Objective: To describe FA2H mutations, one novel, in siblings with SPG35 with symptoms responsive to levodopa.

Background: Hereditary spastic paraplegia (HSP) is a phenotypically and genetically heterogeneous group of inherited neurodegenerative disorders. The cardinal feature is progressive upper motor neuron degeneration leading to spasticity and weakness of the lower extremities. Other findings include cognitive decline, ataxia, epilepsy, and peripheral neuropathy. Mutations in the FA2H gene, involved in lipid ceramide metabolism, result in SPG35, an autosomal recessive form of HSP. SPG35 is characterized by childhood-onset gait impairment, spastic paraparesis, ataxia, and dystonia. Typical brain MRI findings include leukodystrophy, thinning of the corpus callosum, and cerebellar atrophy.

Methods: Indian siblings, a 28 year old female and 32 year old male, presented with progressive neurologic symptoms. Brother developed normally until age 9 when progressive cognitive impairment and gait abnormality began, with need for crutches from age 30. Sister had progressive gait difficulty from age 18, though is still independently ambulatory. On exam, both have bradykinesia, dystonia, hyperreflexia, increased tone, and spastic/ataxic gait, though sister’s symptoms are less severe. Additionally, brother has cognitive impairment with communication difficulty, dysarthria, and sensory neuropathy. Exome sequencing was performed in a clinical testing lab.

Results: Brain MRI in sister showed thinning of the corpus callosum and cerebellar atrophy. Brother’s brain MRIs showed progressive cerebral and cerebellar atrophy, thinning of the corpus callosum, and supratentorial foci of T2 hyperintensity. In both, exome sequencing identified compound heterozygous variants in the FA2H gene, paternally inherited c704G>A, previously reported in SPG35; and maternally inherited variant of uncertain significance (VUS) at c232G>A. Carbidopa/L-dopa reduced bradykinesia and improved gait and balance in both siblings.

Conclusions: We describe siblings with compound heterozygous variants of the FA2H gene associated with SPG35, one novel. SPG11, another type of spastic paraplegia, is both radiologically and phenotypically similar to SPG35 and the only HSP known to be levodopa-responsive. Levodopa-responsiveness in SPG35, as seen in both patients in this case, is a phenomenon not previously described.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/levodopa-responsive-hereditary-spastic-paraplegia-spg35-due-to-fa2h-mutations-in-siblings/