The purpose of the study is to systematically characterize the clinical course of the progressive neuropathy and optic atrophy observe in pediatric and adult patients with biallelic mutations in the solute carrier family 25 member 46 (SLC25A46) gene.

The number of mitochondria in the cell is dynamic and is regulated by two opposite processes, namely fission and fusion. Proteins in both the inner mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM) are involved in mediating these two processes, including OPA1, MFN2 and SLC25A46. Recent work by the investigators as well as other research groups has shown that mutations in SLC25A46 cause abnormal mitochondrial fusion, leading to optic nerve atrophy, axonal peripheral neuropathy and cerebellar degeneration by interfering with mitochondrial fission. Recently, the investigators have used CRISPR genome editing to generate a global Slc25a46 KO mouse model with complete loss of SLC25A46 in all tissues (PMID: 28934388). Similar to patients with biallelic mutations in SLC25A46, these mice exhibit severe ataxia, optic atrophy, peripheral neuropathy related to axonal degeneration, and demyelination due to mitochondrial hyperfusion and defective energy production. In these mice, histological staining revealed a hypotrophic cerebellum with a severe loss of Purkinje cells (PCs) and/or stunted PC dendrites while electron microscopy revealed enlarged mitochondria with swollen cristae and other abnormal morphologies in PC dendrites and sciatic nerves. Furthermore, in primary culture, PCs from these mice exhibited abnormal mitochondrial distribution and movement.

These findings provide compelling evidence indicating that SLC25A46 plays an important role in the regulation of mitochondrial dynamics-including fusion/fission, distribution, and movement, as well as the maintenance of cristae architecture-and that loss of SLC25A46 function has a particularly severe effect on a distinct subset of neuron types with long axonal processes. More recently, the investigators have shown that AAV-based gene therapy can produce dramatic improvements in their Slc25a46 mutant mouse model (PMID: 31943007). These studies in the Slc25a46 mouse model provide the foundation for uncovering the mechanism whereby these this gene causes disease in humans, as well as lay the groundwork for the possible use of gene therapy to ameliorate the disease phenotype in patients.

However, despite this progress, there remains only a handful of studies published on Slc25a46 and the consequences of loss of Slc25a46 function in humans. Given that human SLC25A46-associated phenotypes overlap substantially with DOA and CMT2A, further study of this rare condition presents an opportunity not only to better understand and treat SLC25A46-related disease, but also to elucidate the broader mechanistic link between neurodegeneration and abnormal mitochondrial dynamics. Thus, in order to better understand the clinical manifestations of SLC25A46-related disease and to help lay the groundwork for eventual clinical trials of gene therapy or drug-based treatments, the investigators propose this natural history study of pediatric as well as adult patients with biallelic mutations in the SLC25A46 gene.

Inclusion Criteria:

• Patients who are clinically diagnosed with biallelic mutations in the SLC25A46 gene
• Male and female patients from 2 to 65 years of age
• Patients who have consented to the study
• In the case of a deceased patient whose parent(s) and/or legal guardian(s) have provided informed consent for study participation, the investigators will review the patient's medical records to determine study eligibility.

Exclusion Criteria:

• Significant postnatal complications or congenital anomalies that are not known to be associated with SLC25A46 dysfunction
• Patient has received any experimental treatment for SLC25A46 dysfunction within the 6 months prior to enrollment, or is expected to receive any such therapy during the study period

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