Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 7

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Inheritance

1

Autosomal recessive HP:0000007

Both alleles of VWA1 must be inactivated. Homozygosity for the founder allele and compound heterozygosity for the founder allele with a second truncating variant are both common; consanguinity is reported but is not the usual setting — the fifteen families of the 2024 cohort were mostly non-consanguineous, with consanguinity in two, of Iranian and Pakistani origin. The reported pedigrees are overwhelmingly sporadic — only one of fifteen families in the first cohort had a positive family history.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:33459760 SUPPORT Human Clinical

"Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition"

States the mode of inheritance directly.

PMID:33559681 SUPPORT Human Clinical

"Positive family history was reported only in Family 13, while the rest of the cases were sporadic."

Records that the recessive condition presents sporadically in nearly all families.

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Mechanistic Hypotheses

2

Myopathic change is secondary to chronic denervation

denervation_secondary_myopathy CANONICAL

Evidence balance 2 support

On this model the only primary lesion is in the peripheral nerve: loss of WARP from the nerve basement membrane causes motor axon loss, and every muscle finding — raised creatine kinase, myopathic motor units on needle EMG, dystrophic features on biopsy, fatty replacement on MRI — is a downstream consequence of long-standing denervation and reinnervation. Pagnamenta et al. argued this explicitly, noting that the histological features classically attributed to myopathy are also found in chronically denervated muscle, and that collagen VI immunolabelling was normal in the patient biopsies where it was assessed.

Pathograph links

Chronic Neurogenic Denervation of Skeletal Muscle -> Myopathic Change in Skeletal Muscle INDIRECT KNOWN INTERMEDIATES Under the canonical model, the myopathic findings arise on the background of chronic denervation rather than from a second primary lesion. This edge belongs to that hypothesis group.

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process."

States the canonical position — the myopathic findings are read as a consequence of denervation, not as a second primary lesion.

PMID:33559681 SUPPORT Human Clinical

"Where data were available, immunohistochemical labelling for collagen VI appeared normal."

The collagen VI partner of WARP is normally deposited in patient muscle, which is the observation the secondary-myopathy model leans on: the matrix abnormality expected of a primary muscle-matrix disease was not found.

The muscle is primarily affected through its own extracellular matrix

primary_muscle_matrix_lesion ALTERNATIVE

Evidence balance 3 support

On this model WARP loss injures the muscle directly, because WARP is a constituent of the muscle extracellular matrix as well as of the nerve basement membrane, so the disease is a neuromyopathy with two primary targets rather than a neuropathy with a denervated muscle. The Deschauer cohort named the condition a neuromyopathy on combined myopathological and neurophysiological grounds; a proteomic study of patient white blood cells, plasma and muscle set out explicitly to test for primary muscle vulnerability and reported extracellular accumulation of C-reactive protein and of NEFM in patient muscle; and muscle MRI in two independent reports shows an outside-in vastus lateralis pattern of the kind seen in collagen VI-related myopathy rather than the pattern expected of denervation.

Pathograph links

Depletion of WARP from Nerve and Muscle Basement Membrane -> Muscle Extracellular Matrix Remodeling INDIRECT UNKNOWN INTERMEDIATES Under the primary-muscle-lesion model, loss of WARP from the endomysial matrix is itself the muscle insult. This edge belongs to that hypothesis group and is not asserted under the canonical model.

Muscle Extracellular Matrix Remodeling -> Myopathic Change in Skeletal Muscle INDIRECT UNKNOWN INTERMEDIATES Under the primary-lesion model the matrix abnormality is what makes the muscle myopathic. No study has demonstrated the intervening steps.

Show evidence (3 references)

PMID:33459760 SUPPORT Human Clinical

"Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology."

The cohort that named the condition a neuromyopathy states the combined pathology on which that name rests.

PMID:38652110 SUPPORT Human Clinical

"NEFM showed an increase in cells within the ECM in biopsies of all patients studied."

A muscle-matrix abnormality found in every patient biopsy examined, offered by that study as evidence bearing on primary muscle involvement.

PMID:41331965 SUPPORT Human Clinical

"Muscle magnetic resonance imaging showed a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies."

An imaging pattern characteristic of a primary matrix myopathy rather than of denervation, in a muscle that is also a target of the collagen VI disorders WARP partners with.

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Discussions and Knowledge Gaps

3

Is the muscle involvement in VWA1-related disease a primary lesion of the muscle extracellular matrix, or a secondary consequence of chronic denervation?

CONTROVERSY OPEN vwa1_primary_or_secondary_myopathy

Attached to

pathophysiology#Myopathic Change in Skeletal Muscle pathophysiology#Muscle Extracellular Matrix Remodeling pathophysiology#Chronic Neurogenic Denervation of Skeletal Muscle mechanistic_hypotheses#denervation_secondary_myopathy mechanistic_hypotheses#primary_muscle_matrix_lesion

The two cohorts that described the disease concurrently, in the same journal and the same year, named it differently, and the disagreement has not been resolved by any subsequent study. It is not a naming quibble: the answer determines whether the entity belongs with the motor neuropathies or with the muscular dystrophies for the purposes of gene-panel design, and it determines what a future therapy would have to reach. For a secondary process: needle EMG was neurogenic in 10 of 12 studies and myopathic in a minority; four of seven biopsies were purely neurogenic; collagen VI immunolabelling was normal wherever assessed; the WARP-null mouse has no detectable skeletal muscle abnormality at all; and the histological features attributed to myopathy are known to occur in chronically denervated muscle. For a primary process: WARP is expressed in skeletal muscle as well as nerve and binds collagen VI, whose own disorders are muscular dystrophies; creatine kinase is raised in most patients and reached 2400 U/L; muscle MRI in several patients shows an outside-in vastus lateralis pattern typical of collagen VI myopathy rather than of denervation; proteomics found increased C-reactive protein and NEFM in the extracellular space of patient muscle; and a whole-body MRI series in which gracilis and sartorius were spared in all five VWA1 patients reads that sparing as evidence for a direct muscle effect. What would settle it: WARP immunostaining of patient muscle and nerve alongside quantitative matrix analysis, in patients whose denervation burden is measured independently; or a conditional muscle-restricted Vwa1 knockout. Neither has been reported.

Show evidence (3 references)

PMID:39502942 SUPPORT Human Clinical

"Nevertheless, the true myopathic nature of the disease remained controversial, with some proposing a primarily neurogenic pathology and a secondary myopathic process."

States that the question is open and names both positions, which is exactly what this discussion records.

PMID:42662709 SUPPORT Human Clinical

"It is therefore possible that the preservation of the sartorius and gracilis muscles in SMA indicates a pathophysiologic mechanism involving direct muscle effects and may provide information useful for interpreting VUS."

The most recent argument for a direct muscle effect, from an imaging pattern rather than from histology.

PMID:38652110 SUPPORT Human Clinical

"Moreover, there is no common consent if the muscular affection is a secondary pathology based on vulnerability and dysfunction of motoric axons or if a primary muscle pathology is rather part of the clinical picture."

An independent statement that no consensus exists, from the group that set out to test the question.

Why do some patients with biallelic VWA1 variants have upper motor neuron signs, when the gene product is a peripheral nerve and muscle matrix protein and the largest cohort found none?

KNOWLEDGE GAP OPEN vwa1_upper_motor_neuron_signs

Attached to

phenotypes#Hyperreflexia phenotypes#Spasticity

The first cohort recorded largely normal muscle tone and uniformly negative Babinski signs across its 17 patients. A subsequent two-child report made upper motor neuron signs its title finding, and the 20-patient cohort that followed recorded hyperreflexia, spasticity in two and upgoing plantars in two. No mechanism has been proposed. The possibilities are not distinguished by any published data: ascertainment drift as the phenotype widened, a genuine central component of a protein that is also expressed in the vasculature of neural tissues, or coincidence in a population where one causal allele is carried by roughly one person in 441 and so will sometimes be found alongside an unrelated condition. The third possibility is specifically worth testing for a disease whose defining allele is this common, and no report has excluded it.

Show evidence (2 references)

PMID:35975723 SUPPORT Human Clinical

"Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1."

The report that introduced upper motor neuron signs into the phenotype, and its sample size.

PMID:18314316 SUPPORT PRIMARY RESULT Model Organism

"WARP is expressed in the vasculature of neural tissues and in basement membrane structures of the peripheral nervous system."

Records the one piece of expression data that would make a central component biologically conceivable; it establishes vascular expression in neural tissue, not a corticospinal role.

Does the 2026 Muscle Nerve case report (PMID:41416782) establish minipolymyoclonus and fasciculations as features of VWA1-related disease, and should they be curated as phenotypes?

CURATION TODO OPEN vwa1_2026_minipolymyoclonus_case_full_text

Attached to

phenotypes#Scapular winging phenotypes#Tongue fasciculations

The report's title names minipolymyoclonus, fasciculations and scapular winging in a novel VWA1 variant, and minipolymyoclonus is not currently curated in this entry at all. It cannot be curated from what is available: the record is a Letter, and `just fetch-reference PMID:41416782` returns `content_type: unavailable` with an empty body, so the only text obtainable is the title. A title is not a finding, and curating a phenotype from one would be exactly the fabrication the evidence SOP exists to prevent. This is therefore filed as a task, not written in. Resolving it needs the full text: confirm that minipolymyoclonus was observed in a genetically confirmed patient, find the HP term for it, and check whether the fasciculations are tongue or limb. The scapular winging in the title is already curated from the 2024 cohort and needs no change. Noted because minipolymyoclonus would be a genuinely new feature of the phenotype rather than a restatement — it is a sign of motor-unit loss and would attach to the same axon-loss node as the tongue fasciculations.

Surfaced by the post-hoc deep-research cross-check (research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_7-deep-research-claude_code.md), which asserted the finding on the strength of the title alone. The cache file references_cache/PMID_41416782.md is committed so a later curator can confirm the empty body rather than re-fetching to discover it.

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Pathophysiology

8

Biallelic VWA1 Loss-of-Function Variants

Mechanism confidence: Established

Two loss-of-function alleles of VWA1, the gene encoding the extracellular matrix protein WARP. Reported alleles are predominantly frameshifts and stop-gains, with a small number of missense changes affecting proline residues; the disease-defining allele is the 10 bp exon 1 duplication NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74), which was present in 14 of 15 families in the first reported cohort and in 12 of 15 families in the 2024 cohort. Both homozygosity for that allele and compound heterozygosity for it in trans with a second truncating variant are common.

VWA1 hgnc:30910

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Biallelic germline loss of function; both homozygous and compound heterozygous genotypes are reported, the latter usually with the founder allele in trans.

Downstream

Nonsense-Mediated Decay and Absence of WARP Protein The founder duplication shifts the reading frame and introduces a premature stop 74 codons downstream, and patient fibroblasts show both reduced transcript rescued by a nonsense-mediated decay inhibitor and no detectable protein.

Show evidence (2 references)

PMID:33459760 SUPPORT Human Clinical

"Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder."

Establishes biallelic VWA1 loss of function as the molecular cause of the condition.

PMID:33559681 SUPPORT Human Clinical

"A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15."

Identifies the recurrent founder allele and its frequency within the first reported cohort.

Nonsense-Mediated Decay and Absence of WARP Protein

Mechanism confidence: Established

Transcripts carrying the premature termination codon are partially degraded by nonsense-mediated decay, and no WARP protein is detectable in patient dermal fibroblasts in either the cell layer or the conditioned medium, whereas control fibroblasts secrete detectable protein. In the mouse the protein is abundant in sciatic nerve and is efficiently deposited into the matrix, so the human null state removes a protein that is normally present at the site of disease.

nonsense-mediated decay of the mutant VWA1 transcript GO:0000184 ↑ INCREASED

WARP as a structural constituent of the extracellular matrix GO:0005201 ∅ ABSENT

Downstream

Depletion of WARP from Nerve and Muscle Basement Membrane WARP is an extracellular matrix protein of muscle and peripheral nerve that binds collagen VI and perlecan, so an undetectable protein is an absent matrix constituent at those sites.

Show evidence (2 references)

PMID:33559681 SUPPORT In Vitro

"However, there was no detectable VWA1 in either the conditioned medium or cell layer of the patient’s fibroblast"

Direct demonstration that the patient cell makes no detectable WARP protein to secrete or deposit.

PMID:33559681 SUPPORT Model Organism

"A high level of VWA1 was detected in mouse sciatic nerve extraction. In the primary culture of mouse sciatic nerve, VWA1 was detectable in its cell layer (cytoplasm and ECM) but not in the conditioned medium, indicating the secreted VWA1 was able to deposit as ECM efficiently."

Establishes that the protein lost in patients is normally abundant in peripheral nerve and is deposited into the matrix there.

Depletion of WARP from Nerve and Muscle Basement Membrane

Mechanism confidence: Established

WARP is expressed in the basement membrane structures of the peripheral nervous system and is most abundant, among human tissues surveyed, in tibial nerve. Its loss leaves the nerve basement membrane structurally abnormal: electron microscopy of WARP-deficient mouse sciatic nerve shows partial fusion of the basement membranes of neighbouring axons, and collagen VI is reduced in regions of the peripheral nerve matrix. WARP is co-expressed with collagen VI in the endomysium of muscle, so the same deficit exists on the muscle side, but the mouse showed no histological or behavioural muscle pathology and collagen VI labelling is normal in patient muscle — which is why the muscle arm of this node is curated as contested rather than established.

The muscle is primarily affected through its own extracellular matrix

Schwann cell CL:0002573

basement membrane organization GO:0071711 ⚠ ABNORMAL

basement membrane GO:0005604

tibial nerve UBERON:0001323 skeletal muscle tissue UBERON:0001134

Animal models

Vwa1 (WARP) knockout mouse Mouse partially recapitulates The mouse supplies the ultrastructural nerve-matrix lesion that gives this node its content, since no human nerve has been examined this way.

Downstream

Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation Knockdown and knockout of the zebrafish orthologue shorten spinal motor axons and reduce acetylcholine receptor clustering in skeletal muscle, placing the matrix deficit upstream of motor axon growth and endplate formation.

Non-Length-Dependent Motor Axon Loss WARP loss compromises peripheral nerve structure and function in the knockout mouse, and the human null state produces a motor axonal neuropathy; the steps between the abnormal nerve basement membrane and axon loss are not established.

Muscle Extracellular Matrix Remodeling Under the primary-muscle-lesion model, loss of WARP from the endomysial matrix is itself the muscle insult. This edge belongs to that hypothesis group and is not asserted under the canonical model.

Show evidence (4 references)

PMID:18314316 SUPPORT PRIMARY RESULT Model Organism

"WARP is expressed in the vasculature of neural tissues and in basement membrane structures of the peripheral nervous system. Furthermore, WARP is also expressed in the apical ectodermal ridge of developing limb buds, and in skeletal and cardiac muscle."

The reporter-gene study that established where WARP sits — peripheral nerve basement membrane and skeletal muscle — which is what this node claims is depleted.

PMID:19279005 SUPPORT PRIMARY RESULT Model Organism

"Further ultrastructural analysis revealed reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes, suggesting an important function for WARP in stabilizing the association of the collagenous..."

The primary ultrastructural result defining the lesion at this node, and the authors' own statement of what WARP does there.

PMID:19279005 SUPPORT PRIMARY RESULT Model Organism

"Immunostaining of WARP-interacting ligands demonstrated that the collagen VI microfibrillar matrix was severely reduced and mislocalized in peripheral nerves of WARP-null mice."

Shows that WARP loss disorganises the collagen VI matrix specifically in nerve, which is the mechanistic content of this node's nerve arm.

+ 1 more reference

Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation

Mechanism confidence: Provisional

In the zebrafish model, loss of the vwa1 orthologue significantly reduces spinal motor neuron growth measured across days 2 to 4 of development, with aberrant axon structures from day 3, sparser and disorganised myofibres, and significantly reduced synapse formation in skeletal muscle measured by acetylcholine receptor staining, followed by reduced locomotive behaviour. This places the defect early — at the point where motor axons grow out and form endplates — rather than at a later dying-back stage, which fits the human observation that foot deformity and tendon contracture are present from the first years of life and were congenital in two cases.

motor neuron CL:0000100

motor axon extension GO:0048675 ↓ DECREASED neuromuscular junction development GO:0007528 ⚠ ABNORMAL

Animal models

vwa1 CRISPR knockout and morpholino knockdown zebrafish Zebrafish recapitulates The model is the only experimental evidence that WARP loss affects motor axon growth and endplate formation, and it is what the node is built on.

Downstream

Non-Length-Dependent Motor Axon Loss A developmental deficit in motor axon growth and endplate formation is offered by the authors as the origin of the human motor neuropathy, but the route from an early developmental deficit to progressive adult axon loss is not worked out.

Show evidence (2 references)

PMID:33559681 SUPPORT Model Organism

"CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour."

Summarises the three model readouts that define this node — axon growth, synapse formation, and locomotion.

PMID:33559681 SUPPORT Model Organism

"Phenotypic assessment of the vwa1 crispants/morphants demonstrated a prominent effect on motor neurons including shorter axons and abnormal growth."

The primary axon-growth observation behind this node.

Non-Length-Dependent Motor Axon Loss

Mechanism confidence: Established

Loss of motor axons producing reduced or absent compound motor action potentials with preserved conduction velocities — an axonal, not demyelinating, motor neuropathy — and normal sensory studies in most patients. The distinguishing feature of this disease is that the loss is not graded by axon length: three-quarters of the first cohort had simultaneous proximal and distal lower limb weakness, and in almost half of those the proximal weakness was the more severe. That is the opposite of the distal-first gradient that defines most of the distal hereditary motor neuropathies, and it is why this entry does not conform to the length-dependent peripheral axonal degeneration module.

motor neuron CL:0000100

Downstream

Motor axonal neuropathy Axon loss with preserved conduction velocity is what the nerve conduction study records.

Distal lower limb muscle weakness Loss of the motor axons supplying the distal leg muscles.

Proximal lower limb muscle weakness The same axon loss reaches proximal motor units without an intervening distal-to-proximal progression, which is the non-length-dependent feature.

Foot dorsiflexor weakness Weakness of ankle dorsiflexion producing foot drop, the commonest presenting sign.

Hyporeflexia The motor axon is the efferent limb of the tendon reflex arc, so its loss reduces the reflex; reflexes were diminished in half of the first cohort.

Tongue fasciculations Reported in a minority of adults and grouped by both cohorts with the motor-neuron features of the disease; no study localises the lesion for this sign, so the edge is typed as indirect.

Chronic Neurogenic Denervation of Skeletal Muscle Motor axon loss denervates the muscle fibres of the affected motor units; needle EMG shows chronic neurogenic change without active denervation in most patients, the picture of long-standing denervation with reinnervation.

Show evidence (3 references)

PMID:33559681 SUPPORT Human Clinical

"Motor nerve action potentials from the lower limb nerves were reduced or undetectable with uniformly preserved conduction velocities. Sensory studies were overall normal."

Establishes the lesion as motor axon loss rather than demyelination or a sensorimotor process.

PMID:33559681 SUPPORT Human Clinical

"In almost half of those cases, weakness was more pronounced proximally, and one-quarter had equally weak proximal and distal muscle groups, raising the clinical suspicion of non-length dependent motor axonal neuropathy."

Establishes the non-length-dependent distribution that separates this disease from the rest of the dHMN family.

PMID:35942667 SUPPORT REVIEW SYNTHESIS Other

"Distal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons."

Gives the family definition this disease departs from: length-dependence is the defining feature of the dHMNs in general, and is absent here.

Chronic Neurogenic Denervation of Skeletal Muscle

Mechanism confidence: Established

Muscle downstream of the lost motor axons undergoes denervation with partial reinnervation, producing the classical morphological signature: fibre type grouping, fascicular grouping of type 1 fibres, and neurogenic atrophy, with a moth-eaten pattern on muscle ultrasound in long-standing denervation without reinnervation. Four of seven biopsies in the first cohort showed clear neurogenic changes.

Myopathic change is secondary to chronic denervation

skeletal muscle fiber CL:0008002

Downstream

EMG: chronic denervation signs Chronic denervation with reinnervation is what needle EMG records in most patients.

Fiber type grouping Reinnervation of denervated fibres by surviving motor units regroups fibre types within the fascicle.

Skeletal muscle atrophy Denervation atrophy, predominantly of the distal leg muscles.

Myopathic Change in Skeletal Muscle Under the canonical model, the myopathic findings arise on the background of chronic denervation rather than from a second primary lesion. This edge belongs to that hypothesis group.

Show evidence (2 references)

PMID:39502942 SUPPORT Human Clinical

"Muscle ultrasound of the left tibialis anterior from the same patient shows a moth-eaten pattern consisting of round, dark areas with remaining viable motor units, surrounded by tissue with increased greyscale level reflecting permanently denervated and fibrosed muscle tissue."

Describes denervated muscle tissue directly, with the imaging correlate of surviving versus lost motor units.

PMID:33559681 SUPPORT Human Clinical

"Muscle biopsies were performed in seven cases, of which four were available for review (Fig. 3). In 4/7 of these, clear neurogenic changes were reported."

Gives the proportion of biopsies showing neurogenic change in the first cohort.

Muscle Extracellular Matrix Remodeling

Mechanism confidence: Hypothetical

An abnormality of the muscle extracellular space itself in patients lacking WARP, independent of any denervation. Proteomic profiling of patient white blood cells, plasma and muscle reported increased C-reactive protein in the extracellular space of VWA1-mutant muscle and increased NEFM in cells within the muscle matrix of every patient biopsy examined, and the plasma signature was dominated by proteins related to antioxidative processes. This node exists only under the alternative hypothesis that the muscle is a primary target; it is not asserted under the canonical model.

The muscle is primarily affected through its own extracellular matrix

extracellular matrix organization in skeletal muscle GO:0030198 ⚠ ABNORMAL

Animal models

Vwa1 (WARP) knockout mouse Mouse fails to recapitulate The knockout mouse shows no muscle pathology at all, which is the strongest single piece of evidence against a primary muscle lesion.

