Objective: To describe a case of genetically confirmed Fragile X syndrome presenting with levodopa unresponsive Parkinsonism

Background: Parkinsonism with or without ataxia is well recognised to occur with the premutation expansion of FMR1 gene whereas this is not a recognised clinical presentation for people with the full FMR1 mutation causing Fragile X syndrome. The pathophysiology in cases with premutation is speculated to be a toxic gain-of-function messenger RNA (mRNA) manifesting with the features of fragile X associated ataxia syndrome (FXTAS). The full expansion leads to Fragile X syndrome; a condition predominantly affecting males and manifests with learning disability, autism and epilepsy. Patients who have genetic mosaicism or who have not fully methylated mutations may still express elevated mRNA.

Method: Case report

Results: A 62 year old presented to the outpatient department with a 12 month history of deteriorating mobility described as an increasing frequency of falls and dragging of his right leg. He had a lifelong history of severe learning disability and had two male siblings with learning disability and autism. Examination revealed unilateral rigidity with cogwheeling and bradykinesia, no tremor and normal power and reflexes. His Parkinsonism was managed initially with escalating doses of levodopa. After failing to respond to levodopa, genetic testing was performed identifying full mutation in FMR1 diagnosing Fragile X syndrome.

Conclusion: This is an unusual case of genetically confirmed Fragile X syndrome in a patient who presented with a levodopa unresponsive parkinsonism in later life. This case appears to expand the clinical phenotype for Fragile X and suggests that there may be an alternate hypothesis to explain the gene to phenotype mechanism. As FMR1 mutations were first described only less than 30 years ago, we may start to see more patients manifesting with hitherto unrecognised neurological presentations in later life. Patients who present with parkinsonism and a strong family history of learning disability and autism may benefit from genetic testing for FMR1 mutation.

References: Jacquemont, S., Hagerman, R. J., Hagerman, P. J., & Leehey, M. A. (2007). Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurology, 6(1), 45-55

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fragile-x-syndrome-presenting-with-levodopa-unresponsive-parkinsonism/