASED
cellular_components:
- preferred_term: node of Ranvier
term:
id: GO:0033268
label: node of Ranvier
- preferred_term: axon initial segment
term:
id: GO:0043194
label: axon initial segment
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
whole-cell patch-clamp recordings of patient-derived neuronal cells
revealed a lower threshold for openings, indicating altered Na+ channel
kinetics
explanation: >-
Patient neurons lacking NF186 show altered sodium channel behaviour.
- reference: PMID:28217083
reference_title: "Postnatal Loss of Neuronal and Glial Neurofascins Differentially Affects Node of Ranvier Maintenance and Myelinated Axon Function."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
loss of NF186 individually from postnatal mice leads to progressive
nodal destabilization and axonal degeneration
explanation: >-
NF186 is needed to maintain the nodal complex after it forms, so its loss
has a progressive component.
downstream:
- target: Impaired Saltatory Conduction
causal_link_type: DIRECT
evidence:
- reference: PMID:24719087
reference_title: "Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Nevertheless, there is a 38% reduction in PNS conduction velocity.
explanation: >-
Adult deletion of neuronal neurofascin in mice reduces nodal sodium
channels and slows peripheral conduction.
- target: Cerebellar Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:42052621
reference_title: "Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Other AIS-enriched proteins, including βIV Spectrin (βIVSpec),
voltage-gated sodium (Nav), and potassium (Kv1.2) channels, failed to
properly localize to the AIS and progressively disintegrated between
postnatal days 10 and 30.
explanation: >-
Purkinje cell-specific NF186 knockout fails to localise sodium channels
to the axon initial segment.
- reference: PMID:42052621
reference_title: "Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
By 2 months of age, degeneration of Purkinje cells was evident,
accompanied by cerebellar dysfunction.
explanation: >-
The same model goes on to Purkinje cell degeneration and cerebellar
dysfunction, the mouse counterpart of the ataxia in NF186-deficient
patients.
- reference: PMID:22492029
reference_title: "Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Loss of Nfasc in both Purkinje and basket neurons caused abnormal basket
axon collateral branching and targeting to Purkinje soma/AIS, leading to
extensive pinceau disorganization, Purkinje neuron degeneration, and
severe ataxia.
explanation: >-
Neuronal neurofascin loss in the cerebellum causes Purkinje
degeneration and ataxia in mice.
- name: Impaired Neurite Outgrowth
description: >-
Neurons derived from patients lacking NF186 extend fewer and shorter
neurites during early neurogenesis, a developmental defect that may
contribute to cerebellar and cognitive involvement.
biological_scale: CELLULAR
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In early neurogenesis, differentiating cells with selective depletion of
the NF186 isoform showed significantly reduced neurite outgrowth as well
as fewer emerging neurites.
explanation: >-
Direct observation in patient iPSC-derived neurons.
downstream:
- target: Cerebellar Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired Saltatory Conduction
conforms_to: "schwann_cell_myelin_maintenance#Nerve Conduction Slowing and Conduction Block"
description: >-
Disruption of the paranode and of nodal sodium channel clustering prevents
the normal postnatal transition to saltatory conduction, slowing nerve
conduction in both the central and peripheral nervous system.
biological_scale: TISSUE
evidence:
- reference: PMID:16337912
reference_title: "Neurofascins are required to establish axonal domains for saltatory conduction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our study shows that the two major Neurofascins play essential roles in
assembling the nodal and paranodal domains of myelinated axons;
therefore, they are essential for the transition to saltatory conduction
in developing vertebrate nerves.
explanation: >-
Neurofascin-null mice establish that both isoforms are required for
saltatory conduction.
downstream:
- target: Decreased Nerve Conduction Velocity
causal_link_type: DIRECT
- target: Neonatal Hypotonia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Muscle Weakness
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Peripheral Myelinated Fibre Loss
conforms_to: "schwann_cell_myelin_maintenance#Secondary Axonal Loss and Length-Dependent Deficit"
description: >-
Large myelinated peripheral fibres are lost in a length-dependent pattern
while unmyelinated somatic and autonomic fibres are relatively spared,
giving a chronic demyelinating and axonal neuropathy.
biological_scale: TISSUE
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In general, we observed a severe loss of myelinated fibres with a
preservation of the unmyelinated ones.
explanation: >-
Skin biopsy findings in an affected individual.
downstream:
- target: Demyelinating Peripheral Neuropathy
causal_link_type: DIRECT
- target: Areflexia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Impaired Pain Sensation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Central White Matter Loss
description: >-
Brain MRI in the more severely affected individuals shows loss of cerebral
white matter with atrophy of the corpus callosum and brainstem. NFASC is
most highly expressed in newly formed oligodendrocytes, which links central
paranodal failure to impaired myelination and to the neurodevelopmental
features.
biological_scale: TISSUE
conforms_to: "cns_myelin_failure#Axonal Degeneration and Progressive White Matter Dysfunction"
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MRI studies of Patients 1-3, 7, 9 and 10 showed loss of cerebral white
matter, which was more severe in some affected individuals (Patients 1-3)
and also associated with atrophic changes mainly involving the corpus
callosum and the brainstem
explanation: >-
Direct observation of central white matter loss on patient MRI.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We also found that NFASC expression was highest in newly formed
oligodendrocytes rather than myelin-forming or mature oligodendrocytes.
explanation: >-
Places NFASC in the cells that build central myelin, linking the gene to
the white matter loss.
downstream:
- target: Cerebral White Matter Atrophy
causal_link_type: DIRECT
- target: Corpus Callosum Atrophy
causal_link_type: DIRECT
- target: Brainstem Atrophy
causal_link_type: DIRECT
- target: Global Developmental Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cerebellar Dysfunction
conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
description: >-
Cerebellar involvement (ataxia, dysarthria, nystagmus, vertigo, and in some
cases cerebellar or vermian atrophy) is the dominant feature when neuronal
NF186 is lost, and also occurs in some NF155-predominant families.
biological_scale: TISSUE
cell_types:
- preferred_term: Purkinje cell
term:
id: CL:0000121
label: Purkinje cell
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical presentation is distinct, with symptoms that we interpreted
as cerebellar (ataxia, dysarthria, poor balance, and vertigo) as the main
findings.
explanation: >-
The NF186-deficient siblings present with a cerebellar syndrome.
downstream:
- target: Ataxia
causal_link_type: DIRECT
- target: Dysarthria
causal_link_type: DIRECT
- target: Nystagmus
causal_link_type: DIRECT
- target: Vertigo
causal_link_type: DIRECT
- target: Cerebellar Atrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Neurologic
name: Neonatal Hypotonia
description: >-
Hypotonia from the neonatal period or first months of life is the near
universal presenting sign of the NF155-predominant form.
phenotype_term:
preferred_term: Neonatal hypotonia
term:
id: HP:0001319
label: Neonatal hypotonia
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hypotonia was present from neonatal age in all cases.
explanation: All ten individuals of the largest series had neonatal hypotonia.
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a proband with severe congenital hypotonia, contractures of
fingers and toes, and no reaction to touch or pain.
explanation: The first reported NF155-deficient child had severe congenital hypotonia.
- category: Neurologic
name: Global Developmental Delay
description: >-
Severe global developmental delay in all domains in the NF155-predominant
form; motor delay with largely preserved language in the NF186-predominant
siblings.
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In all patients, psychomotor development was severely delayed (except
Patients 5 and 6) in all domains.
explanation: Severe psychomotor delay in eight of ten individuals.
- category: Neurologic
name: Intellectual Disability
description: >-
Moderate to severe intellectual disability in the NF155-predominant form;
borderline or normal cognition in the NF186-predominant siblings.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Moderate to severe intellectual disability was documented in all cases.
explanation: All ten individuals had moderate to severe intellectual disability.
- category: Neurologic
name: Absent Speech
description: >-
Affected children in the largest series did not acquire intelligible
speech.
phenotype_term:
preferred_term: Absent speech
term:
id: HP:0001344
label: Absent speech
subtype: NF155-predominant
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: None of the affected individuals attained intelligible speech.
explanation: Absent intelligible speech in all ten individuals.
