Andreas Eigentler

Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study

BACKGROUND The European Friedreichs Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreichs ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. METHODS We enrolled patients with genetically confirmed Friedreichs ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits-baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. FINDINGS Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreichs ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (-0·02 points per year [0·01] per year of age) and lower SARA baseline scores (-0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, -0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and -0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. INTERPRETATION Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreichs ataxia. FUNDING European Commission.

Correlation of frataxin content in blood and skeletal muscle endorses frataxin as a biomarker in Friedreich ataxia.

Friedreich ataxia is an autosomal recessive disorder caused by mutations in the frataxin gene, leading to reduced levels of the mitochondrial protein frataxin. Assays to quantitatively measure frataxin in peripheral blood have been established. To determine the validity of frataxin as a biomarker for clinical trials, we assessed frataxin in clinically affected tissue.

Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature

Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site. Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory, executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation, review the respective literature and discuss implications on diagnosis and patient management.

Skeletal Muscle Involvement in Friedreich Ataxia and Potential Effects of Recombinant Human Erythropoietin Administration on Muscle Regeneration and Neovascularization

Abstract Friedreich ataxia (FRDA) is caused by reduced expression of the mitochondrial protein frataxin. Cardiac muscle involvement has been attributed to mitochondrial dysfunction, but involvement of skeletal muscle has not been fully investigated. Improved motor skills in FRDA patients after administration of recombinant human erythropoietin (rhuEPO) have been reported. To elucidate the characteristics of skeletal muscle in FRDA and assess the potential effects of rhuEPO on skeletal muscle neovascularization and regeneration, 7 genetically confirmed FRDA patients underwent biopsy of the gastrocnemius muscle before and after administration of 3,000 international units of rhuEPO 3 times per week for 2 months. Muscle tissue was investigated using standard histologic methods, immunohistochemistry, and biochemical assays of mitochondrial enzymes. In pretreatment FRDA samples, there were neurogenic and myopathic changes and reduced capillary density versus that in healthy control biopsies (n = 4). Satellite cells were increased, but markers of satellite cell activation and differentiation did not differ from controls. Respiratory chain complex and citrate synthase activities were reduced in FRDA and remained unchanged after treatment. Administration of rhuEPO resulted in increases in muscle capillary densities and in endothelial progenitor cells in peripheral blood. These data indicate that there are morphological and biochemical abnormalities of skeletal muscle in FRDA. The rhuEPO-induced changes were subtle, but increased capillary density might result in improved oxygen supply and myofiber function.

Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin.

Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin. Recombinant human erythropoietin (rhuEPO) is suggested to increase frataxin levels, alter mitochondrial function and improve clinical scores in FRDA patients. Aim of the present pilot study was to investigate mitochondrial metabolism of skeletal muscle tissue in FRDA patients and examine effects of rhuEPO administration by phosphorus 31 magnetic resonance spectroscopy (31P MRS). Seven genetically confirmed FRDA patients underwent 31P MRS of the calf muscles using a rest-exercise-recovery protocol before and after receiving 3000 IU of rhuEPO for eight weeks. FRDA patients showed more rapid phosphocreatine (PCr) depletion and increased accumulation of inorganic phosphate (Pi) during incremental exercise as compared to controls. After maximal exhaustive exercise prolonged regeneration of PCR and slowed decline in Pi can be seen in FRDA. PCr regeneration as hallmark of mitochondrial ATP production revealed correlation to activity of complex II/III of the respiratory chain and to demographic values. PCr and Pi kinetics were not influenced by rhuEPO administration. Our results confirm mitochondrial dysfunction and exercise intolerance due to impaired oxidative phosphorylation in skeletal muscle tissue of FRDA patients. MRS did not show improved mitochondrial bioenergetics after eight weeks of rhuEPO exposition in skeletal muscle tissue of FRDA patients. Trial Registration EU Clinical Trials Register 2008-000040-13

The scale for the assessment and rating of ataxia correlates with dysarthria assessment in Friedreich's ataxia