Downstream

Myopathic Change in Skeletal Muscle Under the primary-lesion model the matrix abnormality is what makes the muscle myopathic. No study has demonstrated the intervening steps.

Show evidence (1 reference)

PMID:38652110 SUPPORT Human Clinical

"Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular..."

Reports the plasma protein signature attributed to the disease, weighted toward antioxidative processes.

Myopathic Change in Skeletal Muscle

Mechanism confidence: Established

Myopathic features in patient muscle: a dystrophic pattern with ring fibres in one biopsy, fibre lobulation and whorling of myofibrils in another, marked variation in fibre size with increased endomysial fibrosis and perimysial fatty infiltration, rimmed vacuoles in one case, myopathic motor units on needle EMG in a minority, and raised creatine kinase in most patients. Both hypothesis groups converge on this node; they differ only in what produces it.

skeletal muscle fiber CL:0008002

Downstream

EMG: myopathic abnormalities Myopathic motor unit potentials on needle EMG, reported in a minority of patients in both cohorts.

Increased endomysial connective tissue Endomysial fibrosis with perimysial and endomysial fatty infiltration is one of the myopathic biopsy features listed at this node. Note the same biopsies also show endomysial and perimysial thickening attributed to the chronic neurogenic process, so this edge records where the finding is reported, not that denervation can be excluded as its cause.

Elevated circulating creatine kinase concentration Release of creatine kinase from damaged muscle fibres.

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"In the other three biopsies there was evidence for myopathic features in addition to findings suggestive of an underlying neurogenic process."

Records the coexistence of myopathic and neurogenic features in the same biopsies.

PMID:39502942 SUPPORT Human Clinical

"Histological data were available for three cases, revealing a dystrophic pattern in one with multiple ring fibres, while the other two exhibited extensive fibre grouping indicative of neurogenic changes."

Gives the proportion of biopsies that were dystrophic rather than neurogenic in the second cohort.

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Histopathology

3

Neurogenic atrophy with fibre type grouping FREQUENT

Muscle biopsy in most patients shows chronic neurogenic change: neurogenic atrophy, fascicular grouping of type 1 fibres, thickening of the endomysium and perimysium. Four of seven biopsies in the first cohort were reported as showing clear neurogenic changes.

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Biopsy shows predominantly neuropathic aspects with neurogenic atrophy (arrow) and thickening of the endomysium and perimysium. Fascicular grouping of type 1 fibres implicates a chronic neurogenic process."

Describes the neurogenic biopsy picture in a named patient.

Myopathic and dystrophic features OCCASIONAL

A minority of biopsies show myopathic change alongside the neurogenic change: marked variation in fibre size, fibre hypertrophy, increased endomysial fibrosis with endomysial and perimysial fatty infiltration, rimmed vacuoles in one case, fibre lobulation and whorling of myofibrils in another, and a dystrophic pattern with multiple ring fibres in one patient of the second cohort. Collagen VI labelling was normal wherever it was assessed, which is the single most important negative finding in this disease.

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"Marked variation in fibres size and increased endomysial fibrosis with mostly perimysial fatty infiltration. Rimmed vacuoles are shown with an arrow."

Describes the myopathic features in a named patient biopsy.

PMID:33559681 SUPPORT Human Clinical

"Where data were available, immunohistochemical labelling for collagen VI appeared normal."

Records the normal collagen VI labelling, the negative result that argues against a collagen VI-like primary matrix myopathy.

Motheaten muscle fibers OCCASIONAL

Moth-eaten fibres on NADH-TR staining, recorded in one patient biopsy of the first cohort and explicitly annotated there as a non-specific finding. It is curated because it is part of the published biopsy description, not because it discriminates.

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"NADH-TR shows the presence of moth-eaten fibres (non-specific finding)."

Records the finding together with the authors' own statement that it is non-specific.

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Pathograph

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Phenotypes

25

Head and Neck 1

Tongue fasciculations OCCASIONAL HP:0001308

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"Unique features of VWA1 disease include scapular winging, tongue fasciculations and, recently reported,7 pyramidal signs such as upgoing plantars and/or spasticity in the lower limbs."

Names tongue fasciculation among the distinguishing features of the condition.

Limbs 7

Foot dorsiflexor weakness VERY_FREQUENT HP:0009027

Sequelae: Pes cavus Talipes equinovarus Achilles tendon contracture Tip-toe gait

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Bilateral foot drop, impaired toe walking, forward posture, and wasting in the lower limbs were frequently observed signs."

Records bilateral foot drop as a frequent sign in the first cohort.

Distal lower limb muscle weakness VERY_FREQUENT HP:0009053

Sequelae: Falls

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"The age of onset varied from birth to 12 years, with consistent early involvement of the distal lower limbs, presenting as various foot deformities, gait disturbances, frequent falls and ankle contractures."

Records consistent early distal lower limb involvement and the range of onset ages.

Proximal lower limb muscle weakness FREQUENT HP:0008994

Show evidence (2 references)

PMID:39502942 SUPPORT Human Clinical

"While the most common features of VWA1-related disease include foot drop, foot deformities and distal lower limb weakness, about half of the so far reported individuals develop proximal leg weakness over time, and approximately one-third experience upper limb involvement"

Gives the proportion developing proximal leg weakness across all reported patients.

PMID:39502942 SUPPORT Human Clinical

"A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (VWA1)."

Names early proximal limb involvement as the characterising feature of the entity.

Pes cavus FREQUENT HP:0001761

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"ranging from pes cavus (65%, 11/17) to talipes equinovarus (35%, 6/17)"

Gives the exact frequency of pes cavus in the first cohort.

Talipes equinovarus OCCASIONAL HP:0001762

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Independent walking in the cohort was achieved by the mean age of 1.6 ± 0.8 years and it was remarkably delayed in cases with foot deformities such as severe bilateral equinovarus (18%, 3/17)."

Records severe bilateral equinovarus and its effect on the age of independent walking.

Achilles tendon contracture FREQUENT HP:0001771

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Less frequent but present in more than half of the cohort were flexion tendon contractures typically involving foot plantar flexion, knee, and hip flexion but in some cases, it was also present in the major joints of the upper limbs."

Gives the frequency and distribution of the contractures.

Scapular winging OCCASIONAL HP:0003691

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"spasticity (n = 2), upgoing plantars (n = 2), scapular winging (n = 2), tongue fasciculations (n = 2)"

Gives the count of patients with scapular winging in the 20-patient cohort.

Metabolism 1

Elevated circulating creatine kinase concentration FREQUENT Elevated circulating creatine kinase activity HP:0003236

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"In six affected individuals, creatine kinase levels were elevated (369–1628 IU/l)."

Gives the count and the measured range in the first cohort.

PMID:39502942 SUPPORT Human Clinical

"Blood tests unveiled elevated creatine kinase (CK) levels in the majority of cases, with the highest value reaching up to 2400 U/L."

Gives the frequency and maximum value in the second cohort.

Musculoskeletal 10

Skeletal muscle atrophy FREQUENT HP:0003202

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"the condition may go unnoticed for years to decades due to its relatively benign nature, often presenting mild neurological deficits, the absence of prominent muscle atrophy and slow disease progression"

States both the mildness of the atrophy and the diagnostic consequence of it.

EMG: chronic denervation signs VERY_FREQUENT HP:0003444

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"EMG typically showed chronic neurogenic changes without active denervation (10/12)."

Gives the exact proportion of EMG studies showing chronic neurogenic change.

EMG: myopathic abnormalities OCCASIONAL HP:0003458

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Three EMG studies were reported to suggest myopathic features, albeit for two of them the formal report was unavailable."

Gives the count of myopathic EMG studies and the authors' own caveat about two of them.

Fiber type grouping FREQUENT HP:0033685

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"the other two exhibited extensive fibre grouping indicative of neurogenic changes"

Records fibre grouping in patient biopsies and names its neurogenic significance.

Scoliosis FREQUENT HP:0002650

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Scoliosis and lumbar hyperlordosis were present in half of the series."

Gives the frequency of scoliosis in the first cohort.

Lumbar hyperlordosis FREQUENT HP:0002938

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Scoliosis and lumbar hyperlordosis were present in half of the series."

Gives the frequency of lumbar hyperlordosis in the first cohort.

Spasticity OCCASIONAL HP:0001257

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"Hyperreflexia, especially when combined with spasticity, might mimic conditions on the hereditary spastic paraplegia spectrum."

Records the spasticity and the diagnostic confusion it creates.

Joint hypermobility VERY_RARE HP:0001382

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"hypermobility/hyperlaxity (n = 1) and dystonia (n = 1)"

Records hypermobility in one patient of the 20-patient cohort.

Increased endomysial connective tissue OCCASIONAL HP:0100297

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Images show marked fibre hypertrophy and increased fibrosis with endo and perimysial fatty infiltration."

Describes the endomysial and perimysial change in a named patient biopsy.

Motheaten muscle fibers VERY_RARE HP:0100298

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"NADH-TR shows the presence of moth-eaten fibres (non-specific finding)."

Records the finding and the authors' own non-specificity caveat.

Nervous System 6

Motor axonal neuropathy OBLIGATE HP:0007002

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"Available nerve conduction studies typically revealed findings consistent with a motor axonal neuropathy which was often interpreted as suggestive of a distal spinal muscular atrophy/hereditary motor neuropathy."

Establishes the motor axonal pattern and the diagnostic label it is usually given.

PMID:33559681 SUPPORT Human Clinical

"Three isolated cases had an abnormal sensory examination and this was supported by neurophysiological evidence in only one of them showing asymmetrical sural nerve involvement (Family 6)."

Quantifies how uncommon sensory involvement is, which is what keeps this a motor rather than sensorimotor neuropathy.

Tip-toe gait FREQUENT HP:0030051

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"The mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations."

Names tip-toe walking among the presenting features and dates it.

Hyporeflexia FREQUENT HP:0001265

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"Tendon reflexes were diminished in half of the cohort"

Gives the frequency of diminished reflexes.

Falls OCCASIONAL HP:0002527

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"One-third of the cases experienced frequent falls"

Gives the frequency of falls in the first cohort.

Hyperreflexia OCCASIONAL HP:0001347

Show evidence (3 references)

PMID:39502942 SUPPORT Human Clinical

"However, individuals in this cohort demonstrated additional features such as frequent falls, hyperreflexia and asymmetric presentation."

Records hyperreflexia as a feature of the second cohort.

PMID:35975723 SUPPORT Human Clinical

"We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum."

The report that introduced upper motor neuron signs into the described phenotype.

PMID:33559681 REFUTE Human Clinical

"muscle tone was largely reported to be normal along with uniformly negative Babinski sign"

The first and largest cohort found no upper motor neuron signs at all, which is why this phenotype is curated as occasional and contested rather than as a feature of the disease.

Dystonia VERY_RARE HP:0001332

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"One child showed only proximal lower limb weakness, while her younger brother retained motor strength but exhibited dystonic features in his legs (Patients 19 and 20 from Family 15)."

Records the dystonic features and the intrafamilial variability they illustrate.

🧬

Genetic Associations

1

VWA1 (Biallelic loss-of-function variants in VWA1 are the sole established cause of this condition. The gene encodes the 445-amino-acid extracellular matrix protein WARP, whose highest expression among human tissues surveyed is in tibial nerve.)

Gene: VWA1 hgnc:30910 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:33459760 SUPPORT Human Clinical

"We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent."

Independent multi-family evidence for biallelic truncating VWA1 variants as the cause.

PMID:33559681 SUPPORT Human Clinical

"we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1"

The concurrent, independently ascertained cohort establishing the same gene-disease relationship.

PMID:33559681 SUPPORT BACKGROUND Other

"In humans, VWA1 (von Willebrand factor A domain containing 1) encodes a 445 amino acid ECM protein that is also referred to as von Willebrand factor A domain related protein (WARP)."

Gives the protein length and the WARP synonym; the sentence restates established gene-product biology rather than reporting a new result.

+ 1 more reference

Variants (1)

NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74) Pathogenic

Gene: VWA1 hgnc:30910

A 10 bp duplication in exon 1 of VWA1, expanding an existing 2-copy 10 bp repeat to 3 copies, producing a frameshift with a premature stop 74 codons downstream. It is the disease-defining allele: present in 14 of 15 families in the first reported cohort and 12 of 15 in the second, and carried on a shared 220 kb European founder haplotype. Its GC-rich, repetitive context gives poor sequencing coverage, which is why the gene evaded discovery and why cases are still missed on standard exome pipelines. Maximum population allele frequency in gnomAD v4.0.0 is 0.093% in European non-Finnish and 0.118% in UK Biobank.

Show evidence (4 references)

PMID:39502942 SUPPORT Human Clinical

"This variant involves an expansion of a 10 bp repeat in Exon 1 of VWA1, leading to three copies instead of two compared with normal alleles."

Describes the exact structure of the founder allele.

PMID:39502942 SUPPORT Human Clinical

"The maximum population allele frequency of the most common variant across all databases remained the highest in the European non-Finnish with 0.093% in gnomAD v4.0.0 and 0.118% in UK Biobank"

Gives the population allele frequencies quoted in this record.

PMID:33559681 SUPPORT Human Clinical

"Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago."

Establishes the founder haplotype and its estimated age.

+ 1 more reference

💊

Medical Actions

4

Physical Therapy and Contracture Management

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitation aimed at the contractures and the gait. Achilles tendon contracture, foot plantar flexion, knee and hip flexion contractures are present in more than half of patients and appear early, so they are the component of the disease most open to non-pharmacological management.

Target Phenotypes: Achilles tendon contracture HP:0001771 Tip-toe gait HP:0030051

Ankle-Foot Orthosis for Foot Drop

Action: ankle-foot orthosis fitting Ontology label: Rehabilitation NCIT:C15315

Platform: Device

Orthotic support for the bilateral foot drop that is the commonest functional problem. The device concept is carried as a qualifier because NCIT's Brace/Orthosis term is a medical device and is not reachable from Clinical Intervention or Procedure, so it cannot sit in the treatment_term slot.

Target Phenotypes: Foot dorsiflexor weakness HP:0009027

Orthopedic Surgery for Foot Deformity

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Corrective surgery for the fixed foot deformities — talipes equinovarus in a third of patients, pes cavus in two thirds — and for the tendon contractures.

Target Phenotypes: Talipes equinovarus HP:0001762 Pes cavus HP:0001761

Genetic Counseling and Targeted Founder Allele Testing

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Counselling for an autosomal recessive condition in which one allele is common enough in Western Europe that two unrelated carriers meeting is the usual genetic setting rather than consanguinity. The practical corollary is diagnostic: the founder duplication sits in a GC-rich repeat that standard exome pipelines under-call, so the authors of both original cohorts recommend targeted testing of VWA1 exon 1 and relaxed quality-control filters when re-analysing unsolved neuropathy exomes.

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses."

The concrete diagnostic recommendation this record exists to carry.

PMID:39502942 SUPPORT Human Clinical

"The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies."

Independent restatement of the same recommendation with the yield it is expected to deliver.

🔬

Diagnosis

2

VWA1 sequencing with attention to the exon 1 repeat

Molecular diagnosis rests on detecting biallelic VWA1 variants. The practical difficulty is specific and technical: the founder allele is a 10 bp duplication in a GC-rich 10 bp repeat in exon 1, a context that gives low coverage and defeats standard variant callers, so the diagnosis is missed on otherwise adequate exome data. Both original cohorts recommend re-analysis of unsolved neuropathy exomes at relaxed quality-control thresholds, and targeted Sanger sequencing of exon 1 in a screening cohort of 1341 unsolved neuropathy patients yielded three further diagnoses.

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"In an attempt to replicate the results obtained from genome/exome sequencing, 1341 DNA samples from two independent cohorts of patients (374 from UK, 967 from Germany) with unsolved neuropathies were tested for the p.G25Rfs*74 founder mutation by screening exon 1 using a Sanger sequencing..."

Reports the targeted-screening yield in unsolved neuropathy cohorts.

Mixed neurogenic and myopathic electrodiagnostic pattern

The combination that should raise the question of this gene: an axonal motor neuropathy with preserved conduction velocities and normal sensory responses, chronic neurogenic change on needle EMG, and in a minority superimposed myopathic units, with raised creatine kinase. A whole-body muscle MRI pattern of gluteus maximus and quadriceps involvement with gracilis and sartorius sparing adds a pre-test imaging clue.

Show evidence (1 reference)

PMID:42662709 SUPPORT Human Clinical

"Gene-specific imaging signatures, particularly for VRK1, DYNC1H1, and VWA1, can guide targeted genetic testing and support interpretation of variants of uncertain significance."

States the diagnostic use the imaging pattern is proposed for.

🩻

Imaging Findings

4

Fatty replacement of vastus lateralis and anterior lower leg FREQUENT

T1-weighted muscle MRI shows increased signal or fatty replacement predominantly in the vastus lateralis and the anterior compartment of the lower legs.

Mri Diagnostic

Fatty replacement of skeletal muscle HP:0012548

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"This displayed increased signal intensity or fatty replacement predominantly in the vastus lateralis and anterior compartment of the lower legs on T1-weighted sequences suggesting chronic denervation"

Gives the distribution of the MRI change and the authors' reading of it as denervation.

Gene-specific whole-body muscle MRI pattern FREQUENT

In a whole-body muscle MRI series of non-5q spinal muscular atrophy, all five patients with VWA1 variants shared a reproducible pattern: selective gluteus maximus involvement with iliopsoas sparing, sparing of gracilis and sartorius despite severe quadriceps involvement, and predominant peroneus involvement with relative sparing of extensor digitorum. The pattern was not exclusive — it was also seen in single patients with VRK1 and HEXB variants — but it is specific enough to be proposed as a pre-test guide to which gene to sequence.

Mri Diagnostic

Show evidence (3 references)

PMID:42662709 SUPPORT Human Clinical

"In VWA1-related SMA, the pattern included selective gluteus maximus and quadriceps involvement with iliopsoas, gracilis, and sartorius preservation, and predominant peroneal involvement with relative extensor digitorum longus sparing."

Describes the gene-specific imaging pattern recorded here.

PMID:42662709 SUPPORT Human Clinical

"but was not exclusive because similar patterns were observed in 1 patient with a VRK1 pathogenic variant"

States that the VWA1 imaging pattern is not exclusive to VWA1, which is the limit on the diagnostic claim this record makes.

PMID:42662709 SUPPORT Human Clinical

"However, confirmation in larger cohorts is needed, although this is constrained by the rarity of these disorders."

The authors' own statement of how far the pattern has been validated, which bounds its use as a diagnostic clue.

Outside-in fatty replacement of vastus lateralis resembling collagen VI myopathy OCCASIONAL

An outside-in gradient of fatty replacement within the vastus lateralis, the pattern characteristic of collagen VI-related myopathy, reported in a single Spanish patient and separately in three patients of the whole-body MRI series. It is the imaging counterpart of the argument that the muscle is primarily affected, since the protein WARP binds is the one whose disorders produce that pattern.

Mri

Fatty replacement of skeletal muscle HP:0012548

Show evidence (2 references)

PMID:41331965 SUPPORT Human Clinical

"Muscle magnetic resonance imaging showed a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies."

The case report describing the pattern.

PMID:42662709 SUPPORT Human Clinical

"A distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies, was observed in 3 patients"

Independent replication of the same pattern in a separate cohort.

Moth-eaten pattern on muscle ultrasound OCCASIONAL

Muscle ultrasound of the lower leg shows a moth-eaten pattern — round dark areas of surviving motor units against a background of increased echo intensity — which is the appearance of long-standing denervation without reinnervation. Nerve ultrasound was normal in all three patients examined.

Ultrasound

No ontology term is bound to this imaging finding. HP:0100298 Motheaten muscle fibers exists and is curated separately as a histopathology phenotype, but it names a histological fibre appearance on NADH-TR, not this ultrasound pattern of surviving motor units against fibrosed muscle; the two share a descriptive word and not a referent. Searched with runoak -i sqlite:obo:hp search 't~moth', whose only muscle hit is HP:0100298.

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"In Families 8 and 12, muscle ultrasound demonstrated a moth-eaten pattern in the lower leg muscles, which can be seen in long-standing denervation without reinnervation."

Describes the ultrasound pattern and its interpretation.

📈

Progression

2

Congenital to early childhood onset

Age: birth to 12 years

Onset ranged from birth to 12 years in the second cohort. Symptom recognition in the first cohort was at a mean of 2.0 plus or minus 1.4 years, with tip-toe walking, foot deformity and Achilles contracture; independent walking was achieved at a mean of 1.6 plus or minus 0.8 years and was markedly delayed where equinovarus was severe. Foot deformity and tendon contracture were congenital in two cases.

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"Nonetheless, early-onset foot deformities, contractures, and gait abnormalities have been consistently reported in nearly all individuals with VWA1-related disorder, suggesting an early or even infantile disease onset rather than adult onset."

States the age of onset and the authors' correction of the earlier impression of adult onset.

Slowly progressive adult course with preserved ambulation

Age: second decade onward

Progression is very slow and in several patients static, with isolated reports of worsening after the fifth decade. Ambulation is usually retained: three of seventeen in the first cohort lost independent walking over a median disease duration of 36.5 years, and none of the twenty patients in the second cohort had. Cardiac and respiratory involvement were not reported, and no neurocognitive symptoms were observed.

Show evidence (2 references)

PMID:33559681 SUPPORT Human Clinical

"Overall, the disease progression was very slow or even static in several cases. Isolated cases reported some clinical worsening after the fifth decade of life."

Characterises the rate of progression over the long observed course.

PMID:39502942 SUPPORT Human Clinical

"No associated neurocognitive symptoms were observed. Cardiac or respiratory involvement was not reported. Despite the diverse clinical manifestations, all affected individuals exhibited a slow disease progression and remained ambulatory at the time of investigations."

