| domain | evidence-supported value | ontology/database annotation suggestions | evidence type/limitations |
|---|---|---|---|
| Disease entity | Adult-onset proximal spinal muscular atrophy, autosomal dominant; clinically overlaps the Finkel-type SMA / ALS8 motor-neuron-disease spectrum; MONDO:0008453 (pqac-00000000, pqac-00000011, pqac-00000016) | MONDO:0008453; disease synonyms to capture: Finkel type SMA, late-onset SMA, ALS8-spectrum motor neuron disease | MONDO/Open Targets plus literature synthesis; legacy disease naming is heterogeneous and may overlap with ALS8 rather than a fully separate entity |
| Key identifiers | MONDO resolved as MONDO:0008453; Open Targets links the disease specifically to VAPB; OMIM/Orphanet/ICD/MeSH mappings not securely resolved from retrieved evidence and should be marked unresolved pending manual curation (pqac-00000000) | MONDO:0008453; Open Targets disease-target association; OMIM/Orphanet/ICD/MeSH: unresolved | Identifier evidence strong for MONDO/VAPB only; do not invent external IDs |
| Causal gene | VAPB (VAMP associated protein B and C) is the sole disease-associated target recovered in Open Targets for this disease label (pqac-00000000) | HGNC gene: VAPB; Ensembl target in Open Targets: ENSG00000124164 | Disease-target evidence is consistent, but not a substitute for full locus curation |
| Pathogenic variant | Recurrent causative variant is VAPB p.Pro56Ser (P56S), a missense change in the MSP domain; described as codon 56 proline-to-serine change in exon 2 on chr20q13.33 (pqac-00000001, pqac-00000009, pqac-00000013) | HGVS protein: p.Pro56Ser; variant class: missense SNV; germline | Retrieved evidence supports pathogenicity, but population allele frequency and ClinVar assertion details were not retrieved here |
| Inheritance | Autosomal dominant (pqac-00000001, pqac-00000009, pqac-00000016) | HPO inheritance term suggestion: Autosomal dominant inheritance [HP:0000006] | Strong human family evidence; penetrance not quantitatively established in retrieved sources |
| Founder / population | Initially described in large Brazilian families; evidence supports a Portuguese founder effect in many reported ALS8/Finkel-spectrum families, although review literature notes broader occurrence beyond Brazil (pqac-00000001, pqac-00000005, pqac-00000016) | Population annotation suggestion: founder effect in Brazilian/Portuguese ancestry; geographic note rather than ontology ID | Founder interpretation is literature-based and may not apply to every reported family |
| Typical onset | Late adult/adult onset, average around 50 years (pqac-00000001, pqac-00000007, pqac-00000011) | HPO onset suggestion: Adult onset [HP:0003581] | Mean age estimate is derived from family-series literature; precise distribution not established in retrieved evidence |
| Core phenotype | Slowly progressive lower motor neuron syndrome with proximal weakness and muscle atrophy; clinical heterogeneity ranges from late-onset SMA/Finkel phenotype to slowly progressive ALS and, less commonly, typical severe rapidly progressive ALS (pqac-00000001, pqac-00000009, pqac-00000011, pqac-00000016) | HPO suggestions: Proximal muscle weakness [HP:0003701], Muscle atrophy [HP:0003202], Fasciculations [HP:0002380], Lower motor neuron dysfunction/degeneration [suggest disease annotation], Motor neuron atrophy [HP:0007373] | Phenotype is well supported but frequency of each manifestation was not quantified in retrieved sources |
| Electrophysiology / pathology | Needle EMG shows fasciculations in limbs and tongue, large motor unit potentials with reduced recruitment; sensory studies and motor nerve conduction may remain normal. Muscle pathology is neurogenic, with chronic denervation/reinnervation-type changes (pqac-00000009, pqac-00000015) | Diagnostic annotation suggestions: EMG evidence of chronic neurogenic change; muscle biopsy showing neurogenic atrophy | Detailed clinical-diagnostic data came from limited family/series evidence and model-human comparison |
| Primary anatomy affected | Lower motor neurons, especially spinal cord ventral horn and brainstem motor neurons; downstream involvement of neuromuscular junction and skeletal muscle (pqac-00000003, pqac-00000012, pqac-00000014) | UBERON suggestions: spinal cord ventral horn, brainstem motor nucleus, skeletal muscle, neuromuscular junction; CL suggestions: motor neuron | Strong model support and consistent human clinical inference; human tissue data in retrieved set are limited |
