Abstract Details

Title Classic Parkinson's Disease and Lewy Body Pathology Associated with a Heterozygous PARKIN Dosage Mutation

Topic Movement Disorders

Presentation(s) P05 - (-)

Poster/Presentation
Number 055

Objective

Background BACKGROUND: Only a single autopsy from a heterozygote PARKIN carrier with PD has been described, and no autopsy from a carrier of a heterozygote deletion has been reported in the English literature. The pathogenicity of heterozygous PARKIN mutations remains unclear but some evidence supports causality: dosage mutations seem to be more pathogenic than point mutations and age of onset correlates with number of mutations, even when comparing heterozygotes to controls. Lewy bodies are described in only 2 of 9 autopsies of homozygous or compound heterozygous PARKIN-associated PD cases.

Design/Methods DESIGN/METHODS: Clinical chart of a patient with familial PD and pathological findings are reviewed.

Results RESULTS: A 44-year-old man developed typical asymmetrical tremor-predominant PD. His symptoms progressed slowly and were levodopa-responsive. He developed dementia twenty-seven years after initial symptom onset. Dosage analysis performed using semi-quantitative multiplex polymerase chain reaction revealed a heterozygous PARKIN exon 3-4 deletion. Point mutations in the PARKIN gene were screened by denaturing high performance liquid chromatography and a custom genotyping array. The mutation segregates with disease in this multiplex family: two family members with early onset PD are compound heterozygotes. Post-mortem examination showed severe neuronal loss in the pars compacta of the substantia nigra and nucleus coeruleus with both Lewy bodies and Lewy neurites. Neuronal loss and Lewy bodies were also present in the amygdala but no pathological changes of Alzheimer's were present.

Conclusions CONCLUSIONS: A PARKIN exon 3-4 heterozygous deletion was found in our PD case with Lewy body pathology and late-onset dementia. The deletion was unlikely an incidental finding considering family history and age-at-onset.

Authors/Disclosures
Madeleine Sharp, MD PRESENTER	No disclosure on file
Karen S. Marder, MD, MPH, FAAN (Columbia University)	Dr. Marder has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Marder has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Marder has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Parkinson's Foundation . Dr. Marder has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CHDI. Dr. Marder has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC therapeutics. Dr. Marder has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer LTD. The institution of Dr. Marder has received research support from Vaccinex. The institution of Dr. Marder has received research support from Genentech. The institution of Dr. Marder has received research support from Triplet Therapeutics. The institution of Dr. Marder has received research support from Prilenia.
	No disclosure on file
Lorraine N. Clark, PhD (Columbia University)	No disclosure on file
	No disclosure on file
Roy Alcalay, MD (Columbia University)	Dr. Alcalay has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genzyme/Sanofi. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gain Therapeutics. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vanqua Bio. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biohaven. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Capsida. Dr. Alcalay has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Servier. The institution of Dr. Alcalay has received research support from Michael J. Fox Foundation. The institution of Dr. Alcalay has received research support from Parkinson's Foundation. The institution of Dr. Alcalay has received research support from Silverstein Foundation. Dr. Alcalay has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant with Parkinson's Foundation.
David Miller	No disclosure on file

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