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SLC25A46 – Pontocerebellar Hypoplasia Type 1

Autosomal recessive biallelic variants in SLC25A46 have been implicated in pontocerebellar hypoplasia type 1 (PCH1), a non-5q SMA–like neurodegenerative disorder with antenatal onset, global developmental delay, optic atrophy, microcephaly, spasticity, ataxia, nystagmus, and dystonia. A large literature review and case series of SMN1-negative SMA patients identified SLC25A46 mutations in early-onset PCH1 subtypes with death between 1 day and 17 months, supporting a recessive inheritance mode with no reported segregation data ([PMID:29656927]).

Functional studies demonstrate that loss of SLC25A46 disrupts mitochondrial dynamics: protein stability inversely correlates with disease severity in patient fibroblasts ([PMID:30178502]), stable slc25a46 zebrafish knockouts show genetic compensation versus penetrant F0 crispants with rescue by wild-type mRNA ([PMID:32208444]), and human fibroblast knock-out models exhibit mitochondrial fragmentation, abnormal cristae, and altered OPA1/MFN2 interactions at fission/fusion sites ([PMID:36977595]). Together these data support a loss-of-function mechanism underlying PCH1. Key take-home: SLC25A46 should be included in diagnostic gene panels for early-onset SMA-like and pontocerebellar hypoplasia presentations.

References

  • European Journal of Paediatric Neurology • 2018 • Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature PMID:29656927
  • Human Mutation • 2018 • Insights into the genotype-phenotype correlation and molecular function of SLC25A46 PMID:30178502
  • PLoS One • 2020 • Genetic compensation in a stable slc25a46 mutant zebrafish: A case for using F0 CRISPR mutagenesis to study phenotypes caused by inherited disease PMID:32208444
  • Life Science Alliance • 2023 • The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion PMID:36977595

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Few reported PCH1 probands with recessive SLC25A46 variants; no segregation data ([PMID:29656927])

Genetic Evidence

Limited

Biallelic SLC25A46 variants identified in PCH1 case series with early onset (recessive) ([PMID:29656927])

Functional Evidence

Moderate

Protein stability correlations, zebrafish models, and cell assays demonstrate SLC25A46 loss impairs mitochondrial dynamics consistent with PCH1 pathology ([PMID:30178502]; [PMID:32208444]; [PMID:36977595])