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.

Keywords: hereditary spastic paraplegia; spasticity; intracellular transport; mitochondria; trafficking; motor neuron diseases

Figure 1.

Relative frequencies of the most frequent autosomal spastic paraplegia entities. ARSACS, autosomal recessive spastic ataxia of Charlevoix–Saguenay.

Figure 2.

Molecular diagnosis strategy according to the phenotype and the mode of transmission. SCA, spinocerebellar ataxia; ARSACS, autosomal recessive spastic ataxia of Charlevoix–Saguenay.

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Stevanin, Giovanni(Sep 2010) Molecular Genetics of Hereditary Spastic Paraplegias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022419]