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 usually caused by developmental failure or degeneration of motor 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 HSP, with additional neurological features or extra‐neurological signs. HSPs are transmitted according to all modes of inheritance, and 21 of the 43 genes localised have been identified. In recent years, genetic studies have shown abnormal membrane trafficking, axonal transport, cholesterol homeostasis and mitochondrial dysfunction to be the major physiopathological mechanisms in HSP. A new classification is now emerging taking into account clinical, genetic and pathological mechanisms. 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 non‐neurological signs. Mutations or genomic rearrangements in at least 43 genes can lead to spastic paraplegia. Intracellular trafficking and maintenance of axon/myelin are the main systems altered in these diseases.

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

“…SPG3, SPG4, SPG7, SPG8, SPG10, SPG11, SPG31) [22] and a rational diagnostic scheme is used according to the clinical and genealogical criteria mentioned above (Fig. 1) [156]. Screening for SPG mutations is usually carried out by direct Sanger sequencing coupled with multiplex ligation-dependent probe amplification [157] in several genes.…”