Objective: To offer clinical, genetic and neuropathological information in a novel alpha-synuclein gene (SNCA) missense variant to further our understanding of synucleinopathies.

Background: Around 5–10% of patients with Parkinsons disease are thought to suffer from a monogenic form of the disease with Mendelian inheritance. SNCA was found to be the first disease-causing gen in 1997. (p.A53T mutation). Missense variants (for example p.A30P, p.E46K, p.H50Q, p.G51D, p.A53E ) and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson’s Disease.

Method: A patient with a neurodegenerative disorder and his familiy were studied to characterize a novel SNCA variant. Clinical description of patient and familiy members, genetic testing and neuropathology will be presented.

Results: We identified a novel heterozygous SNCA variant (c.40G>A; p.Gly14Arg) in our patient.  Whole exom sequencing (WES) was performed due to the atypical clinical presentation: at the age of 55 years the patient developed a stuttering speech with palilalia, an atypical bizarre gait and a Horner syndrome. Initially a functional disorder was suspected. But later generalized myocloni, bradykinesia, dystonia of the left arm and apraxia were observed. FP-CIT Spect showed a symmetrical decreased dopamine transporter activity. Bradykinesia was not responsive to l-dopa. After 4 years the patient lost ambulation and he died 2 years later in a nursing home due to complications of pneumonia. Neuropathology showed extensive atypical alpha-synuclein pathology with a fronto-temporal lobar and nigral degeneration pattern with abundant ring-like neuronal inclusions.  Sanger sequencing confirmed the SNCA variant in the healthy, 96 year old father of the patient.

Conclusion: Due to localization of the variant in a highly conserved genomic region and the  atypical neuropathological features that are reminiscent of p.G51D mutation we assume a causal role of the SNCA variant in our patient. The variant carrying healthy father suggests an incomplete penetrance. Further functional analyses are needed to understand the biochemical properties of SNCA missense variants, how they lead to neurodegeneration and what factors might lead to an incomplete penetrance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-alpha-synuclein-gene-snca-missense-variant-in-an-austrian-familiy-with-atypical-neuropathological-features/