Refinement of the DYT15 locus in myoclonus dystonia.

Inherited myoclonus dystonia (MD) is an autosomal dominant disorder in which we previously mapped a novel locus to chromosome18p11 (OMIM number: 607488). Since no further informative STS markers were found within the flanking shared regions, we utilized single nucleotide polymorphisms (SNP) for fine-mapping. All known or predicted genes within this region were directly sequenced. We identified three recombinant SNPs in the distal region but none from the proximal region. Our previous linked region has now been reduced to 3.18 Mb but direct sequencing of all seven known and four predicted genes with EST support did not identify any mutations..     

Analysis of the epsilon-sarcoglycan gene in familial and sporadic myoclonus-dystonia: evidence for genetic heterogeneity.

The epsilon-sarcoglycan gene (SGCE) on human chromosome 7q21 has been reported to be a major locus for inherited myoclonus-dystonia. Linkage to the SGCE locus has been detected in the majority of families tested, and mutations in the coding region have been found recently in families with autosomal dominant myoclonus-dystonia. To evaluate the relevance of SGCE in myoclonus-dystonia, we sequenced the entire coding region of the epsilon-sarcoglycan gene in 16 patients with either sporadic or familial myoclonus-dystonia. No mutations were found. This study suggests that epsilon-sarcoglycan does not play an important role in sporadic myoclonus-dystonia and supports genetic heterogeneity in familial cases.     

Epidemiology of primary dystonias in Japan: comparison with Western countries.

We performed epidemiological studies of primary dystonia in the city of Kyoto. The prevalence was at least 10.1 per 100,000 persons, which was similar to that in Western countries. Facial dystonia was more common than other types, which contrasts with that reported in Europe. Age of onset for both genders was in agreement with that in other countries.     

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. © 2007 Movement Disorder Society     

Clinical and molecular genetic evaluation of patients with primary dystonia

Primary dystonia is a movement disorder characterized by involuntary and sustained muscle contractions causing twisting or abnormal postures and mutations in several genes have been identified. Our goal was to investigate, whether the clinical presentation would differ between patients with a positive family history, and patients without. Furthermore, we have performed mutation analysis in the subgroup of patients with a positive family history. A total of 175 patients with primary dystonia were evaluated. Data on gender, presence and frequency of pain and tremor, age of onset, and the distribution of affected body parts were compared between patients with positive and negative family history. All exons of the torsion dystonia 1, GTP cyclohydrolase 1 and epsilon-sarcoglycan genes were examined in 40 patients by SSCP analysis of PCR products followed by sequencing of variant conformers. Dystonia patients with a positive family history of dystonia had an earlier age of onset and those with a positive family history of tremor more often associated tremor than those with a negative family history. Four new polymorphisms in the epsilon-sarcoglycan gene were found and others confirmed, but no known or new mutations could be detected. Our study supports the notion that primary dystonia is a genetically heterogeneous disease.     

Epidemiology of primary focal dystonias in the western area of Tottori prefecture in Japan: Comparison with prevalence evaluated in 1993.

An epidemiological survey of primary focal dystonias in the western area of Tottori Prefecture in Japan was conducted in 2003, and the results were compared with those of a previous survey in 1993. The service-based prevalence of primary focal dystonia was 13.7 per 100,000 population, representing an increase from that found in the 1993 survey. In 1997, botulinum toxin type A was approved for use in Japan to treat blepharospasm, and the increased number of patients now being evaluated and diagnosed with focal dystonias at medical centers throughout Japan may be responsible for this increased prevalence. Prevalence by subtype per 100,000 population was as follows: facial dystonia, 6.5; spasmodic torticollis, 2.0; writer's cramp, 4.4; and other focal dystonias; 0.8. Facial dystonia showed the most marked increase in service-based prevalence among these subtypes.     