Records the absence of cardiac, respiratory and cognitive involvement and the preserved ambulation.

📊

Prevalence

2

UK and Western European population

Carrier Frequency 226.8 per 100,000 >1 in 1,000 (carriers)

Carrier frequency for the single founder allele c.62_71dup, reported as approximately 1 in 441; 100000/441 = 226.8 per 100,000. This is a carrier rate for one allele, not a disease prevalence, and the two must not be compared. The same paper separately estimates the allele frequency of c.62_71dup at 1/847 in the European population, from which it infers that up to 100 individuals in the UK may be homozygous or compound heterozygous.

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population"

The source of the carrier frequency recorded here.

Worldwide

Cases In Literature Not yet documented

No point prevalence has been published for this condition. As of the 2024 review the published literature totalled 54 patients. That count is not a prevalence estimate and is widely believed to understate the disease: the gene's discoverers estimate biallelic VWA1 variants may account for up to 1% of unexplained hereditary motor neuropathy in Europeans, a diagnostic-yield fraction rather than a population rate.

Show evidence (2 references)

PMID:39502942 SUPPORT Human Clinical

"Results are based on data from 54 patients (n = 20 from presented cohort and n = 34 from previous publications)."

Gives the total number of patients reported in the literature at that time.

PMID:33559681 SUPPORT Human Clinical

"we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans"

The diagnostic-yield estimate that bounds how far the published case count understates the burden.

⚖️

Clinical Burden

Moderate

Lifelong motor disability from early childhood, but rarely loss of ambulation and no reported cardiac, respiratory or cognitive involvement. The dominant burden is diagnostic rather than functional: the condition is described as going unnoticed for years to decades, is routinely mistaken for Charcot-Marie-Tooth disease, spinal muscular atrophy, hereditary spastic paraplegia or a muscular dystrophy, and the causal allele is systematically missed by standard sequencing pipelines because of its GC-rich repetitive context. Patients in the reported cohorts had already been tested for Duchenne muscular dystrophy, facioscapulohumeral dystrophy, SMA and dystonia panels before the right gene was found.

Show evidence (2 references)

PMID:39502942 SUPPORT Human Clinical

"Given the broad phenotypic presentation of the condition, several other patients received preceding genetic investigations including neuropathy/neuromuscular disorder panel, movement disorder/dystonia panel, testing for Duchenne muscle dystrophy, facioscapulohumeral muscular dystrophy and SMA."

Documents the diagnostic odyssey that is the main burden of this condition.

PMID:39502942 SUPPORT Human Clinical

"Therefore, VWA1 should be included in multiple gene panels covering hereditary neuropathies, muscle dystrophies, hereditary spastic paraplegia and SMA to reduce diagnostic delay and identify a large number of undiagnosed individuals."

States the authors' own reading of the burden — diagnostic delay and a large undiagnosed population.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 7:

Spinal muscular atrophy with lower extremity predominance (DYNC1H1, BICD2)

Overlapping Features The closest mimic. Both present with lower-limb-predominant weakness that is proximal as much as distal, tendon contractures, foot and spinal deformity and a forward-stooped posture, and both can show myopathic muscle biopsies.

Distinguishing Features

In the VWA1 series the upper limbs were involved in more than half the cases irrespective of severity, which is not the pattern in SMA with lower extremity predominance.

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"However, in our series, the upper limbs were involved in more than half of the cases irrespective of the disease severity, unlike spinal muscular atrophy with lower extremity predominance."

States the discriminating feature directly.

Distal hereditary motor neuropathy type I

Overlapping Features The paediatric subset of VWA1 patients with only distal lower limb weakness, wasting and foot contractures is clinically indistinguishable from typical dHMN type I at that stage.

Distinguishing Features

Weakness in VWA1 disease tends to progress proximally with age, which the authors give as the feature separating it from that presentation. Raised creatine kinase and any myopathic element are further pointers away from a pure motor neuropathy.

Show evidence (1 reference)

PMID:33559681 SUPPORT Human Clinical

"A subset of paediatric cases in our cohort with only distal lower limb weakness, wasting, and foot contractures resembled the typical distal hereditary motor neuropathy type I presentation"

States the resemblance and the stage at which it holds.

Hereditary spastic paraplegia

Overlapping Features Patients with hyperreflexia, upgoing plantars and lower limb spasticity can be routed into a hereditary spastic paraplegia workup.

Distinguishing Features

The underlying electrophysiology in VWA1 disease is an axonal motor neuropathy with chronic neurogenic change on EMG, so nerve conduction studies and needle EMG are what separate the two.

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"Hyperreflexia, especially when combined with spasticity, might mimic conditions on the hereditary spastic paraplegia spectrum."

Names the mimic and the features that create it.

Juvenile amyotrophic lateral sclerosis

Overlapping Features Tongue fasciculation or atrophy in a young patient with progressive weakness is a classic pointer to juvenile ALS, and it occurs in VWA1 disease.

Distinguishing Features

VWA1 disease progresses very slowly or is static over decades and preserves ambulation in almost all reported patients, with a median disease duration of 36.5 years in the first cohort.

Show evidence (1 reference)

PMID:39502942 SUPPORT Human Clinical

"Tongue fasciculation and/or atrophy favours the diagnosis of juvenile amyotrophic lateral sclerosis associated with several genes including SETX, SPTLC1, SPTLC2, ALS2, FUS and SIGMAR1."

States the diagnostic pull of the sign toward juvenile ALS.

🐁

Animal Models

2

vwa1 CRISPR knockout and morpholino knockdown zebrafish

CRISPR crispants and morpholino morphants targeting exons 1-2 of the zebrafish vwa1 orthologue, whose protein shares 64.7% similarity across a 408 amino acid overlap with human VWA1. Both models showed shortened and aberrantly branching spinal motor axons from day 2, sparser and disorganised myofibres on phalloidin staining, significantly reduced acetylcholine receptor staining with alpha-bungarotoxin, and a consistent trend at 5 days toward reduced distance moved and reduced velocity. They also showed an irregular jaw cartilage phenotype the authors state is not seen in patients.

Species

Zebrafish

Genotype

vwa1 CRISPR crispant and antisense morpholino knockdown, Tg(olig2:dsRed) background

Background

Tg(olig2:dsRed) transgenic reporter line

Genes

VWA1 hgnc:30910

Publication

PMID:33559681

Pathograph links

Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation recapitulates fidelity: moderate observes: cellular The model is the only experimental evidence that WARP loss affects motor axon growth and endplate formation, and it is what the node is built on.

Limitations: The readouts are developmental and were taken at 48-96 hours post-fertilisation; human patients are studied decades later, and no human material has been examined for an endplate or axon-outgrowth defect. Morpholino knockdown carries well-known off-target risk, although the concordance with the CRISPR crispant mitigates it. The model also produces a jaw cartilage phenotype the authors state is not seen in patients, so the phenotypic correspondence is partial in the other direction too.

Readouts

Spinal motor axon length at 48-96 hours post-fertilisation

Direction: DECREASED

Interpretation: Direct morphometric measure of the motor axon outgrowth deficit.

Show evidence (1 reference)

PMID:33559681 SUPPORT Model Organism

"Vwa1 Crispants (n = 29) and morphants (n = 26) showed significantly shortened axons compared to controls (n = 22)."

Reports the measurement, its direction, and the group sizes.

Acetylcholine receptor clustering by alpha-bungarotoxin staining

Direction: DECREASED

Interpretation: Measures endplate formation in skeletal muscle of the knockdown/knockout larva.

Show evidence (1 reference)

PMID:33559681 SUPPORT Model Organism

"examination of neuromuscular junctions, by targeting the acetylcholine receptors (AChR) using alpha-bungarotoxin stain, revealed significantly reduced synaptic formation in the skeletal muscles"

Reports the endplate measurement and its direction.

Show evidence (1 reference)

PMID:33559681 SUPPORT Model Organism

"These results established that vwa1 is required for the proper organization of skeletal muscles and in the formation of neuromuscular junctions."

The authors' own conclusion that the model is informative for this node.

Vwa1 (WARP) knockout mouse

The global WARP-null mouse predates the human disease and is what made VWA1 a candidate gene. The mice are healthy, viable and fertile with no overt abnormality, but show a significantly delayed response to acute painful stimulus and impaired fine motor coordination; the collagen VI microfibrillar matrix is severely reduced and mislocalised in peripheral nerve, fibrillar collagen deposition in the nerve matrix is reduced, and adjacent Schwann cell basement membranes partially fuse. Articular cartilage, intervertebral disc and skeletal muscle showed no detectable abnormality and basement membranes formed normally, which is a point against the primary-muscle-lesion model. The delayed nociceptive response has no clear human counterpart: impaired nociception was not frequently seen in the patient series.

Species

Mouse

Genotype

Vwa1 global knockout by targeted gene replacement (WARP-null)

Genes

VWA1 hgnc:30910

Publication

PMID:19279005

Pathograph links

Depletion of WARP from Nerve and Muscle Basement Membrane partially recapitulates fidelity: moderate observes: tissue The mouse supplies the ultrastructural nerve-matrix lesion that gives this node its content, since no human nerve has been examined this way.

Limitations: It recapitulates the nerve arm and fails the muscle arm — WARP-deficient mice showed no histological or behavioural muscle pathology, so the mouse cannot be used to argue for the muscle side of this node. It also shows impaired nociception that was not frequently seen in patients, so the species mismatch runs in both directions.

Show evidence (1 reference)

PMID:19279005 SUPPORT PRIMARY RESULT Model Organism

"Our data demonstrate that although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves."

The knockout study's own summary of what the model shows: a peripheral nerve lesion, which is the arm of this node it recapitulates.

Muscle Extracellular Matrix Remodeling fails to recapitulate fidelity: low observes: tissue The knockout mouse shows no muscle pathology at all, which is the strongest single piece of evidence against a primary muscle lesion.

Limitations: A negative result in a mouse does not rule out a human primary muscle lesion: the mouse was not examined with the proteomic or matrix-specific methods later applied to patient muscle, and mouse and human skeletal muscle matrix composition differ. The finding constrains the hypothesis rather than closing it.

Show evidence (2 references)

PMID:19279005 REFUTE PRIMARY RESULT Model Organism

"In contrast, other WARP-deficient tissues such as articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities, and basement membranes formed normally."

The primary negative result: removing WARP produced no detectable skeletal muscle abnormality, which is what this link records the model as failing to recapitulate.

+ 1 more reference

Curated from the primary knockout paper PMID:19279005 and the reporter-gene localisation paper PMID:18314316, both fetched into the reference cache for this entry. Where PMID:33559681 restates those findings its quotes are marked BACKGROUND so the two roles stay distinguishable.

