Isolated and combined dystonia syndromes – an update on new genes and their phenotypes

Abstract

Recent consensus on the definition, phenomenology and classification of dystonia centres around phenomenology and guides our diagnostic approach for the heterogeneous group of dystonias. Current terminology classifies conditions where dystonia is the sole motor feature (apart from tremor) as 'isolated dystonia', while 'combined dystonia' refers to dystonias with other accompanying movement disorders. This review highlights recent advances in the genetics of some isolated and combined dystonic syndromes. Some genes, such as ANO3, GNAL and CIZ1, have been discovered for isolated dystonia, but they are probably not a common cause of classic cervical dystonia. Conversely, the phenotype associated with TUBB4A mutations expanded from that of isolated dystonia to a syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). Similarly, ATP1A3 mutations cause a wide phenotypic spectrum ranging from rapid-onset dystonia-parkinsonism to alternating hemiplegia of childhood. Other entities entailing dystonia-parkinsonism include dopamine transporter deficiency syndrome (SLC63 mutations); dopa-responsive dystonias; young-onset parkinsonism (PARKIN, PINK1 and DJ-1 mutations); PRKRA mutations; and X-linked TAF1 mutations, which rarely can also manifest in women. Clinical and genetic heterogeneity also characterizes myoclonus-dystonia, which includes not only the classical phenotype associated with epsilon-sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations. Thus, new genes are being recognized for isolated dystonia, and the phenotype of known genes is broadening and now involves different combined dystonia syndromes.

Youngest presenting patient with dystonia 24 and review of the literature

“…To date, there are 23 identified primary dystonia syndromes and, of these 23 DYTs, twelve have onset in childhood, adolescence, or young adulthood prior to the age of 30 (termed early‐onset): DYT1, DYT2, DYT4, DYT5, DYT6, DYT11, DYT13, DYT16, DYT17, DYT23, DYT24, DYT25 2, 12. The patient presented here carries a variant in the ANO3 gene which has previously been known to cause DYT24 which is a predominantly adult onset (although cases as early as 3‐4 years old) cause of tremor and craniocervical dystonia 11.…”

Estudo Genético nas Distonias Primárias: Recomendações do Grupo de Neurogenética do Centro Hospitalar São João

“…Deve ser oferecida a possibilidade de testar para a presença de mutações DYT-ANO3 (DYT24) aos doentes com distonia mioclónica DYT-SGCE negativa com história familiar de distonia cervical ou distonia com mioclonias, bem como aos doentes com tremor proeminente e distonia ligeira. [10][11][12] (recomendação do GNgen do CHSJ).…”

Recent developments in dystonia

“…Several subsequent commentaries have been published focusing on the rationale and clinical applications of these changes (8–10). The new definition places less emphasis on hypotonia as a core feature of dystonia.…”