Spinocerebellar Ataxia 43 (SCA43) — Comprehensive Research Report

1. Disease Information

Overview: Spinocerebellar ataxia 43 (SCA43) is a rare, autosomal dominant, adult/late-onset, slowly progressive neurodegenerative disorder combining cerebellar ataxia with a peripheral (predominantly motor axonal) polyneuropathy. It was first described in 2016 by Depondt and colleagues in a large five-generation Belgian family, who identified a heterozygous missense mutation in the MME gene (encoding neprilysin/neutral endopeptidase) as the cause (Depondt et al. 2016, Neurology Genetics, PMID: 27583304; PMC4991603). SCA43 is classified within the "ADCA type I" group of dominant ataxias — i.e., cerebellar ataxia plus additional neurological features (here, peripheral neuropathy) rather than pure cerebellar ataxia.

Key identifiers: - OMIM: #617018 (SPINOCEREBELLAR ATAXIA 43; SCA43) — omim.org/entry/617018 - Gene locus (OMIM): MME, #120520 (MEMBRANE METALLOENDOPEPTIDASE), chromosome 3q25.2 - MONDO: MONDO:0014867 (per NCBI MedGen cross-reference) - MedGen: C4310763 - Orphanet: ORPHA:497764 (Spinocerebellar ataxia type 43) - GARD (NIH rare disease): disease ID 17917 — rarediseases.info.nih.gov/diseases/17917 - Allelic disorder: CMT2T — Charcot-Marie-Tooth disease, axonal, type 2T, OMIM #617017 (autosomal recessive, biallelic MME* mutation, no cerebellar involvement)

Synonyms: SCA43; ADCA with neuropathy (MME-related); MME-related ataxia.

Evidence source note: The founding evidence base for SCA43 is a single deeply phenotyped extended pedigree (individual-patient/family-level clinical and genetic data), subsequently supplemented by a small number of independent case reports (aggregated, disease-level literature is sparse — this is a very recently described, ultra-rare entity).

2. Etiology

Disease causal factor: SCA43 is caused by heterozygous (dominant), gain-of-function/dominant-negative-acting missense (and at least one nonsense) variants in MME (membrane metalloendopeptidase; neprilysin, NEP), a zinc-dependent M13-family metalloprotease.

Genetic risk factors: - The founding pathogenic variant is NM_007289.4(MME):c.428G>A, p.(Cys143Tyr) (also written C143Y), identified by linkage analysis + whole-exome sequencing in the Belgian kindred and cosegregating perfectly with disease across 24 of 28 genotyped family members (PMID: 27583304). - A second, distinct pathogenic variant reported in ClinVar is NM_007289.4(MME):c.1342C>T, p.(Arg448Ter) — a nonsense/truncating variant classified pathogenic for SCA43 (ClinVar RCV001196533). - No large case-control allele-frequency or GWAS susceptibility-locus data exist (this is a monogenic Mendelian disorder), but the C143Y variant was confirmed absent from ExAC (60,706 unrelated individuals) and from 96 additional unrelated dominant-ataxia probands screened by the discovery group — supporting pathogenicity via absence from population databases (PMID: 27583304). - In silico pathogenicity of C143Y: SIFT = 0 (damaging), PolyPhen-2 = 1.000 (probably damaging), PROVEAN = −10.185 (deleterious) (PMID: 27583304).

Environmental/lifestyle risk factors: None established; SCA43 is a purely monogenic disorder with no reported environmental, infectious, or lifestyle modifiers of onset or severity in the literature to date.

Protective factors: None reported (genetic or environmental).

Gene-environment interaction: Not described; the extreme rarity of the disorder (essentially a handful of families/cases worldwide) has precluded any GxE study.

Modifier genes: None formally established, though intrafamilial variability in the founding pedigree (see §3/§8) suggests unidentified genetic or stochastic modifiers.

3. Phenotypes

Core clinical picture (from the Belgian founder family, PMID: 27583304)

Of 7 living affected individuals (ages of onset 42–68 years), 6 of 7 had cerebellar ataxia and all but one had sensorimotor axonal polyneuropathy; one individual presented with polyneuropathy alone, without cerebellar signs — indicating incomplete/variable penetrance of the cerebellar component even within one kindred.

Cerebellar/neurological phenotypes: | Phenotype | HPO suggestion | Notes | |---|---|---| | Gait ataxia | HP:0002066 (Gait ataxia) | Core presenting feature; "ataxic gait with difficulties in turning" | | Limb ataxia | HP:0002070 (Limb ataxia) | Mild upper and lower limb ataxia in proband | | Dysarthria | HP:0001260 (Dysarthria) | Reported cerebellar sign | | Nystagmus | HP:0000639 (Nystagmus) | Reported cerebellar sign | | Hypometric saccades | HP:0000571 or HP:0007874 (Saccadic hypometria) | Oculomotor cerebellar sign | | Tremor | HP:0001337 (Tremor) | Reported cerebellar/movement sign; also reported as a presenting feature preceding ataxia in a later case (postural tremor; Prashanth, Cerebellum 2026) | | Cerebellar vermis atrophy (MRI) | HP:0006855 (Cerebellar vermis atrophy) | "Moderate atrophy of the cerebellar vermis" on brain MRI |

Peripheral neuropathy phenotypes: | Phenotype | HPO suggestion | Notes | |---|---|---| | Distal muscle weakness/atrophy | HP:0003693 / HP:0007340 (Distal muscle weakness/atrophy) | "Mild distal lower limb atrophy" | | Pes cavus | HP:0001761 (Pes cavus) | Present in proband | | Areflexia/hyporeflexia (lower limb) | HP:0001284 (Areflexia); HP:0001596/HP:0001265 | "Absent Achilles tendon reflexes," "bilaterally weak knee tendon reflexes" | | Axonal sensorimotor polyneuropathy | HP:0003477 (Axonal neuropathy) | EMG: "progressive, severe motor neuropathy in the lower limbs with significantly increased F-response latency but preserved sensory responses" in most patients; sural nerve biopsy in one patient showed axonal CMT2-type pathology | | Lower limb pain | HP:0012531 (Pain) / HP:0009830-adjacent | Present in some patients | | Distal sensory impairment | HP:0003390 (Impaired distal vibration sensation) or general HP:0003676 | A minority had distal sensory loss (later case reports emphasize vibration loss) |

Skeletal/other: - Pectus carinatum — "not omnipresent" but noted as a distinctive clinical feature of the family (no precise HPO term routinely used for this SCA context but HP:0000768 Pectus carinatum applies). - Cognitive status: In the founding family, no cognitive complaints were reported, though formal neuropsychological testing was not performed — an important negative given NEP's role in Aβ clearance (see §6). This contrasts with a later sporadic case (below).

Extended/atypical phenotypes reported in subsequent literature (expanding the phenotypic spectrum): - A parkinsonian-plus presentation has been described as an SCA43 phenocopy pitfall — "SCA Variant Masquerading as a Parkinsonian-plus Syndrome" (Vijaywargiya et al., abstract, Neurology 2025, DOI 10.1212/WNL.0000000000211725), underscoring diagnostic overlap with parkinsonism. - A sporadic case (Journal of the Neurological Sciences, 2023) described a 40-year-old man with ataxia, dysarthria, fasciculations, anterior horn cell involvement (wasting/weakness of small hand muscles, brisk reflexes, lower-limb spasticity, upper-limb rigidity), and mild cognitive dysfunction (recent memory) — explicitly noted as a rare/atypical association not seen in the founder family. - A 2026 case report (Prashanth, The Cerebellum, DOI 10.1007/s12311-026-02023-0) described a 63-year-old woman with progressive orobuccolingual dystonia and choreiform movements of the right hand preceding gait ataxia by several years, plus postural tremor and distal lower-limb vibratory sensory loss — expanding SCA43 into the hyperkinetic-movement-disorder spectrum (dystonia/chorea), previously undocumented for this gene.

