Spastic Paraplegia 3, Autosomal Dominant

Alternative Names

  • SPG3A
  • SPG3
  • Strumpell Disease
  • Familial Spastic Paraplegia, Autosomal Dominant, 1
  • FSP1
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WHO-ICD-10 version:2010

Diseases of the nervous system

Systemic atrophies primarily affecting the central nervous system

OMIM Number

182600

Mode of Inheritance

Autosomal dominant

Gene Map Locus

14q22.1

Description

The familial spastic paraplegias (FSP) are a group of heterogeneous inherited disorders characterized by progressive lower limb spasticity. The main feature of the disease is progressive weakening and stiffening of the legs, leading to a difficulty in walking or gait disturbances. This is especially true of pure familial spastic paraplegias. However, complex spastic paraplegias may involve other features, including dementia, ataxia, mental retardation, ichthyosis, peripheral neuropathy, distal amyotrophy, retinal changes, and/or hearing loss. The FSPs can be classified according to their mode of inheritance, and further, based on the exact gene defect. SPG3A, or Spastic Paraplegia 3A is an autosomal dominant form of the condition, that usually presents itself within the first or second decades of life. Patients with this form of FSP do not show involvement of any bladder or sensory complications.

The FSPs are diagnosed based on exclusion of all other diagnoses. Differential diagnoses include spinocerebellar ataxias, multiple sclerosis, motor neuron disease, and infectious spastic paraparesis. Although there is no specific treatment for the condition, management is possible by means of regular physical therapy. Medication may also help in reducing the spasticity. Prognosis for the condition also varies according to the severity of the condition. Generally, patients have a normal life expectancy, although the quality of life may be impacted for those with the severe form of the disease.

Mutations in SPG3A (ATL1; Atlastin GTPase 1) gene was identified to be associated with autosomal dominant form of spastic paraplegia. Mutations in SPAST (Spastin) gene are also known to cause autosomal dominant spastic paraplegia in patients with onset age lower than 10 years.

Molecular Genetics

Autosomal dominant spastic paraplegia may be caused due to defects in one of many genetic loci. These include the Spastin, NIPA1 (Nonimprinted Gene in Prader-Willi Syndrome/Angelman Syndrome Chromosome Region 1), KIAA0196 (Strupellin), SSPD1 (Heat-Shock 60-Kd Protein 1), REEP1 (Receptor Expression-Enhancing Protein 1), and ZFYVE27 (Zinc Finger FYVE Domain-Containing Protein 27) genes.

The SPG3 locus was the first locus to be identified with an autosomal dominant form of spastic paraplegia. This locus, on chromosome 14q, was narrowed down to a region of 7cM. The SPG3A gene codes for a GTPase and a Golgi body transmembrane protein, which has been shown to interact with both spastin as well as a mitogen activated protein kinase. It is speculated that this interaction plays a major role in axonal maintenance.

Epidemiology in the Arab World

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Other Reports

Jordan

El-Shanti et al. (1999) identified a large inbred family with several members in multiple generations affected with pure familial spastic paraplegia. The two probands of the family were a 14-year and a 60-year old males. The younger of the two presented with tip-toe walking, which he started in the first year of his life. He had normal muscle tone all over. The older proband started with a shuffling gait in the second decade of his life. This patient had normal muscle tone in the upper limbs, but reduced power and hypotonia in the lower limbs. Both probands had exaggerated deep tendon reflexes in the lower limbs with sustained ankle clonus. All other examinations, including head and spine CT and MRI, EMG, NCS, and ophthalmologic examinations were normal. Only the elder proband showed a plantar reflex that went up bilaterally. Of the entire pedigree, 43 individuals belonging to ten generations were examined. Of these, 13 (9 males, 4 females) were found to be affected. All of these patients were symptomatic. Nine of them presented with pseudohyperthrophy of the calf muscles. A further five family members were classified as possibly affected, based on the findings of gait change in the form of intoeing, and hyperreflexia of the lower extremities. El-Shanti et al. (1999) pointed out the unique features associated with the disease condition in this family including the absence of any sensory involvement, absence of urinary symptoms, normal plantar reflex in patients with a short course of the disease, presence of ankle clonus, and a tendency for pseudohyperthrophy of the calf muscles. Although El-Shanti et al. (1999) could not accurately define the mode of inheritance of the condition in the family, they remarked that both an autosomal dominant model with incomplete penetrance as well as an autosomal recessive model could fit. The autosomal dominant mode was further supported by the tendency for anticipation seen in the family.

Tunisia

Ben Hamida et al. (1986) conducted a genetic study of spinocerebellar hereditary degenerations in Tunisiain 101 genealogical trees of families with spinocerebellar heredo-degeneration. A dominant mode of transmission has been observed in 13 families affected by familial spastic paraplegia (Strumpell-Lorrain). It has also been observed that the consanguinity rate among this group of families is very high (61%) compared with that of the general Tunisian population (25%).

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