| Subcellular localization / mechanism | VAPB is an ER membrane protein; p.Pro56Ser causes mutant protein misfolding/aggregation tendency, loss of normal ER localization/function, altered ER homeostasis, disrupted ER-mitochondria tethering/contact sites, abnormal Ca2+ handling, and NMJ denervation/reinnervation changes (pqac-00000002, pqac-00000007, pqac-00000008, pqac-00000009, pqac-00000010) | GO/CC suggestions: endoplasmic reticulum membrane, mitochondria-associated ER membrane/contact site, neuromuscular junction; GO/BP suggestions: ER stress response, unfolded protein response, calcium homeostasis, autophagy, intracellular protein transport | Mechanistic evidence is largely from cell and animal models; exact dominant-negative vs haploinsufficiency balance remains debated |
| Mechanistic interpretation | Current understanding favors major loss-of-function/haploinsufficiency of VAPB, with possible dominant-negative effects from sequestration of wild-type VAP proteins in some systems (pqac-00000002, pqac-00000008, pqac-00000013, pqac-00000016) | Mechanism tags: loss of function; possible dominant negative | Important unresolved issue: overexpression systems emphasize aggregation, whereas patient-derived cells may show little visible aggregation |
| Environmental / protective factors | No disease-specific environmental triggers, lifestyle risks, infectious causes, or protective factors were identified in retrieved evidence (pqac-00000011, pqac-00000016) | Mark as no disease-specific evidence found | Evidence gap, not evidence of absence |
| Diagnostics | Best-supported approach: clinical recognition of adult-onset proximal/lower-motor-neuron syndrome plus electrophysiology and confirmatory molecular testing of VAPB, especially p.Pro56Ser; broad non-5q SMA / motor neuron disease gene panels or exome/genome sequencing are reasonable when phenotype is atypical (pqac-00000009, pqac-00000011) | Suggested testing workflow: EMG/NCS, targeted VAPB testing, multigene motor neuron disease/non-5q SMA panel, WES/WGS if negative | No disease-specific formal guideline retrieved; recommendation is evidence-bounded inference from reported cases and non-5q SMA review context |
| Differential diagnosis | Differentiate from 5q-SMA (SMN1-related), other non-5q SMAs, hereditary motor neuropathies, and familial/sporadic ALS presentations (pqac-00000011, pqac-00000016) | Differential-diagnosis tags: 5q-SMA, non-5q SMA, hereditary motor neuropathy, ALS | No standardized disease-specific differential algorithm retrieved |
| Epidemiology | Ultra-rare; no robust prevalence or incidence estimate was identified in retrieved sources. Evidence is based mainly on kindreds and founder-associated case series (pqac-00000001, pqac-00000009) | Orphan disease flag; prevalence/incidence unresolved | Major evidence gap |
| Prognosis | Course is usually slowly progressive in classic Finkel/ALS8 families, but marked intrafamilial/interfamilial variability exists, including rapidly progressive ALS phenotypes (pqac-00000001, pqac-00000011, pqac-00000016) | Prognosis tags: chronic progressive disease; variable expressivity | No robust survival curves or validated prognostic biomarkers retrieved |
| Treatment | No approved disease-specific therapy for VAPB-associated adult-onset proximal SMA/Finkel disease was identified; management is supportive and extrapolated from motor neuron disease care (rehabilitation, mobility, respiratory/nutritional surveillance as clinically indicated) (pqac-00000011, pqac-00000016) | NCIT suggestions: Physical Therapy, Occupational Therapy, Supportive Care, Genetic Counseling | Evidence gap for disease-specific efficacy studies; no relevant registered interventional trial was retrieved |
| Prevention / counseling | Primary prevention is not established. Secondary/tertiary prevention centers on early genetic diagnosis, cascade testing in at-risk relatives, and reproductive/genetic counseling for autosomal-dominant transmission risk (pqac-00000016) | NCIT suggestion: Genetic Counseling; HPO inheritance annotation | Counseling recommendation inferred from monogenic AD disease practice; no disease-specific counseling guideline retrieved |
| Model systems | Disease-relevant models include VAPB P56S knock-in mice, VAPB transgenic/knockout mice, Drosophila VAP P58S models, rat ALS8 models, NSC34 motor-neuron-like cells, and patient-derived iPSC motor neurons (pqac-00000003, pqac-00000007, pqac-00000013, pqac-00000014, pqac-00000015) | Model resources: mouse KI/KO/transgenic, fly model, rat model, iPSC motor neuron, cell line model | Strong preclinical ecosystem, but not all models recapitulate the slow human lower-motor-neuron phenotype equally well |


*Table: This table condenses the highest-confidence, evidence-supported facts for VAPB-associated adult-onset proximal spinal muscular atrophy/Finkel-type disease in a knowledge-base-friendly format. It highlights established findings, annotation suggestions, and the main evidence gaps requiring manual curation.*