- category: Neurologic
name: Inability to Walk
description: >-
Most children with the NF155-predominant form never walk independently.
phenotype_term:
preferred_term: Inability to walk
term:
id: HP:0002540
label: Inability to walk
subtype: NF155-predominant
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals did not communicate, and none achieved purposeful
hand movements or independent ambulation.
explanation: No individual in the series achieved independent ambulation.
- category: Neurologic
name: Muscle Weakness
description: >-
Generalised weakness, profound in the most severe frameshift cases and
milder, proximal and distal, in the NF186-predominant siblings.
phenotype_term:
preferred_term: Muscle weakness
term:
id: HP:0001324
label: Muscle weakness
frequency: VERY_FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Phenotypic analysis of affected individuals revealed, in all cases,
global developmental delay and weakness with variable features of chronic
demyelinating neuropathy in some cases.
explanation: Weakness was present in all ten individuals.
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we utilized exome sequencing in two siblings with progressive ataxia
and muscular weakness
explanation: Weakness is also part of the NF186-predominant presentation.
- category: Neurologic
name: Areflexia
description: Absent deep tendon reflexes, reflecting the peripheral neuropathy.
phenotype_term:
preferred_term: Areflexia
term:
id: HP:0001284
label: Areflexia
subtype: NF155-predominant
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Because of muscle weakness and absent reflexes, individuals from Families
1, 2, 4 and 6 underwent detailed neurophysiological investigations
explanation: Absent reflexes prompted nerve conduction studies in four families.
- category: Neurologic
name: Demyelinating Peripheral Neuropathy
description: >-
Early-onset chronic demyelinating, in the most severe cases also axonal,
sensorimotor neuropathy.
phenotype_term:
preferred_term: Demyelinating peripheral neuropathy
term:
id: HP:0007108
label: Demyelinating peripheral neuropathy
frequency: FREQUENT
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients from Families 1 and 2 exhibited the most profound phenotype with
severe demyelinating and axonal neuropathy at neurophysiological
investigations.
explanation: Demyelinating and axonal neuropathy in the most severe families.
- reference: PMID:30850329
reference_title: "Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
find the genetic cause of early-onset cerebellar ataxia and demyelinating
neuropathy in two siblings from a consanguineous Italian family
explanation: Demyelinating neuropathy also occurs with the transmembrane missense variant.
- category: Neurologic
name: Decreased Nerve Conduction Velocity
description: Markedly slowed motor and sensory nerve conduction.
phenotype_term:
preferred_term: Decreased nerve conduction velocity
term:
id: HP:0000762
label: Decreased nerve conduction velocity
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
these showed a severe reduction in peripheral nerve conduction velocities
in all cases
explanation: All individuals who underwent nerve conduction studies had severely reduced velocities.
- category: Neurologic
name: Impaired Pain Sensation
description: >-
The first reported NF155-deficient infant showed no reaction to touch or
pain.
phenotype_term:
preferred_term: Impaired pain sensation
term:
id: HP:0007328
label: Impaired pain sensation
subtype: NF155-predominant
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a proband with severe congenital hypotonia, contractures of
fingers and toes, and no reaction to touch or pain.
explanation: Single-case observation of absent response to pain.
- category: Musculoskeletal
name: Finger Contractures
description: Congenital contractures of fingers and toes in the first reported proband.
phenotype_term:
preferred_term: Contractures of fingers
term:
id: HP:0012785
label: Flexion contracture of finger
subtype: NF155-predominant
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a proband with severe congenital hypotonia, contractures of
fingers and toes, and no reaction to touch or pain.
explanation: Contractures of fingers and toes in the proband.
- category: Neurologic
name: Hypomimic Face
description: Facial hypomimia (amimia), noted in the photographed patients.
phenotype_term:
preferred_term: Hypomimic face
term:
id: HP:0000338
label: Hypomimic face
subtype: NF155-predominant
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: note the facial hypomimia present in all cases
explanation: Figure legend describing Patients 1-3.
- category: Behavioral
name: Motor Stereotypy
description: Hand or head stereotypies and repetitive behaviours.
phenotype_term:
preferred_term: Motor stereotypy
term:
id: HP:0000733
label: Motor stereotypy
subtype: NF155-predominant
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Several patients developed restricted patterns of interests and
repetitive behaviours and frequently exhibited hand or head stereotypies.
explanation: Stereotypies were frequent in the series.
- category: Neurologic
name: Cerebral White Matter Atrophy
description: >-
Loss of cerebral white matter on MRI in the more severely affected
individuals.
phenotype_term:
preferred_term: Cerebral white matter atrophy
term:
id: HP:0012762
label: Cerebral white matter atrophy
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MRI studies of Patients 1-3, 7, 9 and 10 showed loss of cerebral white
matter, which was more severe in some affected individuals (Patients 1-3)
and also associated with atrophic changes mainly involving the corpus
callosum and the brainstem
explanation: White matter loss on MRI in several individuals.
- category: Neurologic
name: Corpus Callosum Atrophy
description: Atrophy of the corpus callosum accompanying white matter loss.
phenotype_term:
preferred_term: Corpus callosum atrophy
term:
id: HP:0007371
label: Corpus callosum atrophy
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MRI studies of Patients 1-3, 7, 9 and 10 showed loss of cerebral white
matter, which was more severe in some affected individuals (Patients 1-3)
and also associated with atrophic changes mainly involving the corpus
callosum and the brainstem
explanation: Corpus callosum atrophy on MRI.
- category: Neurologic
name: Brainstem Atrophy
description: Atrophy of the brainstem accompanying white matter loss.
phenotype_term:
preferred_term: Brainstem atrophy
term:
id: HP:0007366
label: Atrophy/Degeneration affecting the brainstem
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MRI studies of Patients 1-3, 7, 9 and 10 showed loss of cerebral white
matter, which was more severe in some affected individuals (Patients 1-3)
and also associated with atrophic changes mainly involving the corpus
callosum and the brainstem
explanation: Brainstem atrophy on MRI.
- category: Neurologic
name: Ataxia
description: >-
Cerebellar ataxia with poor balance and frequent falls; the dominant sign
in the NF186-predominant form, progressing to wheelchair use in
adolescence.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
clinical_course: PROGRESSIVE
subtype: NF186-predominant
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The sister became wheelchair-bound at the age 12 years, and the brother
uses a walker indoors and a wheelchair outdoors.
explanation: Progressive motor course of the ataxia in the NF186-deficient siblings.
- reference: PMID:30850329
reference_title: "Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
find the genetic cause of early-onset cerebellar ataxia and demyelinating
neuropathy in two siblings from a consanguineous Italian family
explanation: Early-onset cerebellar ataxia with the transmembrane missense variant.
- category: Neurologic
name: Dysarthria
description: Dysarthria from early childhood with otherwise normal language development.
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
subtype: NF186-predominant
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Language development was within normal limits, but dysarthria has been
present from early age.
explanation: Dysarthria in the NF186-deficient siblings.
- category: Neurologic
name: Nystagmus
description: Nystagmus on fixation.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
subtype: NF186-predominant
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nystagmus was seen upon fixation, but there was no manifest nystagmus at
rest.
explanation: Nystagmus in the NF186-deficient sister.
- category: Neurologic
name: Vertigo
description: Disabling vertigo with nausea.
phenotype_term:
preferred_term: Vertigo
term:
id: HP:0002321
label: Vertigo
subtype: NF186-predominant
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, the siblings suffer from disabling vertigo, nausea, and
headache.
explanation: Vertigo in both NF186-deficient siblings.
- category: Neurologic
name: Cerebellar Atrophy
description: >-
Cerebellar or vermian atrophy on MRI in some individuals of both isoform
classes.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:31608123
reference_title: "Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Magnetic resonance imaging (MRI) of the brain at the same ages showed
mild vermian atrophy in the sister and normal findings in the brother
explanation: Vermian atrophy in one of the NF186-deficient siblings.
