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.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. METHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. RESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name "spastic ataxia", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance. CONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.

Decreased retinal sensitivity and loss of retinal nerve fibers in multiple system atrophy.

BACKGROUND AND AIM: In a previous study, retinal nerve fiber layer thickness (RNFLT) loss was shown as part of the neurodegenerative process in multiple system atrophy (MSA). Here, we investigate in a larger cohort of MSA patients whether the RNFLT loss translates into respective visual field defects. METHODS: Spectral domain optical coherence tomography was performed in 20 MSA patients (parkinsonian subtype = 12, cerebellar subtype = 8) to quantify peripapillary RNFLT. Visual field (90°) was analyzed by automated static perimetry to investigate retinal structure/function relationship. Eight data sets did not meet stringent quality criteria, and only 12 data sets were further analyzed. RESULTS: Compared to healthy controls, MSA patients demonstrated a significant reduction of RNFLT in the nasal sectors (p ( nasal-superior ) = 0.02, p ( nasal ) = 0.03, p ( nasal-inferior ) < 0.01), while changes in temporal RNFLT measures (p ( temporal-superior ) = 0.42, p ( temporal ) = 0.34, p ( temporal-inferior ) = 0.25) were not statistically significant compared to healthy controls (ANOVA). MSA patients featured a significant global mean deviation (2.74 dB; p < 0.01) without predominant peripheral visual field defects. Statistical analysis of mean defect in the central (0-30°), peripheral (30-90°) or global (0-90°) visual field revealed no significant correlation (r (2) (central) = 0.11, r (2) (peripheral) = 0.04, r (2) (global) = 0.07) with nasal RNFLT in MSA patients. CONCLUSION: MSA patients feature significant reduction in nasal RNFLT and global mean deviation when compared to healthy controls, consistent with the multi-systemic nature of this neurodegenerative disorder. This finding provides first evidence for two independent deteriorations of the visual system in MSA.

Video game-based coordinative training improves ataxia in children with degenerative ataxia.

OBJECTIVE: Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. METHODS: We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children's home environment. Rater-blinded assessments were performed 2 weeks before laboratory-based training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. RESULTS: Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p = 0.03). CONCLUSIONS: Despite progressive cerebellar degeneration, children are able to improve motor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of young-onset neurologic conditions. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that directed training with Xbox Kinect video games can improve several signs of ataxia in adolescents with progressive ataxia as measured by SARA score, Dynamic Gait Index, and Activity-specific Balance Confidence Scale at 8 weeks of training.

Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .

We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis,intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.

Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.

BACKGROUND: Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive. METHODS: Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. RESULTS: The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. CONCLUSIONS: This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

POLG, but not PEO1, is a frequent cause of cerebellar ataxia in Central Europe.

Nuclear genes, in particular mitochondrial polymerase gamma (POLG) and PEO1, have been increasingly recognized to cause mitochondrial diseases. Both genes assume a complementary role as part of the mitochondrial DNA (mtDNA) replication fork and, accordingly, seem to present with largely overlapping phenotypical spectra. We assessed the frequency and phenotypic spectrum of PEO1 compared to POLG mutations in a cohort of 80 patients with cerebellar ataxia for which common repeat expansion diseases had been excluded. Patients were selected to present additional features previously described for PEO1 mutations, namely early age of onset, progressive external ophthalmoplegia (PEO), or epilepsy. Whereas PEO1 mutations were not found in our cohort, POLG frequently caused ataxia with PEO (47%), psychiatric comorbidities (20%) and, more rarely, with epilepsy (14%). Thus, PEO1 is rare in Central Europe even in those patients displaying characteristic phenotypic features. In contrast, POLG is rather common in Central European ataxia patients. It should be particularly considered in ataxia patients with PEO, psychiatric comorbidities, and/or sensory neuropathy, even if characteristic mitochondrial extra-CNS features are absent.