Movement disorders in Friedreich's ataxia

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.     

Pseudodominant Friedreich's ataxia with phenotypic heterogeneity

OBJECTIVE: A family with a clinically heterogeneous progressive ataxia in two generations is presented. METHODS: Having eliminated mutations within the known dominant spinocerebellar ataxia genes, the family was investigated for expansion at the Friedreich's gene. RESULTS: The affected members (father, son and daughter) were homozygous for the mutation at the Friedreich's gene, while the unaffected (the mother and her sister) were heterozygous. CONCLUSION: This pseudodominant form of Friedreich's ataxia should be considered in families with an apparently autosomal dominant progressive ataxia in conjunction with sensory neuropathy and pyramidal signs.     

Electrophysiological and histological follow-up study in 15 Friedreich's ataxia patients

A clinical and electrophysiological follow-up was carried out for 3 to 7 years on 15 patients with Friedreich's ataxia (FA). Sural nerve biopsy was performed once in all patients, and a second time 6-7 years later in three of them. Clinical worsening and progression of disturbance were evaluated according to IAP and IACR scales. Sensory orthodromic conduction along median and tibial nerves was typical of FA and did not change between first and last examinations, nor were there morphological changes between the first and the second sural nerve biopsies. Peripheral nerve involvement is thought to be a result of defective development of the largest neurons and to remain stable from a very early stage of the disease; the clinical worsening may then be due to a progressive involvement of the pyramidal tracts and the cerebellar pathways.     

Neuronal intranuclear hyaline inclusion disease presenting as Friedreich's ataxia

Summary A case of neuronal intranuclear hyaline inclusion disease (NIHID) is described, and the literature on seven reported cases is briefly reviewed. The patient was a 24-year-old man who died of a chronic progressive neurologic disease starting at the age of 6 years. Clinically, the disease presented as Friedreichs's ataxia, and pathologically it was characterized by multisystem atrophy. An outstanding feature was the presence of widespread intranuclear hyaline inclusions in neurons of the brain, spinal cord, and myenteric plexus of the gut. The inclusions displayed yellow-green autofluorescence under ultraviolet (UV) light and were filamentous ultrastructurally. It seems that cases bearing such peculiar neuronal inclusions represent a distinct disease entity of unknown origin. The disease, which is sometimes familial, usually starts in childhood and affects both sexes. Clinically, it presents as multisystem degeneration with progressive ataxia as the prominent feature. Pathologically, it is characterized by neuronal loss, fiber tract atrophy, and intranuclear neuronal inclusions. In some cases such inclusions were found also in neurons of the myenteric plexus. Since these are accessible to biopsy it is recommended that rectal biopsy be made in every case of atypical system atrophy.     

Friedreich's ataxia presenting with pure sensory ataxia: a long-term follow-up study of two patients

We describe two patients with Friedreich's ataxia whose presenting symptomatology was for years progressive tabetic ataxia. Based upon the initial clinical, electrophysiological and nerve biopsy data, a diagnosis of idiopathic sensory neuropathy was established. Subsequent examination of the kin showed that three sisters of case 1 had Friedreich's ataxia. Upon serial clinical and electrocardiographic study, both patients eventually developed a florid Friedreich's ataxia, including cardiomyopathy. Our findings indicate that at onset Friedreich's ataxia may be indistinguishable from sensory neuropathy and also that serial examination and investigation of kinship are essential steps for accurate diagnosis.     

Friedreich's ataxia II. Biochemical studies in cultured cells

Pyruvate and palmitate oxidations by cultured fibroblast suspensions were measured in optimized conditions and proved to be with normal range in the cells from Friedreich's patients. But when pyruvate oxidation was measured by direct assay of the pyruvate dehydrogenase complex, this enzyme activity proved to be significantly lower in Friedreich's than in controls' cells. These abnormalities were not observed when the cells were sonicated. Moreover, lipoamide dehydrogenase activity Km and Vmax were within the normal range in Friedreich's cells. These data suggest that the low activities of the PDH complex are not a primary defect in Friedreich's ataxia but are more likely to be related to membrane abnormalities in Friedreich's cells.

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Sommario L'ossidazione del piruvato e del palmitato misurata nei fibroblasti in cultura di pazienti affetti da malattia di Friedreich è risultata normale. Il dosaggio del complesso enzimatico piruvico deidrogenasi è invece risultato significativamente diminuito rispetto ai controlli nelle cellule di questi pazienti quando i fibroblasti venivano omogenizzati in glicerolo. Questa diminuzione però non era più evidente se le cellule venivano sonicate. Questi dati suggeriscono che il deficit del complesso PDH nei pazienti con atassia di Freidreich non sia un difetto primario ma rifletta piuttosto anomalie di membrana.

     

Expanded GAA repeats and clinical variation in Friedreich's ataxia

INTRODUCTION: One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease. MATERIALS AND METHODS: We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. RESULTS : The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease. CONCLUSION: GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.     

Exploring mental status in Friedreich's ataxia: a combined neuropsychological, behavioral and neuroimaging study

Despite much evidence of cognitive and affective disorders in Friedreich's ataxia (FRDA), the nature of mental status in FRDA has received little systematic attention. It has been proposed that the cerebellum may interfere indirectly with cognition through the cerebello-cortical loops, whereas the role of pathological changes in different areas of the central nervous system is still undetermined. In the present study, 13 patients with molecularly determined FRDA and a group of matched controls were evaluated by a comprehensive battery of neuropsychological tests and the Minnesota Multiphasic Personality Inventory. A repetitive task of simple visual-reaction times was used to investigate implicit learning in all subjects. Pathological changes in cortical areas were explored comparing cerebral activations of patients and controls during finger movements (functional MRI). The intelligence profile of FRDA patients is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning. FRDA patients show reduced speed of information processing. The learning effect seen in controls was notably absent in patients with FRDA. The patients' personality is characterized by some pathological aspects and reduced defensiveness. Patterns of cortical activation during finger movements are heterogeneous in patients compared to controls. Cognitive impairment, mood disorders and motor deficits in FRDA patients may be the result of the cumulative damage caused by frataxin deficiency not only in the cerebellum and spinal cord but also in other brain areas.     

Fixation instability and oculomotor abnormalities in Friedreich's ataxia

Eye movements were studied in 13 patients with Friedreich's ataxia and correlated with MRI findings to investigate whether oculomotor abnormalities can be traced to cerebellar disturbances in this disease. One of the most prominent eye signs was fixation instability (square-wave jerks, SWJ.). Besides SWJ the patients showed various combinations of cerebellar, vestibular and brain-stem oculomotor signs. Our patients did not comprise a homogeneous group with regard to their oculomotor findings. There was no correlation between the severity of any of the so-called cerebellar oculomotor disturbances and the number of SWJ. We tried to correlate the extent of oculomotor disturbances with floccular atrophy and atrophy of the dorsal vermis on MRI in seven of the patients. None of the oculomotor features (including SWJ) correlated with flocculus or dorsal vermis size. Furthermore, floccular and vermal measurements on MRI were normal. Accordingly, we think it unlikely that the oculomotor disturbances, including SWJ, are attributable to cerebellar pathology per se.     

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

We clinically assessed and performed polymerase chain reaction analysis for the GAA trinucleotide repeat expansion in 103 patients from 73 families in Ireland, with a prior clinical diagnosis of Friedreich's ataxia (FA) or an unclassified progressive ataxic syndrome. The patients were classified as “typical” or “atypical” FA according to Harding's mandatory clinical diagnostic criteria. All patients underwent blood glucose analysis, and electrocardiography and echocardiography was performed in 99 and 101 patients, respectively. Mutation screening for expanded CAG trinucleotide repeats, associated with spinocerebellar ataxia (SCA) 1, 2, 3 and 6 was performed in 86 patients overall, including all GAA negative patients. Forty-nine of 56 typical patients and 13 of 47 atypical patients were either homozygous or heterozygous for the GAA expansion. Seven patients with a typical FA phenotype were negative for the GAA expansion. Although one of these patients had vitamin E deficiency, and two had raised α-fetoprotein levels, three other GAA negative patients with a typical FA phenotype had no other identifiable cause for their ataxia, once again raising the possibility of locus heterogeneity in FA. It is also possible that these patients have two point mutations in the X25 gene, or that they have another ataxic syndrome mimicking the FA phenotype. Two families who were homozygous for the GAA expansion exhibited intrafamilial phenotypic variability. Only one GAA negative patient had the SCA 3 mutation, and this was the only patient in the study with a possible autosomal dominant inheritance pattern. In the homozygous GAA population typical patients had significantly more repeats on the smaller allele than atypical patients, and there was an inverse relationship between the number of repeats on the smaller allele and the age at presentation. There was also an inverse relationship between the repeat size on both the larger and the smaller of the two alleles and the age at becoming wheelchair bound. There was no significant relationship between repeat size and the other indices of disease severity, including the presence or absence of diabetes or cardiomyopathy. This is the first large study of an Irish population with progressive ataxia that has shown a similar phenotype/genotype relationship to studies of FA in other European and non-European populations. The relatively low sensitivity and specificity of Harding's clinical diagnostic criteria must be appreciated when clinically assessing patients with a progressive ataxic patients with a progressive ataxic syndrome. Although molecular genetic analysis now plays an essential role in diagnosis and classification, patients with a typical FA phenotype without any identifiable cause for their ataxia exist. Received: 23 June 1999, Received in revised form: 1 December 1999, Accepted: 12 January 2000     

Friedreich's ataxia presenting as adult-onset spastic paraparesis

We have studied a man with an atypical form of Friedreich's ataxia (FRDA), who presented at age 26 years with a 2-year history of unsteadiness and clumsiness. The predominant feature of his initial neurological examination was a spastic paraparesis, along with a mild distal weakness and hyperreflexia of the upper limbs. He also displayed limb ataxia. Frataxin GAA repeat sizes were 1040/690. This unusual FRDA presentation is not dissimilar to that of Acadian spastic ataxia. Received: January 9, 1998 / Accepted: February 19, 1998     

Molecular analysis of Friedreich's ataxia locus in the Indian population

OBJECTIVES: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by expansion of GAA repeats in the frataxin gene. We have carried out the first molecular analysis at the Friedreich's ataxia locus in the Indian population. MATERIALS AND METHODS: Three families clinically diagnosed for Friedreich's ataxia were analyzed for GAA expansion at the FRDA locus. The distribution of GAA repeats was also estimated in normal individuals of Indian origin. RESULTS: All patients clinically diagnosed for Friedreich's ataxia were found to be homozygous for GAA repeat expansion. The GAA repeat in the normal population show a bimodal distribution with 94% of alleles ranging from 7-16 repeats. CONCLUSION: Indian patients with expansion at the FRDA locus showed typical clinical features of Friedreich's ataxia. The low frequency of large normal alleles (6%) could indicate that the prevalence of this disease in the Indian population is likely to be low.     

Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis

We have generated and characterised transgenic mice that contain the entire Friedreich's ataxia gene (FRDA) within a human YAC clone of 370 kb. In an effort to overcome the embryonic lethality of homozygous Frda knockout mice and to study the behaviour of human frataxin in a mouse cellular environment, we bred the FRDA YAC transgene onto the null mouse background. Phenotypically normal offspring that express only YAC-derived human frataxin were identified. The human frataxin was expressed in the appropriate tissues at levels comparable to the endogenous mouse frataxin, and it was correctly processed and localised to mitochondria. Biochemical analysis of heart tissue demonstrated preservation of mitochondrial respiratory chain function, together with some increase in citrate synthase and aconitase activities. Thus, we have demonstrated that human frataxin can effectively substitute for endogenous murine frataxin in the null mutant. Our studies are of immediate consequence for the generation of Friedreich's ataxia transgenic mouse models, and further contribute to the accumulating knowledge of human-mouse functional gene replacement systems. Electronic Publication     

The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival

Summary Observations have been made on a patient with Friedreich's ataxia who died 52 years after the onset of symptoms. The pathology of the brain and spinal cord was typical of this disorder. Apart from loss of dorsal root ganglion cells, severe loss of secondary sensory neurons was observed, including the nucleus dorsalis in the spinal cord, the spinal and principal trigeminal nuclei and, in particular, the mesencephalic trigeminal nucleus in the brain stem. Morphometric studies on the first sacral nerve root and on the sural nerve at levels from midthigh to ankle revealed a distally accentuated axonal loss that predominantly affected larger myelinated nerve fibres. Regenerative activity was seen, mainly in the spinal root and proximally in the sural nerve. Relative myelin thickness, assessed by g ratios, tended to be reduced. As teased fibre studies showed only limited evidence of demyelination/remyelination and of axonal regeneration, this therefore suggests the presence of hypomyelination. The results confirm the presence of a distal axonopathy and provide no evidence that this is preceded by axonal atrophy.Supported by the Friedreich's Ataxia Group     

Evidence of a genetic marker associated with early onset in Friedreich's ataxia

We evaluated the association between age at onset of Friedreich's ataxia and alleles of two restriction fragment length polymorphisms (RFLP) at D9S15 and D9S5 in the 9gl3–9g21.1 region. We studied 65 Italian patients from 49 families. Age at onset was not normally distributed in our patients, suggesting allelic heterogeneity. Patients homozygous for allele 1 ofMspI RFLP detected by probe MCT112 at D9S15 (M1) had an earlier onset (mean 9.3, SD 3.4 years) than patients homozygous for allele 2 (M2; mean 12.1, SD 4.3). Heterozygotes had an onset age similar to that of the M2 homozygotes. These findings suggest that the M1 allele might be a marker of one allelic early-onset Friedreich's ataxia mutation.     