Quality-of-life impact: No disease-specific EQ-5D/SF-36 data exist for SCA43 specifically; given the slowly progressive gait ataxia and motor polyneuropathy with lower-limb amyotrophy, the expected functional impact (extrapolated from general ADCA-I literature) includes progressive gait/balance impairment, falls risk, need for mobility aids, and functional hand/foot impairment from motor neuropathy — but this has not been formally measured in SCA43 patients.

4. Genetic/Molecular Information

Causal gene: MME (HGNC:7154), encoding neprilysin (NEP; also called neutral endopeptidase, CD10, CALLA — common acute lymphoblastic leukemia antigen). Gene comprises 23 exons on chromosome 3q25.2.

Pathogenic variants for SCA43: 1. c.428G>A, p.(Cys143Tyr) — heterozygous missense; variant type: missense; classification: pathogenic (cosegregation, absence from ExAC, strong in silico predictions); origin: germline; functional consequence: disrupts a highly conserved disulfide bridge (Cys143–Cys411) within the N-terminal peptidase M13 domain — one of 10 conserved cysteines among related M13-family neutral endopeptidases (NEP, ECE, KELL, PEX). Proposed as dominant-negative or gain-of-function-like rather than simple haploinsufficiency (see mechanism, §6). 2. c.1342C>T, p.(Arg448Ter) — heterozygous nonsense/truncating variant, classified pathogenic in ClinVar for SCA43 (RCV001196533).

Gene identifiers: HGNC gene symbol MME; NCBI Gene ID 4311; UniProt P08473 (human neprilysin); Ensembl ENSG00000196549.

Allele frequency: The C143Y variant is absent from gnomAD/ExAC population databases (0 alleles among 60,706 individuals in the original ExAC analysis), consistent with a rare, highly penetrant dominant variant.

Somatic vs. germline: Germline in all reported cases (Mendelian dominant transmission across generations in the founder pedigree).

Functional consequence / mechanism of protein dysfunction: Loss of the Cys143–Cys411 disulfide bond is predicted to destabilize NEP's extracellular peptidase M13 catalytic domain. Critically, this is not modeled as simple loss-of-function/haploinsufficiency, because biallelic (homozygous/compound heterozygous) loss-of-function MME mutations cause a recessive, purely peripheral neuropathy (CMT2T) without cerebellar involvement — heterozygous carriers of null CMT2T alleles are unaffected. This apparent paradox led the discovery authors to propose that the dominant C143Y (and other dominant) variants act via a distinct, possibly dominant-negative or altered-substrate-specificity mechanism (e.g., competing with wild-type NEP for substrate binding without normal catalytic turnover) rather than through simple reduced enzyme dosage (PMID: 27583304).

Modifier genes: None established.

Epigenetic information: Not reported for SCA43.

Chromosomal abnormalities: None reported; SCA43 is caused by point mutations, not structural chromosomal rearrangements.

Allelic disorders (important for differential/genetic counseling): - CMT2T (Charcot-Marie-Tooth disease, axonal, type 2T; OMIM #617017) — autosomal recessive, biallelic (homozygous or compound heterozygous) MME mutations causing slowly progressive sensorimotor axonal polyneuropathy without cerebellar ataxia. First described by Higuchi et al. 2016 (Annals of Neurology, DOI 10.1002/ana.24612). MME mutations are reported as the most frequent cause of autosomal recessive axonal CMT in the Japanese population. Both mono- and biallelic MME mutations can cause late-onset axonal peripheral neuropathy; biallelic mutations are associated with more rapid progression.

5. Environmental Information

No environmental toxin, occupational exposure, radiation, infectious agent, or lifestyle factor (smoking, diet, alcohol) has been implicated in SCA43 causation or modification — consistent with its purely monogenic, highly penetrant dominant inheritance. No infectious trigger is described.

6. Mechanism / Pathophysiology

Protein/pathway biology (normal NEP function): Neprilysin (NEP) is a type II integral membrane, zinc-dependent metalloendopeptidase of the M13 peptidase family (EC 3.4.24.11), with a short N-terminal cytoplasmic domain, a single transmembrane helix, and a large C-terminal extracellular catalytic portion composed of two major α-helical (peptidase M13) domains (PMID: 27583304). NEP cleaves peptide bonds on the amino side of hydrophobic residues and has broad substrate specificity, acting on numerous neuropeptides: glucagon, enkephalins, cholecystokinin, neuropeptide Y, substance P, somatostatin, neurotensin, oxytocin, prodynorphin, and bradykinin, as well as the amyloid-beta (Aβ) peptides (its best-characterized role, as one of the principal Aβ-degrading enzymes in brain).

Expression pattern: - CNS: predominantly neuronal, concentrated in axons and synaptic terminals. - PNS: predominantly in Schwann cells, though NEP protein is also transported along peripheral (sciatic) nerve axons.

Proposed causal chain in SCA43: 1. Dominant MME missense variant (e.g., p.C143Y) disrupts a conserved disulfide bond (Cys143–Cys411) in the extracellular M13 peptidase domain. 2. Because biallelic loss-of-function MME variants cause only peripheral neuropathy (CMT2T) with no cerebellar phenotype, simple haploinsufficiency of catalytic NEP activity cannot fully explain the dominant SCA43 phenotype — the mutant protein is hypothesized to exert a dominant-negative or altered-function effect, e.g., competing with wild-type NEP monomers/dimers for substrate binding while lacking normal catalytic turnover. 3. Leading substrate hypothesis: prodynorphin (precursor of the opioid neuropeptides α-neoendorphin, dynorphin A, and dynorphin B) is a known NEP substrate, and separately, mutations in the prodynorphin gene (PDYN) cause a different dominant ataxia, SCA23. The SCA43 discovery authors hypothesize that mutant NEP (p.C143Y) may have an altered, possibly toxic, effect specifically on dynorphin-peptide processing, "possibly competing with wild-type NEP for substrate affinity and catalytic activity, which eventually triggers cerebellar degeneration" (direct quote, PMID: 27583304). 4. This altered neuropeptide processing in cerebellar Purkinje cell / cerebellar circuitry (site of the observed vermis atrophy) is proposed to drive cerebellar degeneration, while a parallel or independent toxic gain-of-function effect in axons and Schwann cells of peripheral nerves drives the axonal (Wallerian-type/CMT2-pattern) motor-predominant neuropathy, confirmed histologically by sural nerve biopsy showing axonal CMT2 pathology.

Amyloid-beta connection (largely excluded as a disease mechanism here): Despite NEP's prominent role as an Aβ-degrading enzyme (relevant to Alzheimer disease pathobiology and a rationale for genetic studies of MME in AD risk), no cognitive impairment/Alzheimer-like phenotype was observed in the SCA43 founder family, nor in Japanese CMT2 patients with biallelic MME mutations — leading the authors to state that "NEP deficiency does not lead to the development of AD" in this context, arguing against Aβ accumulation as the primary SCA43 mechanism (though one later, atypical sporadic SCA43 case did show mild cognitive dysfunction — see §3).

Cell types implicated (Cell Ontology suggestions): - Cerebellar Purkinje cells (CL:0000121) — presumptive site of cerebellar degeneration (vermis atrophy). - Peripheral motor neurons / lower motor neuron axons (CL:0000100 neuron, or CL:0011103 sympathetic/motor neuron as relevant) — axonal degeneration. - Schwann cells (CL:0002573 or CL:0000381) — principal peripheral site of normal NEP expression; implicated in the peripheral neuropathy arm.

