SLC25A46 was first reported in 2015 associated to an autosomal recessive axonal sensorimotor polyneuropathy with a Charcot-Marie-Tooth phenotype combined with optic atrophy (HMSN6) and, to a variable extent, to further central nervous system manifestations including cerebellar ataxia and spasticity (Abrams et al., PMID: 26168012). The clinical pattern is heterogeneous. In contrast to optic atrophy, single cases have been reported without a detectable neuropathy at the date of examination (PMIDs: 32259769, 28369803). The age at onset varies from congenital to childhood manifestations. 12 missense, 2 nonsense, 2 frameshift, and 2 splice variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 20 probands in 11 separate publications (PMIDs: 26168012, 30178502, 27430653, 27543974, 28653766, 28558379, 28637197, 26951855, 27390132, 32259769, 28369803). This gene-disease relationship is supported by expression studies and animal models. SLC25A46 is a modified carrier protein localized in the outer mitochondrial membrane. It plays a major role in mitochondrial dynamics (fission) (Abrams et al., PMID: 26168012). In HeLa cells, SLC25A46 knockdown resulted in mitochondrial elongation, which was found to be associated to fission defects (electron microscopy, Abrams et al., PMID: 26168012). In a zebrafish model, motor neurons had significantly shorter axons tracts (Abrams et al., PMID: 26168012). In sciatic nerve of Slc25a46-/- mice, mitochondria clumped together with disorganized or abolished cristae (Li et al., PMID: 28934388), whereas AAV–Slc25a46 rescued the abnormal distribution of mitochondria in mice sciatic nerves accordingly improving nerve conduction studies as well (Li Yang et al., PMID:31943007). In summary, SLC25A46 is definitively associated with an autosomal recessive syndrome including axonal Charcot-Marie-Tooth disease, optic atrophy, and variable central nervous system manifestations. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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