{ }

Source YAML

click to show

name: Neuronopathy, Distal Hereditary Motor, Autosomal Recessive 7
creation_date: "2026-09-18T00:00:00Z"
category: Genetic
description: >
  Autosomal recessive distal hereditary motor neuronopathy type 7 (HMNR7; also
  indexed as HMNMYO, "neuropathy, hereditary motor, with myopathic features")
  is caused by biallelic loss-of-function variants in VWA1, which encodes the
  von Willebrand factor A domain-related protein WARP — an extracellular matrix
  protein of muscle and peripheral nerve that interacts with collagen VI and
  perlecan. That is unusual for this family, whose other causal genes cluster on
  motor-axon housekeeping functions — chaperone-mediated protein quality
  control, axonal transport, tRNA charging and RNA metabolism,
  endoplasmic-reticulum function, cation channels — and the clinical picture
  departs from the family template in two ways that follow from it. First, the neuropathy is
  non-length-dependent: onset is distal, with foot deformity and foot drop in
  the first years of life, but weakness commonly involves the proximal lower
  limbs as severely as the distal ones, which is what prompts the differential
  against SMA with lower-extremity predominance rather than against a
  length-dependent dying-back neuropathy. Second, a myopathic component sits
  alongside the neurogenic one — raised creatine kinase, myopathic units on
  needle EMG in a minority, dystrophic muscle biopsies in a minority, and a
  vastus lateralis MRI pattern that mimics collagen VI-related myopathy — which
  led the two independent 2021 cohorts to name the condition differently
  (Deschauer et al. "neuromyopathy"; Pagnamenta et al. "hereditary motor
  neuropathy"). Whether the muscle involvement is a primary matrix lesion or a
  consequence of chronic denervation is unsettled and is curated here as an
  explicit controversy. A single 10 bp duplication in exon 1,
  NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74), is a Western European founder
  allele carried by roughly 1 person in 441, and Pagnamenta et al. estimate that
  biallelic VWA1 variants may explain up to 1% of otherwise unsolved hereditary
  motor neuropathy in Europeans — so this is a rare disease with a common allele,
  and much of its burden is undiagnosed rather than absent. Disease course is
  slow; most reported patients remain ambulant into adult life.
disease_term:
  preferred_term: distal hereditary motor neuronopathy with myopathic features
  term:
    id: MONDO:0030977
    label: neuronopathy, distal hereditary motor, autosomal recessive 7
synonyms:
- HMNR7
- HMNMYO
- neuropathy, hereditary motor, with myopathic features
- VWA1-related neuromyopathy
- VWA1-related distal hereditary motor neuropathy
parents:
- neuronopathy, distal hereditary motor, autosomal recessive
references:
- reference: PMID:33559681
  title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
- reference: PMID:33459760
  title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
- reference: PMID:39502942
  title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
- reference: PMID:38652110
  title: "Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers."
- reference: PMID:35975723
  title: "Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants."
- reference: PMID:41331965
  title: "A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy in Novel VWA1-Related Distal Hereditary Motor Neuronopathy With Myopathic Features in a Patient From Spain."
- reference: PMID:42662709
  title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
- reference: PMID:30768857
  title: "WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes."
- reference: PMID:19279005
  title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
- reference: PMID:18314316
  title: "The extracellular matrix protein WARP is a novel component of a distinct subset of basement membranes."
- reference: PMID:35942667
  title: "Hereditary motor neuropathies."
mechanistic_hypotheses:
- hypothesis_group_id: denervation_secondary_myopathy
  hypothesis_label: Myopathic change is secondary to chronic denervation
  status: CANONICAL
  description: >
    On this model the only primary lesion is in the peripheral nerve: loss of
    WARP from the nerve basement membrane causes motor axon loss, and every
    muscle finding — raised creatine kinase, myopathic motor units on needle
    EMG, dystrophic features on biopsy, fatty replacement on MRI — is a
    downstream consequence of long-standing denervation and reinnervation.
    Pagnamenta et al. argued this explicitly, noting that the histological
    features classically attributed to myopathy are also found in chronically
    denervated muscle, and that collagen VI immunolabelling was normal in the
    patient biopsies where it was assessed.
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process."
    explanation: States the canonical position — the myopathic findings are read as a consequence of denervation, not as a second primary lesion.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where data were available, immunohistochemical labelling for collagen VI appeared normal."
    explanation: >-
      The collagen VI partner of WARP is normally deposited in patient muscle,
      which is the observation the secondary-myopathy model leans on: the matrix
      abnormality expected of a primary muscle-matrix disease was not found.
- hypothesis_group_id: primary_muscle_matrix_lesion
  hypothesis_label: The muscle is primarily affected through its own extracellular matrix
  status: ALTERNATIVE
  description: >
    On this model WARP loss injures the muscle directly, because WARP is a
    constituent of the muscle extracellular matrix as well as of the nerve
    basement membrane, so the disease is a neuromyopathy with two primary
    targets rather than a neuropathy with a denervated muscle. The Deschauer
    cohort named the condition a neuromyopathy on combined myopathological and
    neurophysiological grounds; a proteomic study of patient white blood cells,
    plasma and muscle set out explicitly to test for primary muscle
    vulnerability and reported extracellular accumulation of C-reactive protein
    and of NEFM in patient muscle; and muscle MRI in two independent reports
    shows an outside-in vastus lateralis pattern of the kind seen in collagen
    VI-related myopathy rather than the pattern expected of denervation.
  evidence:
  - reference: PMID:33459760
    reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology."
    explanation: The cohort that named the condition a neuromyopathy states the combined pathology on which that name rests.
  - reference: PMID:38652110
    reference_title: "Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NEFM showed an increase in cells within the ECM in biopsies of all patients studied."
    explanation: >-
      A muscle-matrix abnormality found in every patient biopsy examined, offered
      by that study as evidence bearing on primary muscle involvement.
  - reference: PMID:41331965
    reference_title: "A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy in Novel VWA1-Related Distal Hereditary Motor Neuronopathy With Myopathic Features in a Patient From Spain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle magnetic resonance imaging showed a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies."
    explanation: >-
      An imaging pattern characteristic of a primary matrix myopathy rather than
      of denervation, in a muscle that is also a target of the collagen VI
      disorders WARP partners with.
pathophysiology:
- name: Biallelic VWA1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  role: initiating genetic lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Two loss-of-function alleles of VWA1, the gene encoding the extracellular
    matrix protein WARP. Reported alleles are predominantly frameshifts and
    stop-gains, with a small number of missense changes affecting proline
    residues; the disease-defining allele is the 10 bp exon 1 duplication
    NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74), which was present in 14 of 15
    families in the first reported cohort and in 12 of 15 families in the 2024
    cohort. Both homozygosity for that allele and compound heterozygosity for it
    in trans with a second truncating variant are common.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline loss of function; both homozygous and compound
      heterozygous genotypes are reported, the latter usually with the founder
      allele in trans.
  genes:
  - preferred_term: VWA1
    term:
      id: hgnc:30910
      label: VWA1
  evidence:
  - reference: PMID:33459760
    reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder."
    explanation: Establishes biallelic VWA1 loss of function as the molecular cause of the condition.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15."
    explanation: Identifies the recurrent founder allele and its frequency within the first reported cohort.
  downstream:
  - target: Nonsense-Mediated Decay and Absence of WARP Protein
    causal_link_type: DIRECT
    description: >-
      The founder duplication shifts the reading frame and introduces a
      premature stop 74 codons downstream, and patient fibroblasts show both
      reduced transcript rescued by a nonsense-mediated decay inhibitor and no
      detectable protein.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein."
      explanation: Connects the founder allele directly to transcript decay and loss of the protein product.
- name: Nonsense-Mediated Decay and Absence of WARP Protein
  biological_scale: MOLECULAR
  role: molecular consequence of the lesion
  mechanism_confidence: ESTABLISHED
  description: >
    Transcripts carrying the premature termination codon are partially degraded
    by nonsense-mediated decay, and no WARP protein is detectable in patient
    dermal fibroblasts in either the cell layer or the conditioned medium,
    whereas control fibroblasts secrete detectable protein. In the mouse the
    protein is abundant in sciatic nerve and is efficiently deposited into the
    matrix, so the human null state removes a protein that is normally present
    at the site of disease.
  biological_processes:
  - preferred_term: nonsense-mediated decay of the mutant VWA1 transcript
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  molecular_functions:
  - preferred_term: WARP as a structural constituent of the extracellular matrix
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: ABSENT
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, there was no detectable VWA1 in either the conditioned medium or cell layer of the patient’s fibroblast"
    explanation: Direct demonstration that the patient cell makes no detectable WARP protein to secrete or deposit.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A high level of VWA1 was detected in mouse sciatic nerve extraction. In the primary culture of mouse sciatic nerve, VWA1 was detectable in its cell layer (cytoplasm and ECM) but not in the conditioned medium, indicating the secreted VWA1 was able to deposit as ECM efficiently."
    explanation: >-
      Establishes that the protein lost in patients is normally abundant in
      peripheral nerve and is deposited into the matrix there.
  downstream:
  - target: Depletion of WARP from Nerve and Muscle Basement Membrane
    causal_link_type: DIRECT
    description: >-
      WARP is an extracellular matrix protein of muscle and peripheral nerve
      that binds collagen VI and perlecan, so an undetectable protein is an
      absent matrix constituent at those sites.
    evidence:
    - reference: PMID:33459760
      reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders."
      explanation: >-
        States where the protein normally resides and what it binds; the citing
        paper is restating established protein biology rather than reporting it,
        hence BACKGROUND.
    - reference: PMID:19279005
      reference_title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures."
      explanation: >-
        The primary binding result behind the two partner proteins named
        throughout this entry, and the authors' proposed bridging function.
- name: Depletion of WARP from Nerve and Muscle Basement Membrane
  biological_scale: TISSUE
  role: tissue-level matrix lesion
  description: >
    WARP is expressed in the basement membrane structures of the peripheral
    nervous system and is most abundant, among human tissues surveyed, in tibial
    nerve. Its loss leaves the nerve basement membrane structurally abnormal:
    electron microscopy of WARP-deficient mouse sciatic nerve shows partial
    fusion of the basement membranes of neighbouring axons, and collagen VI is
    reduced in regions of the peripheral nerve matrix. WARP is co-expressed with
    collagen VI in the endomysium of muscle, so the same deficit exists on the
    muscle side, but the mouse showed no histological or behavioural muscle
    pathology and collagen VI labelling is normal in patient muscle — which is
    why the muscle arm of this node is curated as contested rather than
    established.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  locations:
  - preferred_term: tibial nerve
    term:
      id: UBERON:0001323
      label: tibial nerve
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  cellular_components:
  - preferred_term: basement membrane
    term:
      id: GO:0005604
      label: basement membrane
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: basement membrane organization
    term:
      id: GO:0071711
      label: basement membrane organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18314316
    reference_title: "The extracellular matrix protein WARP is a novel component of a distinct subset of basement membranes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "WARP is expressed in the vasculature of neural tissues and in basement membrane structures of the peripheral nervous system. Furthermore, WARP is also expressed in the apical ectodermal ridge of developing limb buds, and in skeletal and cardiac muscle."
    explanation: >-
      The reporter-gene study that established where WARP sits — peripheral
      nerve basement membrane and skeletal muscle — which is what this node
      claims is depleted.
  - reference: PMID:19279005
    reference_title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Further ultrastructural analysis revealed reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes, suggesting an important function for WARP in stabilizing the association of the collagenous interstitial matrix with the Schwann cell basement membrane."
    explanation: >-
      The primary ultrastructural result defining the lesion at this node, and
      the authors' own statement of what WARP does there.
  - reference: PMID:19279005
    reference_title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Immunostaining of WARP-interacting ligands demonstrated that the collagen VI microfibrillar matrix was severely reduced and mislocalized in peripheral nerves of WARP-null mice."
    explanation: >-
      Shows that WARP loss disorganises the collagen VI matrix specifically in
      nerve, which is the mechanistic content of this node's nerve arm.
  - reference: PMID:30768857
    reference_title: "WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The von Willebrand factor A-domain-related protein (WARP) encoded by the VWA1 gene, is an orphan extracellular matrix protein that is expressed in a subset of ECM structures but whose function is poorly understood."
    explanation: >-
      A review of the protein confirms its restricted matrix distribution and
      records that its normal function is not well understood, which bounds how
      strongly any mechanism below this node can be stated.
  downstream:
  - target: Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation
    causal_link_type: DIRECT
    description: >-
      Knockdown and knockout of the zebrafish orthologue shorten spinal motor
      axons and reduce acetylcholine receptor clustering in skeletal muscle,
      placing the matrix deficit upstream of motor axon growth and endplate
      formation.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results established that vwa1 is required for the proper organization of skeletal muscles and in the formation of neuromuscular junctions."
      explanation: The authors' own conclusion from the zebrafish experiments linking loss of the gene to muscle organization and endplate formation.
  - target: Non-Length-Dependent Motor Axon Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      WARP loss compromises peripheral nerve structure and function in the
      knockout mouse, and the human null state produces a motor axonal
      neuropathy; the steps between the abnormal nerve basement membrane and
      axon loss are not established.
    evidence:
    - reference: PMID:33459760
      reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model."
      explanation: >-
        States that removing the protein damages peripheral nerve in vivo; the
        result is the cited knockout study's, restated here as background.
  - target: Muscle Extracellular Matrix Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - primary_muscle_matrix_lesion
    description: >-
      Under the primary-muscle-lesion model, loss of WARP from the endomysial
      matrix is itself the muscle insult. This edge belongs to that hypothesis
      group and is not asserted under the canonical model.
    evidence:
    - reference: PMID:38652110
      reference_title: "Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CRP elevated in plasma also showed an increase in the extracellular space of VWA1-mutant muscle."
      explanation: Reports an abnormality of the muscle extracellular space itself in patients lacking WARP.
- name: Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation
  biological_scale: CELLULAR
  role: developmental effector step
  description: >
    In the zebrafish model, loss of the vwa1 orthologue significantly reduces
    spinal motor neuron growth measured across days 2 to 4 of development, with
    aberrant axon structures from day 3, sparser and disorganised myofibres, and
    significantly reduced synapse formation in skeletal muscle measured by
    acetylcholine receptor staining, followed by reduced locomotive behaviour. This places the defect early — at the point where motor
    axons grow out and form endplates — rather than at a later dying-back stage,
    which fits the human observation that foot deformity and tendon contracture
    are present from the first years of life and were congenital in two cases.
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: motor axon extension
    term:
      id: GO:0048675
      label: axon extension
    modifier: DECREASED
  - preferred_term: neuromuscular junction development
    term:
      id: GO:0007528
      label: neuromuscular junction development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour."
    explanation: Summarises the three model readouts that define this node — axon growth, synapse formation, and locomotion.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Phenotypic assessment of the vwa1 crispants/morphants demonstrated a prominent effect on motor neurons including shorter axons and abnormal growth."
    explanation: The primary axon-growth observation behind this node.
  notes: >-
    Marked PROVISIONAL because the whole node rests on a zebrafish model. No
    human material has been examined for a developmental axon-outgrowth or
    endplate defect, and the zebrafish also showed a jaw cartilage phenotype
    that the authors explicitly note is not seen in patients.
  downstream:
  - target: Non-Length-Dependent Motor Axon Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A developmental deficit in motor axon growth and endplate formation is
      offered by the authors as the origin of the human motor neuropathy, but
      the route from an early developmental deficit to progressive adult axon
      loss is not worked out.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, the defective myofibres’ organization, neuromuscular junctions, secondary motor neuron impairment and reduced larval locomotion may reflect the early vwa1 neuropathy."
      explanation: >-
        The authors' own statement that the developmental findings are what the
        neuropathy amounts to in this model; the hedged wording is why this edge
        is typed as having unknown intermediates.
- name: Non-Length-Dependent Motor Axon Loss
  biological_scale: TISSUE
  role: central effector step
  description: >
    Loss of motor axons producing reduced or absent compound motor action
    potentials with preserved conduction velocities — an axonal, not
    demyelinating, motor neuropathy — and normal sensory studies in most
    patients. The distinguishing feature of this disease is that the loss is not
    graded by axon length: three-quarters of the first cohort had simultaneous
    proximal and distal lower limb weakness, and in almost half of those the
    proximal weakness was the more severe. That is the opposite of the
    distal-first gradient that defines most of the distal hereditary motor
    neuropathies, and it is why this entry does not conform to the
    length-dependent peripheral axonal degeneration module.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor nerve action potentials from the lower limb nerves were reduced or undetectable with uniformly preserved conduction velocities. Sensory studies were overall normal."
    explanation: Establishes the lesion as motor axon loss rather than demyelination or a sensorimotor process.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In almost half of those cases, weakness was more pronounced proximally, and one-quarter had equally weak proximal and distal muscle groups, raising the clinical suspicion of non-length dependent motor axonal neuropathy."
    explanation: Establishes the non-length-dependent distribution that separates this disease from the rest of the dHMN family.
  - reference: PMID:35942667
    reference_title: Hereditary motor neuropathies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Distal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons."
    explanation: >-
      Gives the family definition this disease departs from: length-dependence
      is the defining feature of the dHMNs in general, and is absent here.
  downstream:
  - target: Motor axonal neuropathy
    causal_link_type: DIRECT
    description: Axon loss with preserved conduction velocity is what the nerve conduction study records.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nerve conduction studies consistently indicated axonal motor neuropathy with sensory involvement in three cases, accompanied by chronic neuropathic changes in needle EMG."
      explanation: Confirms the axonal motor pattern across the second large cohort.
  - target: Distal lower limb muscle weakness
    causal_link_type: DIRECT
    description: Loss of the motor axons supplying the distal leg muscles.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most pronounced weakness was observed in the distal lower limbs, with muscle strength ranging from Grades 1 to 3 for toe and foot dorsiflexion or plantarflexion."
      explanation: Quantifies the distal lower limb weakness that the motor axon loss produces.
  - target: Proximal lower limb muscle weakness
    causal_link_type: DIRECT
    description: >-
      The same axon loss reaches proximal motor units without an intervening
      distal-to-proximal progression, which is the non-length-dependent feature.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the cases (75%) were found to have simultaneous proximal and distal lower limb weakness on neurological follow-up."
      explanation: Establishes proximal involvement as a majority finding rather than a late complication.
  - target: Foot dorsiflexor weakness
    causal_link_type: DIRECT
    description: Weakness of ankle dorsiflexion producing foot drop, the commonest presenting sign.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Foot drop, foot deformities and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations."
      explanation: Names foot drop as an initial manifestation of the motor axon loss.
  - target: Hyporeflexia
    causal_link_type: DIRECT
    description: >-
      The motor axon is the efferent limb of the tendon reflex arc, so its loss
      reduces the reflex; reflexes were diminished in half of the first cohort.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Tendon reflexes were diminished in half of the cohort, and muscle tone was largely reported to be normal along with uniformly negative Babinski sign."
      explanation: Records the diminished reflexes, and in the same sentence the normal tone and negative plantars of the original cohort.
  - target: Tongue fasciculations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reported in a minority of adults and grouped by both cohorts with the
      motor-neuron features of the disease; no study localises the lesion for
      this sign, so the edge is typed as indirect.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two adult cases (Families 1 and 3) had shown mild tongue fasciculations or atrophy"
      explanation: Records the sign and its frequency in the first cohort.
  - target: Chronic Neurogenic Denervation of Skeletal Muscle
    causal_link_type: DIRECT
    description: >-
      Motor axon loss denervates the muscle fibres of the affected motor units;
      needle EMG shows chronic neurogenic change without active denervation in
      most patients, the picture of long-standing denervation with reinnervation.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EMG typically showed chronic neurogenic changes without active denervation (10/12)."
      explanation: Gives the electrophysiological signature of chronic denervation and its frequency.
- name: Chronic Neurogenic Denervation of Skeletal Muscle
  biological_scale: TISSUE
  role: downstream tissue consequence
  description: >
    Muscle downstream of the lost motor axons undergoes denervation with
    partial reinnervation, producing the classical morphological signature:
    fibre type grouping, fascicular grouping of type 1 fibres, and neurogenic
    atrophy, with a moth-eaten pattern on muscle ultrasound in long-standing
    denervation without reinnervation. Four of seven biopsies in the first
    cohort showed clear neurogenic changes.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle ultrasound of the left tibialis anterior from the same patient shows a moth-eaten pattern consisting of round, dark areas with remaining viable motor units, surrounded by tissue with increased greyscale level reflecting permanently denervated and fibrosed muscle tissue."
    explanation: Describes denervated muscle tissue directly, with the imaging correlate of surviving versus lost motor units.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies were performed in seven cases, of which four were available for review (Fig. 3). In 4/7 of these, clear neurogenic changes were reported."
    explanation: Gives the proportion of biopsies showing neurogenic change in the first cohort.
  downstream:
  - target: 'EMG: chronic denervation signs'
    causal_link_type: DIRECT
    description: Chronic denervation with reinnervation is what needle EMG records in most patients.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "accompanied by chronic neuropathic changes in needle EMG"
      explanation: Confirms chronic neurogenic needle-EMG change in the second cohort.
  - target: Fiber type grouping
    causal_link_type: DIRECT
    description: Reinnervation of denervated fibres by surviving motor units regroups fibre types within the fascicle.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Muscle biopsy of the vastus lateralis muscle of Patient 8 shows extensive neurogenic abnormalities with many areas of fibre type grouping seen by ATPase (pH 4.6) staining."
      explanation: Records fibre type grouping in patient muscle and names it a neurogenic abnormality.
  - target: Skeletal muscle atrophy
    causal_link_type: DIRECT
    description: Denervation atrophy, predominantly of the distal leg muscles.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mild muscle atrophy, predominantly affecting the distal legs, was common."
      explanation: Records the distribution and frequency of the atrophy.
  - target: Myopathic Change in Skeletal Muscle
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - denervation_secondary_myopathy
    description: >-
      Under the canonical model, the myopathic findings arise on the background
      of chronic denervation rather than from a second primary lesion. This edge
      belongs to that hypothesis group.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hence, neurogenic muscle changes seem to be common in the VWA1 presentation, and it is likely for the observed myopathic process in a few cases to develop on the background of chronic muscle denervation."
      explanation: States the causal claim this edge makes, in the authors' own words, including their hedge.
- name: Muscle Extracellular Matrix Remodeling
  biological_scale: TISSUE
  role: contested parallel lesion
  description: >
    An abnormality of the muscle extracellular space itself in patients lacking
    WARP, independent of any denervation. Proteomic profiling of patient white
    blood cells, plasma and muscle reported increased C-reactive protein in the
    extracellular space of VWA1-mutant muscle and increased NEFM in cells within
    the muscle matrix of every patient biopsy examined, and the plasma signature
    was dominated by proteins related to antioxidative processes. This node
    exists only under the alternative hypothesis that the muscle is a primary
    target; it is not asserted under the canonical model.
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: extracellular matrix organization in skeletal muscle
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38652110
    reference_title: "Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma proteomics unravelled dysregulation of 15 proteins serving as biomarker candidates among which a profound proportion of increased ones (6/11) are mostly related to antioxidative processes and have even partially been described as blood biomarkers for other entities of neuromuscular disorders before."
    explanation: Reports the plasma protein signature attributed to the disease, weighted toward antioxidative processes.
  notes: >-
    Marked HYPOTHETICAL deliberately. The proteomic study states that there is
    no consensus on whether muscle involvement is primary, and it studied six
    patients from two families. Its own authors describe the work as a first
    biomarker study. Treat the node as a placeholder for the alternative model
    rather than as an established lesion.
  downstream:
  - target: Myopathic Change in Skeletal Muscle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - primary_muscle_matrix_lesion
    description: >-
      Under the primary-lesion model the matrix abnormality is what makes the
      muscle myopathic. No study has demonstrated the intervening steps.
    evidence:
    - reference: PMID:33459760
      reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature."
      explanation: >-
        The cohort that treats the condition as a neuromyopathy, i.e. as having
        a muscle disease component in its own right.
- name: Myopathic Change in Skeletal Muscle
  biological_scale: TISSUE
  role: convergent contested outcome
  description: >
    Myopathic features in patient muscle: a dystrophic pattern with ring fibres
    in one biopsy, fibre lobulation and whorling of myofibrils in another,
    marked variation in fibre size with increased endomysial fibrosis and
    perimysial fatty infiltration, rimmed vacuoles in one case, myopathic motor
    units on needle EMG in a minority, and raised creatine kinase in most
    patients. Both hypothesis groups converge on this node; they differ only in
    what produces it.
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the other three biopsies there was evidence for myopathic features in addition to findings suggestive of an underlying neurogenic process."
    explanation: Records the coexistence of myopathic and neurogenic features in the same biopsies.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological data were available for three cases, revealing a dystrophic pattern in one with multiple ring fibres, while the other two exhibited extensive fibre grouping indicative of neurogenic changes."
    explanation: Gives the proportion of biopsies that were dystrophic rather than neurogenic in the second cohort.
  downstream:
  - target: 'EMG: myopathic abnormalities'
    causal_link_type: DIRECT
    description: Myopathic motor unit potentials on needle EMG, reported in a minority of patients in both cohorts.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Myopathic EMG pattern was described in only one individual."
      explanation: Records how uncommon the myopathic EMG pattern was in the 20-patient cohort.
  - target: Increased endomysial connective tissue
    causal_link_type: DIRECT
    description: >-
      Endomysial fibrosis with perimysial and endomysial fatty infiltration is
      one of the myopathic biopsy features listed at this node. Note the same
      biopsies also show endomysial and perimysial thickening attributed to the
      chronic neurogenic process, so this edge records where the finding is
      reported, not that denervation can be excluded as its cause.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Marked variation in fibres size and increased endomysial fibrosis with mostly perimysial fatty infiltration."
      explanation: Reports the endomysial fibrosis alongside the fibre-size variation that defines a myopathic biopsy.
  - target: Elevated circulating creatine kinase concentration
    causal_link_type: DIRECT
    description: Release of creatine kinase from damaged muscle fibres.
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Blood tests unveiled elevated creatine kinase (CK) levels in the majority of cases, with the highest value reaching up to 2400 U/L."
      explanation: Gives the frequency and upper range of the creatine kinase elevation.
phenotypes:
- category: Neurologic
  name: Motor axonal neuropathy
  frequency: OBLIGATE
  diagnostic: true
  description: >
    A pure or predominantly motor axonal neuropathy on nerve conduction
    studies: motor action potentials reduced or absent with conduction
    velocities preserved, and sensory studies normal in most patients. It is the
    finding on which the diagnosis is built. Sensory involvement is the
    exception rather than the rule — three of seventeen in the first cohort had
    an abnormal sensory examination, supported neurophysiologically in only one,
    and three of twenty in the second cohort had sensory involvement.
  phenotype_term:
    preferred_term: Motor axonal neuropathy
    term:
      id: HP:0007002
      label: Motor axonal neuropathy
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Available nerve conduction studies typically revealed findings consistent with a motor axonal neuropathy which was often interpreted as suggestive of a distal spinal muscular atrophy/hereditary motor neuropathy."
    explanation: Establishes the motor axonal pattern and the diagnostic label it is usually given.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three isolated cases had an abnormal sensory examination and this was supported by neurophysiological evidence in only one of them showing asymmetrical sural nerve involvement (Family 6)."
    explanation: Quantifies how uncommon sensory involvement is, which is what keeps this a motor rather than sensorimotor neuropathy.
- category: Neurologic
  name: Foot dorsiflexor weakness
  frequency: VERY_FREQUENT
  description: >
    Foot drop from weakness of ankle dorsiflexion, usually bilateral and usually
    the presenting sign. In the second cohort all cases but two had distal lower
    limb weakness, mostly foot drop; one patient had one-sided foot drop with
    pes cavus on one foot and pes planus on the other, so asymmetry is possible.
  phenotype_term:
    preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral foot drop, impaired toe walking, forward posture, and wasting in the lower limbs were frequently observed signs."
    explanation: Records bilateral foot drop as a frequent sign in the first cohort.
  sequelae:
  - target: Pes cavus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Foot deformity develops in almost 90% of patients, the great majority
      before school age, in feet whose intrinsic and extrinsic muscles are
      unequally weakened.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of note, bilateral foot deformity was a very frequent feature revealed in almost 90% of the cases (15/17), ranging from pes cavus (65%, 11/17) to talipes equinovarus (35%, 6/17)."
      explanation: Gives the frequency of each deformity within the first cohort.
  - target: Talipes equinovarus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The more severe end of the same deformity spectrum, congenital in two reported cases.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In two independent cases, the foot deformities and tendon contractures were congenital suggesting antenatal onset of the disease."
      explanation: Records the congenital instance of the deformity and what the authors infer from it about onset.
  - target: Achilles tendon contracture
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Fixed shortening of the calcaneal tendon, present among the earliest recognised features.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations."
      explanation: Names Achilles contracture among the presenting features and dates their recognition.
  - target: Tip-toe gait
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Walking on the forefoot, the gait consequence of the contracture and of the dorsiflexor weakness.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations."
      explanation: Records tip-toe walking as a presenting feature alongside the contracture that produces it.
- category: Neurologic
  name: Distal lower limb muscle weakness
  frequency: VERY_FREQUENT
  description: >
    Weakness of the distal leg muscles, the most severely affected group in the
    second cohort, with strength for toe and foot dorsiflexion or plantarflexion
    ranging from MRC grade 1 to 3.
  phenotype_term:
    preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age of onset varied from birth to 12 years, with consistent early involvement of the distal lower limbs, presenting as various foot deformities, gait disturbances, frequent falls and ankle contractures."
    explanation: Records consistent early distal lower limb involvement and the range of onset ages.
  sequelae:
  - target: Falls
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Frequent falls, reported in a third of the first cohort, in patients with weak ankles and fixed foot deformity.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One-third of the cases experienced frequent falls but despite the long disease course (median disease duration 36.5 years), only three members of the cohort (twins from Family 12 and index case from Family 6) had lost independent ambulation."
      explanation: Gives the frequency of falls and, in the same sentence, the preserved ambulation that qualifies it.
- category: Neurologic
  name: Proximal lower limb muscle weakness
  frequency: FREQUENT
  diagnostic: true
  description: >
    Weakness of the hip and thigh muscles, present simultaneously with the
    distal weakness rather than following it, and in almost half of those
    patients more pronounced than the distal weakness. This is the feature that
    makes the neuropathy non-length-dependent and is the main reason the
    condition is mistaken for spinal muscular atrophy with lower-extremity
    predominance. About half of all reported individuals develop it.
  phenotype_term:
    preferred_term: Proximal lower limb muscle weakness
    term:
      id: HP:0008994
      label: Proximal lower limb muscle weakness
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the most common features of VWA1-related disease include foot drop, foot deformities and distal lower limb weakness, about half of the so far reported individuals develop proximal leg weakness over time, and approximately one-third experience upper limb involvement"
    explanation: Gives the proportion developing proximal leg weakness across all reported patients.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (VWA1)."
    explanation: Names early proximal limb involvement as the characterising feature of the entity.
- category: Musculoskeletal
  name: Pes cavus
  frequency: FREQUENT
  description: High-arched foot, the commoner of the two foot deformities, in 11 of 17 patients in the first cohort.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ranging from pes cavus (65%, 11/17) to talipes equinovarus (35%, 6/17)"
    explanation: Gives the exact frequency of pes cavus in the first cohort.
- category: Musculoskeletal
  name: Talipes equinovarus
  frequency: OCCASIONAL
  description: >
    Club foot, the more severe deformity, in 6 of 17 patients in the first
    cohort. Severe bilateral equinovarus was associated with markedly delayed
    independent walking.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Independent walking in the cohort was achieved by the mean age of 1.6 ± 0.8 years and it was remarkably delayed in cases with foot deformities such as severe bilateral equinovarus (18%, 3/17)."
    explanation: Records severe bilateral equinovarus and its effect on the age of independent walking.
- category: Musculoskeletal
  name: Achilles tendon contracture
  frequency: FREQUENT
  description: >
    Contracture of the calcaneal tendon, among the earliest features and
    congenital in two reported cases. Flexion contractures were present in more
    than half the first cohort, typically at the ankle, knee and hip, and in
    some patients also in the upper limb joints.
  phenotype_term:
    preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less frequent but present in more than half of the cohort were flexion tendon contractures typically involving foot plantar flexion, knee, and hip flexion but in some cases, it was also present in the major joints of the upper limbs."
    explanation: Gives the frequency and distribution of the contractures.
- category: Neurologic
  name: Tip-toe gait
  frequency: FREQUENT
  description: Walking on the forefoot, recognised at a mean age of 2 years alongside the foot deformities.
  phenotype_term:
    preferred_term: Tip-toe gait
    term:
      id: HP:0030051
      label: Tip-toe gait
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean age of symptom recognition was 2.0 ± 1.4 years with tip-toe walking, foot deformities, Achilles tendon contractures, and recurrent hip and patellar dislocations."
    explanation: Names tip-toe walking among the presenting features and dates it.
- category: Neurologic
  name: Hyporeflexia
  frequency: FREQUENT
  description: Diminished tendon reflexes, in half of the first cohort.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tendon reflexes were diminished in half of the cohort"
    explanation: Gives the frequency of diminished reflexes.
- category: Neurologic
  name: Falls
  frequency: OCCASIONAL
  description: Frequent falls in a third of the first cohort; despite them, ambulation is usually preserved lifelong.
  phenotype_term:
    preferred_term: Falls
    term:
      id: HP:0002527
      label: Falls
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One-third of the cases experienced frequent falls"
    explanation: Gives the frequency of falls in the first cohort.
- category: Neurologic
  name: Skeletal muscle atrophy
  frequency: FREQUENT
  description: Muscle wasting, mild and predominantly in the distal legs; prominent atrophy is characteristically absent, which is part of why the condition goes unrecognised for years.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the condition may go unnoticed for years to decades due to its relatively benign nature, often presenting mild neurological deficits, the absence of prominent muscle atrophy and slow disease progression"
    explanation: States both the mildness of the atrophy and the diagnostic consequence of it.
- category: Laboratory
  name: 'EMG: chronic denervation signs'
  frequency: VERY_FREQUENT
  diagnostic: true
  description: Chronic neurogenic change on needle EMG without active denervation, in 10 of 12 studies in the first cohort.
  phenotype_term:
    preferred_term: 'EMG: chronic denervation signs'
    term:
      id: HP:0003444
      label: 'EMG: chronic denervation signs'
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EMG typically showed chronic neurogenic changes without active denervation (10/12)."
    explanation: Gives the exact proportion of EMG studies showing chronic neurogenic change.
- category: Laboratory
  name: 'EMG: myopathic abnormalities'
  frequency: OCCASIONAL
  diagnostic: true
  description: >
    Myopathic motor unit potentials on needle EMG in a minority of patients —
    three of the first cohort's EMG studies, and one of twenty in the second.
    Together with the neurogenic change in the same patients this is the mixed
    neurogenic-and-myopathic EMG pattern that is the clinical signature of the
    condition, and which the differential-diagnosis literature lists VWA1 among
    the causes of.
  phenotype_term:
    preferred_term: 'EMG: myopathic abnormalities'
    term:
      id: HP:0003458
      label: 'EMG: myopathic abnormalities'
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three EMG studies were reported to suggest myopathic features, albeit for two of them the formal report was unavailable."
    explanation: Gives the count of myopathic EMG studies and the authors' own caveat about two of them.
- category: Laboratory
  name: Elevated circulating creatine kinase concentration
  frequency: FREQUENT
  description: >
    Raised serum creatine kinase, in six of the first cohort at 369-1628 IU/l
    and in the majority of the second cohort with a maximum of 2400 U/L. It is
    the routine laboratory finding that most often redirects the workup toward
