Katrin Bürk

Spectrin Mutations Cause Spinocerebellar Ataxia Type 5

We have discovered that β-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincolns grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. β-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRδ2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant β-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Diagnosis and treatment of Friedreich ataxia: a European perspective.

Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3–4 cases per 100,000 individuals. This autosomal-recessive neurodegenerative disease is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and a positive extensor plantar response. Non-neurological signs include hypertrophic cardiomyopathy and diabetes mellitus. Symptom onset typically occurs around puberty, and life expectancy is 40–50 years. Friedreich ataxia is usually caused by a large GAA-triplet-repeat expansion within the first intron of the frataxin (FXN) gene. FXN mutations cause deficiencies of the iron–sulfur cluster-containing subunits of the mitochondrial electron transport complexes I, II, and III, and of the iron–sulfur protein aconitase. Mitochondrial dysfunction has been addressed in several open-label, non-placebo-controlled trials, which indicated that treatment with idebenone might ameliorate hypertrophic cardiomyopathy; a well-designed phase II trial suggested concentration-dependent functional improvements in non-wheelchair-bound children and adolescents. Other current experimental approaches address iron-mediated toxicity, or aim to increase FXN expression through the use of erythropoietin and histone deacetylase inhibitors. This Review provides guidelines, from a European perspective, for the diagnosis of Friedreich ataxia, differential diagnosis of ataxias and genetic counseling, and treatment of neurological and non-neurological symptoms.

Autosomal dominant cerebellar ataxia type I : oculomotor abnormalities in families with SCA1, SCA2, and SCA3

Abstract Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3.

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3.

Abstract. Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level.

Restless legs syndrome in spinocerebellar ataxia types 1, 2, and 3.

Abstract To identify the prevalence and determinants of restless legs syndrome (RLS) in spinocerebellar ataxia (SCA) we studied 58 patients with a molecular diagnosis of SCA1, SCA2 and SCA3. Data on the symptoms of RLS were collected by a standardized questionnaire, and RLS was diagnosed when patients met the four minimal criteria of the syndrome as recently defined by an international study group. In addition, we studied the relationship between RLS and age, age at ataxia onset, CAG repeat length, and nerve conduction and evoked potentials data. RLS was significantly more frequent in SCA patients than in controls (28 % vs. 10 %). Age at RLS onset in SCA was 49.0 ± 10.9 years. There were no significant differences in nerve conduction or evoked potentials between RLS and non-RLS SCA patients. The probability of developing RLS increased with age but not with CAG repeat length or higher age of ataxia onset. The data provide evidence that patients with SCA1, SCA2 and SCA3 are per se more susceptible to RLS than non-affected individuals. The probability of developing RLS is related principally to the period over which the CAG repeat mutation exerts its effect and not to CAG repeat length or age of ataxia onset.

Cerebellar ataxia with glutamic acid decarboxylase autoantibodies

Article abstract Degenerative cerebellar ataxia with autoantibodies against glutamic acid decarboxylase (GAD) is a rare disorder and may represent a subset of ataxias previously classified as idiopathic. The authors report a patient with progressive cerebellar ataxia, insulin-dependent diabetes mellitus, and GAD antibodies who responded to IV immunoglobulins.

FMR1 premutation as a rare cause of late onset ataxia--evidence for FXTAS in female carriers.

Sirs: Fragile X syndrome (FRAXA, MIM 3009550), the most common form of inherited mental retardation affecting 1:4000 males, is caused by the absence of the fragile X mental retardation protein. The underlying gene defect is an expansion of the (CGG)n repeat in the 5’ untranslated region of the FMR1 gene. In unaffected individuals, the number of repeats ranges from 6 to 52 copies. Individuals with alleles in the premutation range (52 to 200 repeats) are not affected but have a variable risk (depending on the sex of the transmitting parent and the repeat length) to produce offspring with full mutations (> 200 CGG) and the disease phenotype. Recently, the clinical involvement of the fragile X premutation in individuals affected by a characteristic late-onset neurodegenerative disorder has been described [1–8]. The major features of the fragile X-associated tremor/ataxia syndrome (FXTAS) are progressive intention tremor and/or cerebellar gait ataxia, dementia, Parkinsonism, autonomic dysfunction, and peripheral neuropathy. Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. Brain pathology includes ubiquitin-positive neuronal and astroglial intranuclear inclusions. The majority of cases reported are males from families with fragile X syndrome. To explore the presence and frequency of FMR1 premutations among patients with spinocerebellar ataxia (SCA) and age of onset > 50 years, we performed analyses of the FMR1 gene in 269 males as well as in 241 females after exclusion of CAG repeat expansions at the SCA loci 1, 2, 3, 6, 7, 12 and 17. Measurements of the CGG repeat number revealed alleles with 18 to 50 triplets in males and 9 to 53 in females (Table 1). In addition, a female carrying 84 triplets was found. This 73-year-old woman first noticed at age 64 weakness and fatigue in both lower limbs while walking that had led to occasional falls. In the following years gait became more and more unsteady and muscle force of both legs further decreased. At about age 66 she noted an action tremor of both hands, a head tremor and a voice tremor while speaking or singing. She also complained of deterioration of her memory and concentration. Neurological examination at age 70 revealed hypometric saccades, moderate upward gaze palsy and mild dysarthria and hypomimia. There was a marked weakness of distal leg muscles (MRC 1–2) with only mild weakness of proximal leg muscles (MRC 4). Deep tendon reflexes were 2 in the upper extremity, 1 in the knees and absent in the ankles. Babinski response was negative. There were no major deficits of sensation except for a moderately impaired vibration sense at the ankle. She had a bilateral postural and intention tremor of both arms and hands as well as a head and voice tremor. Postural hand tremor markedly improved with propanolol medication (60 mg daily). There was no rest tremor. Dysmetria was present bilaterally in the finger-to-nose and heel-to-shin tests. Gait was ataxic LETTER TO THE EDITORS

SCA2 trinucleotide expansion in German SCA patients

ABSTRACTAutosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. We investigated the (CAG)n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between ‘normal’ and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany.

Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data

BACKGROUND Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. METHODS Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18-50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35-70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. FINDINGS 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was -9 years (IQR -13 to -6) in 50 carriers of the SCA1 mutation, -12 years (-15 to -9) in 31 SCA2 mutation carriers, -8 years (-11 to -6) in 26 SCA3 mutation carriers, and -18 years (-22 to -16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0-1·0] vs 0 [0-0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0-2·0] vs 0 [0-0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (-0·43 [-0·91 to -0·07] vs 0·09 [-0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861-0·959] vs 0·849 [0·764-0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r=0·36, p=0·0112; SCA2: r=0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012-0·016) than in non-carriers (0·019, 0·017-0·021; p=0·0107). INTERPRETATION Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. FUNDING ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

KCNC3: Phenotype, mutations, channel biophysics – a study of 260 familial ataxia patients

We recently identified KCNC3, encoding the Kv3.3 voltage‐gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late‐onset ataxia resulting in a nonfunctional channel subunit with dominant‐negative properties. A French early‐onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channels open conformation. Coding exons were amplified and sequenced in 260 autosomal‐dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late‐onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early‐onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant‐negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late‐onset progressive ataxia. In two families the p.Arg423His mutation was associated with early‐onset slow‐progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early‐onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant‐negative effect. Hum Mutat 31:191–196, 2010.