Genetic Aspects of Myoclonus-Dystonia Syndrome (MDS).

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder with onset in the first two decades of life. Mutations in the epsilon-sarcoglycan gene (SGCE, DYT11) on chromosome 7q21-q31 represent the major genetic cause of M-D in some populations. The syndrome was related with mutations in two other genes (DRD2 and DYT1). A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet. In this review, we discuss genetic aspects of myoclonus-dystonia.

Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.

A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3.

The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

Síndromes postencefalíticos en la literatura médica española / Post-encephalitic syndromes in the spanish medical literature

Objetivo. Un gran número de pacientes de encefalitis letárgica desarrollaba diferentes síndromes postencefalíticos (SPE), de importante impacto medicosocial. Hemos estudiado los aspectos clínicos e históricos de los SPE en España, mediante una revisión de la literatura médica publicada en este país en el período 1918-1936. Desarrollo. No existen datos estadísticos sobre los SPE en España, aunque médicos españoles llamaron la atención sobre su alta prevalencia y su repercusión sociosanitaria. La mayoría de los 140 pacientes revisados (74%) presentaron parkinsonismo predominante, pero en casi todos se apreciaba algún rasgo parkinsoniano. Se describieron otros trastornos del movimiento (distonías focales, corea, mioclonías, crisis oculógiras, anomalías del ritmo respiratorio), así como trastornos del sueño, endocrinos y vegetativos. A menudo se comunicaron alteraciones psiquiátricas: la más frecuente era la bradifrenia asociada a parkinsonismo, pero fue muy característico un cuadro hipomaníaco con conducta impulsiva en jóvenes. El diagnóstico del SPE se realizó una media de dos años después del episodio de encefalitis letárgica aguda, aunque con frecuencia apareció inmediatamente después. En muchos trabajos se discute sobre la contribución de los SPE al desarrollo del conocimiento de la fisiopatología de las enfermedades extrapiramidales y sobre la implicación de los ganglios basales en los trastornos psiquiátricos y de conducta. Conclusiones. En ausencia de datos estadísticos, los autores españoles reflejaron la importante repercusión sociosanitaria de los SPE, así como su papel en el conocimiento de la fisiopatología de los ganglios basales. Predominaron los parkinsonismos, aunque se describieron todo tipo de manifestaciones postencefalíticas

Aim. A large number of patients with encephalitis lethargica developed different post-encephalitic syndromes (PES), which have an important medical and social impact. We studied the clinical and historical aspects of PES in Spain by reviewing the medical literature published in this country between 1918 and 1936. Development. There are no statistical data concerning PES in Spain, although Spanish physicians drew attention to their high rate of prevalence and their repercussions on community health. Most of the 140 patients that were reviewed (74%) presented predominant Parkinsonism, but some features of Parkinsonism were observed in nearly all cases. Other movement disorders (focal dystonias, chorea, myoclonus, oculogyric crises, abnormalities affecting breathing rate) were described, as well as sleep, endocrine and vegetative disorders. Psychiatric disorders were often reported, the most frequent being bradyphrenia associated to Parkinsonism, but a hypomanic picture with impulsive behaviour was very characteristic among young people. PES was diagnosed on average two years after the episode of acute encephalitis lethargica, although it often appeared immediately afterwards. Many studies discuss the contribution made by PES to further our knowledge of the pathophysiology of extrapyramidal diseases and about the involvement of the basal ganglia in psychiatric and behavioural disorders. Conclusions. Despite the absence of statistical data, Spanish authors highlighted the important repercussions the PES had on community health, as well as the role they played in extending our knowledge of the pathophysiology of the basal ganglia. Cases of Parkinsonism were predominant, although all kinds of post-encephalitic manifestations were reported

Early onset torsion dystonia (Oppenheim's dystonia).

Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities.

Onset and progression of primary torsion dystonia in sporadic and familial cases.

Four hundred and sixty records of patients with primary torsion dystonia (296 women and 164 men) were evaluated. The mean age at disease onset was 48.3 +/- 17.7 years; 13 patients carried the DYT1 CAG deletion. The distribution of age at onset was represented by a bi-modal curve, with a nadir at 21 year separating early onset from late onset cases. In 15.9% of cases there was a positive family history of dystonia. Cranial, cervical or lower limb onset was more common amongst women (M:F ratios were 1:2.7, 1:1.9, and 1:3); by contrast, onset in the upper limb was more common in men (M:F ratio 2.2:1). As expected, disease progression was more pronounced in cases with early onset; it was reckoned that onset at or above 32 years was associated with a negligible likelihood to progress to a generalized form. The mean age at onset of familial cases was 44.8 +/- 11.2 years, significantly lower than the mean age at onset of sporadic cases (53.5 +/- 13.4 years). Familial cases were characterized by more sites involved throughout disease course. Familial cases had a higher tendency to progress to a segmental or generalized form than sporadic cases.