    a muscle disease.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In six affected individuals, creatine kinase levels were elevated (369–1628 IU/l)."
    explanation: Gives the count and the measured range in the first cohort.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood tests unveiled elevated creatine kinase (CK) levels in the majority of cases, with the highest value reaching up to 2400 U/L."
    explanation: Gives the frequency and maximum value in the second cohort.
- category: Musculoskeletal
  name: Fiber type grouping
  frequency: FREQUENT
  diagnostic: true
  description: Grouping of fibre types within the fascicle on muscle biopsy, the histological signature of denervation followed by reinnervation.
  phenotype_term:
    preferred_term: Fiber type grouping
    term:
      id: HP:0033685
      label: Fiber type grouping
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the other two exhibited extensive fibre grouping indicative of neurogenic changes"
    explanation: Records fibre grouping in patient biopsies and names its neurogenic significance.
- category: Neurologic
  name: Tongue fasciculations
  frequency: OCCASIONAL
  description: >
    Mild tongue fasciculation or atrophy, in two adults in the first cohort and
    two patients in the second. It is a feature that pushes the differential
    toward juvenile amyotrophic lateral sclerosis, which is one of the ways the
    diagnosis is missed.
  phenotype_term:
    preferred_term: Tongue fasciculations
    term:
      id: HP:0001308
      label: Tongue fasciculations
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unique features of VWA1 disease include scapular winging, tongue fasciculations and, recently reported,7 pyramidal signs such as upgoing plantars and/or spasticity in the lower limbs."
    explanation: Names tongue fasciculation among the distinguishing features of the condition.
- category: Musculoskeletal
  name: Scapular winging
  frequency: OCCASIONAL
  description: >
    Winging of the scapula, in two patients in the second cohort, and listed
    among the features unique enough to point at this gene. Deliberately left
    unconnected in the causal graph: the sources record it as a feature and as a
    diagnostic clue but do not say which mechanism produces it, and periscapular
    weakness is not separately localised in any published patient.
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spasticity (n = 2), upgoing plantars (n = 2), scapular winging (n = 2), tongue fasciculations (n = 2)"
    explanation: Gives the count of patients with scapular winging in the 20-patient cohort.
- category: Musculoskeletal
  name: Scoliosis
  frequency: FREQUENT
  description: >
    Lateral curvature of the spine, in half the first cohort. Left unconnected
    in the causal graph on purpose: axial and trunk weakness is reported in this
    disease, but no source states that the scoliosis follows from it, and
    inventing that edge would assert a mechanism nobody has evidenced.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis and lumbar hyperlordosis were present in half of the series."
    explanation: Gives the frequency of scoliosis in the first cohort.
- category: Musculoskeletal
  name: Lumbar hyperlordosis
  frequency: FREQUENT
  description: >
    Exaggerated lumbar curvature, in half the first cohort, alongside the
    forward-stooped posture the authors describe. Left unconnected for the same
    reason as the scoliosis.
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis and lumbar hyperlordosis were present in half of the series."
    explanation: Gives the frequency of lumbar hyperlordosis in the first cohort.
- category: Neurologic
  name: Hyperreflexia
  frequency: OCCASIONAL
  description: >
    Brisk reflexes, reported in the second cohort and in two young children
    described separately. This is a genuine anomaly for a disease whose lesion
    is in the lower motor neuron, and the literature does not agree on it: the
    first cohort recorded normal tone and uniformly negative plantar responses,
    whereas later reports describe hyperreflexia, upgoing plantars and
    spasticity. Left unconnected in the causal graph because no mechanism for an
    upper motor neuron sign has been proposed, let alone evidenced; it is
    curated as an open question below.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, individuals in this cohort demonstrated additional features such as frequent falls, hyperreflexia and asymmetric presentation."
    explanation: Records hyperreflexia as a feature of the second cohort.
  - reference: PMID:35975723
    reference_title: "Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum."
    explanation: The report that introduced upper motor neuron signs into the described phenotype.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle tone was largely reported to be normal along with uniformly negative Babinski sign"
    explanation: >-
      The first and largest cohort found no upper motor neuron signs at all,
      which is why this phenotype is curated as occasional and contested rather
      than as a feature of the disease.
- category: Neurologic
  name: Spasticity
  frequency: OCCASIONAL
  description: >
    Increased tone in the lower limbs, in two patients in the second cohort.
    When combined with the hyperreflexia it can make the condition resemble a
    hereditary spastic paraplegia. Left unconnected for the same reason as the
    hyperreflexia.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperreflexia, especially when combined with spasticity, might mimic conditions on the hereditary spastic paraplegia spectrum."
    explanation: Records the spasticity and the diagnostic confusion it creates.
- category: Musculoskeletal
  name: Joint hypermobility
  frequency: VERY_RARE
  description: >
    Hypermobility and hyperlaxity, newly reported in one patient of the second
    cohort. Noted here because a connective-tissue sign in a disease of an
    extracellular matrix protein is worth recording even at n = 1, but no
    mechanism is offered by the source and none is asserted here.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypermobility/hyperlaxity (n = 1) and dystonia (n = 1)"
    explanation: Records hypermobility in one patient of the 20-patient cohort.
- category: Neurologic
  name: Dystonia
  frequency: VERY_RARE
  description: >
    Dystonic features, in one child of the second cohort who had otherwise
    retained motor strength; his sister had proximal lower limb weakness. Left
    unconnected: a single observation with no proposed mechanism.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One child showed only proximal lower limb weakness, while her younger brother retained motor strength but exhibited dystonic features in his legs (Patients 19 and 20 from Family 15)."
    explanation: Records the dystonic features and the intrafamilial variability they illustrate.
- category: Histopathology
  name: Increased endomysial connective tissue
  description: >
    Increased endomysial connective tissue on muscle biopsy, with perimysial
    and endomysial fatty infiltration. Wired from the myopathic-change node,
    which is where the sources report it. It does not by itself settle which
    mechanism produced it: the same biopsies also show thickening of the
    endomysium and perimysium attributed to the chronic neurogenic process.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Increased endomysial connective tissue
    term:
      id: HP:0100297
      label: Increased endomysial connective tissue
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Images show marked fibre hypertrophy and increased fibrosis with endo and perimysial fatty infiltration."
    explanation: Describes the endomysial and perimysial change in a named patient biopsy.
- category: Histopathology
  name: Motheaten muscle fibers
  description: >
    Moth-eaten fibres on NADH-TR staining in one reported biopsy. Deliberately
    left unconnected in the causal graph: the source that reports it annotates
    it in the same sentence as a non-specific finding, so attaching it to either
    the neurogenic or the myopathic node would assert more than the source does.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Motheaten muscle fibers
    term:
      id: HP:0100298
      label: Motheaten muscle fibers
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NADH-TR shows the presence of moth-eaten fibres (non-specific finding)."
    explanation: Records the finding and the authors' own non-specificity caveat.
genetic:
- name: VWA1
  gene_term:
    preferred_term: VWA1
    term:
      id: hgnc:30910
      label: VWA1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic loss-of-function variants in VWA1 are the sole established cause
    of this condition. The gene encodes the 445-amino-acid extracellular matrix
    protein WARP, whose highest expression among human tissues surveyed is in
    tibial nerve.
  evidence:
  - reference: PMID:33459760
    reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent."
    explanation: Independent multi-family evidence for biallelic truncating VWA1 variants as the cause.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1"
    explanation: The concurrent, independently ascertained cohort establishing the same gene-disease relationship.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "In humans, VWA1 (von Willebrand factor A domain containing 1) encodes a 445 amino acid ECM protein that is also referred to as von Willebrand factor A domain related protein (WARP)."
    explanation: >-
      Gives the protein length and the WARP synonym; the sentence restates
      established gene-product biology rather than reporting a new result.
  - reference: PMID:35942667
    reference_title: Hereditary motor neuropathies.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1 ."
    explanation: A review of the family places VWA1 among its established causal genes.
  variants:
  - name: NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74)
    description: >
      A 10 bp duplication in exon 1 of VWA1, expanding an existing 2-copy 10 bp
      repeat to 3 copies, producing a frameshift with a premature stop 74 codons
      downstream. It is the disease-defining allele: present in 14 of 15
      families in the first reported cohort and 12 of 15 in the second, and
      carried on a shared 220 kb European founder haplotype. Its GC-rich,
      repetitive context gives poor sequencing coverage, which is why the gene
      evaded discovery and why cases are still missed on standard exome
      pipelines. Maximum population allele frequency in gnomAD v4.0.0 is 0.093%
      in European non-Finnish and 0.118% in UK Biobank.
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: VWA1
      term:
        id: hgnc:30910
        label: VWA1
    evidence:
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This variant involves an expansion of a 10 bp repeat in Exon 1 of VWA1, leading to three copies instead of two compared with normal alleles."
      explanation: Describes the exact structure of the founder allele.
    - reference: PMID:39502942
      reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The maximum population allele frequency of the most common variant across all databases remained the highest in the European non-Finnish with 0.093% in gnomAD v4.0.0 and 0.118% in UK Biobank"
      explanation: Gives the population allele frequencies quoted in this record.
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago."
      explanation: Establishes the founder haplotype and its estimated age.
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions."
      explanation: Explains the technical reason this allele is missed, which is the entry's main diagnostic point.
  notes: >-
    Beyond the founder allele, the reported variant spectrum is dominated by
    truncating changes — stop-gains and frameshifts — with a small number of
    missense changes at proline residues. The second cohort reported 13
    additional variants, 11 of them previously undescribed, 12 seen in compound
    heterozygosity and 8 of those in trans with the founder allele. A reciprocal
    10 bp deletion at the same locus (c.62_71del10, p.G21Afs*12) is more
    common than the duplication in a Middle Eastern-enriched commercial cohort
    and was speculated by Pagnamenta et al. to be a second founder allele, but
    no biallelic case carrying it has been reported; it is recorded here as a
    lead, not as an established disease allele.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Both alleles of VWA1 must be inactivated. Homozygosity for the founder
    allele and compound heterozygosity for the founder allele with a second
    truncating variant are both common; consanguinity is reported but is not the
    usual setting — the fifteen families of the 2024 cohort were mostly
    non-consanguineous, with consanguinity in two, of Iranian and Pakistani
    origin. The reported pedigrees are
    overwhelmingly sporadic — only one of fifteen families in the first cohort
    had a positive family history.
  evidence:
  - reference: PMID:33459760
    reference_title: "Bi-allelic truncating mutations in VWA1 cause neuromyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition"
    explanation: States the mode of inheritance directly.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Positive family history was reported only in Family 13, while the rest of the cases were sporadic."
    explanation: Records that the recessive condition presents sporadically in nearly all families.
prevalence:
- population: UK and Western European population
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 226.8
  rate_denominator: POPULATION
  notes: >-
    Carrier frequency for the single founder allele c.62_71dup, reported as
    approximately 1 in 441; 100000/441 = 226.8 per 100,000. This is a carrier
    rate for one allele, not a disease prevalence, and the two must not be
    compared. The same paper separately estimates the allele frequency of
    c.62_71dup at 1/847 in the European population, from which it infers that up
    to 100 individuals in the UK may be homozygous or compound heterozygous.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reaffirming the 10 bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population"
    explanation: The source of the carrier frequency recorded here.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No point prevalence has been published for this condition. As of the 2024
    review the published literature totalled 54 patients. That count is not a
    prevalence estimate and is widely believed to understate the disease: the
    gene's discoverers estimate biallelic VWA1 variants may account for up to 1%
    of unexplained hereditary motor neuropathy in Europeans, a diagnostic-yield
    fraction rather than a population rate.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results are based on data from 54 patients (n = 20 from presented cohort and n = 34 from previous publications)."
    explanation: Gives the total number of patients reported in the literature at that time.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans"
    explanation: The diagnostic-yield estimate that bounds how far the published case count understates the burden.
progression:
- phase: Congenital to early childhood onset
  age_range: birth to 12 years
  notes: >-
    Onset ranged from birth to 12 years in the second cohort. Symptom
    recognition in the first cohort was at a mean of 2.0 plus or minus 1.4 years,
    with tip-toe walking, foot deformity and Achilles contracture; independent
    walking was achieved at a mean of 1.6 plus or minus 0.8 years and was
    markedly delayed where equinovarus was severe. Foot deformity and tendon
    contracture were congenital in two cases.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonetheless, early-onset foot deformities, contractures, and gait abnormalities have been consistently reported in nearly all individuals with VWA1-related disorder, suggesting an early or even infantile disease onset rather than adult onset."
    explanation: States the age of onset and the authors' correction of the earlier impression of adult onset.
- phase: Slowly progressive adult course with preserved ambulation
  age_range: second decade onward
  notes: >-
    Progression is very slow and in several patients static, with isolated
    reports of worsening after the fifth decade. Ambulation is usually retained:
    three of seventeen in the first cohort lost independent walking over a
    median disease duration of 36.5 years, and none of the twenty patients in
    the second cohort had. Cardiac and respiratory involvement were not
    reported, and no neurocognitive symptoms were observed.
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, the disease progression was very slow or even static in several cases. Isolated cases reported some clinical worsening after the fifth decade of life."
    explanation: Characterises the rate of progression over the long observed course.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No associated neurocognitive symptoms were observed. Cardiac or respiratory involvement was not reported. Despite the diverse clinical manifestations, all affected individuals exhibited a slow disease progression and remained ambulatory at the time of investigations."
    explanation: Records the absence of cardiac, respiratory and cognitive involvement and the preserved ambulation.
clinical_burden:
  burden_level: MODERATE
  rationale: >
    Lifelong motor disability from early childhood, but rarely loss of
    ambulation and no reported cardiac, respiratory or cognitive involvement.
    The dominant burden is diagnostic rather than functional: the condition is
    described as going unnoticed for years to decades, is routinely mistaken for
    Charcot-Marie-Tooth disease, spinal muscular atrophy, hereditary spastic
    paraplegia or a muscular dystrophy, and the causal allele is systematically
    missed by standard sequencing pipelines because of its GC-rich repetitive
    context. Patients in the reported cohorts had already been tested for
    Duchenne muscular dystrophy, facioscapulohumeral dystrophy, SMA and
    dystonia panels before the right gene was found.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the broad phenotypic presentation of the condition, several other patients received preceding genetic investigations including neuropathy/neuromuscular disorder panel, movement disorder/dystonia panel, testing for Duchenne muscle dystrophy, facioscapulohumeral muscular dystrophy and SMA."
    explanation: Documents the diagnostic odyssey that is the main burden of this condition.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, VWA1 should be included in multiple gene panels covering hereditary neuropathies, muscle dystrophies, hereditary spastic paraplegia and SMA to reduce diagnostic delay and identify a large number of undiagnosed individuals."
    explanation: States the authors' own reading of the burden — diagnostic delay and a large undiagnosed population.
histopathology:
- name: Neurogenic atrophy with fibre type grouping
  frequency: FREQUENT
  diagnostic: true
  description: >
    Muscle biopsy in most patients shows chronic neurogenic change: neurogenic
    atrophy, fascicular grouping of type 1 fibres, thickening of the endomysium
    and perimysium. Four of seven biopsies in the first cohort were reported as
    showing clear neurogenic changes.
  finding_term:
    preferred_term: neurogenic muscle atrophy with fibre type grouping
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsy shows predominantly neuropathic aspects with neurogenic atrophy (arrow) and thickening of the endomysium and perimysium. Fascicular grouping of type 1 fibres implicates a chronic neurogenic process."
    explanation: Describes the neurogenic biopsy picture in a named patient.
  notes: >-
    finding_term is left unbound. HP:0033685 (Fiber type grouping) is the
    closest term and is curated as a separate phenotype above; it names one
    component of this composite picture, not the picture. Searched HP with
    runoak -i sqlite:obo:hp search 't~neurogenic atrophy' (no results) and
    't~Neurogenic muscle' (returns only HP:0003202 Skeletal muscle atrophy and
    HP:0003701 Proximal muscle weakness, neither of which is a biopsy finding).
- name: Myopathic and dystrophic features
  frequency: OCCASIONAL
  description: >
    A minority of biopsies show myopathic change alongside the neurogenic
    change: marked variation in fibre size, fibre hypertrophy, increased
    endomysial fibrosis with endomysial and perimysial fatty infiltration,
    rimmed vacuoles in one case, fibre lobulation and whorling of myofibrils in
    another, and a dystrophic pattern with multiple ring fibres in one patient
    of the second cohort. Collagen VI labelling was normal wherever it was
    assessed, which is the single most important negative finding in this
    disease.
  finding_term:
    preferred_term: myopathic change with increased endomysial connective tissue
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked variation in fibres size and increased endomysial fibrosis with mostly perimysial fatty infiltration. Rimmed vacuoles are shown with an arrow."
    explanation: Describes the myopathic features in a named patient biopsy.
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where data were available, immunohistochemical labelling for collagen VI appeared normal."
    explanation: >-
      Records the normal collagen VI labelling, the negative result that argues
      against a collagen VI-like primary matrix myopathy.
  notes: >-
    finding_term is unbound for the same reason as the moth-eaten record below:
    HP:0100297 Increased endomysial connective tissue exists but is outside the
    NCIT-rooted HistopathologyFindingTerm enum, so it is bound on the matching
    category Histopathology phenotype instead. NCIT searched with runoak
    -i sqlite:obo:ncit search 'l~Fibrosis' and 'l~Myopathic'; no morphologic
    finding term for endomysial fibrosis or for myopathic muscle change was
    returned.
- name: Motheaten muscle fibers
  frequency: OCCASIONAL
  diagnostic: false
  description: >
    Moth-eaten fibres on NADH-TR staining, recorded in one patient biopsy of the
    first cohort and explicitly annotated there as a non-specific finding. It is
    curated because it is part of the published biopsy description, not because
    it discriminates.
  finding_term:
    preferred_term: Motheaten muscle fibers
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NADH-TR shows the presence of moth-eaten fibres (non-specific finding)."
    explanation: Records the finding together with the authors' own statement that it is non-specific.
  notes: >-
    finding_term is unbound here even though HP:0100298 Motheaten muscle fibers
    exists, because the HistopathologyFindingTerm dynamic enum is rooted in the
    NCIT Histopathology Result branch (plus HP:0025461) and HP:0100298 is not
    reachable from it. The HP term is bound instead on the matching
    category Histopathology phenotype, following the convention used by
    Bethlem_Myopathy and Ullrich_Congenital_Muscular_Dystrophy. NCIT was
    searched with runoak -i sqlite:obo:ncit search 'l~Muscle Fiber' and
    'l~Denervation'; neither returns a morphologic finding term for this
    appearance.
imaging_findings:
- name: Fatty replacement of vastus lateralis and anterior lower leg
  modality: MRI
  frequency: FREQUENT
  diagnostic: true
  description: >
    T1-weighted muscle MRI shows increased signal or fatty replacement
    predominantly in the vastus lateralis and the anterior compartment of the
    lower legs.
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This displayed increased signal intensity or fatty replacement predominantly in the vastus lateralis and anterior compartment of the lower legs on T1-weighted sequences suggesting chronic denervation"
    explanation: Gives the distribution of the MRI change and the authors' reading of it as denervation.
- name: Gene-specific whole-body muscle MRI pattern
  modality: MRI
  frequency: FREQUENT
  diagnostic: true
  description: >
    In a whole-body muscle MRI series of non-5q spinal muscular atrophy, all
    five patients with VWA1 variants shared a reproducible pattern: selective
    gluteus maximus involvement with iliopsoas sparing, sparing of gracilis and
    sartorius despite severe quadriceps involvement, and predominant peroneus
    involvement with relative sparing of extensor digitorum. The pattern was not
    exclusive — it was also seen in single patients with VRK1 and HEXB variants
    — but it is specific enough to be proposed as a pre-test guide to which gene
    to sequence.
  evidence:
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In VWA1-related SMA, the pattern included selective gluteus maximus and quadriceps involvement with iliopsoas, gracilis, and sartorius preservation, and predominant peroneal involvement with relative extensor digitorum longus sparing."
    explanation: Describes the gene-specific imaging pattern recorded here.
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but was not exclusive because similar patterns were observed in 1 patient with a VRK1 pathogenic variant"
    explanation: >-
      States that the VWA1 imaging pattern is not exclusive to VWA1, which is
      the limit on the diagnostic claim this record makes.
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, confirmation in larger cohorts is needed, although this is constrained by the rarity of these disorders."
    explanation: The authors' own statement of how far the pattern has been validated, which bounds its use as a diagnostic clue.
- name: Outside-in fatty replacement of vastus lateralis resembling collagen VI myopathy
  modality: MRI
  frequency: OCCASIONAL
  description: >
    An outside-in gradient of fatty replacement within the vastus lateralis, the
    pattern characteristic of collagen VI-related myopathy, reported in a single
    Spanish patient and separately in three patients of the whole-body MRI
    series. It is the imaging counterpart of the argument that the muscle is
    primarily affected, since the protein WARP binds is the one whose disorders
    produce that pattern.
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:41331965
    reference_title: "A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy in Novel VWA1-Related Distal Hereditary Motor Neuronopathy With Myopathic Features in a Patient From Spain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle magnetic resonance imaging showed a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies."
    explanation: The case report describing the pattern.
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies, was observed in 3 patients"
    explanation: Independent replication of the same pattern in a separate cohort.
- name: Moth-eaten pattern on muscle ultrasound
  modality: ULTRASOUND
  frequency: OCCASIONAL
  description: >
    Muscle ultrasound of the lower leg shows a moth-eaten pattern — round dark
    areas of surviving motor units against a background of increased echo
    intensity — which is the appearance of long-standing denervation without
    reinnervation. Nerve ultrasound was normal in all three patients examined.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Families 8 and 12, muscle ultrasound demonstrated a moth-eaten pattern in the lower leg muscles, which can be seen in long-standing denervation without reinnervation."
    explanation: Describes the ultrasound pattern and its interpretation.
  notes: >-
    No ontology term is bound to this imaging finding. HP:0100298 Motheaten
    muscle fibers exists and is curated separately as a histopathology
    phenotype, but it names a histological fibre appearance on NADH-TR, not
    this ultrasound pattern of surviving motor units against fibrosed muscle;
    the two share a descriptive word and not a referent. Searched with runoak
    -i sqlite:obo:hp search 't~moth', whose only muscle hit is HP:0100298.
treatments:
- name: Physical Therapy and Contracture Management
  therapeutic_modality: BEHAVIORAL
  description: >
    Rehabilitation aimed at the contractures and the gait. Achilles tendon
    contracture, foot plantar flexion, knee and hip flexion contractures are
    present in more than half of patients and appear early, so they are the
    component of the disease most open to non-pharmacological management.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  - preferred_term: Tip-toe gait
    term:
      id: HP:0030051
      label: Tip-toe gait
  notes: >-
    No trial, cohort or case series of any intervention in VWA1-related disease
    has been published. Two PubMed searches were run and every returned title
    and abstract read: VWA1[Title/Abstract] (46 records) and
    VWA1 AND (therapy[sb] OR treatment OR trial) (10 records). Neither returned
    a therapeutic study of this disease; the hits in the second are cancer,
    stroke, glaucoma and wound-healing expression studies that mention the gene.
    This treatment is recorded without efficacy evidence because it is standard
    management for the contractures the disease produces, not because a source
    evaluates it here; it deliberately carries no evidence block rather than a
    manufactured one.
- name: Ankle-Foot Orthosis for Foot Drop
  therapeutic_modality: DEVICE
  description: >
    Orthotic support for the bilateral foot drop that is the commonest
    functional problem. The device concept is carried as a qualifier because
    NCIT's Brace/Orthosis term is a medical device and is not reachable from
    Clinical Intervention or Procedure, so it cannot sit in the treatment_term
    slot.
  treatment_term:
    preferred_term: ankle-foot orthosis fitting
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: ankle-foot orthosis
        term:
          id: NCIT:C86054
          label: Brace
  target_phenotypes:
  - preferred_term: Foot dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  notes: >-
    Recorded as standard supportive management for foot drop, not as an
    intervention evaluated in this disease. No VWA1-specific orthotic study
    exists; see the note on the physical therapy record for the search that
    established this.
- name: Orthopedic Surgery for Foot Deformity
  therapeutic_modality: SURGERY
  description: >
    Corrective surgery for the fixed foot deformities — talipes equinovarus in a
    third of patients, pes cavus in two thirds — and for the tendon
    contractures.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  - preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  notes: >-
    No published series reports surgical outcomes in VWA1-related disease. The
    record names a management option for a documented deformity rather than
    asserting that it has been evaluated here.
- name: Genetic Counseling and Targeted Founder Allele Testing
  therapeutic_modality: OTHER
  description: >
    Counselling for an autosomal recessive condition in which one allele is
    common enough in Western Europe that two unrelated carriers meeting is the
    usual genetic setting rather than consanguinity. The practical corollary is
    diagnostic: the founder duplication sits in a GC-rich repeat that standard
    exome pipelines under-call, so the authors of both original cohorts
    recommend targeted testing of VWA1 exon 1 and relaxed quality-control
    filters when re-analysing unsolved neuropathy exomes.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses."
    explanation: The concrete diagnostic recommendation this record exists to carry.
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1 disease that may account for up to 1% of unexplained hereditary neuropathies."
    explanation: Independent restatement of the same recommendation with the yield it is expected to deliver.
animal_models:
- name: vwa1 CRISPR knockout and morpholino knockdown zebrafish
  species: Zebrafish
  genotype: vwa1 CRISPR crispant and antisense morpholino knockdown, Tg(olig2:dsRed) background
  background: Tg(olig2:dsRed) transgenic reporter line
  publication: PMID:33559681
  description: >
    CRISPR crispants and morpholino morphants targeting exons 1-2 of the
    zebrafish vwa1 orthologue, whose protein shares 64.7% similarity across a
    408 amino acid overlap with human VWA1. Both models showed shortened and
    aberrantly branching spinal motor axons from day 2, sparser and disorganised
    myofibres on phalloidin staining, significantly reduced acetylcholine
    receptor staining with alpha-bungarotoxin, and a consistent trend at 5 days
    toward reduced distance moved and reduced velocity. They also showed an
    irregular jaw cartilage phenotype the authors state is not seen in patients.
  genes:
  - preferred_term: VWA1
    term:
      id: hgnc:30910
      label: VWA1
  modeled_mechanisms:
  - target: Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model is the only experimental evidence that WARP loss affects motor
      axon growth and endplate formation, and it is what the node is built on.
    limitations: >-
      The readouts are developmental and were taken at 48-96 hours
      post-fertilisation; human patients are studied decades later, and no human
      material has been examined for an endplate or axon-outgrowth defect.
      Morpholino knockdown carries well-known off-target risk, although the
      concordance with the CRISPR crispant mitigates it. The model also produces
      a jaw cartilage phenotype the authors state is not seen in patients, so
      the phenotypic correspondence is partial in the other direction too.
    readouts:
    - name: Spinal motor axon length at 48-96 hours post-fertilisation
      target: Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation
      direction: DECREASED
      interpretation: Direct morphometric measure of the motor axon outgrowth deficit.
      evidence:
      - reference: PMID:33559681
        reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Vwa1 Crispants (n = 29) and morphants (n = 26) showed significantly shortened axons compared to controls (n = 22)."
        explanation: Reports the measurement, its direction, and the group sizes.
    - name: Acetylcholine receptor clustering by alpha-bungarotoxin staining
      target: Impaired Motor Axon Outgrowth and Neuromuscular Junction Formation
      direction: DECREASED
      interpretation: Measures endplate formation in skeletal muscle of the knockdown/knockout larva.
      evidence:
      - reference: PMID:33559681
        reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "examination of neuromuscular junctions, by targeting the acetylcholine receptors (AChR) using alpha-bungarotoxin stain, revealed significantly reduced synaptic formation in the skeletal muscles"
        explanation: Reports the endplate measurement and its direction.
    evidence:
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These results established that vwa1 is required for the proper organization of skeletal muscles and in the formation of neuromuscular junctions."
      explanation: The authors' own conclusion that the model is informative for this node.
- name: Vwa1 (WARP) knockout mouse
  species: Mouse
  genotype: Vwa1 global knockout by targeted gene replacement (WARP-null)
  publication: PMID:19279005
  description: >
    The global WARP-null mouse predates the human disease and is what made VWA1
    a candidate gene. The mice are healthy, viable and fertile with no overt
    abnormality, but show a significantly delayed response to acute painful
    stimulus and impaired fine motor coordination; the collagen VI microfibrillar
    matrix is severely reduced and mislocalised in peripheral nerve, fibrillar
    collagen deposition in the nerve matrix is reduced, and adjacent Schwann cell
    basement membranes partially fuse. Articular cartilage, intervertebral disc
    and skeletal muscle showed no detectable abnormality and basement membranes
    formed normally, which is a point against the primary-muscle-lesion model.
    The delayed nociceptive response has no clear human counterpart: impaired
    nociception was not frequently seen in the patient series.
  genes:
  - preferred_term: VWA1
    term:
      id: hgnc:30910
      label: VWA1
  modeled_mechanisms:
  - target: Depletion of WARP from Nerve and Muscle Basement Membrane
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The mouse supplies the ultrastructural nerve-matrix lesion that gives this
      node its content, since no human nerve has been examined this way.
    limitations: >-
      It recapitulates the nerve arm and fails the muscle arm — WARP-deficient
      mice showed no histological or behavioural muscle pathology, so the mouse
      cannot be used to argue for the muscle side of this node. It also shows
      impaired nociception that was not frequently seen in patients, so the
      species mismatch runs in both directions.
    evidence:
    - reference: PMID:19279005
      reference_title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Our data demonstrate that although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves."
      explanation: >-
        The knockout study's own summary of what the model shows: a peripheral
        nerve lesion, which is the arm of this node it recapitulates.
  - target: Muscle Extracellular Matrix Remodeling
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      The knockout mouse shows no muscle pathology at all, which is the
      strongest single piece of evidence against a primary muscle lesion.
    limitations: >-
      A negative result in a mouse does not rule out a human primary muscle
      lesion: the mouse was not examined with the proteomic or matrix-specific
      methods later applied to patient muscle, and mouse and human skeletal
      muscle matrix composition differ. The finding constrains the hypothesis
      rather than closing it.
    evidence:
    - reference: PMID:19279005
      reference_title: "Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In contrast, other WARP-deficient tissues such as articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities, and basement membranes formed normally."
      explanation: >-
        The primary negative result: removing WARP produced no detectable
        skeletal muscle abnormality, which is what this link records the model
        as failing to recapitulate.
    - reference: PMID:33559681
      reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "WARP-null mice showed that WARP does not have a critical role in stabilizing the ECM localization of collagen VI in muscle as WARP-deficient mice expressed no histological or behavioural evidence of muscle pathology"
      explanation: >-
        The human-disease paper reading the same negative mouse result as an
        argument against a primary muscle-matrix lesion; restated there, hence
        BACKGROUND.
  notes: >-
    Curated from the primary knockout paper PMID:19279005 and the reporter-gene
    localisation paper PMID:18314316, both fetched into the reference cache for
    this entry. Where PMID:33559681 restates those findings its quotes are
    marked BACKGROUND so the two roles stay distinguishable.
diagnosis:
- name: VWA1 sequencing with attention to the exon 1 repeat
  description: >
    Molecular diagnosis rests on detecting biallelic VWA1 variants. The
    practical difficulty is specific and technical: the founder allele is a
    10 bp duplication in a GC-rich 10 bp repeat in exon 1, a context that gives
    low coverage and defeats standard variant callers, so the diagnosis is
    missed on otherwise adequate exome data. Both original cohorts recommend
    re-analysis of unsolved neuropathy exomes at relaxed quality-control
    thresholds, and targeted Sanger sequencing of exon 1 in a screening cohort
    of 1341 unsolved neuropathy patients yielded three further diagnoses.
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an attempt to replicate the results obtained from genome/exome sequencing, 1341 DNA samples from two independent cohorts of patients (374 from UK, 967 from Germany) with unsolved neuropathies were tested for the p.G25Rfs*74 founder mutation by screening exon 1 using a Sanger sequencing approach. This yielded three additional diagnoses"
    explanation: Reports the targeted-screening yield in unsolved neuropathy cohorts.
- name: Mixed neurogenic and myopathic electrodiagnostic pattern
  description: >
    The combination that should raise the question of this gene: an axonal
    motor neuropathy with preserved conduction velocities and normal sensory
    responses, chronic neurogenic change on needle EMG, and in a minority
    superimposed myopathic units, with raised creatine kinase. A whole-body
    muscle MRI pattern of gluteus maximus and quadriceps involvement with
    gracilis and sartorius sparing adds a pre-test imaging clue.
  evidence:
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene-specific imaging signatures, particularly for VRK1, DYNC1H1, and VWA1, can guide targeted genetic testing and support interpretation of variants of uncertain significance."
    explanation: States the diagnostic use the imaging pattern is proposed for.
differential_diagnoses:
- name: Spinal muscular atrophy with lower extremity predominance (DYNC1H1, BICD2)
  description: >
    The closest mimic. Both present with lower-limb-predominant weakness that is
    proximal as much as distal, tendon contractures, foot and spinal deformity
    and a forward-stooped posture, and both can show myopathic muscle biopsies.
  distinguishing_features:
  - >
    In the VWA1 series the upper limbs were involved in more than half the cases
    irrespective of severity, which is not the pattern in SMA with lower
    extremity predominance.
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in our series, the upper limbs were involved in more than half of the cases irrespective of the disease severity, unlike spinal muscular atrophy with lower extremity predominance."
    explanation: States the discriminating feature directly.
- name: Distal hereditary motor neuropathy type I
  description: >
    The paediatric subset of VWA1 patients with only distal lower limb weakness,
    wasting and foot contractures is clinically indistinguishable from typical
    dHMN type I at that stage.
  distinguishing_features:
  - >
    Weakness in VWA1 disease tends to progress proximally with age, which the
    authors give as the feature separating it from that presentation. Raised
    creatine kinase and any myopathic element are further pointers away from a
    pure motor neuropathy.
  evidence:
  - reference: PMID:33559681
    reference_title: "An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A subset of paediatric cases in our cohort with only distal lower limb weakness, wasting, and foot contractures resembled the typical distal hereditary motor neuropathy type I presentation"
    explanation: States the resemblance and the stage at which it holds.
- name: Hereditary spastic paraplegia
  description: >
    Patients with hyperreflexia, upgoing plantars and lower limb spasticity can
    be routed into a hereditary spastic paraplegia workup.
  distinguishing_features:
  - >
    The underlying electrophysiology in VWA1 disease is an axonal motor
    neuropathy with chronic neurogenic change on EMG, so nerve conduction
    studies and needle EMG are what separate the two.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperreflexia, especially when combined with spasticity, might mimic conditions on the hereditary spastic paraplegia spectrum."
    explanation: Names the mimic and the features that create it.
- name: Collagen VI-related dystrophies
  description: >
    The outside-in vastus lateralis fatty replacement seen on muscle MRI in
    several VWA1 patients is the pattern of collagen VI-related myopathy, and
    WARP binds collagen VI, so the two are connected as well as confusable.
  distinguishing_features:
  - >
    Collagen VI immunolabelling of muscle is normal in VWA1 patients, and the
    electrophysiology is neurogenic rather than purely myopathic.
  evidence:
  - reference: PMID:41331965
    reference_title: "A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy in Novel VWA1-Related Distal Hereditary Motor Neuronopathy With Myopathic Features in a Patient From Spain."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one of these reports, as in the current case, the MRI pattern mimicked that of type VI collagen disorders."
    explanation: Records the imaging mimicry between the two conditions.
- name: Juvenile amyotrophic lateral sclerosis
  description: >
    Tongue fasciculation or atrophy in a young patient with progressive weakness
    is a classic pointer to juvenile ALS, and it occurs in VWA1 disease.
  distinguishing_features:
  - >
    VWA1 disease progresses very slowly or is static over decades and preserves
    ambulation in almost all reported patients, with a median disease duration
    of 36.5 years in the first cohort.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tongue fasciculation and/or atrophy favours the diagnosis of juvenile amyotrophic lateral sclerosis associated with several genes including SETX, SPTLC1, SPTLC2, ALS2, FUS and SIGMAR1."
    explanation: States the diagnostic pull of the sign toward juvenile ALS.
discussions:
- discussion_id: vwa1_primary_or_secondary_myopathy
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is the muscle involvement in VWA1-related disease a primary lesion of the
    muscle extracellular matrix, or a secondary consequence of chronic
    denervation?
  attaches_to:
  - pathophysiology#Myopathic Change in Skeletal Muscle
  - pathophysiology#Muscle Extracellular Matrix Remodeling
  - pathophysiology#Chronic Neurogenic Denervation of Skeletal Muscle
  - mechanistic_hypotheses#denervation_secondary_myopathy
  - mechanistic_hypotheses#primary_muscle_matrix_lesion
  rationale: >
    The two cohorts that described the disease concurrently, in the same
    journal and the same year, named it differently, and the disagreement has
    not been resolved by any subsequent study. It is not a naming quibble: the answer
    determines whether the entity belongs with the motor neuropathies or with
    the muscular dystrophies for the purposes of gene-panel design, and it
    determines what a future therapy would have to reach.

