Genes and symptoms overlap
With both the causative genes and clinical presentation overlap between hereditary ataxias and spastic paraplegias, a united classification makes sense. Despite huge advances in genetics knowledge with genetic testing technologies, many test results report no mutation identified. In this context, referral to specialised clinics that also do research is helpful.
Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases.
Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes. However, repeat expansions and large genomic deletions must be considered separately.
Here, we suggest a pragmatic algorithm for genetic testing in hereditary ataxias and spastic paraplegias that we have developed in our specialized outpatient clinics. Detailed phenotyping remains crucial to interpret the multitude of genetic variants discovered by high throughput sequencing techniques. Despite recent technical advances, a substantial proportion of ataxia and spastic paraplegia families are still without a molecular diagnosis. Beside new and so far undetected ataxia and spasticity genes, unusual mutation types including noncoding variants and polygenic inheritance patterns may contribute.
Because of these clinical, genetic, and technological challenges, patients with hereditary ataxias and spastic paraplegias should be referred to specialized centers offering research and clinical studies. This will also help to recruit representative patient cohorts for upcoming interventional trials.
SOURCE: Nervenarzt. 2017 Jul;88(7):720-727. doi: 10.1007/s00115-017-0357-4. PMID: 28600743
Ataxias and hereditary spastic paraplegias.
[Article in German]
Schüle R1,2, Schöls L3,4.
1 Neurologische Klinik und Hertie-Institut für Klinische Hirnforschung, Eberhard-Karls-Universität, Hoppe-Seyler Str. 3, 72076, Tübingen, Deutschland.
2 Deutsches Zentrum für Neurodegenerative Erkrankungen, Tübingen, Deutschland.
3 Neurologische Klinik und Hertie-Institut für Klinische Hirnforschung, Eberhard-Karls-Universität, Hoppe-Seyler Str. 3, 72076, Tübingen, Deutschland. [email protected]
4 Deutsches Zentrum für Neurodegenerative Erkrankungen, Tübingen, Deutschland. [email protected]