Abstract Details

Title Beyond the Eyes: The Clinical Spectrum of AFG3L2 Mutations

Topic Movement Disorders

Presentation(s) P6 - Poster Session 6 (11:45 AM-12:45 PM)

Poster/Presentation
Number 5-032

Objective NA

Background AFG3L2 is a mitochondrial ATPase that belongs to the AAA protease family and is localized in the inner mitochondrial membrane. It is widely expressed, with studies demonstrating it being observed in large-cell neurons, like brainstem motor neurons, pyramidal cells in the hippocampus and neocortex, mitral cells of the olfactory bulb, Purkinje and deep nuclei cells in the cerebellum. Pathogenic variants in the AFG3L2 gene are linked to several neurodegenerative disorders, with heterozygous pathogenic variants causing optic atrophy-12 (OPA12) and spinocerebellar ataxia-28 (SCA28), while biallelic pathogenic variants result in autosomal recessive spastic ataxia-5 (SPAX5). These conditions share overlapping characteristics, suggesting a phenotypic spectrum associated with AFG3L2 pathogenic variants.

Design/Methods NA

Results

A 42-year-old male was referred due to worsening tremors. Besides left-handed predominant action tremor with an onset in the first decade, he had an intellectual delay (FSIQ 46) with primitive reflexes (applause, glabellar, snout, grasp reflexes), left upper extremity dystonic posturing during ambulation, difficulty with coordination, mild dysarthria, and optic nerve atrophy. He had a strong family history of tremors starting in the 60s-70s in father, paternal uncle and paternal grandfather.

Whole genome sequencing was obtained and showed a disease-causing de-novo heterozygous variant in the AFG3L2 gene (c.1064 C>T p.(T355M)).

Conclusions The AFG3L2 variant (c.1064 C>T p.(T355M) is associated with clinical features that include optic atrophy, dopa-responsive dystonia, parkinsonism, intellectual delay, ataxia, dysarthria and tremors. This case highlights the clinical variability associated with AFG3L2 pathogenic variants, as some individuals only present with optic atrophy and no neurologic findings.

Authors/Disclosures
Sarika Mutyala, MBBS PRESENTER	Dr. Mutyala has nothing to disclose.
Hina Rmsha Alfia Khan, MBBS	Dr. Khan has nothing to disclose.
Queenie Tan, MD, PhD	Dr. Tan has received publishing royalties from a publication relating to health care.
Prashant Natteru, MBBS (Mayo Clinic Health System)	Dr. Natteru has nothing to disclose.

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