Biological process (GO) suggestions: - GO:0006508 proteolysis (general NEP catalytic activity) - GO:0004222 metalloendopeptidase activity (molecular function) - GO:0006509 membrane protein ectodomain proteolysis - GO:0097242 amyloid-beta clearance - GO:0007218 neuropeptide signaling pathway (substrate processing, e.g., dynorphin/opioid peptide catabolism — GO:0035812 negative regulation of renal sodium excretion is unrelated; more precisely GO:0090277 positive regulation of peptide hormone secretion is not ideal — best generic terms are GO:0006518 peptide metabolic process and GO:0007218 neuropeptide signaling pathway) - GO:0007049/GO:0008219 not directly implicated; no clear apoptosis/cell-death GO evidence reported specifically for SCA43 mechanism (inferred, not shown).

Molecular profiling / omics: No transcriptomic, proteomic, metabolomic, or single-cell datasets specific to SCA43 patient tissue have been published; the field currently rests entirely on clinical-genetic characterization plus general NEP biochemistry extrapolated from other contexts (Alzheimer disease research, CMT2T).

Tissue damage mechanism: Best characterized as length-dependent axonal degeneration in peripheral nerve (consistent with CMT2-pattern EMG/biopsy findings) combined with cerebellar (vermis) atrophy on imaging, consistent with a neurodegenerative rather than inflammatory or vascular process.

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system — cerebellum (vermis) — UBERON:0002037 (cerebellum); UBERON:0004720 (cerebellar vermis, if available) or more general UBERON term for cerebellar vermis. - Primary: Peripheral nervous system — peripheral (particularly lower-limb) motor and sensory nerves — UBERON:0000010 (peripheral nervous system); UBERON:0001511 (sciatic nerve) or general UBERON:0002211 (peripheral nerve). - Secondary: Skeletal system — anterior chest wall deformity (pectus carinatum) — UBERON:0001911 (sternum)/thoracic skeleton. - Body systems involved: Nervous system (central + peripheral); musculoskeletal system (secondary, distal muscle atrophy, pes cavus, pectus carinatum).

Tissue/cell level: - Cerebellar cortex — Purkinje cell layer implicated by degeneration/atrophy pattern (not directly biopsied in humans; inferred from imaging). - Peripheral nerve axons (motor > sensory) and myelinating Schwann cells — directly demonstrated by sural nerve biopsy (axonal CMT2-type pathology) in the founder family. - Skeletal muscle — secondary distal denervation atrophy (small hand/lower-limb muscles).

Subcellular level: - NEP is a plasma-membrane ectoenzyme (type II integral membrane protein) with its catalytic domain facing the extracellular space — GO:0005886 (plasma membrane), GO:0009986 (cell surface), GO:0016021 (integral component of membrane). - Within neurons, NEP localizes to axonal and synaptic-terminal membranes (GO:0043679 axon terminus / GO:0030424 axon; GO:0045202 synapse).

Localization/lateralization: Bilateral, symmetric involvement in both the cerebellar (vermis, midline structure) and peripheral neuropathy components (lower limbs > upper limbs, length-dependent, bilateral).

8. Temporal Development

Onset: Adult-onset, ranging from age 42 to 68 years in the founding pedigree (proband's initial symptoms at age 58; diagnosed at 69). This places SCA43 among the later-onset dominant ataxias. Onset pattern is insidious/chronic, not acute or subacute.

Progression: Slowly progressive — consistent across all literature descriptions ("slowly progressive neurologic disorder," OMIM #617018). No formal staging system exists specific to SCA43. Disease course is chronic and lifelong (neurodegenerative, non-remitting), with gradual accrual of both cerebellar and peripheral neuropathic deficits over years to decades.

Patterns: - Intrafamilial variability: within the same founder pedigree, one affected individual had isolated peripheral neuropathy without cerebellar ataxia, demonstrating incomplete penetrance/expressivity of the ataxia component even among carriers of the identical C143Y variant. - Some later-reported cases show atypical or unusual sequences of symptom emergence — e.g., a hyperkinetic movement disorder (dystonia, chorea, tremor) preceding classic gait ataxia by several years in one 2026 case report — indicating broader phenotypic and temporal heterogeneity than initially appreciated. - No spontaneous remission has been described; this is a neurodegenerative, progressive disorder. - No defined "critical period" or treatment window has been established, given the very limited natural-history data.

9. Inheritance and Population

Epidemiology: SCA43 is an extremely rare, essentially "cases in literature"-level disorder — to date, described in one large multigenerational Belgian family (7 living affected members across generations) plus a small number of subsequently reported sporadic/atypical cases (parkinsonian-plus phenocopy case; anterior-horn-cell/cognitive-change case; dystonia/chorea-predominant case). No formal prevalence or incidence estimate exists; it should be considered prevalence_class: NOT_YET_DOCUMENTED / ULTRA_RARE in dismech terms. For context, autosomal dominant cerebellar ataxias as a group have an estimated overall prevalence of roughly 1.6–2.7 per 100,000 in European cohorts (e.g., Cantabria, Spain: 1.6/100,000; general dominant ataxia estimates 2–7/100,000), but SCA43 itself represents a vanishingly small fraction of that total given its single-family origin.

Inheritance pattern: Autosomal dominant (HP:0000006). The allelic disorder CMT2T is autosomal recessive (HP:0000007) — an important genetic-counseling distinction, since MME is one of the rare genes producing genuinely different, non-overlapping phenotypes depending on zygosity (heterozygous dominant missense/nonsense → SCA43 with cerebellar+peripheral disease; biallelic loss-of-function → CMT2T, peripheral-only disease).

Penetrance: Appears high but not complete/uniform for the cerebellar component — the founder pedigree included a mutation carrier with neuropathy but no ataxia, suggesting age-dependent or incomplete penetrance for the cerebellar phenotype specifically, while the peripheral neuropathy component may be more consistently penetrant.

Expressivity: Variable — supported by (a) intrafamilial variation in phenotype composition (ataxia+neuropathy vs. neuropathy alone), (b) variable presence of pectus carinatum, and (c) the atypical/expanded phenotypes reported in later, presumably unrelated cases (parkinsonism, dystonia/chorea, anterior horn cell signs, mild cognitive change) — suggesting a broad and still-emerging phenotypic spectrum.

Genetic anticipation: Not reported/established (unlike polyglutamine-repeat SCAs, SCA43 is caused by conventional missense/nonsense point mutations, not a repeat expansion, so anticipation is not mechanistically expected and has not been described).

Germline mosaicism: Not reported.

Founder effects: The C143Y mutation was identified in a single large Belgian founder family; whether it represents a true population founder mutation for Belgium/Northern Europe versus a private familial mutation is not established from available data.

Consanguinity: Not relevant to the dominant SCA43 phenotype (relevant instead to the recessive allelic disorder CMT2T, where biallelic transmission would be favored by consanguinity).

Carrier frequency: Not established for SCA43 (autosomal dominant, so "carrier" framing is less applicable than for recessive CMT2T, whose carrier frequency also has not been formally reported, though MME recessive variants are noted to be a comparatively frequent cause of recessive axonal CMT in the Japanese population specifically).

Population demographics: - Affected populations: Founder family of Belgian (European) ancestry; additional reported cases lack detailed ancestry information in the abstracts reviewed, though the Japanese CMT2T literature is extensive for the allelic recessive disorder. - Geographic distribution: No endemic/regional clustering established beyond the single reported kindred. - Sex ratio: No skew reported/expected (autosomal dominant, non-sex-linked). - Age distribution: Adult (post-40s) onset in all reported cases to date; no pediatric cases described.