- category: Respiratory
name: Respiratory Insufficiency
description: Respiratory insufficiency in infancy in severely affected children.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: PMID:31945734
reference_title: "Case report of two children with auditory neuropathy spectrum disorder related to a neurofascin (NFASC) gene variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented with hypotonia, respiratory insufficiency, and auditory
neuropathy spectrum disorder (ANSD) correlated with NFASC (MIM: 609145)
and the homozygous loss of function variant p.P924RfsX35
explanation: Respiratory insufficiency in two siblings with a homozygous loss-of-function variant.
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The newborn was treated by intubation and mechanical ventilation because
of respiratory insufficiency.
explanation: The first reported NF155-deficient newborn needed mechanical ventilation.
- category: Neurologic
name: Auditory Neuropathy Spectrum Disorder
description: >-
Hearing loss in the most severely affected children: auditory neuropathy
spectrum disorder in two siblings homozygous for a frameshift variant
(Harper 2020), and profound sensorineural hearing loss in the two American
siblings with the p.Pro939Ter frameshift (Efthymiou 2019). The two reports
may describe the same family under different transcript numbering; the
papers do not say, so they are not counted as independent observations.
phenotype_term:
preferred_term: Auditory neuropathy spectrum disorder
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:31945734
reference_title: "Case report of two children with auditory neuropathy spectrum disorder related to a neurofascin (NFASC) gene variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
presented with hypotonia, respiratory insufficiency, and auditory
neuropathy spectrum disorder (ANSD) correlated with NFASC (MIM: 609145)
and the homozygous loss of function variant p.P924RfsX35
explanation: ANSD reported in two siblings.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The two American children had more severe phenotype and also developed
profound sensorineural hearing loss, feeding difficulties requiring
gastrostomy and respiratory difficulties.
explanation: Profound hearing loss in the two most severely affected siblings of the series.
- category: Gastrointestinal
name: Feeding Difficulties
description: >-
Feeding difficulties requiring gastrostomy in the most severely affected
infants, and dysphagia in one of the transmembrane-variant siblings.
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
subtype: NF155-predominant
frequency: OCCASIONAL
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Because of feeding difficulties percutaneous endoscopic gastrostomy was
performed.
explanation: Gastrostomy for feeding difficulties in the first reported proband.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The two American children had more severe phenotype and also developed
profound sensorineural hearing loss, feeding difficulties requiring
gastrostomy and respiratory difficulties.
explanation: Feeding difficulties requiring gastrostomy in two further children.
- category: Neurologic
name: Seizure
description: >-
Epilepsy has been reported in a single individual, the first NF155-deficient
proband, who also had hypoxic-ischaemic changes on MRI, so it may not be
caused by NFASC loss. None of the ten individuals in the largest series had
seizures. This is the main clinical difference from CNTNAP1 disease.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
subtype: NF155-predominant
frequency: VERY_RARE
evidence:
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: At the age of 4 months epilepsy appeared and was treated with valproate.
explanation: Single-case report of epilepsy.
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Non-specific EEG abnormalities including slow background activities were
observed in several families although affected individuals had no history
of seizures.
explanation: >-
No seizures in any of the ten individuals of the largest series, so
seizures are at most a rare feature.
genetic:
- name: NFASC
gene_term:
preferred_term: NFASC
term:
id: hgnc:29866
label: NFASC
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
NFASC (1q32.1) encodes neurofascin. Alternative splicing gives the glial
isoform NF155 (paranodal, with a third fibronectin type III repeat) and the
neuronal isoforms NF186 and NF140 (nodal and axon initial segment).
Reported homozygous variants include p.Arg831Ter (NF155-specific), the
frameshifts p.Pro939Ter and p.Pro924ArgfsTer35, the splice variant
c.3020-1G>A (skips exon 26, removing full-length NF186), and missense
variants p.Asn130Asp, p.Arg359Pro, p.Pro694Thr, p.Ser820Pro, p.Val1077Ala
and p.Val1122Glu.
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The genetic disease caused by biallelic NFASC variants includes
neurodevelopmental impairment and a spectrum of central and peripheral
demyelination as part of its core clinical phenotype.
explanation: Establishes biallelic NFASC variants as the cause of the disorder.
- reference: PMID:30124836
reference_title: "Homozygous mutation in the Neurofascin gene affecting the glial isoform of Neurofascin causes severe neurodevelopment disorder with hypotonia, amimia and areflexia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We propose that the disease in our proband is the first reported example
of genetic deficiency of glial Neurofascin isoforms in humans
explanation: First report of a human NFASC disease.
diagnosis:
- name: Exome or Genome Sequencing
description: >-
Diagnosis rests on identifying bi-allelic NFASC variants by exome or
genome sequencing in a child with hypotonia, developmental delay and
neuropathy or ataxia. Skin biopsy immunostaining for paranodal NF155 and
CASPR1 has been used to confirm the functional effect.
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who were found by exome or genome sequencing to carry one frameshift and
four different homozygous non-synonymous variants in NFASC
explanation: All cases in the series were diagnosed by exome or genome sequencing.
differential_diagnoses:
- name: CNTNAP1-related congenital hypomyelinating neuropathy
description: >-
Bi-allelic CNTNAP1 (CASPR1) variants remove NF155's axonal partner and
cause a similar paranodopathy with brainstem and corpus callosum atrophy,
but with epilepsy, which has not been reported in NFASC disease.
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interestingly, these patients have a similar phenotype to patients with
CNTNAP1/CASPR1 mutations; however, without any epilepsy, which has been
reported in CASPR1-mutated patients.
explanation: Names CNTNAP1 disease as the closest differential.
- name: Anti-neurofascin-155 autoimmune nodopathy
description: >-
IgG4 autoantibodies against NF155 cause an acquired nodopathy (formerly
anti-NF155 CIDP) with distal weakness, sensory ataxia and tremor, which
shares the paranodal lesion of the genetic disease.
evidence:
- reference: PMID:31501903
reference_title: "Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings support possible overlapping molecular mechanisms of
paranodal damage at peripheral nerves in both the immune-mediated and the
genetic disease
explanation: Links the immune-mediated and genetic NF155 disease.
treatments:
- name: Supportive Multidisciplinary Care
therapeutic_modality: OTHER
description: >-
No disease-modifying therapy exists. Management is supportive:
physiotherapy and orthotics for hypotonia, weakness and ataxia, feeding and
respiratory support where needed, audiological assessment, and
developmental and educational support.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
animal_models:
- name: Neurofascin-null mouse (Nfasc-/-)
species: Mouse
genotype: Nfasc-/-
publication: PMID:16337912
modeled_mechanisms:
- target: Paranodal Axoglial Junction Disruption
relationship: RECAPITULATES
fidelity: MODERATE
description: Complete loss of neurofascin prevents formation of paranodal and nodal complexes.
limitations: >-
Removes all isoforms at once and is lethal within the first postnatal
week, so it is more severe than the isoform-selective human genotypes.
evidence:
- reference: PMID:16337912
reference_title: "Neurofascins are required to establish axonal domains for saltatory conduction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In Neurofascin-null mice, neither paranodal adhesion junctions nor nodal
complexes are formed.
explanation: The null mouse lacks both paranodal and nodal complexes.
- name: Myelinating glia-specific Nfasc NF155 null mouse
species: Mouse
genotype: Myelinating glia-specific conditional deletion of Nfasc NF155
publication: PMID:19185024
modeled_mechanisms:
- target: Paranodal Axoglial Junction Disruption
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Glia-specific loss of NF155, the isoform affected in most patients,
prevents paranodal junction formation, slows peripheral conduction and
causes ataxia, paresis and degeneration of myelinated axons.
limitations: >-
The mice die before the third postnatal week, earlier than most
patients, and the cerebral white matter and cognitive features of the
human disease cannot be assessed.
evidence:
- reference: PMID:19185024
reference_title: "Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These mice exhibit severe ataxia, motor paresis, and death before the
third postnatal week.
explanation: >-
Loss of glial NF155 alone reproduces the severe motor phenotype.
