Objective: To describe two probable cases of autosomal recessive ataxia associated with mutations in the PMPCA gene (ATX-PMPCA) secondary to novel compound heterozygous variants.

Background: ATX-PMPCA is a rare autosomal recessive ataxia that associates cerebellar and, in some cases, also spinal cord and brainstem degeneration due to mutations in the PMPCA gene (9q.34.3). ATX-PMPCA’s clinical onset usually occurs in early childhood, and, despite a broad phenotypic variability has been described, most cases exhibit a clinical picture characterised by ataxic gait, limb dysmetria, gaze-evoked nystagmus and a variable degree of intellectual disability.

Method: Case report.

Results: ATX-PMPCA is a rare autosomal recessive ataxia that associates cerebellar and, in some cases, also spinal cord and brainstem degeneration due to mutations in the PMPCA gene. This gene is located in the 9q.34.3 and encodes the α subunit of the mitochondrial-processing peptidase (α-MPP), whose normal functioning is necessary for the correct maturation of most nuclear-encoded mitochondrial proteins. ATX-PMPCA’s clinical onset usually occurs in early childhood, and, despite a broad phenotypic variability has been described, most cases exhibit a clinical picture characterised by ataxic gait, limb dysmetria, gaze-evoked nystagmus and a variable degree of intellectual disability.

With the advance of genetic diagnosis and the discovery of the association of Behr syndrome with mutations in the OPA1 gene, whole-exome sequencing was performed on the younger sister in 2018. Two different mutations in the PMPCA gene were found. One of them (c.6333+1G>A) was predicted as probable pathogenic, and the other (c.1032G>T) was predicted to be a variant of uncertain significance (VUS). Family segregation analysis performing Sanger sequencing of the older sister demonstrated the same variants, thus significantly supporting their pathological causality. An analysis of the mother’s genome is currently being performed in order to completely fulfil the reclassification criteria of the VUS.

Conclusion: ATX-PMPCA exhibits a broad phenotypical variability. However, to our knowledge, the presence of myoclonic jerks as well as papillary and bilateral optic nerve atrophy, has not been reported in these patients. These phenomena should, therefore, be included in the list of potential clinical signs of the disease once these two probable cases of ATX-PMPCA are fully confirmed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/expanding-the-clinical-phenotype-of-ataxia-associated-with-pmpca-mutations/