Objective: To characterize a patient with GBAand ATP13A2gene mutations.

Background: Mutations of GBA(Glucocerebrosidase) and ATP13A2(P5-ATPase) genes are risk factors for Parkinson’s disease (PD). Homozygous mutations of these genes cause rare, early onset disorders: Gaucher disease (GD) and Kufor-Rakeb syndrome (KRS), respectively. We describe a patient with young onset PD and heterozygous mutations ofthese genes. Given that supranuclear gaze palsy (SGP) is characteristic of GD (horizontal SGP) and KRS (vertical SGP) disease, detailed eye movement analysis was performed.

Method: A 28 year-old woman of Ashkenazi Jewish (AJ) ancestry developed left hand tremor at age 23 and was diagnosed with PD. DaTScan was positive. Levodopa response was satisfactory, but she soon developed motor fluctuations and dyskinesia. Early age of onset, despite a negative family history, prompted genetic testing. Clinical and video-oculographic (VOG) (EyeLink 1000+) eye movement assessments were completed.

Results: Metabolic/neurological genetic panel for disorders common in AJ population and Invitae PD panel showed heterozygous pathogenic mutations of the GBA(N370S) and the ATP13A2(3057delC) gene. Clinical exam revealed convergence insufficiency, motor impersistence with difficulty maintaining fixation, and a suggestion of subtle vertical (downward) saccade slowing (though with intact optokinetic downward quick phases). Motor impersistence was confirmed by VOG. Smooth pursuit, antisaccades and self-paced saccades were abnormal, and large vertical saccades were low in frequency. Larger vertical and horizontal saccades were at the lower limits of normal for saccadic velocity, but definitive SGP was not evident.

Conclusion: A growing number of pathogenic genetic mutations have been identified in familial and sporadic PD, some of which only represent risk factors, such as GBAand ATP13A2. Both of these genes are important for membrane trafficking and for the endo-lysosomal compartment. We suspect the ‘double hit’ to the same metabolic pathway is responsible for the phenotype of our patient. Screening for multiple genetic mutations should be considered, especially in early onset PD, to improve understanding of the pathogenic mechanisms. The lack of classic SGP, as seen here, is likely due to milder clinical effects of heterozygous mutations, though eye movements were abnormal and monitoring for future SGP evolution is warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-and-atp13a-mutation-and-pd-clinical-phenotype-eye-movements-and-pathogenic-implications/