Recent advances in the molecular pathogenesis of dystonia-plus syndromes and heredodegenerative dystonias

Abstract

The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.

Keywords: Dystonia- plus syndrome; Mitochondria.; Molecular pathogenesis; Neurodegeneration; Secondary dystonia.

Fig. (1)

he biosynthetic pathway of dopamine. Tetrahydrobiopeterin (BH4) is generated from Guanosine triphosphate (GTP) by consecutive catalytic steps involving the enzymes GTP cyclohydrolase (GCH1), 6-pyrovoyl-tetrahydropetrin synthase (PTPS) and sepiapterin reductase (SR). A pool of BH4 is maintained by the action of Dihydropterine reductase (DHPR) and carbinaloamine-4a-dehydratase (PCD). Tyrosine Hydroxylase (TH) is dependent on BH4 to catalyze the first step in the biosynthesis of dopamine and Aromatic L-amino acid decarboxylase (AADC) generates Dopamine from its precursor L-dopa. Mutations in any of the underlined enzymes have been linked to DRD.