Leukodystrophy and Neurogenic EMG Changes Associated with Variants in POLR3A and PMP22 (P5.263)

Le résumé fourni par la source

Objective: We describe a patient with clumsiness, cognitive deficits, hyperreflexia and denervation changes on electromyography, who was found to have a heterozygous pathogenic variant in PMP22 and a heterozygous variant of uncertain significance in POLR3A. Background:Copy number gains encompassing PMP22 cause Charcot-Marie Tooth disease (CMT) whereas copy number losses encompassing PMP22 cause Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). PMP22 abnormalities have been associated with demyelination in the Central Nervous System, although abnormalities in nerve conduction studies (NCS) are prominent. Several reports have linked pathogenic homozygous and compound heterozygous variants in the POLR3A gene to childhood-onset leukodystrophies. Methods: A 19-year old Caucasian male was evaluated for childhood-onset gait deficit and motor incoordination. Cognitive deficits, myopia and visual field constriction had developed during middle school. Exam revealed lower extremity hyperreflexia, foot drop, extensor plantar responses, and spastic gait. Results: Spinal MRIs were normal, but brain MRI revealed T2 posterior white matter hyperintensities including the optic radiations, atrophy out of proportion for age. NCS was normal, but electromyography showed neurogenic changes in the extremities. Genetic testing showed heterozygous variants in PMP22 (c [353 C > T)] p [Thr118Met] and in POLR3A (c[1745G>T] p[Arg582Leu]). Conclusions: Our patient exhibited impairments deriving from both central and peripheral nervous systems. HNPP and CMT have occasionally been associated with white matter changes and cognitive impairment, but normal NCS is inconsistent with these diagnoses. Pathogenic POLR3A variants have been associated with a childhood-onset leukodystrophy that presents with motor incoordination and ataxia, often followed by cognitive difficulties and myopia. Selective brain hypomyelination, cerebellar atrophy and thinning of the corpus callosum can be seen. The pathogenicity of the POLR3A c.[1745G>T] variant is uncertain - all previously reported leukodystrophycases with POLR3A abnormalities are homozygotes or compound heterozygotes. Further investigation of the patient and his first-degree relatives is planned.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.