- name: Purkinje cell-specific Nfasc NF186 knockout mouse
species: Mouse
genotype: Purkinje cell-specific conditional deletion of Nfasc NF186
publication: PMID:42052621
modeled_mechanisms:
- target: Cerebellar Dysfunction
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Loss of NF186 from Purkinje cells disrupts the axon initial segment,
mislocalises sodium and potassium channels, and leads to Purkinje cell
degeneration with cerebellar dysfunction.
limitations: >-
Deletion is restricted to Purkinje cells, whereas the patient splice
variant removes full-length NF186 from all neurons.
evidence:
- reference: PMID:42052621
reference_title: "Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
By 2 months of age, degeneration of Purkinje cells was evident,
accompanied by cerebellar dysfunction.
explanation: >-
Cerebellar dysfunction follows Purkinje-specific NF186 loss.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Overview. NEDCPMD is an autosomal recessive disorder caused by biallelic variants in NFASC, the gene encoding neurofascin, an L1-family immunoglobulin-superfamily cell adhesion molecule that exists as a glial isoform (Nfasc155, at the paranodal axoglial junction of myelinating oligodendrocytes and Schwann cells) and neuronal isoforms (Nfasc186 and Nfasc140, at the node of Ranvier and axon initial segment). The phenotype is highly variable and tracks the isoform affected: variants abolishing Nfasc155 produce a severe neonatal picture (congenital hypotonia, areflexia, respiratory and feeding failure, demyelinating neuropathy, central white matter loss, profound developmental impairment), whereas variants restricted to Nfasc186 produce a later-onset progressive cerebellar ataxia with milder cognition and little or no peripheral neuropathy.
The OMIM-derived summary (via MedGen) reads: NEDCPMD is "an autosomal recessive neurologic disorder with a highly variable phenotype." At the severe end "patients may have hypotonia apparent from birth, necessitating mechanical respiration and tube-feeding, and global developmental delay"; at the milder end "patients may present with infantile-onset progressive ataxia and demyelinating peripheral neuropathy" (MedGen 1674767).
The defining cohort paper states: "We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC" (Efthymiou et al., Brain 2019, PMID:31501903).
Identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0032698 (label: neurodevelopmental disorder with central and peripheral motor dysfunction; related synonym NEDCPMD) (OLS) |
| OMIM | #618356 (phenotype); *609145 (NFASC gene) |
| MedGen / UMLS | 1674767 / C5193049 |
| Orphanet | No ORPHA entry found. An ORDO search for "neurofascin" returns only the autoimmune entities ORPHA:730233 (Anti-NF155 nodopathy) and ORPHA:730238 (Anti-pan-neurofascin nodopathy); a search on the disease name returns nothing. Do not cite an ORPHA: reference for this disease. |
| KEGG DISEASE | H02990 |
| ICD-10/ICD-11 | No specific code; would fall under G60.8/G60.9 (other/unspecified hereditary neuropathy) or F8x/G93 developmental codes. Not disease-specific. |
| HGNC | NFASC = HGNC:29866 (repository form hgnc:29866; not yet in cache/hgnc/terms.csv, so just validate-terms must populate it) |
| NCBI Gene | 23114 |
| UniProt | O94856 |
Synonyms. NEDCPMD; NFASC-related neurodevelopmental disorder; "autosomal recessive ataxia with demyelinating neuropathy" (Monfrini 2019 framing); "hereditary nodo-paranodopathy" (Karakaya & Wirth 2019 framing, PMID:31560060). PanelApp England originally listed the gene under "Cerebellar ataxia, Demyelinating neuropathy" before renaming to the OMIM phenotype (PanelApp Hereditary ataxia panel 20).
Source type. All information is from individual-patient case reports and small family series, aggregated by OMIM/MedGen/HPO. There are no EHR cohorts, registries, or natural-history studies.
Causal factor. Biallelic (homozygous in every reported family) pathogenic variants in NFASC. Monogenic; no environmental, infectious, or multifactorial component is described.
Genetic risk factors. Consanguinity is the dominant risk context. Of the reported families, Moroccan, Iraqi, Israeli, Saudi Arabian, Algerian, Italian, and Pakistani families were consanguineous. The Polish proband's parents denied consanguinity, but runs-of-homozygosity analysis found the variant "within a relatively long (>3 Mb) ROH together with high (∼90 percentile) summed length of ROHs," and three great-grandparents came from the same village, which the authors read as "a low but distinct degree of parental consanguinity" (Smigiel et al. 2018, PMID:30124836). The American sibling pair was born to nonconsanguineous parents yet carried a homozygous frameshift (Harper et al. 2020, PMID:31945734).
Heterozygote constraint. gnomAD scores NFASC as strongly intolerant of heterozygous loss of function: pLI ≈ 1.00, observed/expected LoF 0.29 (43 observed vs 147 expected), LOEUF 0.376, o/e missense 0.78 (gnomAD API, GRCh38). This sits awkwardly beside a strictly recessive disease and is worth recording as a knowledge gap: GenCC carries one "Limited" autosomal-dominant submission (Ambry, 2018) with no published dominant phenotype (GenCC HGNC:29866). Heterozygous parents in every report were healthy.
Modifier genes. None identified. Efthymiou et al. caution that "Given the history of consanguineous marriages in these families, other recessive variants may also have contributed to the clinical phenotype, as in Proband 8 from Family 5 who died prematurely" (PMID:31501903).
Protective factors, gene-environment interactions. None reported; not applicable at the current evidence level.
Frequencies below are counts out of the ~16 reported individuals where the feature was assessed, drawn from Table 2 of Efthymiou 2019 (which also tabulates the Smigiel and Monfrini cases), the Kvarnung siblings, and the Harper siblings. Official HPO annotations for OMIM:618356 (37 terms) are at HPO annotation API; HPO IDs below were checked against the repository's cache/hp/terms.csv.
