AMA Publishing Group: Parkinson Disease/Parkinsonian Disorders Topic Collection

C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex C9orf72 Hexanucleotide Repeat Expansion in Guam

Dombroski BA, Galasko DR, Mata IF, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

High-prevalence foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) exist in Japanese on the Kii Peninsula of Japan and in the Chamorros of Guam. Clinical and neuropathologic similarities suggest that the disease in these 2 populations may be related. Recent findings showed that some of the Kii Peninsula ALS cases had pathogenic C9orf72 repeat expansions, a genotype that causes ALS in Western populations.

Objectives

To perform genotyping among Guam residents to determine if the C9orf72 expanded repeat allele contributes to ALS-PDC in this population and to evaluate LRRK2 for mutations in the same population.

Design and Setting

Case-control series from neurodegenerative disease research programs on Guam that screened residents for ALS, PDC, and dementia.

Participants

Study participants included 24 with ALS and 22 with PDC and 43 older control subjects with normal cognition ascertained between 1956 and 2006. All but one participant were Chamorro, the indigenous people of Guam. A single individual of white race/ethnicity with ALS was ascertained on Guam during the study.

Main Outcomes and Measures

Participants were screened for C9orf72 hexanucleotide repeat length. Participants with repeat numbers in great excess of 30 were considered to have pathogenic repeat expansions. LRRK2 was screened for point mutations by DNA sequencing.

Results

We found a single individual with an expanded pathogenic hexanucleotide repeat. This individual of white race/ethnicity with ALS was living on Guam at the time of ascertainment but had been born in the United States. All Chamorro participants with ALS and PDC and control subjects had normal repeats, ranging from 2 to 17 copies. No pathogenic LRRK2 mutations were found.

Conclusions and Relevance

Unlike participants with ALS from the Kii Peninsula, C9orf72 expansions do not cause ALS-PDC in Chamorros. Likewise, LRRK2 mutations do not cause Guam ALS-PDC.

A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies Glucocerebrosidase Mutations in DLB

Nalls MA, Duran R, Lopez G, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.

Objective

To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).

Design

We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.

Setting

Eleven centers from sites around the world performing genotyping.

Participants

Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.

Main Outcome Measures

Frequency of GBA1 mutations in cases and controls.

Results

We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores.

Conclusions and Relevance

Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.

Glucocerebrosidase Mutations Tipping Point Toward Parkinson Disease and Dementia? Glucocerebrosidase Mutations

Klein C, Krainc D. — Sat, 01 Jun 2013 00:00:00 GMT

The accumulation and aggregation of mutant proteins that are commonly observed in different neurodegenerative disorders is suggestive of a shared pathogenic mechanism. Recent data indicate that the elimination of the accumulation of mutant proteins can halt the symptomatic progression of neurodegeneration and can also lead to the regression of disease. This has been best demonstrated through conditional mouse models, in which the elimination of the expression of disease-linked proteins such as α-synuclein (SNCA) and mutant huntingtin resulted in a reversal of the pathological phenotype. The evidence is most compelling in Parkinson disease (PD) because clinical and genetic studies point to a clear dosage relationship between SNCA and disease. For example, a duplication of 1 of the 2 wild-type SNCA alleles can lead to parkinsonism similar to idiopathic PD in about one-half of the mutation carriers. However, 1 additional copy (triplication of 1 of the 2 wild-type alleles) confers full penetrance with clinical features that can encompass PD and dementia with Lewy bodies (DLB). Therefore, alterations in expression levels of SNCA are sufficient to cause a wide spectrum of disease. These findings hold promise for potential causative treatment approaches: if SNCA can somehow be cleared, the disease could possibly be reversed or even prevented. Clearance of aggregation-prone proteins is largely achieved through the autophagy-lysosomal system. However, one of the main challenges is to identify the specific mechanisms and targets involved in the clearance of these proteins in order to develop specific therapeutics. Recent studies of rare lysosomal storage disorders that commonly exhibit neurodegeneration and are caused by mutations in genes involved in lysosomal function have offered intriguing and novel insights into the pathogenesis of neurodegeneration.