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. 2010 Sep 15;25(12):1791-800.
doi: 10.1002/mds.23221.

Early-onset L-dopa-responsive Parkinsonism With Pyramidal Signs Due to ATP13A2, PLA2G6, FBXO7 and Spatacsin Mutations

Free PMC article

Early-onset L-dopa-responsive Parkinsonism With Pyramidal Signs Due to ATP13A2, PLA2G6, FBXO7 and Spatacsin Mutations

Coro Paisán-Ruiz et al. Mov Disord. .
Free PMC article


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.

Conflict of interest statement

Potential conflict of interest: Nothing to report.


FIG. 1
FIG. 1
Pedigrees of families reported here. Manifesting members are shown in bold. A: PLA2G6 family, B: ATP13A2 family, C and D: FBXO7 families. m/m: homozygous mutation carriers, wt/m: heterozygous mutation carriers, wt/wt: homozygous carriers for the wild type sequence.
FIG. 2
FIG. 2
Histological and ultrastructural analysis of the sural nerve biopsy of Family B (ATP13A2): Paraffin sections (A, B, C) show a reduction of myelinated fibre density with frequent formation of myelin digestion chambers (arrows) (A). Immunohistochemical staining for CD68 on a transverse section shows frequent endoneurial macrophages (B), a characteristic finding in florid axonal neuropathies. Very occasionally, there were endoneurial and scattered epineurial T-cells (CD3 immunohistochemistry; C). Resin semi thin sections (D, E, F) show a mild generalized axon loss, subperineurial, and endoneurial oedema (D) and significant numbers of degenerating axons (E, blue arrow). Strikingly, there are numerous small cytoplasmic inclusion (E, red arrows and F, red arrows). These inclusions were found in the endoneurium, in smooth muscle cells of vessels and in the perineurium. Electron microscopy (G, H, I) confirms the presence of electron dense inclusions of circa 1 μm size, which are always located intracellularly, and are most frequently seen in the cytoplasm of Schwann cells (G, red arrows) and in smooth muscle cells (H, I). Scale bar 40 μm (E, F), 60 μm (A, C), 120 μm (B), 230 μm (D).

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