| Phenotype | HPO | Onset / frequency / notes |
|---|---|---|
| Global developmental delay | HP:0001263 | All 13 tabulated cases. "In all patients, psychomotor development was severely delayed (except Patients 5 and 6) in all domains." (Efthymiou) |
| Severe global developmental delay | HP:0011344 | NF155-affecting and both-isoform cases |
| Intellectual disability | HP:0001249 | 11/13 tabulated; "Moderate to severe intellectual disability was documented in all cases" of the Efthymiou cohort. Mild in NF186-only cases: Kvarnung sister full-scale IQ 79–86; brother "within the normal span". |
| Absent speech | HP:0001344 | Efthymiou cohort: "None of the affected individuals attained intelligible speech." |
| Dysarthria | HP:0001260 | NF186-only ataxic cases (Kvarnung: "dysarthria has been present from early age") |
| Hypotonia / generalized hypotonia | HP:0001252 / HP:0001290 | Neonatal or first 6 months in all NF155-affecting cases: "Hypotonia was present from neonatal age in all cases." Mild general hypotonia in Kvarnung siblings. |
| Delayed ability to walk; no independent ambulation | HP:0031936 | Efthymiou: "none achieved purposeful hand movements or independent ambulation." Kvarnung: independent walking at 2 y (brother) and 4 y (sister). |
| Ataxia / gait ataxia | HP:0001251 / HP:0002066 | NF186-only cases (Monfrini siblings; Kvarnung siblings; Efthymiou patient 10 "Hypotonia/ataxia started at 15–16 months") |
| Dysmetria, dysdiadochokinesis, intention tremor | HP:0001310, HP:0002075, HP:0002080 | OMIM synopsis (Monfrini family) |
| Nystagmus | HP:0000639 | Kvarnung sister: abnormal vertical OKN; nystagmus on fixation |
| Vertigo | HP:0002321 | Kvarnung siblings: "disabling vertigo, nausea, and headache" |
| Spasticity, hyperreflexia, Babinski sign | HP:0001257, HP:0001347, HP:0003487 | Monfrini sister: "Spastic limb hypertonia, hyperreflexia"; Kvarnung: mild patellar hyperreflexia |
| Hypertonia (generalized, upper limb) | HP:0001276 | Saudi patient 8 |
| Myoclonus | HP:0001336 | Monfrini sister: "myoclonic jerks" |
| Seizure | HP:0001250 | Smigiel proband only (onset 4 months, valproate). Efthymiou: "affected individuals had no history of seizures." Rare. |
| Impaired social interaction / autistic features; motor stereotypy | HP:0000717, HP:0000733 | Efthymiou: "Impaired social interaction and only brief and occasional visual contact ... Several patients developed restricted patterns of interests and repetitive behaviours and frequently exhibited hand or head stereotypies." |
| Anxiety; aggressive behavior | HP:0000739, HP:0000718 | Monfrini brother: "Episodes of aggression, intense anxiety" |
| Absent response to touch/pain, no pupillary light response | (no precise HP; consider HP:0007328 Impaired pain sensation) | Smigiel proband: "no reaction to touch or pain, narrow, symmetric pupils, no response to light" |
| Phenotype | HPO | Notes |
|---|---|---|
| Demyelinating peripheral neuropathy | HP:0007108 | Efthymiou: NCS "showed a severe reduction in peripheral nerve conduction velocities in all cases" tested (families 1, 2, 4, 6); "Patients from Families 1 and 2 exhibited the most profound phenotype with severe demyelinating and axonal neuropathy". Monfrini: "demyelinating neuropathy". Absent in NF186-only Kvarnung siblings (normal ENeG at 9 and 14 y) and Efthymiou family 6. |
| Decreased (motor) nerve conduction velocity | HP:0000762 / HP:0003431 | As above |
| EMG: neuropathic changes | HP:0003445 | Patient 3 "Acute and chronic denervation, PSW"; patients 9–10 "Chronic denervation-reinnervation" |
| Areflexia / hyporeflexia | HP:0001284 / HP:0001265 | Smigiel: "areflexia"; Efthymiou patients 1–2 "absent reflex" |
| Muscle weakness | HP:0001324 (not verified in cache; HP:0003324 Generalized muscle weakness also exists) | All cases. Kvarnung 5-/5 proximal and distal |
| Auditory neuropathy spectrum disorder / sensorineural hearing loss | HP:0000365; HP:0008527 | Harper 2020: two siblings "presented with hypotonia, respiratory insufficiency, and auditory neuropathy spectrum disorder (ANSD)"; Efthymiou: "The two American children ... developed profound sensorineural hearing loss". These are very likely the same family (same NM_015090 c.2771delC / p.P924fs allele, both American sibling pairs with SNHL); treat as one family, not two. |
| Phenotype | HPO | Notes |
|---|---|---|
| Decreased fetal movement; polyhydramnios | HP:0001558 | Smigiel: "The pregnancy was affected by polyhydramnios and weak fetal movements." |
| Neonatal respiratory distress; respiratory insufficiency; respiratory failure requiring ventilation | HP:0002643, HP:0002093, HP:0002878 | Smigiel: intubation, later tracheostomy. Harper siblings: respiratory insufficiency. |
| Feeding difficulties; dysphagia | HP:0011968, HP:0002015 | Smigiel: PEG; American children "feeding difficulties requiring gastrostomy"; Monfrini sister dysphagia |
| Congenital contractures / flexion contracture of finger | HP:0002803 / HP:0012785 | Smigiel: "contractures of finger in hands and feet" |
| Facial hypomimia (amimia) | (consider HP:0000338 Hypomimic face; not cache-verified) | Smigiel "amimia"; Efthymiou "note the facial hypomimia present in all cases" (families 1–2) |
| Narrow forehead (bitemporal narrowing), wide/prominent nasal bridge, micrognathia, glossoptosis, high palate, cleft palate, hypertelorism | HP:0000341, HP:0000431, HP:0000426, HP:0000347, HP:0000162, HP:0000218, HP:0000175, HP:0000316 | Efthymiou: "several craniofacial dysmorphisms including bi-temporal narrowing, high and wide nasal bridge, micrognathia, glossoptosis and highly arched palate". Kvarnung siblings: no dysmorphology. |
| Microcephaly; small anterior fontanelle | HP:0000252, HP:0000237 | OMIM synopsis (rare) |
| 11 pairs of ribs; chest deformity | HP:0000878 | Saudi patient 8 "skeletal chest deformities" |
| Hyperextensibility of finger joints | HP:0001187 | OMIM synopsis (Anazi family) |
| Failure to thrive | HP:0001508 | OMIM synopsis |
| Recurrent respiratory infections | HP:0002205 | Kvarnung siblings in infancy |
| Phenotype | HPO | Notes |
|---|---|---|
| Abnormal cerebral white matter / white matter loss | HP:0002500, HP:0012447 | Efthymiou: "MRI studies of Patients 1–3, 7, 9 and 10 showed loss of cerebral white matter ... also associated with atrophic changes mainly involving the corpus callosum and the brainstem" |
| Hyperintensity of cerebral white matter on MRI | HP:0030890 | Patient 7 "Diffuse white matter T2 hyperintensity"; Monfrini siblings "mild diffuse white matter T2 hyperintensity" |
| Hypoplasia / atrophy of corpus callosum | HP:0002079 | Patients 2–3 "thin corpus callosum" |
| Ventriculomegaly | HP:0002119 | Patient 1 "enlarged lateral ventricles ... indicative of cortical volume loss" |
| Cerebellar atrophy; cerebellar vermis atrophy | HP:0001272; (HP:0001320 is hypoplasia; use with care) | NF186-only cases: patients 9–10 "Cerebellar atrophy"; Monfrini "Mild cerebellar atrophy"; Kvarnung sister "mild vermian atrophy" |
| Normal MRI | — | Efthymiou patients 5–6 (Israeli, S820P) and Kvarnung brother |
Quality of life. No instrument-based QoL data exist. Functional outcome is severe: non-ambulatory and non-verbal in most, gastrostomy/tracheostomy dependence in the severe tier, wheelchair dependence by adolescence in the ataxic tier (Kvarnung sister "wheelchair-bound at the age 12 years").
Causal gene. NFASC (HGNC:29866; OMIM *609145; 1q32.1; NCBI Gene 23114; UniProt O94856). Protein: neurofascin, 1,347-aa precursor, single-pass type I membrane protein with 6 Ig-like C2 domains (aa 41–603) and 5 fibronectin type III domains (aa 630–1206); 13 annotated UniProt isoforms, with the paper literature focusing on Nfasc186 (NM_001005388, 1241 aa; neuronal, nodal/AIS) and Nfasc155 (NM_001160331, 1165 aa; glial, paranodal) (UniProt O94856). Kvarnung notes the pre-mRNA "undergoes extensive alternative splicing and results in more than 50 different isoforms such as 186, 180, 166, and 155 kDa" (PMID:31608123).
Gene-disease validity. GenCC: Strong AR (Labcorp Genetics, evaluated 2021-04-16; PanelApp Australia, evaluated 2025-01-17), Moderate AR (Ambry, 2019), Limited AD (Ambry, 2018) (GenCC). ClinGen: no gene-disease validity, dosage, or actionability curation (ClinGen); the repository's cache/clingen/gene_validity.csv likewise has no NFASC row, so no CGGV: evidence can be cited. PanelApp England: Green on the Hereditary ataxia panel, biallelic, citing PMIDs 30850329, 31608123, 31501903 (PanelApp). ClinVar: 30 pathogenic/likely-pathogenic records for NFASC (ClinVar E-utilities query, 2026-10-15).
