Molecular characterisation of SGCE-associated myoclonus-dystonia ...

Molecular characterisation of SGCE-associated myoclonus-dystonia ...

Introduction 3

1.2 Dystonia

In 1897, Lluis Barraquer-Roviralta described a patient with generalized dystonia under the

term of athetosis (Barraquer-Roviralta, 1897), a term which was used earlier by William

Alexander Hammond. He had identified abnormalities in the structure of the basal ganglia in

his athetosis patients when he investigated their brain post-mortem (Hammond, 1871). These

findings and the twisting, sustained character and action exacerbation observed in dystonia as

well as athetosis aroused a first interest of clinicians and researchers for the peculiar brain

area. Focal dystonias were appreciated earlier than generalized dystonia and were categorized

as cramps or “occupational spasms.” In 1836 Johann Heinrich Kopp described the features of

writer’s cramp in his German medical monograph (Kopp, 1830-45). In 1908 the clinical

picture of dystonia was further expanded by Markus Walter Schwalbe who described the

hereditary pattern and progression of generalized torsion dystonia (Schwalbe, 1908). The term

dystonia” was introduced by Hermann Oppenheim in 1911 to reflect his conclusion that the

disorder was associated with a generalized abnormality of tone with coexistent hypo- and

hypertonia (Oppenheim, 1911).

To date, the prevalence of dystonia is estimated to be at least 10 per 100,000 persons in

different populations (Butler et al., 2004; Matsumoto et al., 2003). Several different

classification schemes have been used to categorize the various forms of dystonia. The

simplest classification of dystonia distinguishes primary and secondary forms: In the primary

form, dystonia (with the exception of tremor) is the only symptom of the disease, and the

cause is either unknown or genetic. In the secondary form, dystonia is usually one of several

disease manifestations and the cause is identifiable (e. g. lesion, drugs/toxins, metabolic

disorders). From those two a third form denominated as dystonia-plus syndromes is

distinguished. There are uncertainties about placing the dystonia-plus group that is considered

a special subcategory associated with, but not secondary to other types of movement disorders

(Klein, 2005).

In the past decade, monogenic defects have been found to underlie many forms of primary

dystonia and dystonia-plus syndromes. These monogenetic forms have recently been

classified according to the gene or gene loci involved. Currently, 15 different types of

dystonia are distinguished genetically, which are designated DYT1-13, DYT15 and DYT16

(Table 1). Six of these 15 dystonias are primary forms (DYT1, 2, 4, 6, 7, and 13). While three

types of the dystonias represent recessive or X-linked forms (DYT2, 3 and 5b), the majority

are inherited in an autosomal dominant fashion. Genes have been identified for seven (DYT1,

3, 5, 8, 11, 12 and 16), and the chromosomal location is known for another six forms (DYT6,

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