    For a secondary process: needle EMG was neurogenic in 10 of 12 studies and
    myopathic in a minority; four of seven biopsies were purely neurogenic;
    collagen VI immunolabelling was normal wherever assessed; the WARP-null
    mouse has no detectable skeletal muscle abnormality at all; and the
    histological features attributed to myopathy are known to occur in
    chronically denervated muscle.

    For a primary process: WARP is expressed in skeletal muscle as well as
    nerve and binds collagen VI, whose own disorders are muscular dystrophies;
    creatine kinase is raised in most patients and reached 2400 U/L; muscle MRI
    in several patients shows an outside-in vastus lateralis pattern typical of
    collagen VI myopathy rather than of denervation; proteomics found increased
    C-reactive protein and NEFM in the extracellular space of patient muscle;
    and a whole-body MRI series in which gracilis and sartorius were spared in
    all five VWA1 patients reads that sparing as evidence for a direct muscle
    effect.

    What would settle it: WARP immunostaining of patient muscle and nerve
    alongside quantitative matrix analysis, in patients whose denervation burden
    is measured independently; or a conditional muscle-restricted Vwa1 knockout.
    Neither has been reported.
  evidence:
  - reference: PMID:39502942
    reference_title: "Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, the true myopathic nature of the disease remained controversial, with some proposing a primarily neurogenic pathology and a secondary myopathic process."
    explanation: States that the question is open and names both positions, which is exactly what this discussion records.
  - reference: PMID:42662709
    reference_title: "Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is therefore possible that the preservation of the sartorius and gracilis muscles in SMA indicates a pathophysiologic mechanism involving direct muscle effects and may provide information useful for interpreting VUS."
    explanation: The most recent argument for a direct muscle effect, from an imaging pattern rather than from histology.
  - reference: PMID:38652110
    reference_title: "Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, there is no common consent if the muscular affection is a secondary pathology based on vulnerability and dysfunction of motoric axons or if a primary muscle pathology is rather part of the clinical picture."
    explanation: An independent statement that no consensus exists, from the group that set out to test the question.
- discussion_id: vwa1_upper_motor_neuron_signs
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do some patients with biallelic VWA1 variants have upper motor neuron
    signs, when the gene product is a peripheral nerve and muscle matrix protein
    and the largest cohort found none?
  attaches_to:
  - phenotypes#Hyperreflexia
  - phenotypes#Spasticity
  rationale: >
    The first cohort recorded largely normal muscle tone and uniformly negative
    Babinski signs across its 17 patients. A subsequent two-child report
    made upper motor neuron signs its title finding, and the 20-patient cohort
    that followed recorded hyperreflexia, spasticity in two and upgoing plantars
    in two. No mechanism has been proposed. The possibilities are not
    distinguished by any published data: ascertainment drift as the phenotype
    widened, a genuine central component of a protein that is also expressed in
    the vasculature of neural tissues, or coincidence in a population where one
    causal allele is carried by roughly one person in 441 and so will sometimes
    be found alongside an unrelated condition. The third possibility is
    specifically worth testing for a disease whose defining allele is this
    common, and no report has excluded it.
  evidence:
  - reference: PMID:35975723
    reference_title: "Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1."
    explanation: The report that introduced upper motor neuron signs into the phenotype, and its sample size.
  - reference: PMID:18314316
    reference_title: "The extracellular matrix protein WARP is a novel component of a distinct subset of basement membranes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "WARP is expressed in the vasculature of neural tissues and in basement membrane structures of the peripheral nervous system."
    explanation: >-
      Records the one piece of expression data that would make a central
      component biologically conceivable; it establishes vascular expression in
      neural tissue, not a corticospinal role.
- discussion_id: vwa1_2026_minipolymyoclonus_case_full_text
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Does the 2026 Muscle Nerve case report (PMID:41416782) establish
    minipolymyoclonus and fasciculations as features of VWA1-related disease,
    and should they be curated as phenotypes?
  attaches_to:
  - phenotypes#Scapular winging
  - phenotypes#Tongue fasciculations
  rationale: >
    The report's title names minipolymyoclonus, fasciculations and scapular
    winging in a novel VWA1 variant, and minipolymyoclonus is not currently
    curated in this entry at all. It cannot be curated from what is available:
    the record is a Letter, and `just fetch-reference PMID:41416782` returns
    `content_type: unavailable` with an empty body, so the only text obtainable
    is the title. A title is not a finding, and curating a phenotype from one
    would be exactly the fabrication the evidence SOP exists to prevent.