Reported pathogenic variants (all homozygous). Nomenclature as given in the source papers; GRCh37 coordinates from Efthymiou Table 1.
| Family (origin) | Variant (Nfasc186 NM_001005388 / Nfasc155 NM_001160331) | Domain | Isoform(s) hit | Functional evidence | Phenotype tier | Source |
|---|---|---|---|---|---|---|
| Smigiel (Polish) | NM_015090.3 c.2491C>T p.Arg831Ter; = NM_001160331 c.2536C>T p.Arg846Ter; intronic in NM_001005388 (c.2470+2039C>T); rs755160624; chr1:204953187C>T | 3rd FNIII repeat of Nfasc155-specific exon | Nfasc155 only | Patient skin biopsy: Nfasc155 absent at paranodes, Caspr lost, nodal isoforms intact | Severe neonatal; epilepsy | PMID:30124836 |
| Efthymiou F2 (American; = Harper 2020 siblings) | NM_001160331 c.2816delC p.Pro939Ter (NM_015090.3 c.2771delC p.Pro924Ter; Harper: p.P924RfsX35); chr1:204986105delC | C-terminal to FNIII, before TM | Nfasc155 (and transcript 3) | HEK: no surface or intracellular protein; abolished CNTN1/CASPR1 binding; patient 3 skin: "CASPR1 immunoreactivity was completely absent in the paranodal regions" | Most severe: SNHL/ANSD, gastrostomy, respiratory failure, severe NCV slowing, white matter loss | PMID:31501903, PMID:31945734 |
| Efthymiou F1 (Moroccan) | c.2080C>A p.Pro694Thr / c.2113C>A p.Pro705Thr; chr1:204948591C>A | FNIII | Both | Reduced Nfasc155 protein; abolished CNTN1/CASPR1 aggregation; skin: severe loss of myelinated fibres, partial Nfasc155 loss | Severe; demyelinating + axonal neuropathy | PMID:31501903 |
| Efthymiou F3 (Arab Iraqi) | c.388A>G p.Asn130Asp / c.298A>G p.Asn124Asp; chr1:204923488A>G | Ig-like | Both | Normal surface expression and protein level; MD simulation suggests altered H-bond network | Neonatal hypotonia, severe DD | PMID:31501903 |
| Efthymiou F4 (Israeli, 2 sibs) | c.2458T>C p.Ser820Pro / c.2491T>C p.Ser831Pro; chr1:204951136T>C | FNIII | Both | Reduced Nfasc155 protein; reduced aggregation | Infantile hypotonia, no walk, normal MRI; relatively milder | PMID:31501903 |
| Efthymiou F5 (Saudi, 2 sibs; = Anazi 2017) | c.1076G>C p.Arg359Pro / c.1109G>C p.Arg370Pro; chr1:204939816G>C | Ig-like | Both | Normal protein level; reduced CNTN1/CASPR1 aggregation | Infantile hypotonia; one died at 4 months | PMID:31501903; PMID:28940097 |
| Efthymiou F6 (Algerian, 2 sibs) | c.3230T>C p.Val1077Ala (NM_001005388 only); chr1:204971817T>C | NF186-specific region | Nfasc186 only | Not functionally tested | Later onset (15–16 months), ataxia, cerebellar atrophy, normal NCS | PMID:31501903 |
| Monfrini (Italian, 2 sibs) | c.3365T>A p.Val1122Glu (NM_001005388) | Transmembrane domain ("highly conserved hydrophobic transmembrane domain residue") | Numbered on Nfasc186; TM domain is shared | "led to significant loss of Neurofascin protein in the iPSC-derived neurons of affected siblings" | Early-onset cerebellar ataxia + demyelinating neuropathy; spasticity; ID in brother | PMID:30850329 |
| Kvarnung (Pakistani, 2 sibs) | c.3020-1G>A (NM_001005388), splice acceptor intron 25 → in-frame skipping of exon 26 | NF186-specific exon | Full-length Nfasc186 lost; Nfasc155 non-significant trend down | Fibroblast RT-PCR/qPCR; iPSC neurons: no NF186, reduced ankyrin-G, fewer/shorter neurites, altered Na+ currents | Progressive ataxia, mild weakness, mild cognitive impairment, normal NCS | PMID:31608123 |
| Farwell Hagman 2017 | Homozygous splice-site variant (details in supplementary data of a diagnostic-lab paper) | — | — | — | "neurodevelopmental impairment, hypotonia and areflexia" (as cited by Efthymiou) | PMID:28106320 (NFASC not in abstract) |
Variant classes. Nonsense (1), frameshift (1), splice-acceptor with in-frame exon skip (2 reported: Kvarnung; Farwell Hagman), missense (6). Germline in all; no somatic or mosaic cases. ACMG classifications in ClinVar: the Smigiel, Efthymiou, and Kvarnung alleles are deposited as pathogenic/likely pathogenic; the full list of 30 P/LP records has not been reviewed allele by allele here.
Allele frequency. rs755160624 (Smigiel allele) in gnomAD v2.1: exomes 2/251,448 (AF ≈ 8 × 10⁻⁶), genomes 2/31,386, no homozygotes (gnomAD); Smigiel reported four heterozygotes, "European population frequency of 1 in 21114 subjects". The Efthymiou alleles were absent from 1000G, ESP6500, ExAC and gnomAD (Table 1); the Kvarnung allele "was not present in gnomAD (v2.1)".
Functional consequence. Loss of function in every case, with isoform specificity as the discriminating axis. Efthymiou: "Only the p.P939Ter variant strikingly affected the expression of Nfasc155"; "The protein levels of p.P705T, p.S807P and p.P939Ter mutants were found importantly decreased compared to wild-type Nfasc155"; "Both p.P705T and p.P939Ter variants abolished the interaction between Nfasc155 and CNTN1/CASPR1". Nfasc186 surface expression and gliomedin binding were unaffected by any missense variant. Karakaya & Wirth summarise: "Only variants in the fibronectin type III domain significantly reduced protein levels" (PMID:31560060). For dismech: functional_impact_category: LOSS_OF_FUNCTION (complete, for the NF155-abolishing frameshift and nonsense alleles) or PARTIAL_LOSS_OF_FUNCTION (FNIII missense with reduced protein and binding); the Ig-domain missense alleles (N130D, R359P) with normal expression but reduced partner binding are best described as loss of adhesive function rather than reduced abundance.
Modifier genes, epigenetics, chromosomal abnormalities. None reported. No NFASC deletions/CNVs reported in patients; no methylation data. Not applicable.
Not applicable. No environmental, lifestyle, or infectious contributors are described. The only acquired "neurofascinopathy" is immune-mediated (IgG4 anti-Nfasc155 / anti-Nfasc186 / pan-neurofascin autoimmune nodopathy), which is a distinct disease with overlapping paranodal pathology (see Section 10, differential diagnosis).
Branch A: glial Nfasc155 loss (neonatal-onset tier)
2A. Loss or truncation of Nfasc155 in oligodendrocytes and Schwann cells → failure of the paranodal ternary complex Nfasc155–CNTN1–CASPR1. Demonstrated in patients: "Caspr was absent from the paranodes of the proband confirming the disruption of the paranodal junction" (Smigiel); "CASPR1 immunoreactivity was completely absent in the paranodal regions" (Efthymiou patient 3). Demonstrated in vitro: FNIII-domain variants and the frameshift "abolished the interaction between Nfasc155 and CNTN1/CASPR1". 3A. Loss of the paranodal septate-like junction → loss of axonal domain segregation: juxtaparanodal Kv1 channels encroach toward the node, nodal Nav clusters loosen. Inferred from mice (Pillai 2009: "paranodal axoglial junctions fail to form, axonal domains fail to segregate", PMID:19185024); the patient skin biopsy showed "several nodes that appeared larger, however less compacted than in the control skin" and "a granular distribution of Nav ... along the axonal profiles of large fibres devoid of myelin" (Efthymiou). 4A. Domain disorganization → severely reduced conduction velocity and prolonged latencies (demonstrated in patients by NCS; mice show ~50% reduction: "we would predict a further 50% reduction in conduction velocities in these peripheral nerves", Smigiel). 5A. Unstable paranodes → length-dependent loss of large myelinated fibres with preserved unmyelinated fibres (demonstrated in patient skin: "a severe loss of myelinated fibres with a preservation of the unmyelinated ones"; "a severe effect on myelination and/or maintenance of myelin and survival of large fibres, which appears to be length-dependent"). This is the demyelinating-plus-axonal neuropathy on EMG/NCS. 6A. Peripheral conduction failure and fibre loss → hypotonia, weakness, areflexia, reduced nociception, auditory neuropathy, bulbar and respiratory failure (demonstrated clinically; the auditory-nerve link is inferred from the ANSD phenotype in the Harper/Efthymiou F2 siblings). 7A. In parallel, loss of oligodendrocyte Nfasc155 → impaired CNS myelin targeting and sheath growth (inferred from zebrafish/mouse: "loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies", Klingseisen 2019, PMID:31761670) → cerebral white matter loss, thin corpus callosum, brainstem atrophy (demonstrated on MRI) → contributes to global developmental delay, intellectual disability, absent speech, and in some patients spasticity/hyperreflexia (the clinical link is plausible but not mechanistically demonstrated in humans).
