Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has ...not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinson's disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson's disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson's disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.
Purpose of Review
Since the advent of next-generation sequencing, the number of genes associated with dystonia has been growing exponentially. We provide here a comprehensive review of the latest ...genetic discoveries in the field of dystonia and discuss how the growing knowledge of biology underlying monogenic dystonias may influence and challenge current classification systems.
Recent Findings
Pathogenic variants in genes without previously confirmed roles in human disease have been identified in subjects affected by isolated or combined dystonia (
KMT2B
,
VPS16
,
HPCA
,
KCTD17
,
DNAJC12
,
SLC18A2
) and complex dystonia (
SQSTM1
,
IRF2BPL
,
YY1
,
VPS41
). Importantly, the classical distinction between isolated and combined dystonias has become harder to sustain since many genes have been shown to determine multiple dystonic presentations (e.g.,
ANO3
,
GNAL
,
ADCY5
, and
ATP1A3
). In addition, a growing number of genes initially linked to other neurological phenotypes, such as developmental delay, epilepsy, or ataxia, are now recognized to cause prominent dystonia, occasionally in an isolated fashion (e.g.,
GNAO1
,
GNB1
,
SCN8A
,
RHOBTB2
, and
COQ8A
). Finally, emerging analyses suggest biological convergence of genes linked to different dystonic phenotypes.
Summary
While our knowledge on the genetic basis of monogenic dystonias has tremendously grown, their clinical boundaries are becoming increasingly blurry. The current phenotype-based classification may not reflect the molecular structure of the disease, urging the need for new systems based on shared biological pathways among dystonia-linked genes.
OBJECTIVE:To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC).
METHODS:We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) ...who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue.
RESULTS:The c.1252C>T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic). The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend.
CONCLUSIONS:Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.
Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby ...horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12‐13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β‐tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β‐tubulin autoregulatory MREI (methionine–arginine–glutamic acid–isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild‐type β‐tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis. Ann Neurol 2013;73:546–553
Parkin Disease: A Clinicopathologic Entity? Doherty, Karen M; Silveira-Moriyama, Laura; Parkkinen, Laura ...
JAMA neurology,
05/2013, Letnik:
70, Številka:
5
Journal Article
Recenzirano
Odprti dostop
IMPORTANCE Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic ...reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE To investigate whether parkin -linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.
The NUS1 gene was recently associated with Parkinson's disease (PD) in the Chinese population. Here, as part of the International Parkinson's Disease Genomics Consortium, we have leveraged ...large-scale PD case-control cohorts to comprehensively assess damaging NUS1 variants in individuals of European descent. Burden analysis of rare nonsynonymous damaging variants across case-control individuals from whole-exome and -genome data sets did not find evidence of NUS1 association with PD. Overall, single-variant tests for rare (minor allele frequency<0.01) and common (minor allele frequency>0.01) variants, including 15 PD-GWAS cohorts and summary statistics from the largest PD GWAS meta-analysis to date, also did not uncover any associations. Our results indicate a lack of evidence for a role of rare damaging nonsynonymous NUS1 variants in PD in unrelated case-control cohorts of European descent, suggesting that the previously observed association could be driven by extremely rare population-specific variants.
Dystonia is a clinically, genetically, and biologically heterogeneous hyperkinetic movement disorder caused by the dysfunctional activity of neural circuits involved in motor control. Our ...understanding of the molecular mechanisms underlying dystonia pathogenesis has tremendously grown thanks to the accelerated discovery of genes associated with monogenic dystonias (DYT-genes). Genetic discoveries, together with the development of a growing number of cellular and animal models of genetic defects responsible for dystonia, are allowing the identification of several areas of functional convergence among the protein products of multiple DYT-genes. Furthermore, unexpected functional links are being discovered in the downstream pathogenic molecular mechanisms of DYT-genes that were thought to be unrelated based on their primary molecular functions. Examples of these advances are the recognition that multiple DYT-genes are involved in (1) endoplasmic reticulum function and regulation of the integrated stress response (ISR) through Eukaryotic initiation factor 2 alpha signaling; (2) gene transcription modulation during neurodevelopment; (3) pre-and post-synaptic nigrostriatal dopaminergic signaling; and (4) presynaptic neurotransmitter vesicle release. More recently, genetic defects in the endo-lysosomal and autophagy pathways have also been implicated in the molecular pathophysiology of dystonia, suggesting the existence of mechanistic overlap with other movement disorders, such as Parkinson’s disease. Importantly, the recognition that multiple DYT-genes coalesce in shared biological pathways is a crucial advance in our understanding of dystonias and will aid in the development of more effective therapeutic strategies by targeting these convergent molecular pathways.
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