Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35)

German A, Jukic J, Laner A, Arnold P, Socher E, Mennecke A, Schmidt M, Winkler J, Abicht A, Regensburger M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Genes Molecular Diversity Preservation International (MDPI)

Book Volume: 15

Pages Range: 14

Issue: 1

DOI: 10.3390/genes15010014

Abstract

Fatty acid hydroxylase-associated neurodegeneration (FAHN/SPG35) is caused by pathogenic variants in FA2H and has been linked to a continuum of specific motor and non-motor neurological symptoms, leading to progressive disability. As an ultra-rare disease, its mutational spectrum has not been fully elucidated. Here, we present the prototypical workup of a novel FA2H variant, including clinical and in silico validation. An 18-year-old male patient presented with a history of childhood-onset progressive cognitive impairment, as well as progressive gait disturbance and lower extremity muscle cramps from the age of 15. Additional symptoms included exotropia, dystonia, and limb ataxia. Trio exome sequencing revealed a novel homozygous c.75C>G (p.Cys25Trp) missense variant in the FA2H gene, which was located in the cytochrome b5 heme-binding domain. Evolutionary conservation, prediction models, and structural protein modeling indicated a pathogenic loss of function. Brain imaging showed characteristic features, thus fulfilling the complete multisystem neurodegenerative phenotype of FAHN/SPG35. In summary, we here present a novel FA2H variant and provide prototypical clinical findings and structural analyses underpinning its pathogenicity.

Authors with CRIS profile

Alexander German Department of Molecular Neurology Jelena Jukic Department of Molecular Neurology Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie Eileen Socher Lehrstuhl für Funktionelle und Klinische Anatomie Angelika Mennecke Department of Neuroradiology Manuel Schmidt Department of Neuroradiology Jürgen Winkler Professur für Molekulare Neurologie Martin Regensburger Department of Molecular Neurology

Involved external institutions

Medizinisch Genetisches Zentrum (MGZ) / Medical Genetics Center DE Germany (DE)

How to cite

APA:

German, A., Jukic, J., Laner, A., Arnold, P., Socher, E., Mennecke, A.,... Regensburger, M. (2023). Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35). Genes, 15, 14. https://doi.org/10.3390/genes15010014

MLA:

German, Alexander, et al. "Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35)." Genes 15 (2023): 14.

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