Hereditary spastic paraplegia

Daniela Lanzlinger MBBS (

Dr. Lanzlinger of the University of British Columbia has no relevant financial relationships to disclose.

)
Anita Datta MD (Dr. Datta of the University of British Columbia has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.

)
Originally released November 12, 2003; last updated November 28, 2018; expires November 28, 2021

This article includes discussion of hereditary spastic paraplegia, SPG, hereditary spastic paraparesis, familial spastic paraplegia, familial spastic paraparesis, Strümpell disease, Strumpell disease, Strumpell Lorrain disease, Strumpell Lorrain syndrome, pure hereditary spastic paraplegia, complicated hereditary spastic paraplegia, autosomal recessive hereditary spastic paraplegias, autosomal dominant hereditary spastic paraplegias, and X-linked hereditary spastic paraplegias. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

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. Autosomal dominant forms are the most common and are mainly caused by SPAST, ATL1, and REEP1 pathogenic variants. Autosomal recessive, X-linked, and mitochondrial forms also exist.

 

• How different genes with many different biological functions, including axonal transport, mitochondrial functions, fatty acid and cholesterol pathways and DNA repair defects, cause hereditary spastic paraplegia is still largely unknown.

 

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

 

• 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

Hereditary spastic paraplegia 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. 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 (Strumpell 1880). 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 (Lorrain 1898). 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 reviewed a clinical and genetic study of 22 families with pure hereditary spastic paraplegias, and she devised the “type I” and “type II” clinical classifications of pure autosomal dominant spastic paraplegia. Type I autosomal dominant 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. Type II was defined as having late onset (older than 35 years), with rapidly developing symptoms and muscle weakness that was more prominent than spasticity. She also noted that autosomal recessive pure forms were almost always early onset, and the severity of the dominant and recessive forms did not differ. In 1983, Harding published a classification of hereditary ataxias and paraplegias, and she classified hereditary spastic paraplegias into pure and complicated forms (Harding 1983). 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 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) (Fink et al 1996). 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). They are generally designated in the order of their discovery, but some designations have been reserved for unpublished loci (Fink 2004).

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