Molecular Genetics of Hereditary Spastic Paraplegias

Abstract

Hereditary spastic paraplegias (HSPs), also known as Strümpell–Lorrain disease, are rare neurological conditions characterised by gradual spasticity and weakness of the lower limbs caused by developmental failure and/or degeneration of motor neuron axons in the corticospinal tract. The course is generally slowly progressive, with considerable variation in age at onset and severity of spasticity. There are also complex forms of HSPs, with additional neurological features or extraneurological signs. HSPs are transmitted according to all classical modes of inheritance and are extremely heterogeneous genetically as >80 causative genes or loci have been identified. The altered cellular functions include mainly intracellular trafficking, endoplasmic reticulum shaping, lipid metabolism and mitochondrial functions. The multiple inheritance modes and phenotypic presentation of several HSP genes together with the clinical and genetic overlap of HSPs with other neurological disorders complicate greatly their diagnosis in clinical practice. Key Concepts Hereditary spastic paraplegias are among the most highly heterogeneous neurodegenerative disorders. The clinical presentation in patients can be pure or complex, variably associating additional, neurological and nonneurological signs. Mutations or genomic rearrangements in >80 genes/loci can lead to spastic paraplegia. Their diagnosis in clinical practice is complicated by (1) their heterogeneity, (2) the multiple inheritance modes of some of the genes involved and (3) by their overlap with other neurological disorders in terms of phenotype and causative genes, calling for a new nosology. A relatively small number of functions are altered in these diseases, mainly intracellular trafficking, endoplasmic reticulum shaping, lipid metabolism and mitochondrial functions. Only few biological markers can be used in clinical practice for follow‐up and diagnosis confirmation.