A Peruvian family with a novel PARK2 mutation: Clinical and pathological characteristics

Abstract

Background Mutations in PARK2 result in autosomal recessive young onset Parkinson’s disease (YOPD). Although there have been a number of reports on the clinical characteristics of PARK2-related PD, there is limited information available on the associated neuropathologic changes. Design We describe the clinical and pathological characteristics of a Peruvian family with YOPD. The proband and one unaffected sibling were screened for PARK2 dosage and point mutations. One affected sibling had detailed neuropathologic examination. Setting Instituto Nacional de Ciencias Neurologicas (INCN) in Lima, Peru Results The proband and two of her four siblings developed YOPD and both parents were unaffected. The clinical course has been characterized by akinetic-rigid parkinsonism predominantly affecting the lower limbs and dyskinesias. Analysis of PARK2 showed that the proband is compound heterozygous for a novel acceptor splice site mutation in intron 5 (IVS5-1G>A) and an exon 7 deletion. Neuropathologic assessment of an affected sibling revealed severe neuronal loss in the substantia nigra (SN) and loss of tyrosine hydroxylase immunopositive fibers in the striatum. No Lewy body pathology was observed using standard histology or immunohistochemistry for α-synuclein. Conclusions Consistent with most neuropathologic reports of patients with PARK2 mutations, we did not observe Lewy body inclusions, despite marked SN degeneration and severe dopaminergic denervation of the striatum. These data describe a novel splice site mutation and further extend the clinicopathological characterization of PARK2-associated PD.

Neurogenética en el Perú, ejemplo de investigación traslacional

“…El hallazgo inesperado de la alta frecuencia del polimorfismo Q1111H en el gen LRRK2 en población mestiza peruana, permitió desestimar este polimorfismo como un factor de riesgo para EP (23) ; 3). El descubrimiento de potenciales nuevas mutaciones asociadas a EP familiar, como la encontrada en tres hermanos portadores en el gen PARK2 en tres hermanos prtadores (24) ; y 4). La descripción del caso de una mujer peruana de edad avanzada asintomática, portadora de la mutación R1441G en el gen LRRK2, que apoya la hipótesis de una penetrancia variable de esta mutación (25) .…”

A Case of Parkinson’s Disease with No Lewy Body Pathology due to a Homozygous Exon Deletion in Parkin

“…The clinical spectrum of Parkin -associated PD has been widened by different phenotypes including cervical dystonia, autonomic dysfunction, and peripheral neuropathy [ 8 ]. Increasing number of studies has reported autopsy findings in Parkin mutations carriers, in most cases with isolated neuronal loss in SNpc and no diffuse LB pathology [ 9 – 18 ]. A few studies have reported the presence of LBs in Parkin patients, mainly in compound heterozygous [ 10 , 19 – 21 ] and in two cases with homozygous mutation carriers [ 22 , 23 ].…”

The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot

“…We excluded those variants that did not meet standard quality values, had a minor allele frequency >1% in the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org), or were classified as low impact by SnpEff prediction tools [Cingolani et al, ]. In addition, SNCA , PARK2 , PINK1 , and PARK7 were screened for copy number variation using multiplex ligation‐dependent probe amplification (MLPA; MRC‐Holland, Amsterdam, Netherlands) as previously described [Cornejo‐Olivas et al, ].…”