10. Diagnostics

Clinical tests: - Nerve conduction studies/EMG: Demonstrates progressive, predominantly motor axonal neuropathy in the lower limbs, with significantly increased F-wave latency and typically preserved sensory nerve action potentials in most affected individuals (LOINC/electrophysiology testing category). - Nerve biopsy (sural nerve): Shows axonal pathology consistent with CMT2-type polyneuropathy (performed in at least one patient in the founder family). - Brain MRI: Shows moderate cerebellar vermis atrophy — a supportive but non-specific imaging finding (Radiopaedia/RadLex: cerebellar atrophy, vermian atrophy). - No specific validated biomarker (blood/CSF) has been identified for SCA43.

Genetic testing: - Recommended approach: Given the extreme rarity and the fact that only two pathogenic variants are so far described, MME sequencing is typically included as part of a broader hereditary ataxia gene panel or via exome/genome sequencing in patients with combined cerebellar ataxia + peripheral (especially motor axonal) neuropathy, once more common causes (SCA1/2/3/6, Friedreich ataxia, etc.) have been excluded. - Whole exome sequencing (WES) was the discovery method used in the founder family (Agilent SureSelect All Exon v1 capture, Illumina HiSeq2000), combined with prior genome-wide linkage analysis (400 microsatellite markers, ~8.7 cM spacing) that localized the locus to a 31.3 Mb region on chromosome 3q23–q26.31 (LOD score Z = 2.47). - Single-gene MME Sanger sequencing can confirm/screen a suspected pathogenic variant once identified by WES/panel. - No specific chromosomal microarray, karyotype, FISH, mitochondrial DNA testing, or repeat-expansion testing is relevant, as SCA43 is not caused by a repeat expansion or structural/chromosomal abnormality.

Clinical diagnostic criteria: No formal consensus/society diagnostic criteria exist specifically for SCA43 (too recently described, too few cases); diagnosis rests on the combination of adult-onset progressive cerebellar ataxia + axonal (typically motor-predominant) peripheral neuropathy + a confirmed pathogenic heterozygous MME variant, after exclusion of more common dominant ataxias.

Differential diagnosis: Other ADCA type I disorders with combined ataxia+neuropathy phenotype (e.g., SCA1, SCA2, SCA3/Machado-Joseph disease, SCA4), Friedreich ataxia (though typically recessive/early-onset), CMT2 subtypes with incidental ataxia, and — per the reported phenocopy literature — atypical parkinsonian syndromes and adult-onset dystonia/chorea syndromes, given the expanding movement-disorder phenotypic overlap now reported for SCA43.

Screening: No population or newborn screening applicable (adult-onset, ultra-rare, family-specific mutation); cascade genetic testing/counseling of at-risk relatives in identified families is the relevant screening approach once a family-specific MME variant is known.

11. Outcome/Prognosis

No formal survival, life-expectancy, or standardized quality-of-life outcome data exist for SCA43 given the small number of reported cases. The disorder is described as slowly progressive, implying a chronic, non-remitting course over years to decades, with progressive gait/limb ataxia and progressive lower-limb motor neuropathy (weakness, atrophy, areflexia) as the dominant drivers of disability. Complications would be expected to parallel other ADCA/CMT2-overlap disorders: falls, mobility impairment, foot deformity progression (pes cavus), and — in the atypical cases — additional motor system involvement (anterior horn cell signs, rigidity) or hyperkinetic movement-disorder features that may further impact function. No disease-specific prognostic biomarkers have been identified.

12. Treatment

No disease-modifying or curative therapy exists for SCA43. Management is entirely symptomatic and supportive, following general practice for autosomal dominant cerebellar ataxias:

• Pharmacotherapy (symptomatic):
• Tremor: beta-blockers, primidone (MAXO: pharmacotherapy; specific agents not SCA43-validated but general ADCA practice).
• Dystonia (in cases with the expanded dystonic phenotype): botulinum toxin injections.
• Parkinsonism (in phenocopy/overlap presentations): levodopa trial.
• Mood/depression: antidepressants as needed.
• Neuropathic pain (lower-limb pain component): standard neuropathic pain agents (not specifically studied in SCA43).
• Rehabilitative/supportive care (MAXO:0000011 physical therapy; MAXO:0000950 supportive care):
• Physical therapy, occupational therapy, and speech therapy have been noted to produce gradual functional improvement in general ADCA management and would be the mainstay for SCA43 gait/balance and motor neuropathy symptoms.
• Orthotic management (e.g., ankle-foot orthoses) for pes cavus/foot drop from motor neuropathy.
• Genetic counseling (MAXO:0000079): Recommended for affected families given autosomal dominant transmission with ~50% risk to offspring, and for distinguishing SCA43 (dominant) from the biallelic recessive CMT2T allelic disorder in relatives.
• Experimental/targeted therapy: None specific to SCA43 in clinical trials (searched ClinicalTrials.gov context — no SCA43-specific trials identified). Of note, neprilysin itself is a drug target in an unrelated context — the ARNI drug sacubitril/valsartan (LCZ696), an FDA-approved neprilysin inhibitor combined with an angiotensin receptor blocker, is used in heart failure with reduced ejection fraction (PARADIGM-HF trial) to raise natriuretic peptide levels by blocking their NEP-mediated degradation. This is mechanistically the opposite direction relevant to SCA43 (SCA43 arises from NEP dysfunction/altered activity, not from a state where further pharmacologic NEP inhibition would be therapeutic) — worth noting only as a caution that MME/NEP is already a pharmacologically manipulated target in a different clinical context, and is not itself a suggested treatment avenue for SCA43.
• Treatment algorithms/combination therapy: No SCA43-specific clinical pathway exists; management follows general multidisciplinary ataxia/neuropathy care (neurology + physiatry + genetics).

13. Prevention

No primary prevention exists (monogenic dominant disorder). Prenatal genetic counseling and cascade predictive testing of at-risk relatives in a known SCA43 family is the only applicable preventive/risk-stratification measure once a family-specific pathogenic MME variant has been identified — standard ACMG/genetic-counseling practice for autosomal dominant adult-onset neurodegenerative disease, though no SCA43-specific prenatal or preimplantation genetic diagnosis (PGD) case has been reported in the literature reviewed. No vaccination, public health, or environmental intervention is applicable.

14. Other Species / Natural Disease

No naturally occurring SCA43 has been described in non-human species. MME/neprilysin is highly conserved across mammals (mouse ortholog Mme, MGI:97004), but no spontaneous or naturally occurring animal disease analogous to human SCA43 has been reported (searched OMIA and general veterinary literature — no hits). No zoonotic or cross-species transmission relevance (this is a non-infectious, monogenic disorder).

15. Model Organisms

Mouse (Mme knockout, MGI:97004; e.g., allele Mme^tm1Cge, MGI:2137696): Constitutive Mme-null mice have been characterized primarily in the context of amyloid-beta metabolism and innate immune/inflammatory phenotypes, not ataxia: - Increased brain and plasma amyloid-beta peptide levels, in a gene-dose-dependent manner — neprilysin deficiency impairs both degradation of exogenously administered Aβ and suppression of endogenous Aβ. - Regional brain Aβ levels in Mme-deficient mice follow the order hippocampus > cortex > thalamus/striatum > cerebellum (lowest) — notably, the region least affected by Aβ accumulation in this model (cerebellum) is the region most affected in human SCA43, arguing against a simple Aβ-accumulation mechanism for the cerebellar phenotype (consistent with the human genetic authors' own conclusion that "NEP deficiency does not lead to the development of AD" in SCA43 patients). - Non-neurological phenotypes: enhanced allergic contact dermatitis responses; diffuse hepatic necrosis after LPS shock or combined TNF/IL-1β treatment — reflecting NEP's broader immunomodulatory/neuropeptide-degrading roles outside the nervous system.