Branch B: neuronal Nfasc186 loss (later-onset ataxic tier)
2B. Absence of full-length Nfasc186 → reduced ankyrin-G and failure of axon initial segment (AIS) assembly/maintenance (demonstrated in patient iPSC neurons: "a significant reduction of ankyrin-G in patient neurons"; mice: adult Purkinje Nfasc inactivation "causes rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier" with AIS disintegration, Zonta 2011, PMID:21382554). 3B. AIS failure → altered neuronal excitability: patient neurons showed Na⁺ currents "activated at about 10-mV more negative membrane potentials" with lower peak current density (Kvarnung); mouse Purkinje cells lose "the spontaneous tonic discharge typical of Purkinje cells" (Zonta). 4B. Loss of Nfasc186 during neurogenesis → impaired neurite outgrowth and delayed neuronal maturation (demonstrated in patient iPSC neurons: "fewer and shorter neurites"; SLIT3 upregulated; DCX/MAP2 under-induced). Contributes to cognitive impairment (inferred). 5B. In cerebellum, Nfasc186 loss in Purkinje and basket cells → pinceau synapse disorganization, Purkinje degeneration (mouse: Buttermore 2012, PMID:22492029; Shi 2026, PMID:42052621, where "Purkinje cell-specific loss of NF186 predominantly activated immune-inflammatory pathways") → progressive cerebellar ataxia with cerebellar/vermian atrophy (demonstrated clinically and on MRI in NF186-only patients). 6B. Postnatal Nfasc186 loss at nodes → progressive nodal destabilization and axonal degeneration (mouse: Taylor 2017, PMID:28217083); peripheral nerves were clinically normal in the Kvarnung siblings at 9 and 14 y, so this step is a predicted late risk rather than an observed one ("we cannot exclude subclinical affection of the PNS or the emergence of peripheral symptoms with time").
Branch C: both isoforms (missense in shared Ig/FNIII exons) → both A and B operate, with severity scaled by how much protein/binding is lost; Efthymiou's cohort is largely this branch.
cache/go/terms.csv.cache/cl/terms.csv.progression:: (1) neonatal/infantile hypotonic-respiratory phase; (2) established neurodevelopmental disability with demyelinating neuropathy; and, for the NF186 tier, (1) delayed motor milestones, (2) progressive ataxia with loss of ambulation.measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE, with the count in notes. No Orphanet epidemiology row exists.just loinc-seed-cache). EMG: acute/chronic denervation. Normal NCS does not exclude the NF186 tier. EEG: non-specific slowing without seizures in most. ABR/OAE: auditory neuropathy pattern (Harper 2020).Congenital_Hypomyelinating_Neuropathy already carries a "Paranodal Axo-Glial Junction Failure" node naming NF155. (3) GLDN (gliomedin) lethal arthrogryposis (Maluenda 2016, PMID:27616481), the nodal partner of Nfasc186. (4) Hypomyelinating leukodystrophies and CMT4/CHN (entries exist in kb/disorders/). (5) Autoimmune anti-Nfasc155/pan-neurofascin nodopathy — acquired, antibody-positive, treatable; shares paranodal pathology and, in up to 8% of anti-Nfasc155 CIDP, CNS demyelination. (6) Recessive early-onset ataxias (for the NF186 tier).There is no disease-modifying therapy. All management is supportive and extrapolated from the individual case reports; no treatment has been formally evaluated.
| Intervention | Reported in | Suggested NCIT term (cached) |
|---|---|---|
| Mechanical ventilation, intubation, tracheostomy | Smigiel 2018; Harper 2020 | Supportive Care NCIT:C15747; Surgical Procedure NCIT:C15329 (tracheostomy, with preferred_term carrying the specificity) |
| Percutaneous endoscopic gastrostomy / tube feeding | Smigiel 2018; Efthymiou 2019 (American children) | Nutritional Support NCIT:C15433 (review modality by hand; see CLAUDE.md caution) and Surgical Procedure NCIT:C15329 |
| Antiseizure medication (valproate) | Smigiel 2018: "epilepsy appeared and was treated with valproate" | Pharmacotherapy NCIT:C15986 + therapeutic_agent valproic acid CHEBI:39867 (cached) |
| Physiotherapy, occupational therapy, speech therapy, mobility aids (walker, wheelchair) | Kvarnung 2019 (walker/wheelchair); general | Physical Therapy NCIT:C15302; Occupational Therapy NCIT:C121351; Speech Language Therapy NCIT:C159273; Rehabilitation NCIT:C15315 |
| Hearing habilitation for ANSD (amplification, cochlear implant candidacy, early language intervention) | Harper 2020: delays "can impact patient's language acquisition and spoken language skills" | Rehabilitation NCIT:C15315; for a device, follow the cochlear-implant qualifier pattern in CLAUDE.md |
| Palliative care | Smigiel 2018 | Supportive Care NCIT:C15747 |
| Genetic counselling, carrier testing | All families | Genetic Counseling NCIT:C15240 |
Pharmacogenomics, gene/cell/RNA therapy, targeted or immunotherapy. None exist or are in development for the genetic disease. Immunotherapies (rituximab, IVIG) apply only to the autoimmune nodopathies and must not be imported.
Clinical trials. ClinicalTrials.gov search for "NFASC OR neurofascin" (2026-10-15) returns only four CIDP/combined central-peripheral demyelination studies (NCT04480450, NCT06325943, NCT05877040, NCT04664647); none concerns the genetic disorder.
Treatment outcomes. Not reported beyond survival on support.
