Leber's hereditary optic neuropathy with dystonia in a Japanese family
Introduction
The combination of progressive dystonia and optic atrophy is extremely rare, although dystonia is the movement disorder most commonly encountered after parkinsonism [1]. Primary hereditary dystonia associated with the DYT1 gene is the most severe and common form of hereditary dystonia. It is inherited in an autosomal dominant fashion with almost all cases resulting from a deletion of GAG triplets that removes one glutamate codon in the ATP binding protein, torsinA [2]. Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease causing acute or subacute bilateral blindness and occurs predominantly in young males [3]. An association between LHON and various neurological diseases has been suggested and referred to as a Leber's plus [4]. Since a number of the mitochondrial DNA (mtDNA) mutations have been reported to be associated with LHON [5], a mtDNA defect may also underlie the etiology of a disorder consisting of Leber's like optic neuropathy and dystonia. Indeed, mtDNA mutations have been identified in some of these families [6], [7], [8].
We studied two sisters with generalized dystonia, which was reported previously as familial torsion dystonia [9], and late-onset optic neuropathy using molecular genetic analysis.
Section snippets
Pedigree
After obtaining informed consent, we studied a three generation pedigree with members affected by progressive dystonia, optic neuropathy and schizophrenia. The pedigree numbers, clinical features and ages of individuals in this study are shown in Fig. 1.
Patient 1
K.U., the fifth child of the family (proband), was born after an uneventful pregnancy and delivery. The proband is a 40-year-old female, of small stature (130 cm). She showed an onset of mild manifestations of focal dystonia (distal portion of
Results
We identified a total of 42 nucleotide substitutions from the reference sequence. The majority of the substitutions were silent mutations or reported as normal polymorphisms according to a human mitochondrial genome database [11]. Three substitutions were examined for their frequency in a population of 200 healthy Japanese and the A14605G substitution was identified as a polymorphism (Table 1). The substitutions, A3203G in 16S rRNA and G14459A in NADH dehydrogenase subunit (ND) 6, were absent
Discussion
The clinical features of the patients in this Japanese family include progressive generalized dystonia, which was attributed to striatal degeneration, optic atrophy, mental retardation and deterioration, short stature, corticospinal tract sign and psychiatric disorder. Both patients had been diagnosed as familial torsion dystonia [9]. Initially, we examined the DYT1 gene, a mutation in which causes the most severe and common form of early-onset hereditary dystonia [12]. However, we were unable
Acknowledgements
We thank Dr. M. Segawa for performing the DNA diagnosis for DYT1.
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