    This is therefore filed as a task, not written in. Resolving it needs the
    full text: confirm that minipolymyoclonus was observed in a genetically
    confirmed patient, find the HP term for it, and check whether the
    fasciculations are tongue or limb. The scapular winging in the title is
    already curated from the 2024 cohort and needs no change.

    Noted because minipolymyoclonus would be a genuinely new feature of the
    phenotype rather than a restatement — it is a sign of motor-unit loss and
    would attach to the same axon-loss node as the tongue fasciculations.
  notes: >-
    Surfaced by the post-hoc deep-research cross-check
    (research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_7-deep-research-claude_code.md),
    which asserted the finding on the strength of the title alone. The cache
    file references_cache/PMID_41416782.md is committed so a later curator can
    confirm the empty body rather than re-fetching to discover it.
notes: >-
  Curation decisions worth recording. (1) entry_type DISEASE rather than SUBTYPE.
  MONDO:0030977 is absent from kb/ on main, and VWA1 appears there only inside a
  quoted EMG snippet in Distal_Hereditary_Motor_Neuronopathy_Type_2A.yaml, which
  is an HSPB8-related dominant entry with no has_subtypes rows. The MONDO parent
  MONDO:0015363 is curated as Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive,
  whose has_subtypes rows cover HMNR1/IGHMBP2, HMNR2/SIGMAR1, HMNR4/PLEKHG5 and
  RTN2 but not HMNR7. A separate entry was chosen because the causal gene is a
  basement-membrane matrix protein rather than a motor-neuron housekeeping
  protein, the neuropathy is non-length-dependent where the family template is
  length-dependent, and the disease carries a myopathic component the family
  template does not. The same precedent already exists in this KB: HMNR1/SMARD1
  is both a has_subtypes row on that umbrella and a standalone entry
  (Spinal_Muscular_Atrophy_with_Respiratory_Distress_Type_1). Adding a matching
  has_subtypes row to the umbrella, and adding this entry as a member of the
  Distal_Hereditary_Motor_Neuropathies grouping, are both warranted follow-ons;
  they were left out of this PR to avoid editing two heavily-referenced shared
  files concurrently with other curation work. (2) No conforms_to is declared.
  peripheral_axonal_degeneration was inspected and rejected: its chain runs
  through axonal-transport and mitochondrial bioenergetic failure to a node named
  Length-Dependent Nerve Fiber Dysfunction, and non-length-dependence is the
  defining feature of this disease rather than an incidental one.
  neuromuscular_transmission_failure was also inspected and rejected: it is
  organised around loss of the safety factor producing fatigable weakness with a
  decremental response to repetitive stimulation. Neither appears in the VWA1
  literature — grep for fatigab, decrement and repetitive nerve stim across the
  five cached VWA1 sources (PMID:33559681, PMID:33459760, PMID:39502942,
  PMID:38652110, PMID:42662709) returns no match in any of them. The zebrafish
  endplate finding is
  a developmental synapse-formation deficit, not a transmission-safety-factor
  lesion, so it does not license conformance either. (3) No GeneReviews chapter
  covers this disease; see the entry-level comment in the PR and the check
  recorded below. (4) Some phenotypes are deliberately left unwired in the causal
  graph — scoliosis, lumbar hyperlordosis, scapular winging, hyperreflexia,
  spasticity, joint hypermobility and dystonia. Each says so in its own
  description. No source states a mechanism for any of them in this disease.
  (5) Literature provenance. The primary sweep for this entry was done by hand
  against PubMed before any deep-research pass, and every returned title and
  abstract was read. The queries and their record counts, re-confirmed against
  E-utilities on 2026-09-19: VWA1[Title/Abstract] returns 46 records, which is
  the entire VWA1 literature and is mostly expression studies in unrelated
  diseases; VWA1[Title/Abstract] AND neuropathy returns 6;
  VWA1 AND (therapy[sb] OR treatment OR trial) returns 10 and contains no
  therapeutic study of this disease; WARP[Title] AND (nerve OR basement membrane
  OR Vwa1) returns 10 and is what surfaced the primary Allen knockout and
  reporter-gene papers now cited as PMID:19279005 and PMID:18314316;
  genereviews[book] AND VWA1 returns 0. Two records returned by the first query
  were fetched and then dropped because the cache held no quotable body
  (PMID:33693694, a Brain commentary; PMID:41416782, a Muscle Nerve letter).
  (6) Deep-research cross-check. research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_7-deep-research-claude_code.md
  was generated AFTER this entry was curated and is a post-hoc cross-check, not
  a source: nothing in this entry was taken from it. It returned no reference
  the manual sweep had missed — it cites the same eleven PMIDs plus
  PMID:41416782, the title-only letter now filed as a CURATION_TODO above. Its
  own validation recorded 15/15 references resolving with a 0.0 confabulation
  rate, but flagged one unsupported quote and two mislabelled terms, and all
  three were checked here. The unsupported quote is an ellipsis-elided
  paraphrase attributed to PMID:39502942, which replaces "with VWA1-related
  disorder," with an ellipsis; the verbatim sentence is already quoted correctly
  in progression[0]. The two mislabelled terms are MONDO:0030977 called "MONDO"
  and GO:0000184 called "NMD", which are the report abbreviating rather than
  misbinding. Two of its claims were refused. It assigns VWA1 to cytogenetic
  band 1p36.33; the only band appearing anywhere in the cited caches is a bare
  "1p36" in PMID:33559681, and it occurs there in a sentence about 1p36 deletion
  syndrome rather than as a locus assignment, so the sub-band is unsupported at
  that precision and is not written here. It also reports an in-frame deletion
  in the variant spectrum; the 2024 cohort enumerates 3 stop-gains, 7
  frameshifts and 3 proline missense changes among its 13 additional variants,
  and the string "in-frame" appears in none of the eleven cited cache files. Two of its
  suggestions were accepted after lookup and are now bound on the
  basement-membrane node: GO:0005604 basement membrane and UBERON:0001134
  skeletal muscle tissue, both confirmed with runoak against the local builds.
review_notes: >-
  GeneReviews baseline: no GeneReviews chapter exists for VWA1-related disease.
  Checked offline against cache/bookshelf/genereviews.csv (958 chapters in the 2026-09-10 snapshot; no hit
  for VWA1, neuromyopathy, or distal hereditary motor neuropathy) and online
  against PubMed with genereviews[book] AND VWA1, which returns 0 records.
  GeneReviews does carry chapters on other hereditary motor and sensory
  neuropathies (MFN2, SH3TC2, GDAP1), none of which covers this gene or this
  entity. StatPearls likewise has no chapter; nothing in this KB treats
  StatPearls as a baseline in any case.

📚

References & Deep Research

References

11

PMID:33559681

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

No top-level findings curated for this source.

PMID:33459760

Bi-allelic truncating mutations in VWA1 cause neuromyopathy.

No top-level findings curated for this source.

PMID:39502942

Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations.

No top-level findings curated for this source.

PMID:38652110

Proteomic studies in VWA1-related neuromyopathy allowed new pathophysiological insights and the definition of blood biomarkers.

No top-level findings curated for this source.

PMID:35975723

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants.

No top-level findings curated for this source.

PMID:41331965

A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy in Novel VWA1-Related Distal Hereditary Motor Neuronopathy With Myopathic Features in a Patient From Spain.

No top-level findings curated for this source.

PMID:42662709

Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications.

No top-level findings curated for this source.

PMID:30768857

WARP: A Unique Extracellular Matrix Component of Cartilage, Muscle, and Endothelial Cell Basement Membranes.

No top-level findings curated for this source.

PMID:19279005

Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.

No top-level findings curated for this source.

PMID:18314316

The extracellular matrix protein WARP is a novel component of a distinct subset of basement membranes.

No top-level findings curated for this source.

PMID:35942667

Hereditary motor neuropathies.

No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (2)

Record notes

Curation decisions worth recording. (1) entry_type DISEASE rather than SUBTYPE. MONDO:0030977 is absent from kb/ on main, and VWA1 appears there only inside a quoted EMG snippet in Distal_Hereditary_Motor_Neuronopathy_Type_2A.yaml, which is an HSPB8-related dominant entry with no has_subtypes rows. The MONDO parent MONDO:0015363 is curated as Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive, whose has_subtypes rows cover HMNR1/IGHMBP2, HMNR2/SIGMAR1, HMNR4/PLEKHG5 and RTN2 but not HMNR7. A separate entry was chosen because the causal gene is a basement-membrane matrix protein rather than a motor-neuron housekeeping protein, the neuropathy is non-length-dependent where the family template is length-dependent, and the disease carries a myopathic component the family template does not. The same precedent already exists in this KB: HMNR1/SMARD1 is both a has_subtypes row on that umbrella and a standalone entry (Spinal_Muscular_Atrophy_with_Respiratory_Distress_Type_1). Adding a matching has_subtypes row to the umbrella, and adding this entry as a member of the Distal_Hereditary_Motor_Neuropathies grouping, are both warranted follow-ons; they were left out of this PR to avoid editing two heavily-referenced shared files concurrently with other curation work. (2) No conforms_to is declared. peripheral_axonal_degeneration was inspected and rejected: its chain runs through axonal-transport and mitochondrial bioenergetic failure to a node named Length-Dependent Nerve Fiber Dysfunction, and non-length-dependence is the defining feature of this disease rather than an incidental one. neuromuscular_transmission_failure was also inspected and rejected: it is organised around loss of the safety factor producing fatigable weakness with a decremental response to repetitive stimulation. Neither appears in the VWA1 literature — grep for fatigab, decrement and repetitive nerve stim across the five cached VWA1 sources (PMID:33559681, PMID:33459760, PMID:39502942, PMID:38652110, PMID:42662709) returns no match in any of them. The zebrafish endplate finding is a developmental synapse-formation deficit, not a transmission-safety-factor lesion, so it does not license conformance either. (3) No GeneReviews chapter covers this disease; see the entry-level comment in the PR and the check recorded below. (4) Some phenotypes are deliberately left unwired in the causal graph — scoliosis, lumbar hyperlordosis, scapular winging, hyperreflexia, spasticity, joint hypermobility and dystonia. Each says so in its own description. No source states a mechanism for any of them in this disease. (5) Literature provenance. The primary sweep for this entry was done by hand against PubMed before any deep-research pass, and every returned title and abstract was read. The queries and their record counts, re-confirmed against E-utilities on 2026-09-19: VWA1[Title/Abstract] returns 46 records, which is the entire VWA1 literature and is mostly expression studies in unrelated diseases; VWA1[Title/Abstract] AND neuropathy returns 6; VWA1 AND (therapy[sb] OR treatment OR trial) returns 10 and contains no therapeutic study of this disease; WARP[Title] AND (nerve OR basement membrane OR Vwa1) returns 10 and is what surfaced the primary Allen knockout and reporter-gene papers now cited as PMID:19279005 and PMID:18314316; genereviews[book] AND VWA1 returns 0. Two records returned by the first query were fetched and then dropped because the cache held no quotable body (PMID:33693694, a Brain commentary; PMID:41416782, a Muscle Nerve letter). (6) Deep-research cross-check. research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_7-deep-research-claude_code.md was generated AFTER this entry was curated and is a post-hoc cross-check, not a source: nothing in this entry was taken from it. It returned no reference the manual sweep had missed — it cites the same eleven PMIDs plus PMID:41416782, the title-only letter now filed as a CURATION_TODO above. Its own validation recorded 15/15 references resolving with a 0.0 confabulation rate, but flagged one unsupported quote and two mislabelled terms, and all three were checked here. The unsupported quote is an ellipsis-elided paraphrase attributed to PMID:39502942, which replaces "with VWA1-related disorder," with an ellipsis; the verbatim sentence is already quoted correctly in progression[0]. The two mislabelled terms are MONDO:0030977 called "MONDO" and GO:0000184 called "NMD", which are the report abbreviating rather than misbinding. Two of its claims were refused. It assigns VWA1 to cytogenetic band 1p36.33; the only band appearing anywhere in the cited caches is a bare "1p36" in PMID:33559681, and it occurs there in a sentence about 1p36 deletion syndrome rather than as a locus assignment, so the sub-band is unsupported at that precision and is not written here. It also reports an in-frame deletion in the variant spectrum; the 2024 cohort enumerates 3 stop-gains, 7 frameshifts and 3 proline missense changes among its 13 additional variants, and the string "in-frame" appears in none of the eleven cited cache files. Two of its suggestions were accepted after lookup and are now bound on the basement-membrane node: GO:0005604 basement membrane and UBERON:0001134 skeletal muscle tissue, both confirmed with runoak against the local builds.

Review round 1: add post-hoc deep-research cross-check and literature provenance (PR #12291) · 2026-09-19T09:56:23Z · View source

Review round 1 on PR #12291 (ai4c-reviewer, CHANGES_REQUESTED, 2026-09-19). One blocking finding, procedural: the new entry shipped no research/*-deep-research-*.md artifact, which .claude/skills/dismech-pr-review states as a MUST for new entries, and the absence was not signalled in notes:, review_notes:, or the history record. The reviewer verified that the only family-level report, Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive -deep-research-falcon.md, contains zero mentions of VWA1 or WARP and so provides no coverage; that was independently re-confirmed here by grep. The reviewer explicitly recorded that the entry is NOT under-consumed on any Content-Completeness dimension, so the gap was provenance, not content. Accepted. Both remedies the reviewer offered were taken rather than one: First, a deep-research pass was run as a post-hoc cross-check and committed: research/Neuronopathy_Distal_Hereditary_Motor_Autosomal_Recessive_7-deep-research-claude_code.md plus its .citations.md sidecar (provider claude_code, 197 s, 12 citations; no _artifacts/ directory was produced). It is explicitly a cross-check, not a source — the entry was curated before it existed and nothing in the entry was taken from it. just preflight-dr returns PASS against MONDO:0030977 with VWA1 mentioned 37 times and the OMIM id matching. The outcome is that it found NOTHING NEW: it cites exactly the same eleven PMIDs the manual sweep had already curated, plus PMID:41416782, a 2026 Muscle Nerve letter whose cache has content_type: unavailable, so only its title is obtainable. Its own validation recorded 15/15 references resolving, confabulation rate 0.0, but needs_review: true on both reference and term validation. All three flags were checked rather than trusted. The one unsupported quote is an ellipsis-elided paraphrase attributed to PMID:39502942 that replaces "with VWA1-related disorder," with an ellipsis; the verbatim sentence was already quoted correctly in progression[0] and no change was needed. The two mislabelled terms are MONDO:0030977 reported as "MONDO" and GO:0000184 reported as "NMD", both the report abbreviating rather than misbinding. Two report claims were refused. It assigns VWA1 to cytogenetic band 1p36.33; the only band string in any cited cache is a bare "1p36" in PMID:33559681, and it appears there in a sentence about 1p36 deletion syndrome rather than as a locus assignment, so the sub-band is unsupported at that precision. It also reports an in-frame deletion in the variant spectrum; the 2024 cohort enumerates 3 stop-gains, 7 frameshifts and 3 proline missense changes among its 13 additional variants, and grep for "in-frame" returns nothing across all eleven cited cache files. Two report suggestions were accepted after independent lookup and are now bound on the Depletion of WARP from Nerve and Muscle Basement Membrane node: GO:0005604 basement membrane as a cellular_components entry (confirmed present and under GO:0005575 via runoak against both the local build and ols:), and UBERON:0001134 skeletal muscle tissue added to locations (confirmed under UBERON:0001062). Binding the basement-membrane compartment is a real gain: the node named it in prose without grounding it, and this is a basement-membrane disease. The report's title-only claim that a 2026 case adds minipolymyoclonus and fasciculations to the phenotype was NOT written in. A title is not a finding and the cache holds no body, so it is filed as a CURATION_TODO discussion (vwa1_2026_minipolymyoclonus_case_full_text) naming what full text would be needed to resolve it. references_cache/PMID_41416782.md is committed alongside so a later curator can see the empty body rather than re-fetching to find out. Second, the manual literature provenance was lifted to a top-level notes: item (5). It names the five PubMed queries actually run and their record counts, re-confirmed against E-utilities on 2026-09-19: VWA1[Title/Abstract] = 46, VWA1[Title/Abstract] AND neuropathy = 6, VWA1 AND (therapy[sb] OR treatment OR trial) = 10, WARP[Title] AND (nerve OR basement membrane OR Vwa1) = 10, genereviews[book] AND VWA1 = 0. It also records the two records fetched and then dropped for having no quotable cached content (PMID:33693694, PMID:41416782), whose cache files were deliberately not committed. Non-blocking suggestion accepted: the PR description said the Bookshelf index holds 959 chapters where it holds 958. The YAML had already been corrected in c24334a02; only the PR prose was stale, and it was edited in place rather than pushed, since a body edit is not a commit. Nothing was conceded on content. The reviewer raised no content findings and positively endorsed the two-hypothesis-group modelling of the neuromyopathy nosology dispute, the atomic 8-node pathograph, the FAILS_TO_RECAPITULATE mouse link with its REFUTE evidence item, and the NCIT device-qualifier pair. The reviewer's own snippet checker flagged 1 of 129 snippets (PMID:39502942, a quote eliding a trailing "(Fig. 1H)" figure callout) and the reviewer deferred to the repository validator, calling it a false positive of stricter normalisation. Re-checked here: just validate-disorders reports 129/129 snippets verified and the repository's literal_bracket_patterns configuration strips numeric and figure callouts before matching, so no change was made.

Claude Code ▸

1. Disease Information

claude-fable-5, claude-haiku-4-5-20251001 12 citations 2026-09-19T02:43:39.144125

1. Disease Information

Overview. Autosomal recessive distal hereditary motor neuronopathy type 7 (HMNR7) is a childhood-onset, slowly progressive motor neuropathy caused by biallelic loss-of-function variants in VWA1, which encodes the extracellular matrix protein WARP (von Willebrand factor A domain-related protein). The disease was defined simultaneously by two independent 2021 cohorts in Brain: Pagnamenta et al. described it as a non-length-dependent "hereditary motor neuropathy" (PMID:33559681), while Deschauer et al. described the same entity as a "neuromyopathy" with combined neurogenic and myopathic pathology (PMID:33459760). It presents in the first years of life with foot deformity, tip-toe gait, and foot drop, with weakness that — unusually for this disease family — involves proximal lower limbs as severely as distal ones, plus a myopathic component (raised CK, occasional myopathic EMG/biopsy findings).

Key identifiers:

Resource	Identifier
MONDO	MONDO:0030977
OMIM (phenotype)	#619216 (HMNR7) — omim.org/entry/619216
OMIM (gene)	*611901 (VWA1) — omim.org/entry/611901
HGNC	HGNC:30910 (VWA1)
Orphanet	No dedicated ORPHA code identified in this search
ICD-10	G60.0 (hereditary motor and sensory neuropathy, closest applicable code; no disease-specific code)
Locus	Chromosome 1p36.33

Synonyms: HMNR7; HMNMYO ("neuropathy, hereditary motor, with myopathic features"); VWA1-related neuromyopathy; VWA1-related distal hereditary motor neuropathy; VWA1-related disorder.

Data provenance. All clinical knowledge derives from aggregated case-series/cohort literature (54 published patients as of late 2024: "Results are based on data from 54 patients (n = 20 from presented cohort and n = 34 from previous publications)" — PMID:39502942), not EHR-level data.

2. Etiology

Causal factor (established): Biallelic germline loss-of-function variants in VWA1. "Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder" (PMID:33459760, 2021). Independently: "we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1" (PMID:33559681, 2021).

Genetic risk factors. The dominant risk allele is the Western European founder duplication NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74) — carrier frequency ~1 in 441 in the UK/Western European population (PMID:39502942, 2024). It arose on "a shared 220 kb region suggesting that this founder mutation arose >7000 years ago" (PMID:33559681). Because one allele is this common, the usual genetic setting is two unrelated carriers meeting rather than consanguinity; only one of fifteen families in the first cohort had a positive family history, the rest being sporadic.

Environmental risk/protective factors: None reported. This is a fully penetrant-appearing monogenic Mendelian disease; no environmental triggers, lifestyle modifiers, protective variants, or gene–environment interactions have been described in any published cohort. (CTD, GWAS Catalog: no relevant entries for this phenotype.)

3. Phenotypes

All frequencies below come from the two founding cohorts (17 patients, PMID:33559681; 15 patients, PMID:33459760) and the 2024 20-patient cohort/54-patient literature synthesis (PMID:39502942).

