Leber's hereditary optic neuropathy with dystonia in a Japanese family

doi:10.1016/j.jns.2005.11.003

Journal of the Neurological Sciences

Volume 243, Issues 1–2, 15 April 2006, Pages 31-34

https://doi.org/10.1016/j.jns.2005.11.003 Get rights and content

Abstract

We investigated a Japanese family with generalized dystonia attributed to striatal degeneration, which occurred in childhood, and late-onset optic neuropathy. We determined the entire nucleotide sequence of mitochondrial DNA (mtDNA) from the proband and compared our findings with the 2001 Revised Cambridge Reference Sequence. The mtDNA of the proband showed a total of 42 nucleotide changes. We identified two A3203G and G14459A mutations, which were completely absent in a population of 200 healthy Japanese, by estimating the frequency of each nucleotide change. The nucleotide G14459A mutation occurs in NADH dehydrogenase subunit 6, and has been suggested previously as the disease-causing mutation in Hispanic, African–American and Caucasian families of Leber's hereditary optic neuropathy (LHON) and/or dystonia. The significance of the A3203G mutation remains unknown. To our knowledge, this is the first case of LHON with dystonia that revealed a mtDNA mutation 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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Neurometabolic causes of dystonia are heterogenous and can be challenging to diagnose, yet many of these disorders are potentially treatable. The first step in the workup is to clinically phenotype the underlying condition, followed by ordering selected diagnostic tests based on the clinician's judgement and clinical suspicion. In this review, we highlight the diagnostic clues to various disorders, including lysosomal storage diseases, mitochondrial cytopathies, metal storage disorders, organic acidurias, disorders in carbohydrate metabolism, neurotransmitter diseases and vitamin and cofactor deficiencies. We discuss key diagnostic clues to the presence of these conditions, as well as currently available treatments. We highlight that recognition and characterization of these secondary causes of dystonia facilitate their management, including possible treatment of the underlying neurometabolic disorder.
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MON in MIDs is more frequent than usually anticipated. MON may occur in specific as well as non-specific MIDs. In specific and non-specific MIDs, MON may be a prominent or non-prominent phenotypic feature and due to mutations in genes located either in the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). Clinically, MON manifests with painless, bilateral or unilateral, slowly or rapidly progressive visual impairment and visual field defects. In some cases, visual impairment may spontaneously recover. The most frequent MIDs with MON include LHON due to mutations in mtDNA-located genes and autosomal dominant optic atrophy (ADOA) or autosomal recessive optic atrophy (AROA) due to mutations in nuclear genes. Instrumental investigations for diagnosing MON include fundoscopy, measurement of visual acuity, visual fields, and color vision, visually-evoked potentials, optical coherence tomography, fluorescein angiography, electroretinography, and MRI of the orbita and cerebrum. In non-prominent MON, work-up of the muscle biopsy with transmission electron microscopy may indicate mitochondrial destruction. Treatment is mostly supportive but idebenone has been approved for LHON and experimental approaches are promising.
MON needs to be appreciated, requires extensive diagnostic work-up, and supportive treatment should be applied although loss of vision, as the most severe outcome, can often not be prevented.
Bilateral striatal necrosis caused by a founder mitochondrial 14459G > A mutation in two independent Japanese families
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Citation Excerpt :
All three cases in the present study harbored both the 14605A > G SNP and the 14459G > A mutation, and plasmid sequencing of the ND6 coding region confirmed the linkage of both substitutions on the same mtDNA. In contrast, in the previous report describing familial LHON with dystonia, the mutations were detected in a different area and the cases exhibited distinct clinical phenotypes [5]. In conclusion, our finding of a link between the pathogenic mutation and rare SNP on the same mtDNA suggests that the families in the present case and the previously reported family share a genetic founder.
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Furthermore, using transmitochondrial cybrids, it was subsequently shown that this mutation induced a marked reduction in complex I activity (Jun et al., 1996). Subsequent reports from different ethnic backgrounds confirmed the pathogenicity of the mutation and the phenotype of childhood-onset dystonia with basal ganglia lesions (Shoffner et al., 1995; Gropman et al., 2004; Tarnopolsky et al., 2004; Watanabe et al., 2006). In all published reports, there is significant clinical variability, with some patients developing only the movement disorder, some only the ophthalmological symptoms, and some both.
This chapter discusses the movement disorders and mitochondrial disease. Mitochondrial disorders present a major dilemma to the clinician, given their massive heterogeneity and the lack of simple diagnostic tests even when the diagnosis is considered. The morphology of mitochondria varies across species and cell types, their basic structure remains unchanged; they are demarcated from the cytoplasm by two membranes, an outer and an inner, separated by the intermembrane space. Movement disorders are clearly a common component of mitochondrial disorders and heterogeneity of movement disorder phenotype is common, even in patients with the same underlying genetic mutation. Leigh syndrome (LS) and leigh-like syndrome (LLS) appear to be the mitochondrial syndromes associated with the widest spectrum of movement disorders, dystonia being the most common.
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The poorly understood aetiology of schizophrenia is known to involve a major genetic contribution even though the genetic factors remain elusive. Most genetic studies are based on Mendelian rules and focus on the nuclear genome, but current studies indicate that other genetic mechanisms are probably involved. This review focuses on mitochondrial DNA (mtDNA), a maternally inherited, 16.6-Kb molecule crucial for energy production that is implicated in numerous human traits and disorders. The aim of this review is to summarise the studies that have explored mtDNA in schizophrenia patients and those which provide evidence for its implication in this illness. Alterations in mitochondrial morphometry, brain energy metabolism, and enzymatic activity in the mitochondrial respiratory chain suggest a mitochondrial dysfunction in schizophrenia that could be related to the genetic characteristics of mtDNA. Moreover, evidence of maternal inheritance and the presence of schizophrenia symptoms in patients suffering from a mitochondrial disorder related to an mtDNA mutation suggest that mtDNA is involved in schizophrenia. The association of specific variants has been reported at the molecular level; however, additional studies are needed to determine whether the mitochondrial genome is involved in schizophrenia.
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Leber's hereditary optic neuropathy with dystonia in a Japanese family

Abstract

Introduction

Section snippets

Pedigree

Patient 1

Results

Discussion

Acknowledgements

Dystonia

The early-onset torsion dystonia gene (DYT-1) encodes an ATP-binding protein

Nat Genet

Uber hereditare und congenital angelegte Sehnervenleiden

Arch Ophthalmol

Leber's “plus”: neurological abnormalities in patients with Leber's hereditary optic neuropathy

J Neurol Neurosurg Psychiatry

Leber's hereditary optic neuropathy, new genetic consideration

Arch Neurol

Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia

Mol Cell Biol

Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation

Ann Neurol