Hereditary Ataxia

Genetics of ataxia

Hereditary ataxias are rare diseases, however, they do not comprise a single entity but subdivide in multiple genetic subtypes. For autosomal dominant ataxias at present 28 gene loci have been identified and 13 genes causing dominantly inherited ataxias have been cloned (Table "Autosomal dominant ataxias"). For genes causing dominant ataxias the somewhat misleading heading "spinocerebellar ataxia" was coined irrespectively whether spinal structures are affected by the disease. In families with genetically uncharacterised types of dominant ataxia we search for new genes by sequencing of candidate genes, haplotyping, whole genome scans and positional cloning approaches.
Autosomal recessive ataxias frequently present with early onset. More than 20 genetic subtypes have been defined but routine diagnostic is limited to Friedreich’s ataxia as the most frequent form of autosomal recessive ataxia. We investigate clinical, electrophysiological, biochemical and MR-morphological markers as predictors of the underlying genotype. In an European cooperation we look for new genes responsible for autosomal recessive ataxia.

Spinocerebellar ataxia

The spinocerebellar ataxias type SCA1, SCA2, SCA3 and SCA6 are the most frequent subtypes in Germany and account for about 70% of dominant ataxias. In a research project sponsored by the European Community, EURO-SCA (http://www.eurosca.org/), we study the natural course of the disease by clinical rating scales, nerve conduction studies and magnetic resonance tomography. In a prospective study we generate data about the annual progression of the disease in terms of changes in a newly developed and evaluated rating scale (SARA) and functional tests. Furthermore, we aim to establish electrophysiological parameters and regional atrophy on MRI as progression markers for SCA. These data are essential for power calculation and planning of forthcoming therapeutical trials.
Special effort is put on the affection of basal ganglia in SCA. In cooperation with the Institute of Functional Anatomy in Frankfurt (Dr. Rüb) we study degenerative changes in the substantia nigra in SCA. Preliminary results show similar affection as in Parkinson’s disease but the patients do not necessarily develop Parkinsoninan symptoms. In a combined imaging approach sponsored by the Deutsche Forschungsgemeinschaft we assess basal ganglia structure and function in vivo using transcranial sonography, MRI and multiple PET tracers in SCA2 and SCA3 patients.

Figure1: Neuronal loss in the substantia nigra is similar in SCA2 (C) and SCA3 (D) as in Parkinson’s disease (B) in comparison to controls (A). Courtesy of Dr. U. Rüb, Institute of Clinical Neuroanatomy, Frankfurt

Friedreich’s ataxia

Figure 2: Assessment of left ventricular mass on cardiac MRI. Endocardiac and epicardiac boundaries of every slice are traced manually. Interobserver variability for left ventricular mass is less than 5%. A: Enddiastolic series. (B) Endsystolic series.

Friedreich’s ataxia (FA) is frequently associated with cardiomyopathy that is believed to be the most frequent cause of death in FA. FA associated cardiomyopathy is commonly regarded to be of hypertrophic type. Therapeutic trials of idebenone, coenzyme Q10 and vitamin E aim to reduce left ventricular mass. We assess the frequency and natural history of cardiac hypertrophy in FA by cardiac MRI in comparison to echocardiography and analyse which cardiac parameters have functional implications or prognostic relevance in Friedreich’s cardiomyopathy.
In cooperation with the Karolinska-Institute in Stockholm, the Institute for Human Nutrition in Jena and the Diabetes Center in Tübingen we study glucose metabolism and insulin oscillations in FA. About 18% of patients with FA develop diabetes mellitus and 80% of heterozygous mutation carriers show impaired insulin resistance.

Fragile X-premutation associated tremor ataxia syndrome (FXTAS)

Premutations in the FMR1-gene with 55 – 200 CGG-repeats were recently shown to cause tremor and ataxia predominantly in older men. Full mutations in FMR1 with more than 200 CCG repeats result in fragile X syndrome, the most frequent cause of mental retardation. We characterize the phenotypic spectrum of FXTAS by electrophysiological means and and novel MRI techniques including volumetry and spectroscopy.

Idiopathic ataxia

Patients with sporadic (non familiar) ataxia have to be investigated intensively for secondary forms of ataxia like paraneoplastic disease, gliadin antibody mediated ataxia, vitamin deficiency, cerebrotendinosis xanthomatosa and toxicity induced ataxia because of potentially causative treatment options. Additionally, we search for primary coenzyme Q10 deficiency, mitochondrial cytopathy, and adult leukodystrophies.