Dysarthria is an acquired neurogenic sensorimotor speech symptom and an integral part within the clinical spectrum of ataxia syndromes. Ataxia measurements and disability scores generally focus on the assessment of motor functions. Since comprehensive investigations of dysarthria in ataxias are sparse, we assessed dysarthria in ataxia patients using the Frenchay Dysarthria Assessment. The Frenchay Dysarthria Assessment is a ten-item validated test in which eight items focus on the observation of oral structures and speech functions. Fifteen Friedreichs ataxia patients and 15 healthy control individuals were analyzed using clinical and logopedic methodology. All patients underwent neurological assessment applying the Scale for the Assessment and Rating of Ataxia. In Friedreichs ataxia patients, the Frenchay sub-item voice showed to be most affected compared to healthy individuals followed by items such as reflexes, palate, tongue, and intelligibility. Scoring of lips, jaw, and respiration appeared to be mildly affected. Ataxia severity in Friedreichs ataxia patients revealed a significant correlation with the Frenchay dysarthria sum score. The introduction of a binary Adapted Dysarthria Score additionally allowed allocation to distinct dysarthria pattern in ataxias. The Frenchay Dysarthria Assessment proved to be a valid dysarthria measure in Friedreichs ataxia. Its availability in several languages provides a major advantage regarding the applicability in international clinical studies. Shortcomings of the Frenchay test are the multiplicity of items tested and its alphabetic coding. Numerical scoring and condensation of assessments in a modified version may, however, provide an excellent clinical tool for the measurement and scoring of dysarthria in ataxic speech disorders.

Acquired ataxias: the clinical spectrum, diagnosis and management

Acquired ataxias represent a large group of disorders defined by the common clinical feature of ataxia and the absence of a clear genetic basis for it. Based on the aetiology, the group can be subdivided into autoimmune, toxic, infectious and vitamin deficiency causes. Cerebellar ataxia may occur as an isolated syndrome in this spectrum of disorders but is often accompanied by additional neurological manifestations. Clinical work-up is challenging and mainly includes biochemical analyses, whereas imaging is of minor significance. Diagnosis is essential as many of these disorders represent potential treatable conditions and early therapy may prevent progressive cerebellar ataxia. The clinical findings, the implications for diagnosis and management of this heterogeneous group of disorders are discussed in this review.

Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

Objective: To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. Methods: The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. Results: The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. Conclusions: Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. ClinicalTrials.gov registration: NCT02701036.

Autonomic function testing in Friedreich’s ataxia

BackgroundFriedreich ataxia (FRDA) is an inherited movement disorder which manifests with progressive gait instability, sensory loss and cardiomyopathy. Peripheral neuropathy is an established feature of FRDA. At neuropathological examination, a depletion of large, myelinated axons is evident, but also unmyelinated fibers are affected which may result in a variety of sensory and autonomic signs and symptoms. Impaired temperature perception, vasomotor disturbances of lower extremities and a high prevalence of urinary symptoms have been documented in FRDA, but data from autonomic function testing in genetically confirmed cases are lacking.MethodsGenetically confirmed FRDAs were recruited in an outpatient setting. In a screening visit, general and neurological examination, laboratory testing, ECG and echocardiography were performed. Autonomic functions were evaluated by means of systematic questionnaires (SCOPA-Aut, OHQ), skin sympathetic reflex and cardiovascular autonomic function testing (CAFT). For the latter, a comparison with matched healthy controls was performed.Results20 patients were recruited and 13 underwent CAFT. Symptoms referred to multiple autonomic domains, particularly bladder function, thermoregulation and sweating were reported. SCOPA-Aut scores were significantly predicted by disease severity. At CAFT, FRDAs did not differ from controls except for increased heart rate at rest and during orthostatic challenge. Two patients had non-neurogenic orthostatic hypotension (14%). Skin sympathetic responses were pathologic in 3 out of 10 patients (of whom 2 aged > 50).ConclusionsFRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.

Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment

Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9–15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.