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Título

A rare cause of sensory-motor axonal neuropathy with hearing impairment and cerebelar ataxia

RESUMO

A 32-year-old adopted man with a history of frequent falls since childhood presented to our neurogenetic outclinic. He had normal motor milestones achievement but presented with progressive unsteady gait and tremors from the age of five. He has also complained of sensory disturbance, especially at distal legs and feet, dysarthria and hearing loss since 8 years old. He denied any cognitive impairment, seizures, cardiologic or pulmonary involvement.
In the examination he had multidirectional nystagmus and mild dysarthria. His strength and DTR were normal throughout. Pinprick and vibration sense were impaired distally. He had bilateral severe dysmetria and dysdiadochokinesia, and an ataxic gait with a broad base, besides a positive Romberg test, suggesting a mixed sensory-cerebellar ataxia.
Nerve conduction studies revealed a non length dependent sensory-motor nerve axonal impairment. Needle examination revealed diffuse chronic denervation affecting cranial, cervical, thoracic and lumbo-sacral segments. Brain MRI showed only diffuse mild cortical atrophy. Severe neurosensorial hearing loss in the right ear and mild loss in the left ear were evinced in audiometry.. His muscle biopsy was unremarkable.
Initial molecular analysis ruled out Friedreich ataxia, SCA2, SCA3, CMT1A, CMT1B and CMTX1. WES revealed a hemizygous missense pathogenic variant (c.512T>C;p.Met171Thr) in the AIFM1 gene. The pathogenicity of the variant is supported by this location in a hotspot, deleterious computation prediction (13 out of 16), high conservation score (phyloP100: 8.692) and absence on Genome Aggregation Database.
Discussion: AIFM1 gene is a nuclear gene related to the transcription of a mitochondrial homodimeric protein that is required to maintain the mitochondrial respiratory complex I. AIFM1 related disorders include X-linked deafness, combined oxidative phosphorylation deficiency 6, spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy and Cowchock syndrome, CMTX4. Our case highlights the clinical heterogeneity of this rare variant, pointing out that in a patient with sensory-motor axonal neuropathy with hearing impairment and ataxia, features mostly seen in mitochondrial disorders, AIFM1 gene must be considered.
Final conclusion: AIFM1 gene variants are extremely rare. Here we describe a case of progressive ataxia, hearing impairment and sensory-motor neuropathy in a male patient without known family history, in that a hemizygous AIFM1 variant has been found.

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