Clinical diagnosis and genetics of hereditary spastic paraplegias

Even before the advent of next generation sequencing (NGS), multiple loci for hereditary spastic paraplegias (HSPs) had already been identified. In the last 2 years, dozens of new disease genes have been added, accounting for a total of 52 established HSP loci and 35 known HSP disease genes. With overlapping phenotypes for distinct genetic entities, the clinical diagnosis is often demanding and high-throughput genetic testing has to parallel a diagnostic workflow. Notwithstanding this aspect, spastin (SPAST) mutations evidently constitute the most important genetic cause in autosomal dominant paraplegia 4 (SPG4). Recently, large studies established that SPAST mutations are even causative in roughly 10% of sporadic HSP patients. In this review, we suggest a diagnostic routine for HSP and elaborate on how detailed phenotyping and extensive genotyping will assist in the diagnosis of many more HSP subtypes. This ultimately will set a basis for selective clinical observations and therapy development.