Objective: To describe p.P626L missense mutation of FMR1 gene in a patient with clinical phenotype of Fragile X Associated Tremor and Ataxia Syndrome (FXTAS).

Background: FXTAS is a progressive neurologic disorder comprising intention tremor, gait disturbance, cognitive decline, parkinsonism and generalized brain atrophy among older men with the Fragile X premutation. The Fragile X mental Retardation 1 (FMR1) gene permutation is present in about 1/130-260 females and 1/250-810 males in the general population with estimated prevalence of 1/3,000 among males in China. Premutation carriers may have autoimmune, endocrine, neurological and psychiatric involvement. There have not been any reports on patients with FXTAS phenotype with FMR1 missense mutation. Here we report a 37 year-old Chinese male without history of trauma or toxic exposure presented with parkinsonism, intention tremor, anxiety, and orthostatic hypotension. He was subsequently treated with Madopar (levodopa + benserazide), entacapone, amantadine, and selegiline. His parkinsonism improved moderately. He then was operated with DBS targeting bilateral GPi with modest symptomatic response. Given the FXTAS-like phenotype and young onset of parkinsonism, he underwent extensive laboratory and genetic assessment.

Methods: All of the 17 exons of FMR1 gene were sequenced with the first generation sequencing method. Gene testing for GCH1, DYT1, Park1,2,6,7,8 were performed, Bioinformatics predictive analysis of Missense Mutation p.P626L in FMR1 was conducted with Conservative analysis of the C-terminal of FMRP, Chou-Asman & Fasman Secondary Structure Prediction (CFSSP), Protein Analysis Through Evolutionary Relationships (PANTHER), Sort Intolerant From Tolerant (SIFT Blink), Polymorphism Phenotyping Program 2 (PolyPhen2), and PMut predict.

Results: Wilson’s Disease, Dopamine-Reactive Dystrophy(GCH1), DyT1 Dystonia (DYT1), and Park1, 2, 6, 7, 8 were excluded. CGG repeats were normal (29 repeats). DCFSSP showed marked reduction of coils. Helix and Sheet were increased in the C-terminus of p.P626L FMRP.SIFT demonstrates p.P626L mutation sites of pathogenicity with the degree of harm score of 0.19 (tolerant). PolyPhen2 predicts P626L mutation pathogenicity with the degree of harm score of 0.962, suggesting “probably damaging”; and PMut predict NN Output scores was 0.9352 (Pathological).

Conclusions: p.P626L Missense mutation is probably damaging and pathological. It is associated with the phenotype of FXTAS among patients with prominent tremor and parkinsonism. The dopaminergic response in this case remains elusive.

References: Hagerman RJ and Hagerman PJ (2016) Fragile X-associated Tremor/Ataxia Syndrome-features, mechanisms and management. Nature Reviews Neurology 12:403-412. doi 10.1038/nrneurol2016.82.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fxtas-like-phenotype-with-p-p626l-missense-mutation-a-case-report/