Large deletions account for an increasing number of mutations in SGCE

Myoclonus‐dystonia (M‐D) (MIM 159900) is a rare “dystonia plus” syndrome, characterized by rapid myoclonic jerks, predominantly in the neck and upper limbs, in combination with dystonia. Mutations in the gene ε‐sarcoglycan (SGCE) are known to be responsible for approximately one‐third of cases. We screened 21 probands diagnosed with M‐D for large deletions who were mutation negative as determined by PCR‐direct sequencing. Multiplex PCR and quantification of PCR products was performed using a modified application of denaturing high performance liquid chromatography (dHPLC). We have identified two novel large multiexonic deletions of SGCE, which were confirmed by amplifying and sequencing the deletion breakpoints. Five other families were found to harbor small mutations identified by direct sequencing. Analysis of the region surrounding the deletions demonstrates that both deletions are the result of nonhomologous recombination with homologous end joining. This is only the second report of intragenic deletions with SGCE and it highlights the need to include exonic copy number variation when performing mutational analysis of SGCE. © 2007 Movement Disorder Society     

No muscle involvement in myoclonus-dystonia caused by ɛ-sarcoglycan gene mutations

Mutations in the ɛ-sarcoglycan gene ( SGCE ) can cause autosomal dominant inherited myoclonus-dystonia (M-D). Defects in other sarcoglycans; α-, β-, γ-, and δ can cause autosomal recessive inherited limb girdle muscular dystrophies. ɛ- and α-sarcoglycans are very homologous and may substitute for one-another in different tissues. We therefore investigated whether mutations in SGCE also cause abnormalities of skeletal and myocardial muscle.
Six patients with clinically and genetically verified M-D and no signs of limb-girdle muscular dystrophy were included. Skeletal muscle biopsies were obtained from all patients, and endomyocardial muscle biopsy from one of the patients. Morphological and immunohistological investigations were performed and compared with controls.
Histological and immunohistological investigations of muscle and clinical assessment of muscle strength and mass showed no difference between M-D patients and controls.
Our findings indicate that patients with M-D have no signs or symptoms of muscle disease. This suggests a different role of the sarcoglycan complex ɛβγδ versus αβγδ complex in humans, as earlier suggested in rodents.     

A novel conserved mutation in SGCE gene in 3 unrelated patients with classical phenotype myoclonus–dystonia syndrome

Abstract

Objective and importance: Myoclonus–dystonia syndrome (MDS, DYT11) is an inherited disorder characterized by clinical and genetic heterogeneity. MDS is inherited in autosomal dominant pattern and caused by heterozygous mutations in the gene encoding epsilon-sarcoglycan (SGCE) on chromosome 7q21. SGCE gene mutations are present in about 30–50% patients classified as definite-MDS. Earlier onset of motor symptoms is indicated in MDS patients who are SGCE mutations carriers. We present clinical phenotype of three unrelated MDS patients bearing novel, not described yet, mutation in SGCE gene.

Clinical presentation: Presence of a substantial mutation in exon 3, changing aspartic acid to asparagine in codon 96 (D96N) of SGCE protein has been revealed. Three unrelated individuals, bearing the same mutation have diversity of symptoms, with some common features. Age of onset of our patients differs: 2, 14 to 38 years of age.

Intervention/technique: Detection of mutations in SGCE gene was performed via direct sequencing of SGCE gene.

Conclusions: Our results confirm the role of the SGCE gene in the pathogenesis of MDS and call into question the impact of SGCE mutations on the age of onset. The existing list of known mutations and diversity of symptoms in patients bearing the same mutation indicates that there is a lack of genotype–phenotype correlation. Heterogeneity of disease indicates necessity for further research in order to find the molecular fingerprint which may be a landmark in diagnostic studies of MDS.     

Myoclonus-dystonia syndrome with severe depression is caused by an exon-skipping mutation in the epsilon-sarcoglycan gene.

We describe two affected individuals in a family with myoclonus-dystonia syndrome complicated with severe depression. One individual committed suicide. Molecular genetic analysis revealed a heterozygous point mutation in the epsilon-sarcoglycan gene, which we show leads to skipping of exon 5. This report suggests that the psychiatric spectrum of MDS includes more severe depression.     

