Journal
MOVEMENT DISORDERS
Volume 25, Issue 12, Pages 1791-1800Publisher
WILEY
DOI: 10.1002/mds.23221
Keywords
parkinsonism; recessive; ATP13A2; PLA2G6; FBXO7; Spatacsin
Categories
Funding
- The Bachmann Strauss Foundation
- The Medical Research Council
- The Brain Research Trust
- Ataxia UK
- The BMA Vera Down Award
- Iran National Science Foundation
- National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000958-05]
- NIHR UCLH/UCL Comprehensive Biomedical Research Centre
- Medical Research Council [G0802760, G0701075] Funding Source: researchfish
- Parkinson's UK [G-0907] Funding Source: researchfish
- MRC [G0701075, G0802760] Funding Source: UKRI
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Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido- pyramidal syndrome. (C) 2010 Movement Disorder Society
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