Age at onset as a factor in determining the phenotype of primary torsion dystonia.

BACKGROUND: The genetic basis of most forms of primary torsion dystonia (PTD) is unknown; multiplex families are uncommon due to low penetrance. Intrafamilial, age-related, phenotypic heterogeneity was noted in 14 PTD families. The authors hypothesized that the clinical presentation of PTD was modulated by the age at onset of the dystonia, irrespective of the genotype. METHODS: This hypothesis was addressed in a study of 14 PTD families and a meta-analysis of 83 published series of PTD. RESULTS: In 12 families with adult-onset PTD, the index cases presented with cervical dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer's cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia. In the two other PTD families, the probands and all 10 symptomatic relatives had limb-onset dystonia at <20 years of age. There were differences between the median ages at onset of the different phenotypes (p = 0.0037). Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1 dystonia (11.3 years; 10.3 to 12.2), writer's cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm-oromandibular dystonia (55.7; 55.1 to 56.4). CONCLUSION: Phenotypic variation in PTD presentation is due to the effect of age at onset modulating the expression of a genetic disorder with a caudal-to-rostral change in the site of onset.

[Molecular-genetic analysis of torsion dystonia in Russia]. / Molekuliarno-geneticheskii analiz torsionnoi distonii v Rossii

For the first time in Russia, analysis of the GCH-I and DYT1 genes was carried out for the purpose of direct DNA diagnostics in families with various forms of hereditary torsion dystonia (TD). Four new missense mutations (Met102Lys, Thr94Lys, Cys141Trp, and Ser176Thr) in the GCH-I gene were found in patients with dopa-responsive dystonia (DRD), testifying to a genetic heterogeneity of this clinical form of TD. The distribution of the major del GAG mutation in exon 5 of the DYT1 gene was studied in patients with non-dopa-responsive dystonia (NDRD). In total, the mutation was found in 68% of the patients. The frequency of this mutation in Ashkenazi Jews with NDRD was 100% (twice higher than in Slavonic families), suggesting the founder effect reported for NDRD in this ethnic group. Mutations of the GCH-I and DYT1 genes were also found in patients with atypical and questionable cases of TD, which are difficult to diagnose with methods other than DNA analysis. The data obtained made it possible to extend the spectrum of clinical signs of DRD and NDRD and to revise the views on true penetrance of the corresponding mutant genes, which is important for medical genetic counseling in affected families.

Dystonia update.

Dystonia is a syndrome of sustained muscle spasms of presumed central nervous system origin. Recent advances in molecular biology have permitted clearer understanding of the genetics of various forms of dystonia and suggest pathophysiological deficits at the origin of the clinical signs. Treatment has involved centrally-acting drugs, specifically the anticholinergic medications, as well as peripherally acting agents that block neuromuscular transmission (botulinum toxin). Some forms of dystonia are particularly responsive to levodopa. A systematic approach to the diagnostic and treatment evaluation of dystonic patients permits optimal care for long-term management.

[Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. Apropos of a case]. / Traitement de la dystonie généralisée à début précoce par stimulation chronique bilatérale des globus pallidus internes. A propos d'un cas.

Dystonia musculorum deformans is an inherited severe disease, with a wide clinical polymorphism. The most severe clinical forms with early onset carry a high risk of life-threatening complications. In the absence of any efficient medical treatment, bilateral pallidotomy has previously been reported to be of value in the management of this disease. We report the first clinical case of a severe early-onset generalized dystonia dramatically improved by a bilateral stimulation of the internal globus pallidus. In November 1996, we proposed this neurosurgical procedure for a 8-year-old girl, who had suffered since the age of 3 from severe generalized dystonia, and who progressively became totally dependent and bedridden. She had been under sedation and permanent controlled respiratory assistance for the last two months. The etiology of the disease remained unknown (the DYT1 mutation was absent). Under general anesthesia, we bilaterally implanted a four-contacts electrode in the internal globus pallidus, using the Leksell's stereotactic frame and a 1.5 tesla MRI control. A dramatic improvement was noted 6 weeks later and led us to connect the two electrodes to neurostimulators inserted under the abdominal skin.

The TOR1A (DYT1) gene family and its role in early onset torsion dystonia.

Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on human chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junctions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N = 17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal region (N = 5), or in a representative Ashkenazic Jewish individual with late onset dystonia, who shared a common haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human genome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch.

Prevalence of focal dystonias in the western area of Tottori Prefecture in Japan.

We evaluated the prevalence of focal dystonias in the western area of Tottori Prefecture in Japan. The population of the area was 244,935 on October 1, 1992. Because four patients with blepharospasm and three patients with writer's cramp did not visit any hospitals or clinics in 1993 and did not reply to our question letter, we could not confirm their present condition: with or without focal dystonia in 1993. Four patients with facial dystonia including blepharospasm and oromandibular dystonia, seven with spasmodic torticollis, and four with writer's cramp were observed. The prevalence of focal dystonias was 6.12 per 100,000 persons, which may be lower than that in western countries. Although the reasons for this difference are still unclear, a genetic factor may be one implication.

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Laterality of onset in idiopathic torsion dystonia.

Idiopathic torsion dystonia (ITD) is a dominantly inherited disorder with incomplete penetrance. It is important to identify factors that may cause dystonia or prevent its occurrence in a genetically predisposed individual. Because dystonia may be precipitated by peripheral triggers, we have investigated whether the preferential use of a limb affects the development of dystonia. Analysis of the correlation between the side of motor dominance and the limbs in which dystonic symptoms first appeared was performed in 49 patients with ITD ascertained in a country-wide survey in Israel. The dominant motor side was determined in 45 cases (92%). Among 29 patients with lateralized limb onset, 24 showed right-side motor dominance, of whom 21 had dystonia onset in a right limb. The first sign was in a left limb for all five cases with left-side motor dominance (90% coincidence). The pattern of limb involvement was studied. Detection bias could be ruled out. The highly significant relationship between the motor dominance and the laterality of limb onset in ITD patients suggests that the preferred use of a limb may trigger the onset of dystonia.

Neuropathology of lubag (x-linked dystonia parkinsonism).

Lubag is an x-linked recessive dystonia parkinsonism that affects Filipino men originating principally from the Panay Island. Linkage analysis has confirmed the mode of inheritance and localized the disease gene to the proximal long arm of the x-chromosome. We studied the brain of a 34 year old Filipino man affected with lubag. He developed truncal dystonia at age 30, which subsequently generalized. With disease progression, he also presented with parkinsonism including, rigidity, bradykinesia, and impaired balance. His symptoms were largely unaffected by medication and, at age 34, he underwent a right cryothalamotomy. He died suddenly 2 days after the procedure. The principal neuropathological findings were neuronal loss and a multifocal mosaic pattern of astrocytosis restricted to the caudate and lateral putamen. Similar findings have been reported in two other men with dystonia--one Filipino and the other non-Filipino. The similar pathology of the two Filipino men suggests that this is the pathology of lubag. Recognition of this pathology in a non-Filipino man suggests that the mutation causing lubag may not be restricted to the Filipino population.

The autosomal dominant dystonias.

Dystonia is a term used to describe a specific set of abnormal movements that can occur as a symptom of a variety of neurologic disorders, but also as a disease entity in its own right. This review focuses on the primary dystonias and delineates the genetic contribution to these disorders. Included is a description of the well recognized forms of primary dystonias which manifest autosomal dominant inheritance, especially the "classic" type of early onset, generalized torsion dystonia, but also other clinically distinct forms such as myoclonic dystonia, paroxysmal dystonia, and DOPA-responsive dystonia. Also, a summary of the molecular genetic studies pertinent to these disorders and a discussion of the implications of recent genetic research for delineating the wide spectrum of this phenotypically and genetically heterogeneous group of diseases are forthcoming.

Inheritance of idiopathic torsion dystonia among Jews.

Idiopathic torsion dystonia (ITD) has long been considered to be genetically determined, but the pattern of inheritance has been unclear. It has been suggested that inheritance may differ in Jews and non-Jews. In the present study, data gathered in a nationwide survey of ITD in Israel were analysed. Between 1969 and 1980, 47 patients were collected, of whom 40 were of European origin. In these European Jews, the ITD frequency was about 1:23 000 live births, which was five-fold greater than in Jews of Afro-Asian origin. Assuming that all cases fit the same genetic model, an X linked or a simple autosomal recessive model of inheritance did not agree well with our data. An autosomal dominant model with low penetrance could have accounted for our observations and would yield an ITD gene frequency in European Jews of 3 to 4:100 000. In view of the increased ages of their fathers, the isolated cases may have included some new mutations. Multifactorial inheritance was also possible. However, it may be inappropriate to assume that all cases have the same genetic basis, or even that all are inherited.