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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