A neurophysiological study of myoclonus in patients with DYT11 myoclonus‐dystonia syndrome

Mutations in the ?‐sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus‐dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11‐MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 ± 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo‐rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle‐like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long‐loop reflexes were normal, as was silent period and long‐term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short‐term intracortical inhibition revealed subtle impairment, and event‐related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11‐MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11‐MDS may justify the involvement of different brain areas. © 2008 Movement Disorder Society     

Relative risk of spread of symptoms among the focal onset primary dystonias.

Adult-onset primary torsion dystonia (PTD) may spread to multiple body parts, but the relative risk of spread by site of onset of dystonia has not been well characterized. We retrospectively identified 602 patients with PTD out of 1,500 dystonia patients in our electronic database and extracted age at onset, site of onset, family history, and spread. Survival analyses were performed for groups based on site of onset, and hazard ratios compared relative risk of spread across groups. Patients with adult-onset blepharospasm were more likely to spread (31% past the head) than those with dystonia starting in the neck (9%), larynx (12%), or upper extremities (16%). Hazard ratios proved that the blepharospasm group had the greatest relative risk of spread. The rate of spread after onset varied significantly between the different groups. Most spread occurred in the first 1 to 2 years after onset of blepharospasm, whereas the risk of spread was relatively constant over time in cervical and laryngeal dystonia. Different sites of onset of PTD confer different risks of spread, important for clinical prognosis. Different risks of spread may provide clues about underlying pathogenesis of adult-onset primary dystonias.     

Novel Italian family supports clinical and genetic heterogeneity of primary adult-onset torsion dystonia.

We report on an Italian kindred with adult-onset primary torsion dystonia (PTD). A detailed clinical examination of the six definitely affected family members revealed a mild, purely focal phenotype. The disease involved only one body part (eyes, neck, or arm). PTD in this family was not linked to the known disease loci (DYT1, DYT6, DYT7, and DYT13), and the 3-bp deletion in the DYT1 gene was also excluded. These findings support genetic heterogeneity of PTD and indicate that a novel unassigned gene is responsible for focal dystonia in this family.     

A novel mutation of the ε‐sarcoglycan gene in a Chinese family with myoclonus‐dystonia syndrome

In a Chinese myoclonus‐dystonia syndrome (MDS) family presented with a phenotype including a typical MDS, cervical dystonia, and writer's cramp, genetic analyses revealed a novel 662 + 1insG heterozygous mutation in exon 5 in the ε‐sarcoglycan (SGCE) gene, leading to a frameshift with a down stream stop codon. Low SGCE mRNA levels were detected in the mutation carriers by real‐time PCR, suggesting that the nonsense mutation might interference with the stability of SGCE mRNA. This is the first report on Chinese with a SGCE mutation leading to MDS. Our data support the fact that same mutation of SGCE gene can lead to a varied phenotype, even in the same family. © 2008 Movement Disorder Society     

Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients

OBJECTIVES: Dystonia is a common movement disorder. The purpose of this study is to examine the relative distribution of the primary dystonia subtypes and identify mutation (s) in the DYT1 gene in Indian patients. MATERIALS AND METHODS: Primary dystonia patients (n = 178) and controls (n = 63), lacking any symptoms of the disease, were recruited for the study from eastern India. The nucleotide variants in the DYT1 gene were identified by carrying out polymerase chain reaction, single stranded conformation polymorphism, and DNA sequencing. RESULTS: Unlike other reports, pain and/or tremor was more common in our sporadic patients than in familial cases. Three reported and two novel changes were identified in this gene. The homozygous genotype (G,G) for a missense variant (c.646G > C; Asp216His) was significantly over-represented in the patients compared with controls (P < 0.05). However, the commonly reported 3 bp deletion (904-906delGAG) was not detected. CONCLUSION: Our results suggest that the DYT1 gene might have a limited role in causation of dystonia in the Indian population.     

Clinical and genetic features of myoclonus-dystonia in 3 cases: a video presentation.

Many cases of myoclonus-dystonia (M-D) are caused by mutations in the epsilon-sarcoglycan (SGCE) gene. We describe 3 children with a similar clinical picture of autosomal dominant M-D and an SGCE mutation in only one of them, suggesting that M-D is genetically heterogeneous.     

Phenotypic characterization of DYT13 primary torsion dystonia.

We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD.