Friedreich Ataxia Phenotype Research Articles

Friedreich’s ataxia: clinical heterogeneity in two sisters

Diagnostic evaluation of two sisters affected by ataxia, with similar age of onset, revealed a characteristic trinucleotide expansion in the Friedreich's ataxia (FRDA) locus and two different phenotypic presentations. At onset the elder sister had retained deep tendon reflexes (FARR), while the younger sister presented classic FRDA. The GAA expansion in the patients' alleles proved to be similar in both siblings, ruling out that age at onset and clinical heterogeneity could be due to different FRDA mutations. On the whole, clinical and genetic data on these patients confirmed that FARR is a variant phenotype of FRDA.

Efficacious vitamin E treatment in a child with ataxia with isolated vitamin E deficiency

Vitamin E deficiency can cause a progressive spinocerebellar ataxia similar to Friedreich ataxia phenotype [2, 3]. Differential diagnosis between the two forms is based on serum level of vitamin E and is very important for prognosis because in patients with ataxia with isolated vitamin E deficiency (AVED) vitamin E supplementation allows a stabilization of the neurological conditions [3, 6] and may lead to clinical improvement [4]. We report the case of a young patient with AVED with a complete regression of ataxia after early and long-term vitamin E oral supplementation. Our case strongly suggests early recognition and treatment of vitamin E deficiency to improve disease outcome. AVED (OMIM #277460) is a rare autosomal recessive neurodegenerative disease caused by mutations in the αtocopherol transfer protein (TTPA) gene, which maps to locus 8q13.1-q13.3 on chromosome 8 [3]. The deficit reduces the capacity to incorporate α-tocopherol (the most biologically active form of vitamin E) into very low density lipoproteins secreted by the liver and therefore into plasma and tissues [1]; it affects particularly the nervous system, where neurons are more vulnerable to free-radical damage [5]. The disease was characterized clinically and the defective gene localized to proximal chromosome 8q by Ben Hamida et al. in 1993 [2]. Neurological findings include spinocerebellar degeneration and mild to moderate axonal sensory neuropathy (less severe than in Freidreich ataxia), with clinical picture of ataxia, areflexia, dysarthria, and impaired proprioception. AVED should be differentiated from other syndromes with vitamin E deficiency, which can be caused by intestinal and liver diseases, malabsorption or malnutrition [1]. An 8-year-old girl came to our attention for progressive ataxia since the age of 3 years. She was the only child of healthy consanguineous parents (3rd degree) with a family history of a not defined ataxia in the father’s line. Neurological examination disclosed spinocerebellar degeneration with clinical features of important trunkal ataxia, head tremor, dysmetria, areflexia, bilateral Babinski sign, pes cavus with retraction of Achilles tendon on left the side. Tests for cholestatic liver disease, fat malabsorption and abetalipoproteinemia showed no pathologic alterations. Brain and spine magnetic resonance imaging, fundus examination, electroencephalogram, electrocardiogram, as well as motor conduction velocity (MCV) on peroneal and median nerves resulted unrevealing. Alphafetoprotein (to rule out Ataxia-Telangiectasia) and molecular DNA analysis for Friedereich ataxia were both negative. Sensory conduction velocity (SCV) on sural and median nerves were suggestive of axonal sensory neuropathy and somatosensory evoked potentials (SEP) showed the alteration of bilateral somatosensory conduction. Alpha-tocopherol level was below the sensitivity of the test (normal values 0.5–2.0 mg/dl) and thus high-dose vitamin E supplementation was given at the dosage of 1200– 1500 mg/day until the serum concentration raised to 1.23 mg/dL. DNA analysis for the detection of the two most common mutations of the α-TTP gene in patients from Mediterranean population [6] showed homozygous 744delA mutation. After only six months we witnessed complete resolution of trunkal and limb ataxia as well as SCVand SEP normalization. Deep tendon reflexes remained abolished and the foot deformity persisted requiring surgical correction. We want to highlight the importance of the assay of vitamin E serum levels in Friedreich-like ataxia. In our case the truncating homozygous 744delA mutation caused the complete abolishment of α-TTP synthesis with a severe and early phenotype of the disease [1, 4]. However, early and high-dose oral supplementation could lead to complete L. Doria-Lamba (*) . E. De Grandis . E. Cristiani . I. Fiocchi . L. Montaldi . P. Grosso Operative Unit of Child Neuropsychiatry, Department of Neurosciences, Ophthalmology and Genetics, G Gaslini Institute, University of Genoa, L.go Gaslini 5, 16148 Genoa, Italy e-mail: lauradoria@ospedale-gaslini.ge.it Tel.: +39-010-5636702 Fax: +39-010-381303

Extension of the mutation spectrum in Friedreich's ataxia: detection of an exon deletion and novel missense mutations.

Friedreich's ataxia (FRDA), the most common autosomal recessively inherited ataxia, is due to a homozygous GAA triplet repeat expansion in the first intron of the FRDA gene in about 96% of patients. Approximately 4% of FRDA patients are compound heterozygotes with a GAA repeat expansion in one allele and a point mutation in the coding region of the second allele. To reinvestigate the mutation spectrum, we searched for mutations including exon deletions in six patients heterozygous for the GAA repeat expansion and found two unknown missense mutations, p.Asn146Lys and p.Leu186Arg, in trans to the expanded FRDA allele. Interestingly, we detected a heterozygous 2776 bp deletion including exon 5a in one of our patients. This deletion removes 50 of the 210 residues of the frataxin. Furthermore, since no FRDA case with two-point mutations is known, we screened eight patients with FRDA phenotype but GAA alleles within the normal range but did not reveal a mutation within the FRDA gene. In addition, DNA polymorphisms have been found in four out of 100 control individuals in this study.

Expanded GAA repeats and clinical variation in Friedreich's ataxia.

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. We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. 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. 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.

Serum Vitamin E and Lipid-adjusted Vitamin E Assessment in Friedreich Ataxia Phenotype Patients and Unaffected Family Members

Friedreich ataxia (FA) is an autosomal recessive spinocerebellar syndrome with onset before age 25, characterized by progressive cerebellar ataxia, dysarthria, areflexia, sensory loss in lower limbs, pyramidal weakness, and Babinski signs (1). It is caused by an intronic expanded unstable GAA repeat in the frataxin gene (2) located on chromosome 9q13-q21 (3). Investigating five Tunisian families with typical FA phenotype, Ben Hamida et al. (4) had excluded linkage to the locus of FA in two families and provided evidence for genetic heterogeneity of the disease. Patients belonging to families not linked to the locus of FA showed very low serum vitamin E (VE) with no evidence of lipid malabsorption. The role of VE in maintaining human nervous system function is established, and the role of VE deficiency in neurologic disorders of a-β-lipoproteinemia and biliary atresia is well accepted (5)(6). Several reports (4)(7)(8)(9)(10) have described patients with a progressive spinocerebellar syndrome associated with very low serum VE in the absence of fat malabsorption or a-β-lipoproteinemia. This disease, termed ataxia with VE deficiency (AVED), is inherited with an autosomal recessive pattern (3)(4). The abnormal gene was mapped to chromosome 8q (11) and identified as the gene encoding for α-tocopherol transfer protein (α-TTP) (12). Because it is difficult to distinguish on the basis of clinical features between AVED patients in whom VE supplementation may be beneficial (7)(13)(14) and those with classic FA, we assessed serum VE, total cholesterol (TC), and triglycerides (TGs) in our patients with FA clinical phenotype …

Friedreich ataxia with minimal GAA expansion presenting as adult-onset spastic ataxia

Around a quarter of Friedreich ataxia (FA) patients, despite being homozygous for GAA expansion within the FRDA gene, show atypical presentations. Our aim is to describe the case of three brothers with long-term follow-up suffering from late onset FA manifested with spastic ataxia. The three patients belong to a family with occipital dysplasia (OD) and Chiari I malformation previously reported by us. We have carried out serial examinations since 1977. Electrophysiological and neuroimaging studies, and molecular genetic analyses of hereditary ataxias are available in all three patients. Onset of symptoms occurred between 25 and 35 years. The clinical picture consisted of progressive spastic gait, truncal and limb ataxia, dysarthria, nystagmus, hyperreflexia with knee and ankle clonus and extensor plantar response, and mild hypopallesthesia. Ages at present vary between 50 and 59. One patient is wheelchair-bound but the other two are able to walk with support. Leaving OD aside, skeletal anomalies are not prominent. All three patients showed cardiomyopathy. MR imaging revealed atrophy of the cerebellum and spinal cord. Motor and sensory nerve conduction velocities were normal. Central conduction time of both motor and sensory pathways was delayed or unobtainable. All three patients were homozygous for the GAA expansion, the smaller expanded allele ranging between 131 and 156 repeats. Four heterozygotic carriers were detected among non-ataxic relatives including one with OD; furthermore, an asymptomatic OD patient showed normal genotype. We conclude that adult onset spastic ataxia is a distinctive FA phenotype associated with minimal GAA expansion. This phenotype represents a new cause of selective distal degeneration of central sensory axons. The present concurrence of OD and FA reflects coincidental cosegregation of two different inherited disorders.

Mapping of the second Friedreich's ataxia (FRDA2) locus to chromosome 9p23-p11: evidence for further locus heterogeneity.

Friedreich's ataxia (FRDA), the most-common form of autosomal recessive ataxia, is inherited in most cases by a large expansion of a GAA triplet repeat in the first intron of the frataxin (X25) gene. Genetic heterogeneity in FRDA has been previously reported in typical FRDA families that do not link to the FRDA locus on chromosome 9q13. We report localization of a second FRDA locus (FRDA2) to chromosome 9p23-9p11, and we provide evidence for further genetic heterogeneity of the disease, in a family with the classic FRDA phenotype.

Hereditary Ataxias

Hereditary Ataxias

Typical Friedreich's ataxia without GAA expansions and GAA expansion 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 alpha-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 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.

G130V, a common FRDA point mutation, appears to have arisen from a common founder.

Friedreich ataxia (FRDA) is the most common inherited ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA. The other 2% are point mutations. Of the 17 point mutations so far described, three appear to be more common. One of these is the G130V mutation in exon 4 of FRDA. G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype. Haplotype analysis was undertaken on the four families who have been described with this mutation. The results suggest a common founder for this mutation. Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events.

Electrophysiological and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency

The authors report a comparative study of peripheral nerve conductions and nerve biopsy and somatosensory evoked potentials between 15 patients with Friedreich's ataxia and 15 patients with Friedreich's ataxia phenotype with selective vitamin E deficiency. The patients in the two groups are of similar age, age of onset, and clinical phenotype. Peripheral motor nerve action potential amplitude, and conduction velocities are within normal ranges in the two groups. In the Friedreich's ataxia group there is an early and severe peripheral sensory axonal neuronopathy, characterised by an important reduction of the amplitude of sensory action potential, and important loss of myelinated fibres with complete disappearance of large myelinated fibres without any regenerative process. In the Friedreich's ataxia phenotype with selective vitamin E deficiency group there is slight-to-moderate axonal sensory neuropathy with normal to moderate decrease of large myelinated fibre density and important regeneration in nerve biopsy. Somatosensory evoked potentials are markedly involved in the two groups asserting a severe involvement of somatosensory pathway in lumbar, thoracic and cervical spinal cord. These findings suggest that the pathological mechanism involved in the two diseases are different: central peripheral axonopathy in Friedreich's ataxia and central distal axonopathy in Friedreich's ataxia phenotype with selective vitamin E deficiency.

Friedreich's ataxia. Revision of the phenotype according to molecular genetics.

Friedreich's ataxia is an autosomal recessively inherited neurodegenerative disorder caused by expansions of an unstable GAA trinucleotide repeat in the STM7/X25 gene on chromosome 9q. We studied the (GAA)n polymorphism in 178 healthy controls and 102 patients with idiopathic ataxia. The repeat size ranged from 7 to 29 (GAA)n motifs on normal chromosomes and from 66 to 1360 trinucleotide repetitions in Friedreich's ataxia patients. Meiotic instability of expanded alleles was observed without significant differences in maternal and paternal transmissions. Thirty-six of 102 patients were typed homozygous for expanded (GAA)n alleles. Twenty-seven of these presented with the typical Friedreich's ataxia symptoms and nine patients with an atypical Friedreich's ataxia phenotype. Before molecular genetic diagnosis had been performed seven of these patients had been classified as early onset cerebellar ataxia and two as idiopathic sporadic cerebellar ataxia of late onset. In contrast, in one family with typical Friedreich's ataxia phenotype we did not find an expanded allele; this suggests that there can be either point mutations in the X25 gene on both chromosomes or locus heterogeneity in Friedreich's ataxia. The phenotypic spectrum of Friedreich's ataxia is much broader than considered before. Early onset, areflexia, extensor plantar responses and reduced vibration sense should no longer be considered essential diagnostic criteria of Friedreich's ataxia. In comparison with the non-Friedreich's ataxia group hypertrophic cardiomyopathy seems to be the only symptom specific for Friedreich's ataxia. However, it is not obligatory. The phenotype is significantly influenced by the number of GAA repeats with close genotype-phenotype relationships when the smaller of the two alleles is considered. Repeat length correlated inversely with age at onset, onset of dysarthria and progression rate. In conclusion, molecular genetic analysis appears mandatory for the diagnosis and genetic counselling of Friedreich's ataxia. The molecular genetic test should be applied not only to patients with typical Friedreich's ataxia phenotype but also in all cases of idiopathic autosomal recessive or sporadic ataxia.

Broadened Friedreich's ataxia phenotype after gene cloning. Minimal GAA expansion causes late-onset spastic ataxia.

We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia.

A family with isolated vitamin E deficiency and Friedreich ataxia phenotype not linked to chromosome 8q

A family with isolated vitamin E deficiency and Friedreich ataxia phenotype not linked to chromosome 8q

Hereditary cerebellar ataxias: from hammer to genetics

The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease/SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion-chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementation with vitamin E. Familial episodic ataxias with (EA1-chromosome 12p) and without (chromosome 19p-EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 11q) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.

Ataxia with isolated vitamin E deficiency in four siblings

We describe 4 siblings of a consanguineous Bedouin family with Friedreich ataxia phenotype in whom low serum vitamin E levels without other indicators of fat malabsorption were detected. Although age of onset and some of the clinical features were alike in all 4 patients, the electrophysiological parameters were markedly abnormal in 2, but normal in the other 2. Erythrocytes revealed both membranous and intracellular evidence of oxidative damage. The mutations described in other families with ataxia with isolated vitamin E deficiency were not detectable, nor was an abnormal single-stranded conformation polymorphism pattern apparent in the three exons at the 3′ region of the gene. Vitamin E administration in pharmacological doses improved the neurological condition in 2 patients and also corrected some of the patients' erythrocyte cell abnormalities. The finding of vitamin E deficiency in other cases of Friedreich ataxia phenotype may allow treatment at an early stage of the disease, when large dose Vitamin E therapy may reverse the neurological lesions.

A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA locus

Friedreich ataxia is an autosomal recessive neurodegenerative disorder. The genetic homogeneity to the FRDA locus on chromosome 9q13-21.1 has been observed in families from different ancestries. We report a Spanish family with two affected and three unaffected children. The segregated classical Friedreich ataxia did not show the expected linkage. The analysis focusses on flanking markers FR1, FR2, FR7 and FR5, excluding linkage 1 cM around the FRDA locus. The unique clinical hallmark in this family was the absence of cardiomyopathy after a long-term follow-up in the two affected children. In both patients serum vitamin E levels were normal. The present observations support the existence of a second locus in Friedreich ataxia, and we suggest that this form could be clinically characterized by the absence of muscular heart disease.

A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA locus

A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA locus

Friedreich's ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families.

Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, the disease locus (FRDA) of which has been assigned to 9q13-q21.1 by genetic linkage analysis in affected families. We report two large inbred Tunisian families with FA manifestations that did not show the expected linkage. The disease locus could be excluded from a large (12 cMo) region around FRDA. This is the first report providing evidence for nonallelic genetic heterogeneity for the FA clinical phenotype. On subsequent analysis, all patients had very low levels of serum vitamin E whereas the parents and healthy sibs had normal vitamin E levels. This establishes that the selective vitamin E deficiency with normal fat absorption is an autosomal recessive trait, which is associated in the two families reported here with the FA phenotype.

Normal fibroblast mitochondrial malic enzyme activity in Friedreich's ataxia.

Mitochondrial and cytoplasmic malic isoenzymes were assayed fluorometrically in digitonin-fractionated fibroblasts from three patients with Friedreich's ataxia (FA). Normal activity was found, failing to verify an earlier report of reduced fibroblast mitochondrial malic enzyme activity in FA. The previously reported disturbance in fibroblast mitochondrial malic enzyme may be an epiphenomenon in patients with the FA phenotype. Further studies are necessary to define the primary genetic defect in this inherited disorder.