Movement disorders in Friedreich's ataxia

doi:10.1016/S0022-510X(02)00321-0

Journal of the Neurological Sciences

Volume 206, Issue 1, 15 January 2003, Pages 59-64

https://doi.org/10.1016/S0022-510X(02)00321-0 Get rights and content

Abstract

Since the discovery of the gene mutation causing Friedreich's ataxia (FA), the rich spectrum of clinical manifestations of this autosomal recessive disorder is being increasingly recognized. Movement disorders besides ataxia, however, have not been fully characterized in patients with FA. We describe here two young male patients who, in addition to progressive ataxia, kinetic tremor and other typical features of FA, also manifest axial and limb dystonia. The primary purpose of this report is to draw attention to the broad spectrum of hyperkinetic movement disorders that can present as or be associated with FA.

Introduction

The identification of the gene mutation specifically causing Friedreich's ataxia (FA) has broadened the spectrum of clinical symptoms and findings associated with this autosomal recessive neurodegenerative disorder. In this report, the phenomenology of movement disorders associated with FA will be reviewed (Table 1).

Section snippets

Case 1

This 20-year-old man from Saudi Arabia with progressive balance and gait difficulties since 4 years of age was evaluated in our Movement Disorders Clinic in 1995 and again in 2001. When initially evaluated by us at age 14, he complained of stiffness of the neck and trunk muscles, he was still able to walk, but was unsteady and had frequent falls, resulting in injuries. His speech was fluent without dysarthria. Examination showed marked proximal and distal weakness and atrophy of all four

Discussion

We describe here two patients with FA who, in addition to the typical signs of this autosomal recessive ataxia, also manifest dystonia. Patient 1 was the proband in one of the initial families whose DNA analysis led to the discovery of the FA gene mutation [1]. The most common form of spinocerebellar degeneration, FA is characterized clinically by progressive ataxia of the limbs and trunk, sensory neuropathies in the lower limbs, dysarthria, and pyramidal signs [5], [6]. Symptoms develop

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However, neurological manifestations, including action tremor of the arms and head, dystonia, cerebellar and pyramidal signs, as well as late-onset complications (e.g., premature ovarian failure (POF)) have been reported despite strict dietary galactose restriction since birth [129]. Table 3 provides brief summaries of the above-mentioned and other AR tremor disorders [87,88,93,103–136]. FXTAS is a late-onset neurodegenerative disorder affecting around 40% of males carrying a premutation (CGG trinucleotide expansion of 55–200 repeats) allele in the 5’ untranslated region of fragile X mental retardation gene (FMR1; chromosome Xq27.3).
The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines “isolated” and “combined” tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired.
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Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia-plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can also be present. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1, respectively. Although significant recent progress has been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.
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Usually starting before 25 years of age, FRDA typically manifests with progressive limb ataxia, dysarthria, sensory neuropathy and signs of pyramidal pathway dysfunction (Schols et al., 1997). However, atypical cases with later onset, dominant spasticity, chorea, dystonia or tremor have been described (Hou and Jankovic, 2003). Other symptoms of FRDA are cardiomyopathy, diabetes mellitus and scoliosis.
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Among the SCAs, dystonia is most common in SCA17, SCA3, and SCA2 (van Gaalen et al., 2011). Although relatively infrequent, dystonia, appendicular and cervical, has been well documented in Friedrich ataxia (FA) (Hou and Jankovic, 2003). FA is perhaps the most common and intensively studied of the hereditary ataxias.
Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can be present as well. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1. Mutations in THAP1 and CIZ1 have been associated with sporadic and familial adult-onset dystonia. Although significant recent progress had been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.

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Movement disorders in Friedreich's ataxia

Abstract

Introduction

Section snippets

Case 1

Discussion

J. Biol. Chem.

Neuroscience

J. Neurol. Sci.

Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion

Science

Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and permutations

Proc. Natl. Acad. Sci. U. S. A.

Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic ataxia

Neurology

The Friedreich ataxia GAA triplet repeat: permutation and normal alleles

Hum. Mol. Genet.

Clinical and genetic abnormalities in patients with Friedreich's ataxia

N. Engl. J. Med.

Friedreich ataxia: an overview

J. Med. Genet.

Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features

Brain

Mapping of mutation causing Friedreich's ataxia to human chromosome 9

Nature

Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes

Ann. Neurol.

Frataxin gene of Friedreich's ataxia is targeted to mitochondria

Ann. Neurol.

Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia

Ann. Neurol.

Molecular basis of Friedreich ataxia

Mov. Disord.

Pathological study of corticospinal-tract degeneration in Friedreich's ataxia

Neuropathol. Appl. Neurobiol.

The neuropathology of “typical” Friedreich's ataxia in Quebec

Can. J. Neurol. Sci.

Compartmentalized cerebellar functions upon the stabilization of body posture

Rev. Neurol. (Paris)

Characteristic alterations of long-loop “reflexes” in patients with Friedreich's disease and late atrophy of the cerebellar anterior lobe

J. Neurol. Neurosurg. Psychiatry

Quantification of postural sway in normals and patients with cerebellar diseases

Electroencephalogr. Clin. Neurophysiol.

Tremor

Control of isometric finger force in patients with cerebellar disease

Brain

Extrapyramidal motor signs in degenerative ataxias

Arch. Neurol.

Dystonia in spinocerebellar ataxia type 6

Mov. Disord.