Critical model limitation: No mouse model carrying the human-specific dominant missense variant (p.C143Y) or a comparable dominant-negative Mme allele has been reported. The discovery authors explicitly caution that standard Mme loss-of-function/knockout mice would likely not recapitulate the human SCA43 phenotype, precisely because the human disease appears to depend on a dominant, likely non-haploinsufficient mechanism (possibly dominant-negative competition for substrate, e.g., dynorphin processing) rather than simple reduced NEP dosage — a mechanism a simple knockout cannot model. This represents a clear, currently unaddressed need for an appropriately engineered knock-in mouse model (e.g., Mme^C143Y/+) to test the dominant-negative/altered-substrate-specificity hypothesis in vivo, and is a candidate HUMAN_MODEL_MISMATCH consideration if this disease is curated into dismech (existing Mme-null mouse phenotypes should not be assumed to validate or recapitulate the human SCA43 cerebellar/neuropathy phenotype).

Other species: No zebrafish, Drosophila, C. elegans, or iPSC/organoid models specific to the SCA43 dominant variant have been reported in the literature surveyed.

Summary Table of Key Ontology Term Suggestions

Sources

• Entry - #617018 - SPINOCEREBELLAR ATAXIA 43; SCA43 - OMIM
• MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43) - PMC (full text)
• MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43) - PubMed, PMID: 27583304
• MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43) - Neurology Genetics
• Entry - *120520 - MEMBRANE METALLOENDOPEPTIDASE; MME - OMIM
• Entry - #617017 - CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2T; CMT2T - OMIM
• Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2 - Higuchi et al., Annals of Neurology
• NM_007289.4(MME):c.1342C>T (p.Arg448Ter) AND Spinocerebellar ataxia 43 - ClinVar
• Spinocerebellar ataxia 43 - GARD (NIH Genetic and Rare Diseases Information Center)
• spinocerebellar ataxia 43 - National Organization for Rare Disorders
• Spinocerebellar ataxia 43 (Concept Id: C4310763) - MedGen - NCBI
• Orphanet: Spinocerebellar ataxia type 43
• A case of sporadic spino cerebellar ataxia-43 presenting as ataxia, rigidity, anterior horn cell involvement and cognitive changes - Journal of the Neurological Sciences
• Tremor and Craniofacial Dystonia Preceding Ataxia in SCA43: Expanding the Phenotypic Spectrum of MME-related Ataxia - The Cerebellum
• Spinocerebellar Ataxia (SCA) Variant Masquerading as a Parkinsonian-plus Syndrome (P6-5.022) - Neurology
• Mme MGI Mouse Gene Detail - MGI:97004
• LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor (ARNI) - PMC
• Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis - PubMed

Spinocerebellar Ataxia Type 43 (SCA43): Disease-Characteristics Report

Executive summary and evidence appraisal

Spinocerebellar ataxia type 43 (SCA43) is an exceptionally rare, late-onset, autosomal-dominant neurologic disorder characterized by axonal polyneuropathy plus cerebellar ataxia. The disease was defined in 2016 in one five-generation Belgian family carrying heterozygous MME p.Cys143Tyr (p.C143Y). Among seven living affected relatives, all seven had late-onset sensorimotor axonal polyneuropathy and six had cerebellar ataxia. Consequently, most phenotype frequencies, penetrance estimates, and prognostic statements remain family-specific rather than population-level facts. No replicated SCA43 cohort, disease-specific treatment trial, validated biomarker, or pathogenic-variant model was identified through the 2024 literature horizon. (depondt2016mmemutationin pages 1-2)

Table: This table summarizes the strongest disease-specific evidence currently available for spinocerebellar ataxia type 43. It highlights the core clinical-genetic findings and the major limitations created by single-family ascertainment and lack of replication, epidemiology, treatment trials, omics, and validated models.

Evidence labels used below: [Human—direct] denotes the Belgian SCA43 family; [Human—indirect] denotes other MME-associated neuropathies; [Model] denotes animal evidence; and [Inference] denotes biologically plausible but unproven interpretation.

1. Disease information

Definition

SCA43 is a Mendelian neurodegenerative disease in which dominantly inherited MME dysfunction produces a slowly progressive, late-onset combination of cerebellar and peripheral-nerve disease. It is not a repeat-expansion SCA. The defining publication described it as “dominant spinocerebellar ataxia with neuropathy.” (depondt2016mmemutationin pages 4-5, depondt2016mmemutationin pages 1-2)

Identifiers and synonyms

• MONDO: MONDO:0014867.
• EFO: EFO:0009060.
• Causal target association: MME, Ensembl ENSG00000196549. (OpenTargets Search: spinocerebellar ataxia type 43-MME)
• Synonyms: spinocerebellar ataxia 43; spinocerebellar ataxia type 43; SCA43; dominant spinocerebellar ataxia with neuropathy; MME-related dominant ataxia with neuropathy.
• OMIM/Orphanet: a stable disease-specific identifier was not established from the retrieved primary evidence; these should be verified directly before database ingestion rather than inferred.
• ICD-10/ICD-11 and MeSH: no SCA43-specific code was identified. Broader hereditary ataxia/polyneuropathy codes are used clinically but are not uniquely identifying.

The evidence is aggregated family-level research, not an EHR-derived patient registry: 28 relatives were sampled, seven living affected relatives were characterized, and clinical records were reviewed. (depondt2016mmemutationin pages 1-2)

2. Etiology

Causal factor

[Human—direct] The established cause is a germline heterozygous missense variant in MME, encoding neprilysin: p.Cys143Tyr/p.C143Y. It cosegregated with disease in the five-generation pedigree and was absent from dbSNP, EVS, and ExAC, the latter then comprising 60,706 individuals. It was also absent from 96 additional unrelated people with genetically unexplained dominant ataxia. (depondt2016mmemutationin pages 3-4)

The original genomic coordinate was reported as a G→A transition at chromosome 3q25.2, position 156,317,031. Because transcript/build-dependent HGVS expressions were not fully resolved in the retrieved evidence, a clinical report should state the reference transcript and genome build explicitly before assigning a cDNA HGVS expression. (depondt2016mmemutationin pages 3-4)

Risk factors

• Genetic: carrying the familial heterozygous p.Cys143Tyr allele is the only demonstrated SCA43 risk factor. Family history compatible with autosomal-dominant late-onset ataxia/neuropathy materially raises prior probability.
• Age: manifestations occurred at 42–68 years, making increasing age an expression-related factor rather than an independent cause. (depondt2016mmemutationin pages 2-3)
• Sex, ancestry, modifiers, environment, occupation, toxins, alcohol, smoking, diet, infection: no SCA43-specific associations are known.

Other MME variants may cause dominant late-onset axonal neuropathy or biallelic recessive neuropathy without cerebellar disease. These entities should not automatically be labeled SCA43. In particular, simple MME loss of function appears insufficient to explain the distinctive dominant cerebellar phenotype. (depondt2016mmemutationin pages 4-4, depondt2016mmemutationin pages 4-5)

Protective factors and gene–environment interaction

No genetic protective allele, environmental protective factor, or validated gene–environment interaction has been reported. Avoiding neurotoxic exposures and excess alcohol is reasonable general ataxia/neuropathy care, but it is not evidence-based primary prevention for SCA43.

3. Phenotypes

The frequencies below are descriptive proportions from seven affected relatives and have wide uncertainty.