Phenotype	HPO term	Frequency	Onset/severity/course
Motor axonal neuropathy	HP:0007002	Obligate (diagnostic)	Reduced/absent CMAPs, preserved velocities, normal sensory studies
Foot dorsiflexor weakness (foot drop)	HP:0009027	Very frequent	Usually bilateral, presenting sign
Distal lower limb weakness	HP:0009053	Very frequent	MRC 1–3 for foot/toe movements; onset birth–12 y
Proximal lower limb weakness	HP:0008994	~50% (frequent)	Simultaneous with distal — the non-length-dependent hallmark
Pes cavus	HP:0001761	65% (11/17)	Mostly before school age
Talipes equinovarus	HP:0001762	35% (6/17)	Congenital in two cases
Achilles tendon contracture	HP:0001771	>50%	Early; contractures also at knee/hip, sometimes upper limb
Tip-toe gait	HP:0030051	Frequent	Mean symptom recognition 2.0 ± 1.4 y
Hyporeflexia	HP:0001265	~50%
Skeletal muscle atrophy	HP:0003202	Frequent but mild	Prominent atrophy characteristically absent
Elevated CK	HP:0003236	Frequent	369–1628 IU/L (cohort 1); up to 2400 U/L (cohort 2)
EMG: chronic denervation signs	HP:0003444	10/12 studies	Without active denervation
EMG: myopathic abnormalities	HP:0003458	Minority (3/12; 1/20)	Mixed neurogenic-myopathic signature
Fiber type grouping (biopsy)	HP:0033685	Frequent	Denervation-reinnervation signature
Scoliosis / lumbar hyperlordosis	HP:0002650 / HP:0002938	~50% each
Falls	HP:0002527	~33%	Ambulation nonetheless preserved
Tongue fasciculations	HP:0001308	Occasional (2+2 patients)	Pushes differential toward juvenile ALS
Scapular winging	HP:0003691	Occasional (n=2)	Also in the new 2026 case (PMID:41416782)
Hyperreflexia / spasticity (UMN signs)	HP:0001347 / HP:0001257	Occasional, contested	Absent in first cohort ("uniformly negative Babinski sign"), reported in later cohorts (PMID:35975723, PMID:39502942)
Joint hypermobility	HP:0001382	n=1
Dystonia	HP:0001332	n=1
Increased endomysial connective tissue	HP:0100297	Occasional
Motheaten muscle fibers	HP:0100298	Rare, non-specific

Key supporting quotes: "Of note, bilateral foot deformity was a very frequent feature revealed in almost 90% of the cases (15/17), ranging from pes cavus (65%, 11/17) to talipes equinovarus (35%, 6/17)" (PMID:33559681). "While the most common features of VWA1-related disease include foot drop, foot deformities and distal lower limb weakness, about half of the so far reported individuals develop proximal leg weakness over time, and approximately one-third experience upper limb involvement" (PMID:39502942).

A 2026 case report added minipolymyoclonus and fasciculations to the spectrum (Sharma et al., Muscle & Nerve 2026, PMID:41416782).

Quality-of-life impact: No formal QoL instrument (EQ-5D/SF-36) study exists. Functionally the disease is comparatively benign: "the condition may go unnoticed for years to decades due to its relatively benign nature, often presenting mild neurological deficits, the absence of prominent muscle atrophy and slow disease progression" (PMID:39502942). Only 3/17 patients lost independent ambulation over a median 36.5-year disease duration.

4. Genetic/Molecular Information

Causal gene: VWA1 (HGNC:30910; OMIM *611901; chromosome 1p36.33), encoding the 445-amino-acid extracellular matrix protein WARP: "In humans, VWA1 (von Willebrand factor A domain containing 1) encodes a 445 amino acid ECM protein that is also referred to as von Willebrand factor A domain related protein (WARP)" (PMID:33559681).

Founder/pathogenic variants: - NM_022834.5:c.62_71dup p.(Gly25ArgfsTer74) — the disease-defining allele: a 10-bp duplication expanding a 2-copy 10-bp repeat in exon 1 to 3 copies ("This variant involves an expansion of a 10 bp repeat in Exon 1 of VWA1, leading to three copies instead of two compared with normal alleles" — PMID:39502942). Present in 14/15 families in the first cohort (homozygous in 10/15) and 12/15 in the 2024 cohort. Classification: Pathogenic. Allele frequency: "The maximum population allele frequency of the most common variant across all databases remained the highest in the European non-Finnish with 0.093% in gnomAD v4.0.0 and 0.118% in UK Biobank" (PMID:39502942); the discovery paper estimated ~1/847 European allele frequency. - The wider spectrum is dominated by truncating variants (stop-gains, frameshifts) plus a few missense changes at proline residues and one in-frame deletion in the VWA domain. Deschauer: "We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent" (PMID:33459760). The 2024 cohort reported 13 additional variants (11 novel), mostly compound heterozygous with the founder allele in trans. - A reciprocal 10-bp deletion (c.62_71del, p.G21Afs*12) exists at the same locus and was speculated to be a second founder allele, but no biallelic case has been reported.

Functional consequence: loss of function via NMD. "Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein" (PMID:33559681).

Origin: Germline in all cases; no somatic contribution. Modifier genes, epigenetics, chromosomal abnormalities: none described.

Critical technical note for variant detection: "This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions" (PMID:33559681). This is the single most important practical fact about the gene.

5. Environmental Information

Not applicable. No environmental, lifestyle, occupational, or infectious factors cause, trigger, or modify this monogenic disease in any published report.

6. Mechanism / Pathophysiology

Causal chain (numbered; branch point marked):

Biallelic VWA1 loss-of-function variants (germline; predominantly the exon 1 founder duplication) lead to →
Nonsense-mediated decay of mutant transcript and absence of WARP protein (demonstrated in patient fibroblasts: "there was no detectable VWA1 in either the conditioned medium or cell layer of the patient's fibroblast" — PMID:33559681) results in →
Depletion of WARP from nerve (and muscle) basement membranes. WARP is normally abundant in peripheral nerve — highest human tissue expression in tibial nerve — where it binds collagen VI and perlecan ("WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures" — PMID:19279005). In the knockout mouse this loss produces "reduced fibrillar collagen deposition within the peripheral nerve extracellular matrix and abnormal partial fusing of adjacent Schwann cell basement membranes" and a collagen VI matrix that "was severely reduced and mislocalized in peripheral nerves of WARP-null mice" (PMID:19279005). This leads to (branch):
4a. Impaired motor axon outgrowth and neuromuscular junction formation (zebrafish; inferred for humans): "CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour" (PMID:33559681). The route from this developmental deficit to adult axon loss is not demonstrated.
4b. (Contested branch) Primary muscle extracellular-matrix lesion — see controversy below.
Non-length-dependent motor axon loss results in reduced/absent CMAPs with preserved velocities, simultaneous proximal + distal weakness ("Most of the cases (75%) were found to have simultaneous proximal and distal lower limb weakness" — PMID:33559681), foot drop, hyporeflexia. Leads to →
Chronic neurogenic denervation of skeletal muscle (EMG chronic neurogenic change 10/12; fiber type grouping; neurogenic atrophy) which, on the canonical model, produces →
Secondary myopathic change — raised CK, dystrophic biopsy features, myopathic EMG in a minority — culminating in the clinical picture of an early-onset, slowly progressive neuromyopathy with foot deformity and contractures.

The central unresolved controversy — is the muscle involvement secondary to denervation (canonical) or a primary matrix lesion (alternative)? Explicitly open in the literature: "there is no common consent if the muscular affection is a secondary pathology based on vulnerability and dysfunction of motoric axons or if a primary muscle pathology is rather part of the clinical picture" (PMID:38652110, 2024). - For secondary: "We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process" (PMID:33559681); collagen VI immunolabelling normal in patient muscle; the WARP-null mouse shows no muscle pathology ("articular cartilage, intervertebral discs, and skeletal muscle showed no detectable abnormalities" — PMID:19279005). - For primary: "Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology" (PMID:33459760); 2024 proteomics found "CRP elevated in plasma also showed an increase in the extracellular space of VWA1-mutant muscle" and "NEFM showed an increase in cells within the ECM in biopsies of all patients studied" (PMID:38652110); muscle MRI shows "a distinctive outside-in pattern of fatty replacement in the vastus lateralis, resembling that seen in type VI collagen-related myopathies" (PMID:41331965, 2025; replicated in 3 patients in PMID:42662709, 2026).

Ontology suggestions: GO:0000184 (NMD), GO:0005201 (ECM structural constituent), GO:0071711 (basement membrane organization), GO:0048675 (axon extension), GO:0007528 (NMJ development), GO:0030198 (ECM organization); CL:0000100 (motor neuron), CL:0002573 (Schwann cell), CL:0008002 (skeletal muscle fiber).

Molecular profiling (2024): Plasma proteomics identified 15 dysregulated biomarker candidates, "a profound proportion of increased ones (6/11) are mostly related to antioxidative processes" (PMID:38652110). No transcriptomic, single-cell, spatial, or metabolomic studies exist.

7. Anatomical Structures Affected

Primary: Peripheral motor nerves/lower motor neurons (UBERON:0001323 tibial nerve — site of highest WARP expression; spinal motor axons); skeletal muscle (UBERON:0001134), especially anterior lower-leg compartment, vastus lateralis, gluteus maximus, peroneal muscles.
Secondary/musculoskeletal: Feet (pes cavus, equinovarus), Achilles tendon, spine (scoliosis, hyperlordosis), knee/hip joints (contractures, recurrent hip and patellar dislocations).
Explicitly spared: heart, respiratory muscles, cognition — "No associated neurocognitive symptoms were observed. Cardiac or respiratory involvement was not reported" (PMID:39502942); sensory nerves in most patients.
Cellular: motor neurons (CL:0000100), Schwann cells (CL:0002573; basement membrane fusion in the mouse), skeletal muscle fibers (CL:0008002).
Subcellular/matrix compartment: the basement membrane / extracellular matrix (GO:0005604 basement membrane) — this is an ECM disease, not an organelle disease.
Lateralization: typically bilateral; asymmetric presentations occur (one patient with unilateral foot drop, pes cavus on one side and pes planus on the other).

8. Temporal Development

Onset: birth to 12 years; mean symptom recognition 2.0 ± 1.4 years (tip-toe walking, foot deformity, Achilles contracture); foot deformity congenital in two cases, "suggesting antenatal onset of the disease" (PMID:33559681). The 2024 review corrects earlier impressions: "early-onset foot deformities, contractures, and gait abnormalities have been consistently reported in nearly all individuals … suggesting an early or even infantile disease onset rather than adult onset" (PMID:39502942).
Course: chronic, lifelong, insidious. "Overall, the disease progression was very slow or even static in several cases. Isolated cases reported some clinical worsening after the fifth decade of life" (PMID:33559681).
No remissions, no episodic pattern. Independent walking achieved at mean 1.6 ± 0.8 y, delayed with severe bilateral equinovarus.
Critical window: early childhood for contracture/deformity management (inference from natural history, not a studied intervention window).

9. Inheritance and Population

Inheritance: Autosomal recessive (HP:0000007); homozygosity for the founder allele or compound heterozygosity (usually with the founder allele in trans). Pedigrees overwhelmingly appear sporadic ("Positive family history was reported only in Family 13, while the rest of the cases were sporadic" — PMID:33559681).
Carrier frequency: ~1 in 441 for c.62_71dup in UK/Western Europeans (PMID:39502942) — remarkably high for a "rare" disease.
Founder effect: yes — 220-kb shared haplotype, >7,000 years old (PMID:33559681).
Consanguinity: reported but not the usual setting (2/15 families in the 2024 cohort, Iranian and Pakistani).
Penetrance/expressivity: formally unquantified; intrafamilial variability documented (one sibling with proximal weakness, the other with only dystonic features — PMID:39502942). No anticipation, no germline mosaicism reported.
Prevalence: no published point prevalence; 54 patients in the literature as of 2024. The burden is believed to be substantially under-ascertained: "we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans" (PMID:33559681); Pagnamenta et al. inferred up to ~100 undiagnosed biallelic individuals in the UK alone. Reported ancestries: Western European, German, Arabic, Roma, Iranian, Pakistani, North American, Spanish, Indian. No sex bias established.

10. Diagnostics

Electrophysiology (cornerstone): motor axonal neuropathy — "Motor nerve action potentials from the lower limb nerves were reduced or undetectable with uniformly preserved conduction velocities. Sensory studies were overall normal" (PMID:33559681); needle EMG with chronic neurogenic change (10/12), occasionally mixed with myopathic units.
Laboratory: elevated CK (up to 2400 U/L) — the finding that misdirects workups toward muscular dystrophy.
Muscle MRI: T1 fatty replacement predominantly vastus lateralis + anterior lower leg; a gene-specific whole-body pattern: "selective gluteus maximus and quadriceps involvement with iliopsoas, gracilis, and sartorius preservation, and predominant peroneal involvement with relative extensor digitorum longus sparing" (PMID:42662709, 2026) — proposed as a pre-test guide to sequencing, though "not exclusive." Outside-in vastus lateralis gradient mimicking collagen VI myopathy (PMID:41331965).
Muscle ultrasound: moth-eaten pattern of chronic denervation; nerve ultrasound normal.
Biopsy: neurogenic atrophy with fiber type grouping (majority); dystrophic/myopathic features in a minority (ring fibres, rimmed vacuoles, endomysial fibrosis); collagen VI immunolabelling normal — the key negative.
Genetic testing (definitive): WES/WGS or gene panel — but the founder allele is systematically missed by standard pipelines (GC-rich repeat, low coverage). Recommendations: relaxed QC filters on exome re-analysis ("Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses" — PMID:33559681) and targeted Sanger of exon 1 (a screen of 1,341 unsolved neuropathy samples yielded 3 additional diagnoses). "VWA1 should be included in multiple gene panels covering hereditary neuropathies, muscle dystrophies, hereditary spastic paraplegia and SMA" (PMID:39502942).
Differential diagnosis: SMA with lower-extremity predominance (DYNC1H1/BICD2 — distinguished by upper-limb involvement in >half of VWA1 cases), dHMN type I, hereditary spastic paraplegia (when UMN signs present), collagen VI-related dystrophies (distinguished by normal collagen VI staining and neurogenic electrophysiology), juvenile ALS (tongue fasciculations; distinguished by decades-long benign course), Duchenne/FSHD (CK elevation).
Newborn/carrier screening: none established.

11. Outcome / Prognosis

Survival: no reported disease-related mortality; lifespan apparently normal (no cardiac or respiratory involvement).
Ambulation: preserved in nearly all — 3/17 lost independent walking over median 36.5-year duration (PMID:33559681); 0/20 in the 2024 cohort.
Morbidity: lifelong motor disability from early childhood — foot deformity, contractures, falls (one-third), gait limitation; cognition spared.
Prognostic factors: severe bilateral equinovarus predicts delayed walking; isolated worsening after the fifth decade in some. Prognostic biomarkers: the 2024 plasma proteomic panel (antioxidative-process proteins) is a first biomarker candidate set, not yet validated (PMID:38652110).

12. Treatment

No disease-modifying therapy exists, and no interventional trial has been published. (Curator-verified searches: PubMed VWA1[Title/Abstract] and VWA1 AND therapy/treatment/trial returned no therapeutic studies in this disease; ClinicalTrials.gov shows no VWA1 trial.) Management is supportive, extrapolated from standard neuromuscular care:

Intervention	NCIT term	Target
Physical therapy / contracture management	NCIT:C15302 (Physical Therapy)	Achilles contractures, gait
Ankle-foot orthoses	NCIT:C15315 (Rehabilitation) + device qualifier NCIT:C86054	Foot drop
Orthopedic surgery	NCIT:C16186 (Orthopedic Surgical Procedure)	Equinovarus, pes cavus, contractures
Genetic counseling + targeted founder-allele testing	NCIT:C15240 (Genetic Counseling)	Family risk; diagnostic yield

No pharmacotherapy, gene therapy, ASO, or cell therapy program exists for this disease. The theoretical appeal of the target (a secreted ECM protein; a single founder allele accounting for most disease chromosomes) has been noted but not advanced to preclinical therapeutics.

13. Prevention

Primary prevention: none possible beyond reproductive genetic counseling. Given the ~1/441 carrier frequency of the founder allele in Western Europeans, carrier screening of partners of known carriers is rational; no population program exists.
Secondary prevention: early molecular diagnosis (the main modifiable burden is the diagnostic odyssey — patients were tested for DMD, FSHD, SMA and dystonia panels before VWA1 was found; PMID:39502942). Cascade testing in families; prenatal/preimplantation diagnosis feasible once familial variants are known.
Tertiary prevention: contracture and deformity management to preserve gait.

14. Other Species / Natural Disease

No naturally occurring VWA1-deficiency disease is reported in any non-human species (no OMIA entry identified). Orthologs are conserved across vertebrates — mouse Vwa1 (NCBI Gene 246228) and zebrafish vwa1 (64.7% protein similarity to human across a 408-aa overlap; PMID:33559681). No zoonotic dimension. Comparative point of note: the mouse knockout shows delayed nociceptive response and impaired fine motor coordination without weakness — a partial, species-divergent phenocopy.

15. Model Organisms

Mouse — Vwa1/WARP global knockout (Allen et al. 2009, PMID:19279005; predates the human disease and made VWA1 a candidate gene): - Healthy, viable, fertile; but "although WARP is not essential for basement membrane formation or musculoskeletal development, it has critical roles in the structure and function of peripheral nerves" (PMID:19279005). - Recapitulates the nerve lesion (collagen VI matrix "severely reduced and mislocalized in peripheral nerves"; Schwann cell basement membrane fusion) but fails to recapitulate muscle pathology ("skeletal muscle showed no detectable abnormalities") — a key constraint on the primary-myopathy hypothesis. - Limitations: nociceptive phenotype has no clear human counterpart; no progressive weakness.

Zebrafish — vwa1 CRISPR crispants and morpholino morphants (PMID:33559681, Tg(olig2:dsRed) background): - "Vwa1 Crispants (n = 29) and morphants (n = 26) showed significantly shortened axons compared to controls"; "significantly reduced synaptic formation in the skeletal muscles" (α-bungarotoxin); reduced locomotion. "These results established that vwa1 is required for the proper organization of skeletal muscles and in the formation of neuromuscular junctions." - Limitations: developmental readouts (48–96 hpf) vs. a decades-long human disease; a jaw-cartilage phenotype not seen in patients; morpholino off-target risk (mitigated by CRISPR concordance).

Human cellular models: patient dermal fibroblasts (NMD/protein-absence demonstration). No iPSC-motor-neuron, organoid, or conditional mouse model published — a conditional muscle-restricted knockout is the experiment both camps agree would settle the primary-vs-secondary myopathy controversy.

Key Primary References

Pagnamenta AT, et al. An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. Brain. 2021. PMID:33559681 — academic.oup.com/brain
Deschauer M, et al. Bi-allelic truncating mutations in VWA1 cause neuromyopathy. Brain. 2021. PMID:33459760
Record CJ, et al. Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations. Brain Commun. 2024. PMID:39502942 — PMC11535570
Athamneh M, et al. Proteomic studies in VWA1-related neuromyopathy… J Cell Mol Med. 2024. PMID:38652110 — Wiley
Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants. 2022. PMID:35975723
A Distinctive MRI Pattern Resembling Type VI Collagen Myopathy… 2025. PMID:41331965 — PubMed
Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy. 2026. PMID:42662709
Allen JM, et al. Mice lacking the extracellular matrix protein WARP… J Biol Chem. 2009. PMID:19279005
Allen JM, et al. WARP is a novel component of a distinct subset of basement membranes. 2008. PMID:18314316
Fitzgerald J. WARP: A Unique Extracellular Matrix Component… 2019. PMID:30768857
Hereditary motor neuropathies (review). 2022. PMID:35942667
Sharma S, et al. HMNR7 as a Neuromyopathy — A Novel VWA1 Variant With Minipolymyoclonus, Fasciculations, and Scapular Winging. Muscle Nerve. 2026. PMID:41416782 — Wiley

Sources: OMIM #619216 · OMIM *611901 · GeneCards VWA1 · Brain Communications 2024 cohort · Genetic alterations of VWA1 (Brain commentary) · J Cell Mol Med proteomics · PMID:41331965 · Muscle & Nerve 2026 case · MalaCards HMNR7

Note on provenance: all direct quotes above were verified against cached source abstracts/records in this repository's snippet-validated knowledge base entry for MONDO:0030977; identifiers and 2026 literature were confirmed by web search on 2026-09-19.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	30
Quoted claims found in source	29
Quoted claims not found in source	1
References weighed for topical relevance	15
On topic	10
Off topic	0

Quotes not found in the cited source

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:

PMID:39502942: "early-onset foot deformities, contractures, and gait abnormalities have been consistently reported in nearly all individuals … suggesting an early or even infantile disease onset rather than adult onset"
closest text in source: "Nonetheless, early-onset foot deformities, contractures, and gait abnormalities have been consistently reported in nearly all individuals with VWA1-related disorder, suggesting an early or even infantile disease onset rather than adult onset"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	45
Resolved	44
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	35
Terms named correctly	24
Terms named as a different term	2
Terms whose name is worth a second look	9

Terms the report names something else

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:

MONDO:0030977 (3 mentions) - the report calls it "MONDO"; MONDO calls it neuronopathy, distal hereditary motor, autosomal recessive 7
GO:0000184 (1 mention) - the report calls it "NMD"; GO calls it nuclear-transcribed mRNA catabolic process, nonsense-mediated decay

Terms whose name is worth a second look

The 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:0009027 (1 mention) - the report calls it "Foot dorsiflexor weakness (foot drop)"; HP calls it Foot dorsiflexor weakness
HP:0009053 (1 mention) - the report calls it "Distal lower limb weakness"; HP calls it Distal lower limb muscle weakness
HP:0008994 (1 mention) - the report calls it "Proximal lower limb weakness"; HP calls it Proximal lower limb muscle weakness
HP:0003236 (1 mention) - the report calls it "Elevated CK"; HP calls it Elevated circulating creatine kinase activity, and lists "Elevated serum CPK" among its other names
HP:0033685 (1 mention) - the report calls it "Fiber type grouping (biopsy)"; HP calls it Fiber type grouping
GO:0005201 (1 mention) - the report calls it "ECM structural constituent"; GO calls it extracellular matrix structural constituent
GO:0007528 (1 mention) - the report calls it "NMJ development"; GO calls it neuromuscular junction development
GO:0030198 (1 mention) - the report calls it "ECM organization"; GO calls it extracellular matrix organization
CL:0000100 (2 mentions) - the report calls it "motor neuron", "Cellular: motor neurons"; CL calls it motor neuron**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

CL:0000100 - called "motor neuron", "Cellular:** motor neurons"

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Primary References

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