Friedreich's ataxia I. Clinical, Neurophysiological and in vivo biochemical studies

Eighteen patients with the presumptive diagnosis of Friedreich's ataxia were studied. Clinical, neurophysiological and biochemical data were concordant in 14 patients and led to the diagnosis of typical Friedreich's ataxia in this group of patients: the remaining 4 patients differed from the typical patients in several respects but mainly in the cardiological findings. It is concluded that so far no single clinical or laboratory finding is typical of F.A.. Multidisciplinary approaches are essential to the diagnosis of Friedreich's ataxia.

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Sommario Si presenta uno studio clinico, neurofisiologico e biochimico di 18 pazienti con diagnosi presuntiva di atassia di Friedreich. I dati portano ad inquadrare nella malattia di Friedreich tipica solo 14 pazienti, gli altri 4 si differenziano per diversi aspetti clinici di cui il più rilevante è la normalità cardiaca. Si conclude quindi che per giungere alla diagnosi di malattia di Friedreich che permetta in seguito uno studio biochimico della malattia, sia necessario un approccio multidisciplinare.

     

Intrafamilial phenotype variation in Friedreich's disease: possible exceptions to diagnostic criteria

Summary Three families are described which include members with typical Friedreich's disease (FD) and others who are ataxic but do not satisfy all the diagnostic criteria for that disease. In family A two patients have an early-onset, rapidly progressive FD, while two others have a late-onset, more benign form. In families B and C one member has typical FD, and another has a similar ataxic syndrome, except for preservation of knee jerks. Laboratory evaluation is consistent with the diagnosis of FD in all cases. FD diagnosis appears justified in secondary cases with late onset or preserved tendon reflexes, provided that the index case fulfils all diagnostic criteria. Whether the diagnosis of FD is tenable in sporadic atypical cases remains to be seen. Echocardiographic and neurophysiological examination may be valuable in classifying such cases.     

Different phenotypes of Friedreich's ataxia within one 'pseudo-dominant' genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features

We examined a large Turkmen family with 'pseudo-dominant' inheritance of Friedreich's ataxia resulting from consanguineous marriage of a Friedreich's ataxia patient to a heterozygote carrying an ancestral mutated allele. Two distinct phenotypes of the disease co-segregated within this genealogy. Two brothers from the younger generation exhibited 'classical' Friedreich's ataxia with onset of symptoms before 10 years and a rapidly progressive course. In contrast, three patients (two sisters from the younger generation and their father) had a more benign phenotype of late-onset Friedreich's ataxia with the onset at 26, 45 and 48 years and slow progression over decades. The patients with 'classical' Friedreich's ataxia were homozygous for a common ancestral expanded allele of the X25 gene containing 700-800 GAA repeats, while the patients with late-onset Friedreich's ataxia had two different mutated alleles, the shorter 250-repeat expansion of paternal origin and the longer 700-repeat expansion of maternal origin. One may conclude that clinical variability of Friedreich's ataxia in our patients is accounted for predominantly by a modifying effect of one of the two (shorter or longer) expanded alleles inherited from their affected father. Our observation clearly demonstrates the significance of variable-sized alleles for the phenotypic expression of the disease.     

Limited somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes

OBJECTIVES: Friedreich's ataxia (FRDA), the most common inherited ataxia, is associated with an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9. We investigated the mosaicism of expanded alleles to elucidate the basis for genotype phenotype correlations. PATIENTS AND METHODS: We studied the instability of the GAA repeat in blood leukocytes from 45 individuals including 20 FRDA patients and 20 non-affected controls using small pool PCR combined with Southern blotting and hybridization. RESULTS: Expanded GAA repeats could be resolved into distinct alleles showing differences in length up to 1,000 triplets for an individual genome. We found a significant correlation between the size of the largest allele and the range of mosaicism. CONCLUSION: The somatic mosaicism for expanded repeats observed in FRDA patients rendered the precise measurement of allele sizes more difficult and may influence the results of studies correlating the clinical spectrum with the genotype. Following, a confidential prediction of the prognosis deduced from the repeat length is hardly possible for an individual FRDA patient.