• Axonal sensorimotor polyneuropathy: 7/7 reported affected individuals; late onset and progressive. Suggested HPO: HP:0000763 (sensory neuropathy), HP:0007002 (motor axonal neuropathy), HP:0009830 (peripheral axonal neuropathy). Electrophysiology was motor-predominant, with prolonged F-response latency, preserved sensory responses, and normal conduction velocity in reported examinations. (depondt2016mmemutationin pages 1-2, depondt2016mmemutationin pages 2-3)
• Cerebellar ataxia: 6/7; mixed cerebellar and afferent gait dysfunction, slowly progressive. HPO: HP:0001251 (ataxia), HP:0002066 (gait ataxia), HP:0002072 (cerebellar atrophy). (depondt2016mmemutationin pages 1-2, depondt2016mmemutationin pages 2-3)
• Gait/balance impairment: common presenting problem; the proband developed balance difficulty at approximately 58 years. HPO: HP:0001288 (gait disturbance), HP:0002321 (falls, if documented prospectively). (depondt2016mmemutationin pages 2-3)
• Distal weakness/amyotrophy and pes cavus: lower-limb wasting and cavus feet were reported. HPO: HP:0003693 (distal muscle weakness), HP:0008944 (distal lower-limb amyotrophy), HP:0001761 (pes cavus). (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)
• Areflexia/hyporeflexia and sensory loss: absent Achilles reflexes and hypoesthesia were reported. HPO: HP:0001284 (areflexia), HP:0001265 (hyporeflexia), HP:0003474 (sensory impairment). (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)
• Dysarthria: HPO HP:0001260. (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)
• Oculomotor findings: hypometric saccades and cerebellar nystagmus. HPO suggestions: HP:0000641 (dysmetric saccades) and HP:0000639 (nystagmus). (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)
• Tremor, cogwheel rigidity, and palmomental reflex: present in individual relatives; frequencies cannot be generalized. HPO: HP:0001337 (tremor), HP:0002063 (rigidity). (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)
• Pectus carinatum: distinctive but inconstant; HPO HP:0000768. (depondt2016mmemutationin pages 3-4)
• Cognition: no cognitive impairment was reported in the family. This is an observed absence, not proof that cognition is invariably preserved. (depondt2016mmemutationin pages 4-5, depondt2016mmemutationin pages 2-3)

Quality-of-life effects

No EQ-5D, SF-36, PROMIS, SARA-based longitudinal quality-of-life, or caregiver-burden study exists for SCA43. Nevertheless, progressive imbalance, distal weakness, sensory impairment, and dysarthria plausibly impair walking, fall safety, communication, employment, and activities of daily living. This is clinical inference rather than quantified SCA43 evidence.

4. Genetic and molecular information

• Gene: MME (membrane metalloendopeptidase; neprilysin/CD10), chromosome 3q25.2; Ensembl ENSG00000196549. (OpenTargets Search: spinocerebellar ataxia type 43-MME, depondt2016mmemutationin pages 3-4)
• Protein: neprilysin/NEP, a zinc-dependent M13-family metalloprotease with a short cytoplasmic N terminus, transmembrane helix, and large extracellular catalytic domain. It is expressed broadly, including neurons, CNS axons/synaptic terminals, and peripheral Schwann cells. (depondt2016mmemutationin pages 4-5, depondt2016mmemutationin pages 4-4)
• Defining variant: heterozygous germline p.Cys143Tyr missense variant. Cys143 is invariant across examined species and forms a disulfide bridge with Cys411; substitution is predicted to disrupt protein structure. SIFT, PolyPhen-2, and PROVEAN predicted damage. (depondt2016mmemutationin pages 4-5, depondt2016mmemutationin pages 3-4)
• Population frequency: absent from the cited historical databases, including ExAC n=60,706; a current gnomAD version and exact transcript should be rechecked during curation. (depondt2016mmemutationin pages 3-4)
• Classification: compelling disease-candidate evidence includes rarity, segregation, conservation, computational predictions, and phenotypic fit. However, the retrieved study predates or did not provide a modern ClinGen expert-panel classification, independent-family replication, or variant-specific functional assay. A knowledge base should preserve the submitting laboratory’s current ClinVar classification rather than automatically assigning “pathogenic.”
• Origin: constitutional/germline; no somatic disease mechanism is implicated.
• Mechanistic class: dominant-negative or altered-function/gain-of-abnormal-function is more plausible than simple haploinsufficiency, because complete/biallelic MME loss causes peripheral neuropathy without the same dominant cerebellar phenotype. This remains unproven. (depondt2016mmemutationin pages 4-4, depondt2016mmemutationin pages 4-5)

No SCA43 modifier genes, epigenetic signature, pathogenic structural variant, chromosomal rearrangement, anticipation mechanism, or repeat expansion is known.

5. Environmental information

No toxin, radiation exposure, pollutant, occupation, dietary pattern, smoking behavior, alcohol exposure, exercise pattern, or infectious agent has been shown to cause or trigger SCA43. The disorder is not infectious or transmissible. Environmental evaluation remains important diagnostically because alcohol, medications, vitamin deficiencies, immune disease, and toxins can cause acquired ataxia or neuropathy and may compound disability, but they are differential diagnoses rather than established SCA43 determinants.

6. Mechanism and pathophysiology

Supported molecular framework

Neprilysin cleaves multiple bioactive peptides, including neuropeptides and amyloid-β. Cys143 lies in the N-terminal peptidase M13 region and normally forms a disulfide bridge with Cys411. The p.Cys143Tyr substitution is therefore predicted to perturb folding, trafficking, stability, catalytic behavior, substrate selectivity, or intermolecular interactions. Variant-specific biochemical evidence is absent. (depondt2016mmemutationin pages 4-5)

Proposed causal chain

1. Upstream trigger: germline heterozygous MME p.Cys143Tyr.
2. Protein-level event: disruption of the Cys143–Cys411 disulfide bond and altered neprilysin structure/function.
3. Cellular event: abnormal peptide processing and/or toxic dominant interference in neurons, axons, synaptic terminals, or Schwann cells.
4. Tissue effects: progressive long-axon degeneration produces distal motor-predominant neuropathy; cerebellar circuit dysfunction/degeneration produces vermian atrophy and ataxia.
5. Clinical effects: gait imbalance, distal weakness and wasting, areflexia, sensory symptoms, dysarthria, and oculomotor abnormalities. Steps 2–4 remain mechanistic hypotheses rather than experimentally proven SCA43 pathways. (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4, depondt2016mmemutationin pages 4-5)

The authors suggested altered processing of dynorphin peptides as one hypothesis because dynorphins are neprilysin substrates and PDYN causes another dominant ataxia, SCA23. This is pathway convergence, not proof of dynorphin accumulation in SCA43. (depondt2016mmemutationin pages 4-5)

Ontology suggestions

• GO biological process: proteolysis (GO:0006508), neuropeptide catabolic process (GO:0010813), regulation of synaptic signaling, axon maintenance (GO:0048675), peripheral nervous system development/maintenance, and cerebellar neuron differentiation. Only protease/neuropeptide terms are direct MME-function annotations; degeneration terms are disease-level suggestions.
• GO molecular function: metalloendopeptidase activity (GO:0004222), zinc-ion binding (GO:0008270).
• GO cellular component: plasma membrane (GO:0005886), neuronal projection/axon and synaptic terminal; precise curated MME annotations should be imported from GO/UniProt.
• Cell Ontology: neuron (CL:0000540), cerebellar Purkinje cell (CL:0000121, plausible but not histologically demonstrated), Schwann cell (CL:0002573), peripheral sensory neuron (CL:0000101) and motor neuron (CL:0000100).