| Model | Isoform(s) lost | Key phenotypes | Fidelity to NEDCPMD | Source |
|---|---|---|---|---|
| Nfasc-null mouse | All | Die ~P7 at onset of saltatory conduction; "neither paranodal adhesion junctions nor nodal complexes are formed"; "sodium channels remain diffusely distributed along the axon"; glial Nfasc155 transgene restores paranodes but not nodes | Models the combined-isoform severe tier; lethality precludes neurodevelopmental readouts | Sherman 2005, PMID:16337912 |
| Nfasc-null + neuronal Nfasc186 or Nfasc140 transgene | Nfasc155 only (effectively) | Survive to adulthood, ataxic, PNS conduction velocity ~50% of normal | Models Nfasc155-only loss with neuronal compensation | Sherman 2005; Zonta 2008 (cited in Smigiel) |
| Glia-specific Nfasc155 cKO (Cnp-Cre / P0-Cre) | Nfasc155 | "severe ataxia, motor paresis, and death before the third postnatal week" (P16–17); conduction velocity roughly halved; transverse bands absent; Caspr/contactin fail to localise; Kv1.1 mislocalised; Purkinje axon swellings | High for Branch A; Smigiel: "the phenotype of our proband reflects the severity of the murine phenotype" | Pillai 2009, PMID:19185024 |
| Adult-onset Nfasc155 ablation (Plp-CreER) | Nfasc155 | Gradual paranode disorganisation over 60–90 days; CV modestly reduced; Kv1.1 migrates toward node | Models maintenance role; relevant to progression | Pillai 2009 |
| Neuron-specific Nfasc186 cKO | Nfasc186 | Nodes disrupted; "the paranodal domains invade the nodal space"; reduced nodal Nav and ankyrin-G | Branch B nodal component | Thaxton 2011, PMID:21262464 |
| Postnatal Nfasc186 ± Nfasc155 ablation | Nfasc186; both | "progressive nodal destabilization and axonal degeneration"; Nfasc155 loss alone "does not disrupt nodes"; double loss accelerates | Predicts late PNS involvement in NF186 tier | Taylor 2017, PMID:28217083 |
| Adult Purkinje-cell Nfasc inactivation | Nfasc186 (AIS) | "rapid loss of Nfasc186 from the AIS but not from nodes of Ranvier"; AIS disintegrates; motor-learning impairment; tonic Purkinje firing abolished; "basic motor abilities remain intact" | Branch B cerebellar component (milder than human) | Zonta 2011, PMID:21382554 |
| Developmental Purkinje ± basket cell Nfasc cKO | Nfasc186 | AIS maturation blocked; pinceau disorganisation; "Purkinje neuron degeneration, and severe ataxia" | High for the ataxic tier | Buttermore 2012, PMID:22492029 |
| Purkinje-specific NF186 / AnkG / double cKO | Nfasc186 | AIS cytoskeleton disrupted; Nav/Kv mislocalised P10–30; Purkinje degeneration and cerebellar dysfunction by 2 months; NF186 loss "predominantly activated immune-inflammatory pathways" | Newest cerebellar model | Shi 2026, PMID:42052621 |
| Zebrafish nfasca mutants / oligodendrocyte Nfasc loss | Glial and neuronal | Myelin mistargeted to cell bodies, reduced sheath growth; longer and irregular internodes | CNS myelination component of Branch A | Klingseisen 2019, PMID:31761670; Vagionitis 2022, PMID:35172135 |
| Patient iPSC-derived neurons (c.3020-1G>A) | Nfasc186 | No NF186 mRNA/protein; ankyrin-G reduced; neurites fewer (8 vs 12) and shorter (123 vs 270 µm); SLIT3 up; DCX/MAP2 under-induced; Na⁺ current activates ~10 mV more negative with lower density | Human, IN_VITRO; directly links NF186 loss to neurogenesis and excitability | Kvarnung 2019, PMID:31608123 |
| Patient iPSC-derived neurons (p.V1122E) | Transmembrane | "significant loss of Neurofascin protein" | Human, IN_VITRO | Monfrini 2019, PMID:30850329 |
| HEK293 / N2A heterologous assays | Nfasc155, Nfasc186 variants | Surface expression, immunoblot abundance, CNTN1/CASPR1 aggregation, gliomedin binding | IN_VITRO variant functional grading | Efthymiou 2019 |
| 500 ns molecular dynamics of mutant ectodomains (PDB 3P3Y template) | — | p.N130D "slightly compressed"; p.R370P disrupts β-strand H-bond network | COMPUTATIONAL | Efthymiou 2019 |
Limitations. No mouse model carries a patient allele; all are null or conditional. Mouse Nfasc155 cKO lethality at P17 is more severe than the human NF155-only phenotype permits study of; adult Purkinje ablation is milder than the human ataxia. None reproduces the human cortical white-matter loss or intellectual disability directly. A HUMAN_MODEL_MISMATCH discussion is warranted for the CNS cognitive phenotype.
Resources. MGI lists 22 Nfasc alleles (7 targeted, 7 gene-trap, 3 transgenic, 2 endonuclease, 2 chemically induced, 1 radiation) and 24 phenotype annotations (MGI:104753).
DISEASE entry anchored to MONDO:0032698 is right; the two tiers are best handled as has_subtypes (for example "NF155-deficient" and "NF186-deficient") stratifying onset, neuropathy, MRI pattern, and prognosis, rather than as separate entries. OMIM, MONDO, GenCC and PanelApp all treat it as one disease.schwann_cell_myelin_maintenance#Nerve Conduction Slowing and Conduction Block and #Secondary Axonal Loss and Length-Dependent Deficit fit Branch A; cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath and #Axonal Degeneration and Progressive White Matter Dysfunction fit the central white-matter arm; cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration → #Cerebellar Ataxia fits Branch B. Congenital_Hypomyelinating_Neuropathy already has a "Paranodal Axo-Glial Junction Failure" node that is the natural cross-reference for the CNTNAP1 sibling disease.ORPHA: record (none exists), any CGGV: record (ClinGen has not curated NFASC), or trial NCT identifiers (none are relevant).Sources consulted (primary): Smigiel 2018, Hum Mol Genet · Monfrini 2019, Parkinsonism Relat Disord · Efthymiou 2019, Brain · Karakaya & Wirth 2019, Brain commentary · Kvarnung 2019, Front Genet · Harper 2020, Int J Pediatr Otorhinolaryngol · Anazi 2017, Hum Genet · Sherman 2005, Neuron · Pillai 2009, J Neurosci Res · Thaxton 2011, Neuron · Zonta 2011, Neuron · Buttermore 2012, J Neurosci · Taylor 2017, Front Cell Neurosci · Klingseisen 2019, Dev Cell · Vagionitis 2022, Cell Rep · Shi 2026, Front Cell Neurosci · Maluenda 2016, AJHG · MedGen 1674767 · HPO annotations OMIM:618356 · GenCC NFASC · ClinGen NFASC · PanelApp Hereditary ataxia · gnomAD NFASC · UniProt O94856 · MGI Nfasc · KEGG H02990
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 19 |
| Resolved | 19 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 6 |
| Quoted claims found in source | 5 |
| Quoted claims not found in source | 1 |
| Quoted claims with nothing to check against | 2 |
| References weighed for topical relevance | 19 |
| On topic | 7 |
| Off topic | 3 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:35172135 (abstract only): "prefigure the position of a subset of nodes"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:31761670 (6 mentions) - Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.PMID:27616481 (4 mentions) - Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.PMID:35172135 (6 mentions) - Clusters of neuronal neurofascin prefigure the position of a subset of nodes of Ranvier along individual central nervous system axons in vivo.Weighed against this report's own most characteristic terms: efthymiou, patient, smigiel, loss, nfasc, kvarnung, paranodal, phenotype, sibling, variant, monfrini, severe, harper, nfasc155, disease, node, failure, motor, ataxia, tier.
There was no text to compare these against, so they are neither confirmed nor contradicted:
PMID:31560060: "hereditary nodo-paranodopathy"PMID:31560060: "Only variants in the fibronectin type III domain significantly reduced protein levels"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 122 |
| Resolved | 117 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 5 |
| Terms whose name was checked | 21 |
| Terms named correctly | 15 |
| Terms named as a different term | 1 |
| Terms whose name is worth a second look | 5 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0001276 (1 mention) - the report calls it "Hypertonia (generalized, upper limb)"; HP calls it HypertoniaThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0031936 (1 mention) - the report calls it "Delayed ability to walk; no independent ambulation"; HP calls it Delayed ability to walkHP:0001558 (1 mention) - the report calls it "Decreased fetal movement; polyhydramnios"; HP calls it Decreased fetal movement, and lists "Decreased fetal movements" among its other namesHP:0000878 (1 mention) - the report calls it "11 pairs of ribs; chest deformity"; HP calls it 11 pairs of ribsHP:0001187 (1 mention) - the report calls it "Hyperextensibility of finger joints"; HP calls it Hyperextensibility of the finger jointsHP:0002079 (1 mention) - the report calls it "Hypoplasia / atrophy of corpus callosum"; HP calls it Hypoplasia of the corpus callosum, and lists "Hypoplasia of corpus callosum" among its other namesTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, MGI.