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  • Updated 11.20.2020
  • Released 11.12.2003
  • Expires For CME 11.20.2023

Hereditary spastic paraplegia

Introduction

Overview

Hereditary spastic paraplegia (HSP) is the name given to a group of diseases that are heterogenous and inherited, in which the main clinical feature is progressive spasticity of the lower limbs.

Key points

• Hereditary spastic paraplegias are a heterogeneous group of disorders that can be categorized into “pure” or “complex” forms based on the presence or absence of significant additional neurologic or extraneurologic abnormalities.

• Over 80 genetic types have been described with all patterns of inheritance seen.

• Genetic mutations affect many different biological functions, including axonal transport, mitochondrial functions, fatty acid and cholesterol pathways and DNA repair defects, causing hereditary spastic paraplegia.

• Significant overlap exists between hereditary spastic paraplegia and other neurodegenerative disorders both from a clinical and genetic perspective.

• Diagnosis is by clinical history, neurologic examination, investigations, neuroimaging, molecular genetic testing, and exclusion of the alternative differential diagnoses.

• Treatment is largely supportive with the hope that increasing knowledge regarding the genetics and pathogenesis of these disorders will translate into effective therapeutic strategies.

Historical note and terminology

The original description of hereditary spastic paraplegia was made by Strümpell in 1880. He described “a pure spastic movement disorder of the legs” in 2 brothers who developed a spastic gait at the ages of 37 and 56 years. Their father was said to be “a little lame,” suggesting that the mode of inheritance might be autosomal dominant (268). He later defined additional cases and described the pathological changes of the spinal cord, especially the degeneration of the pyramidal tracts. At the end of 19th century, Lorrain published 3 cases with similar clinical features (159). The disease was also called Strümpell-Lorrain syndrome. Many cases with additional neurologic features were added to the literature, and many case reports seem to have given different names to possibly the same disease.

In 1981, Harding studied the clinical and genetic patterns of 22 families with pure hereditary spastic paraplegias. Pure hereditary spastic paraplegia (Strümpell disease) was then divided into 3 forms according to the mode of inheritance: autosomal dominant, autosomal recessive, or X-linked recessive. In 1983, Harding published an article in the Lancet journal, “Classification of hereditary ataxias and paraplegias”. The classification of hereditary spastic paraplegias into pure and complicated forms was then formally proposed.

Pure hereditary spastic paraplegia was then subdivided into 2 groups, “type I” and “type II” according to the age of onset:

• Type I autosomal dominant hereditary spastic paraplegia was defined as having early onset (younger than 35 years) with slow, progressive symptoms and spasticity that was more marked than muscle weakness. Most patients remain ambulatory for most of their lives, with only few requiring a wheelchair in old age.

• Type II hereditary spastic paraplegia was defined as having late onset (older than 35 years), with rapidly developing muscle weakness that was more prominent than spasticity. Most patients lost the ability to walk by 60 to 70 years of age. In addition, it was noted that autosomal recessive pure forms were almost always early onset, and the severity of the dominant and recessive forms did not differ (217).

In 1996, Fink and colleagues offered a useful subclassification based on the mode of inheritance and the chromosomes patients showed linkages to (eg, autosomal dominant chromosome 2p-linked, uncomplicated hereditary spastic paraplegia) (87). They also suggested an alternative classification of the Genome Database designation for X-linked and autosomal hereditary spastic paraplegia loci, like SPG1, SPG2 (X-linked), and SPG3 (chromosome 14q). The numbers given are generally in the order of their discovery, but some designations have been reserved for unpublished loci (83). The modern genetic classification is based on the mode of inheritance, chromosomal locus, and the causative mutation, if identified.

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