No SCA43-specific transcriptomic, single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, methylomic, CRISPR-screen, or multi-omic dataset was identified. There is likewise no demonstrated immune, inflammatory, mitochondrial, autophagic, or oxidative-stress signature.

7. Anatomical structures affected

• Primary systems: central and peripheral nervous systems.
• CNS: cerebellum, particularly the vermis on MRI; clinically, cerebellar motor/oculomotor circuits. Suggested UBERON: cerebellum UBERON:0002037, cerebellar vermis UBERON:0004728.
• PNS: peripheral motor and sensory nerves, especially long lower-limb axons. UBERON suggestions: peripheral nervous system UBERON:0000010, peripheral nerve UBERON:0001021.
• Musculoskeletal secondary manifestations: distal lower-limb muscle atrophy and pes cavus arise downstream of neuropathy.
• Subcellular: cell surface/plasma membrane and extracellular catalytic domain of neprilysin; axons and synaptic terminals are expression/localization sites. (depondt2016mmemutationin pages 2-3, depondt2016mmemutationin pages 4-4)

Disease is bilateral/systemic rather than characteristically unilateral. No SCA43 autopsy series establishes Purkinje-cell loss, regional neuropathology, or subcellular inclusions.

8. Temporal development

Onset is adult/late adult, chronic, and insidious, reported from 42 to 68 years. The proband developed gait/balance problems and distal lower-limb pain at approximately 58 years and was examined at 69. The course was slowly progressive, with increasing motor neuropathy and cerebellar disability. (depondt2016mmemutationin pages 2-3)

A practical descriptive staging scheme—not a validated SCA43 scale—is:

1. Early: distal pain/sensory symptoms or subtle imbalance.
2. Intermediate: evident gait ataxia, areflexia, pes cavus, distal weakness/amyotrophy, dysarthria or eye-movement signs.
3. Advanced: severe motor axonal neuropathy and increasing mobility impairment.

There are no established remission patterns, episodic attacks, critical treatment windows, annual SARA progression rate, or median disease duration. The disease should be regarded as chronic and lifelong after onset.

9. Inheritance and population

• Inheritance: autosomal dominant, with vertical transmission and complete cosegregation in the reported pedigree. (depondt2016mmemutationin pages 1-2, depondt2016mmemutationin pages 3-4)
• Penetrance: apparently high among older carriers in this family, but exact lifetime penetrance cannot be estimated from seven affected individuals. Age dependence is likely because onset was after age 42.
• Expressivity: variable; one affected person had neuropathy without recognized cerebellar ataxia, while others had combined disease. (depondt2016mmemutationin pages 1-2)
• Anticipation: not reported and biologically not expected for a missense variant.
• Mosaicism, founder effect, consanguinity, carrier frequency: unknown/not demonstrated.
• Sex ratio: not estimable.
• Geography/ancestry: defining pedigree was Belgian; no population enrichment has been established.
• Prevalence/incidence: unknown. Failure to find the variant among 96 additional dominant-ataxia cases supports extreme rarity but is not a prevalence estimate. (depondt2016mmemutationin pages 3-4)

For counseling, a heterozygous affected person has a theoretical 50% transmission probability per pregnancy, but age-dependent penetrance and phenotype severity cannot be predicted accurately.

10. Diagnostics

Clinical evaluation

Suspect SCA43 when an adult has a family history consistent with dominant inheritance and the combination of slowly progressive cerebellar ataxia and axonal neuropathy. Assessment should include neurologic examination, pedigree, formal ataxia rating such as SARA, gait/fall assessment, ocular-motor examination, strength, reflexes, sensory testing, and cognition.

• MRI: assess cerebellar/vermian atrophy and exclude structural disease. Vermian atrophy supports but does not uniquely diagnose SCA43. (depondt2016mmemutationin pages 2-3)
• Nerve conduction/EMG: document axonal motor-sensory neuropathy; reported findings included progressive severe motor involvement, prolonged F responses, preserved sensory responses, and normal velocities. (depondt2016mmemutationin pages 2-3)
• Biopsy: one nerve biopsy showed CMT2-type axonal pathology, but biopsy is neither specific nor routinely required when molecular testing is available. (depondt2016mmemutationin pages 2-3)
• Laboratory exclusion: test for acquired/treatable causes according to presentation—vitamin B12, vitamin E, thiamine, thyroid disease, diabetes, paraproteinemia, autoimmune/paraneoplastic disease, infection, medication and toxic exposures. No SCA43 biochemical biomarker exists.

Genetic testing strategy

1. Exclude common dominant repeat expansions and other high-priority ataxia causes according to ancestry/phenotype; standard exome sequencing can miss repeat expansions.
2. Use a comprehensive ataxia-plus-neuropathy panel that includes MME, or WES/WGS with copy-number and mitochondrial analysis as indicated.
3. Confirm candidate MME variants by orthogonal sequencing and perform familial segregation.
4. Interpret inheritance and phenotype carefully: biallelic MME loss is associated mainly with recessive axonal neuropathy, while monoallelic variants may confer incompletely penetrant neuropathy susceptibility; not every MME variant establishes SCA43. (depondt2016mmemutationin pages 4-4, depondt2016mmemutationin pages 4-5)

The founding discovery combined linkage analysis with WES and Sanger confirmation. Linkage localized a 3q23–q26.31 interval with LOD 2.47. (depondt2016mmemutationin pages 2-3)

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion assays do not directly detect a single-nucleotide MME missense variant, though they may be used in unresolved differential diagnosis. RNA sequencing, proteomics, metabolomics, epigenomics, and liquid biopsy have no validated SCA43 diagnostic role.

Differential diagnosis

Important alternatives include common repeat-expansion SCAs; RFC1-related CANVAS; FGF14 GAA-expansion ataxia; SPG7; SETX-related ataxia; POLG and other mitochondrial ataxias; COA7-related ataxia-neuropathy; sensory ataxias; recessive or dominant MME-related CMT2; multiple-system atrophy-cerebellar type; immune, nutritional, toxic, and paraneoplastic ataxias. The combined dominant pedigree, axonal neuropathy, and pathogenic MME variant distinguish SCA43, but none of the clinical findings alone is specific.

Screening

There is no population or newborn screening. Once a familial variant is established, targeted cascade testing is technically straightforward. Predictive testing of asymptomatic adults should occur with genetic counseling because onset, penetrance, and severity are uncertain. Prenatal and preimplantation genetic testing are technically possible for a confirmed familial pathogenic variant.

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, five- or ten-year survival, hospitalization rate, or disease-specific cause-of-death analysis exists. Available evidence supports slow progression rather than acute lethality. Major expected morbidity includes falls, impaired ambulation, distal weakness/wasting, sensory complications, communication difficulty, and loss of independence. (depondt2016mmemutationin pages 2-3)

There is no evidence of spontaneous recovery or remission. No validated prognostic biomarker exists. Plausible clinical prognostic indicators include age at onset, baseline gait impairment, neuropathy severity, fall frequency, assistive-device requirement, SARA trajectory, and MRI progression, but none has been validated in SCA43.

12. Treatment

Disease-modifying treatment

No approved SCA43-specific pharmacotherapy, neprilysin-directed therapy, gene therapy, CRISPR therapy, antisense oligonucleotide, siRNA, cell therapy, or immunotherapy exists. No SCA43-specific interventional trial or NCT identifier was identified. Because neprilysin has many substrates and systemic cardiovascular/renal roles, empirically increasing or inhibiting it could have unintended effects and is not justified outside research.

