Dena Hernandez

Lewy bodies and parkinsonism in families with parkin mutations

Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early‐onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early‐onset Parkinsons disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2‐27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinsons disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early‐onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinsons disease.

Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians

We describe several families of African origin with SCA3/Machado‐Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L‐dopa–responsive Parkinsons disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis‐acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans‐acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.

Case-control study of the extended tau gene haplotype in Parkinson's disease

We investigated the association of Parkinsons disease with tau gene haplotypes. In a sample of 319 unrelated Parkinsons disease patients and 196 control subjects, we observed an increased risk of Parkinsons disease for persons with the H1/H1 genotype (odds ratio = 1.5; 95% confidence interval: 0.98–2.23); however, the finding was not statistically significant. The results remained similar after adjusting for the possible misclassification of progressive supranuclear palsy patients as Parkinsons disease, but became statistically significant after restricting the analysis to nondemented subjects.

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD

Mutations in DJ-1 are a cause of autosomal recessive parkinsonism. Polymorphism of genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson’s disease (PD). The authors analyzed whether a polymorphism (g.168_185del) within exon 1 of DJ-1 contributes to the risk of sporadic PD in a Finnish case-control series. This gene does not play a major role in the genetic predisposition to PD in this population.

Genetic analysis of synphilin-1 in familial Parkinson's disease.

alpha-Synuclein is present in Lewy bodies of patients with both sporadic and familial Parkinsons disease. However, pathogenic mutations Ala30Pro and Ala53Thr in alpha-synuclein are rare causes of disease. Synphilin-1 has been demonstrated to associate with alpha-synuclein and promote the formation of cytosolic inclusions in vitro. Two-point genetic linkage analysis of a dinucleotide repeat within the synphilin-1 gene initially implicated this locus as a cause of Parkinsons disease in three of nine families. However, subsequent haplotype, sequencing, and association analyses in these three families and an independent case-control series suggest that variability within the locus does not confer susceptibility to Parkinsons disease.

X‐linked dystonia (“Lubag”) presenting predominantly with parkinsonism: A more benign phenotype?

Lubag, or Filipino X-linked dystonia, typically presents with either pure dystonia (that inexorably becomes generalized) or combined dystonia-parkinsonism. We report on three cases of Lubag presenting with isolated parkinsonism without dystonia or late-onset dystonia and a slower course.

Additional file 7: Table S16. of Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe

All identified sentinel cis eQTLs. List of possible causal variant cis eQTL based on location and lowest p value including CAGE-cluster and SNPs chromosomal positions; gene ID; biotype class according to GENCODE; FDR values and RegulomeDB scores. (XLSX 419 kb)