Patricia de Carvalho Aguiar

Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Classification and genetics of dystonia

Dystonia is a syndrome characterised by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. The dystonic syndromes include a large group of diseases that have been classified into various aetiological categories, such as primary, dystonia-plus, heredodegenerative, and secondary. The diverse clinical features of these disorders are reflected in the traditional clinical classification based on age at onset, distribution of symptoms, and site of onset. However, with an increased awareness of the molecular and environmental causes, the classification schemes have changed to reflect different genetic forms of dystonia. To date, at least 13 dystonic syndromes have been distinguished on a genetic basis and their loci are referred to as DYT1 to DYT13. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances.

ε-Sarcoglycan mutations found in combination with other dystonia gene mutations

Myoclonus‐dystonia is a movement disorder associated with mutations in the ε‐sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus‐dystonia remain to be determined.

Narrowing the DYT6 dystonia region and evidence for locus heterogeneity in the Amish-Mennonites.

The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21‐q22 in two Amish–Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish–Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish–Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish–Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6‐linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21‐22 and does not account for all familial PTD in Amish–Mennonites.

Genetic and environmental findings in early‐onset Parkinson's disease Brazilian patients

Parkinsons disease (PD) etiology has been attributed both to genetic and environmental factors. In this study, we investigated Brazilian early‐onset PD (EOPD) patients for mutations in PARK2 and PARK8, exposure to environmental factors and possible correlations between PARK2 polymorphisms, environmental exposure, and disease age of onset. We enrolled 72 EOPD index patients and 81 healthy volunteers. Both groups were investigated for environmental exposure. EOPD patients were screened for PARK2 and PARK8 mutations. PARK2 coding polymorphisms Ser167Asn and Val380Leu were investigated in both groups. Mutations were present in 18% of the patients and in 32% of those with a positive family history. PARK2 mutations represented 12.5% and PARK8 mutations accounted for 5.5% of the mutations. A novel PARK2 mutation (D53X) was identified in 2 patients. A positive correlation was found between EOPD and well water drinking. In patients exposed to well water, a later age of onset was observed for those who carried at least one PARK2 380Leu allele. PARK2 mutations have an important role in EOPD Brazilian patients and PARK8 might be the second most important disease causing gene in this group. Well water drinking exposure represents a risk factor for EOPD and the PARK2 coding polymorphism Val380Leu might be interacting with environmental factors acting as a disease modifier.

Phenotypic spectrum and sex effects in eleven myoclonus‐dystonia families with ε‐sarcoglycan mutations

Myoclonus‐dystonia (M‐D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys (P < 0.0097). We found no association between mutation type and phenotype.

Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Objectives To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinsons Disease. Methods A retrospective study of genetic Parkinsons diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated. Results Scans were available from 37 cases of monogenetic Parkinsons disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinsons disease with GBA or LRRK2 mutations was greater than that for Parkinsons disease with alpha synuclein, PINK1 or Parkin mutations. Conclusions The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.

Inherited myoclonus-dystonia and epilepsy: Further evidence of an association?

Epilepsy and electroencephalogram (EEG) abnormalities have been considered exclusion criteria for the clinical diagnosis of myoclonus‐dystonia (M‐D). We report on the second M‐D family in which several clinically affected ϵ‐sarcoglycan gene (SGCE) mutation carriers have seizures in addition to myoclonus and dystonia, adding to the evidence that epilepsy and EEG abnormalities may form part of the phenotypic spectrum of the condition. A nonsense mutation in exon 3 (289C→T) of SGCE resulting in the insertion of a premature stop codon (R97X) was detected in affected members of this family.

Examination of the SGCE gene in Tourette syndrome patients with obsessive–compulsive disorder

Mutations in the ϵ‐sarcoglycan gene (SGCE) have been reported in families with myoclonus–dystonia (M‐D). In addition to abnormal movements, obsessive–compulsive disorder (OCD) has also been described in families with M‐D. OCD is a common feature in another movement disorder, namely Tourette syndrome (TS). The comorbidity of these disorders suggests that common genetic factors might be involved in their susceptibility. To evaluate this, we performed two sets of experiments. An association study using a polymorphism within an intron of the SGCE gene was assessed in patients with TS and OCD versus controls, and the SGCE gene itself was screened for mutations in all TS/OCD patients, followed by direct sequencing of the gene in a limited number of these patients. No correlation was found by either method.

Milestones in Friedreich ataxia: more than a century and still learning

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.