Symptomatic and rehabilitative management

Management should be individualized and multidisciplinary:

• Physical therapy: balance, coordination, strength, aerobic conditioning, gait training, fall prevention, and home exercise. Suggested MAXO: physical therapy (MAXO:0000011) and exercise therapy.
• Occupational therapy: activities-of-daily-living adaptation, home safety, driving/work assessment, and energy conservation.
• Mobility aids/orthotics: cane, walker, wheelchair when necessary; ankle-foot orthoses and podiatry/orthopedic review for foot deformity. Suggested MAXO concepts: assistive device prescription and orthotic management.
• Speech-language therapy: dysarthria assessment and augmentative communication; swallowing evaluation if dysphagia emerges.
• Neuropathic pain: standard individualized agents such as gabapentinoids, serotonin–norepinephrine reuptake inhibitors, or tricyclics may be considered, accounting for sedation and fall risk. No SCA43 response rate is available.
• Tremor/rigidity: phenotype-directed symptomatic trials may be considered by a movement-disorders specialist, but evidence is anecdotal/non-specific.
• Surveillance: falls, mobility, pain, foot ulcers, contractures, nutrition/swallowing, mood, sleep, and caregiver needs.

No treatment algorithm or pharmacogenomic association specific to SCA43 has been validated. Surgical treatment is not disease modifying; orthopedic intervention is reserved for severe deformity. Deep-brain stimulation and noninvasive stimulation remain experimental for degenerative ataxia and have no SCA43-specific evidence.

13. Prevention

• Primary prevention: no lifestyle or medication prevents expression in a carrier. Reproductive options after counseling include donor gametes, prenatal diagnosis, or preimplantation genetic testing.
• Secondary prevention: cascade testing can identify adult relatives at risk; periodic neurologic examination may detect early gait or neuropathy manifestations, although evidence that presymptomatic surveillance alters biology is absent.
• Tertiary prevention: fall prevention, exercise, orthoses, foot care, pain treatment, swallowing/speech surveillance, vaccination and general health maintenance can reduce complications but do not prevent the genetic disease.
• Immunization, antimicrobial prophylaxis, environmental remediation, and public-health control: not disease-specific or applicable.

Suggested MAXO concepts include genetic counseling, familial variant testing, prenatal genetic testing, preimplantation genetic testing, fall-risk assessment, and rehabilitation therapy.

14. Other species and natural disease

MME orthologues are evolutionarily conserved in mammals, and conservation of Cys143 supports functional importance. However, no naturally occurring veterinary disorder was identified as a direct SCA43 analogue, and there is no zoonotic or cross-species transmission. (depondt2016mmemutationin pages 3-4)

Relevant taxa for comparative work include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). Orthologue-specific NCBI Gene IDs should be imported directly from NCBI/Alliance rather than inferred from the human identifier.

15. Model organisms and experimental systems

No validated p.Cys143Tyr knock-in mouse, rat, zebrafish, Drosophila, organoid, patient-derived iPSC, or Purkinje-cell model was identified. Mme-null mice do not develop the severe axonal neuropathy seen in humans, demonstrating species differences and making a knockout an inadequate direct model of dominant SCA43. (depondt2016mmemutationin pages 4-5)

Priority models should include:

1. heterozygous Mme p.Cys143Tyr knock-in mice with longitudinal gait, rotarod, eye-movement, nerve-conduction, cerebellar MRI, and histopathology;
2. patient-derived iPSC sensory neurons, motor neurons, Schwann cells, and cerebellar/Purkinje-like neurons;
3. isogenic CRISPR-corrected controls;
4. assays of neprilysin abundance, membrane trafficking, dimerization, zinc-dependent catalytic activity, and substrate-specific peptide processing;
5. proteomic/neuropeptidomic comparison of wild-type, heterozygous missense, and biallelic-null states.

Such systems could distinguish haploinsufficiency from dominant-negative or neomorphic action and test why the cerebellum is affected by p.Cys143Tyr but generally spared in biallelic loss-of-function neuropathy.

Key primary source and abstract quotations

Depondt et al., “MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43),” Neurology: Genetics, published October 2016. DOI: https://doi.org/10.1212/NXG.0000000000000094. The abstract states: “Affected individuals presented with late-onset sensorimotor axonal polyneuropathy; all but one also had cerebellar ataxia.” It also states: “We identified a variant in the MME gene, p.C143Y, that was absent from control databases, cosegregated with the phenotype, and was predicted to have a strong damaging effect.” Finally, the authors concluded that “Functional studies are needed to identify the mechanisms underlying these differences.” (depondt2016mmemutationin pages 1-2)

Research priorities and curation cautions

The highest priorities are independent case replication, current ClinVar/gnomAD reassessment of p.Cys143Tyr, standardized phenotyping with SARA and neuropathy scales, longitudinal MRI/electrophysiology, variant-specific biochemical studies, and a knock-in model. Until such evidence exists, SCA43 should be represented as a single-family, MME-associated dominant ataxia-neuropathy syndrome. Database curators should not merge it indiscriminately with recessive MME-related CMT2T, dominant late-onset MME neuropathy without ataxia, or nonspecific MME susceptibility alleles. (depondt2016mmemutationin pages 4-4, depondt2016mmemutationin pages 4-5, depondt2016mmemutationin pages 3-4)

References

1. (depondt2016mmemutationin pages 1-2): Chantal Depondt, Simona Donatello, Myriam Rai, François Charles Wang, Mario Manto, Nicolas Simonis, and Massimo Pandolfo. mme mutation in dominant spinocerebellar ataxia with neuropathy (sca43). Neurology Genetics, Oct 2016. URL: https://doi.org/10.1212/nxg.0000000000000094, doi:10.1212/nxg.0000000000000094. This article has 47 citations.

2. (OpenTargets Search: spinocerebellar ataxia type 43-MME): Open Targets Query (spinocerebellar ataxia type 43-MME, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

3. (depondt2016mmemutationin pages 4-5): Chantal Depondt, Simona Donatello, Myriam Rai, François Charles Wang, Mario Manto, Nicolas Simonis, and Massimo Pandolfo. mme mutation in dominant spinocerebellar ataxia with neuropathy (sca43). Neurology Genetics, Oct 2016. URL: https://doi.org/10.1212/nxg.0000000000000094, doi:10.1212/nxg.0000000000000094. This article has 47 citations.

4. (depondt2016mmemutationin pages 3-4): Chantal Depondt, Simona Donatello, Myriam Rai, François Charles Wang, Mario Manto, Nicolas Simonis, and Massimo Pandolfo. mme mutation in dominant spinocerebellar ataxia with neuropathy (sca43). Neurology Genetics, Oct 2016. URL: https://doi.org/10.1212/nxg.0000000000000094, doi:10.1212/nxg.0000000000000094. This article has 47 citations.

5. (depondt2016mmemutationin pages 2-3): Chantal Depondt, Simona Donatello, Myriam Rai, François Charles Wang, Mario Manto, Nicolas Simonis, and Massimo Pandolfo. mme mutation in dominant spinocerebellar ataxia with neuropathy (sca43). Neurology Genetics, Oct 2016. URL: https://doi.org/10.1212/nxg.0000000000000094, doi:10.1212/nxg.0000000000000094. This article has 47 citations.

6. (depondt2016mmemutationin pages 4-4): Chantal Depondt, Simona Donatello, Myriam Rai, François Charles Wang, Mario Manto, Nicolas Simonis, and Massimo Pandolfo. mme mutation in dominant spinocerebellar ataxia with neuropathy (sca43). Neurology Genetics, Oct 2016. URL: https://doi.org/10.1212/nxg.0000000000000094, doi:10.1212/nxg.0000000000000094. This article has 47 citations.

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