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.
In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients ...an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in
SOD1
,
FUS
,
TARDBP
,
ANG
,
OPTN
, and
C9ORF72
. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247;
p
< 0.01). Among patients with OCBs, two patients had the
TARDBP
p.A382T mutation (one of which in homozygous state), and one the
ANG
p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both
TARDBP
and
ANG
genes may disrupt the blood–brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant
TARDBP
and
ANG
genes on BBB integrity of ALS patients warrants further investigation.
Abstract Churg-Strauss syndrome (CSS) is a rare systemic vasculitis, almost invariably accompanied by asthma, nasal polyposis, paranasal sinus abnormalities, and increased peripheral blood eosinophil ...count. Neurological involvement as peripheral neuropathy is a common feature, whereas cerebral involvement is extremely rare. Herein, we report the case of a young man who presented with sudden onset of right-side emiparesis and aphasia, whose head CT scan showed the presence of large haemorrhage in the left striatum nucleus involving part of the temporal lobe. Based on clinical and laboratory findings (asthma, eosinophilia > 10%, paranasal sinus abnormalities and mononeuritis multiplex) a diagnosis of CSS was made. Cerebral angiography resulted normal, excluding the presence of vascular malformations or signs of vessel abnormalities. Pharmacotherapy with (intravenous and afterwards oral) corticosteroid and immunosuppressors (cyclophosphamide and then azathioprine) was initiated. The outcome was good with neurological follow-up showing a nearly complete recover. Our case points out that intracerebral haemorrhage can be, despite rare, a presenting feature of CSS. Previously reported patients affected by cerebral haemorrhage and CSS are summarized and briefly reviewed.
ABSTRACT
Background
Myoclonus‐Dystonia syndrome (M‐D) is an autosomal‐dominant movement disorder related to SGCE gene pathogenic variants. Although there can be observed variability in clinical ...findings, here we describe intrafamilial variability in a Turkish family with a novel nonsense SGCE pathogenic variant.
Methods
A family with variable clinical symptoms resembling M‐D were referred to our clinic. After preliminary diagnosis, patients were tested for mutations in the SGCE gene by Sanger sequencing.
Results
Novel pathogenic heterozygous nonsense mutation in exon 3, c.272T>G; p.Leu91* (NM_003919.2) were observed in affected family members.
Conclusion
Intrafamilial clinical variability, despite the same pathogenic variant described in this work, suggests that there are regulatory factors, epigenetic or environmental modifiers, which are the subject of a matter for future studies.
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The aim of the study was to describe the effects of aripiprazole, a new atypical antipsychotic drug that acts as a partial dopamine agonist on motor, behavioral and cognitive functions in patients ...with genetically confirmed Huntington's disease (HD).
Three HD patients were evaluated for Unified Huntington Disease Rating Scale part I and II and Beck Depression Inventory at baseline, after two months and one-year treatment. Aripiprazole effectively controlled involuntary movements and psychiatric symptoms, with effects on cognitive functions.
Our case reports suggest that aripiprazole is well tolerated, remarkably improving some of the motor and behavioral symptoms in patients affected by HD. Randomized, controlled, long-term studies are warranted.
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Neurodegeneration with brain iron accumulation (NBIA) mostly has its disease onset in childhood, adolescence, or early adulthood and usually presents with predominant ...bulbar and axial dystonia along with signs such as spasticity, indicating an involvement of additional neurological systems. Because of their early onset and presentation with a combination of dystonia plus other neurological symptoms, they are usually not considered as differential diagnosis for late‐onset isolated (idiopathic) craniocervical dystonia. In this case series, we present 4 genetically proven cases of NBIA (including neuroferritinopathy, pantothenate‐kinase‐associated neurodegeneration, and aceruloplasminemia) with late disease onset, which resembled isolated adult‐onset craniocervical dystonia at disease onset. We also want to highlight the importance of taking NBIA into consideration when dealing with putatively isolated late‐onset dystonias and of picking up unusual signs at later stages of the disease.
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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.
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