Spastic Paraplegia 5A, Autosomal Recessive

Alternative Names

  • SPG5A
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WHO-ICD-10 version:2010

Diseases of the nervous system

Systemic atrophies primarily affecting the central nervous system

OMIM Number

270800

Mode of Inheritance

Autosomal recessive

Gene Map Locus

8p12-q13

Description

Hereditary Spastic Paraplegias (SPG) are a group of disorders characterized by progressive spasticity of the lower extremities. There are several subtypes of SPGs, each with a distinct genetic locus responsible for the condition. SPG5A is an uncomplicated or 'pure' form of spastic paraplegia. In this form, the spasticity is limited to the lower extremities, and is accompanied with urinary bladder disturbance, and mild reduction of lower extremity vibration sensation as well as joint position sensation. Patients experience progressive difficulty in walking. However, the upper extremities of these patients remain unaffected, and they retain normal strength and dexterity. In addition, no involvement of speech, chewing, or swallowing can be noticed. SPG5A has its age of onset from anywhere between 1 and 20-years of age.

SPGs are diagnosed based on the clinical symptoms. The diagnosis can be complicated by several other disorders that share similar features. Differential diagnoses include Lou Gehrig's disease, Vitamin B12 Deficiency, and Multiple Sclerosis, among others. Although the gene responsible for SPG5A is known, genetic testing is not available at this point of time. Similarly, no specific treatment is available for SPG. Focus of treatment is at relief of symptoms and physical therapy for improving muscle strength and mobility. SPG5A is compatible with a normal life span, although it does cause debilitations. Patients often require canes, walkers, or wheelchairs.

 

Molecular Genetics

Initial studies of SPG5A indicated that the disorder was linked to chromosome 8. Using refined markers more detailed studies identified the exact locus as the cytochrome P450-7B1 (CYP7B1) gene. CYP7B1 plays a role in cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. It is therefore, believed that the altered cholesterol metabolism is what leads to the development of this motor-neuron degenerative disease.

Epidemiology in the Arab World

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Other Reports

Jordan

El-Shanti et al. (1999) described a large multigenerational inbred family with pure familial spastic paraplegia. The two male probands of this family (aged 14 and 60-years old) were noticed to have gait problems (tip-toe walking in the younger and shuffling gait in the older subject); neither had any hearing difficulty or urinary sphincteric symptoms. Deep tendon reflexes were exaggerated in the lower limbs, although they were normal in the upper limbs. The younger patient had normal muscle power and tone all over, while the older patient showed reduced muscle power in the lower limbs. Detailed examination of the family was performed and a pedigree constructed spanning 10 generations of the family, including about 240 individuals, 50 of who were found to be affected. A total of 43 members of this family (24 males, 19 males) were examined, and 13 of them were found to be affected. All affected members were symptomatic, but had purely motor symptoms without any sensory involvement. The upper limbs were uninvolved in all of the patients. The plantar reflex was normal in younger patients, whereas those in the advanced stage of the disease had an obvious extensor response. All those affected showed the presence of ankle clonus. Interestingly, nine of the affected patients, including one of the probands, showed increased muscle bulk of the calf, similar to Duchenne Muscular Dystrophy. The pedigree analysis supported both autosomal recessive mode of inheritance and autosomal dominant mode with incomplete penetrance or variable expressivity. El-Shanti et al. (1999) also noted that the younger generations seemed to have an earlier age of disease onset than the older generations.

Kuwait

Alhasel et al. (2004) described two Kuwaiti brothers affected with a pure form of HSP. The parents were second cousins. The proband was 41-years old when diagnosed. He presented with a 3-year history of slowly progressive lower limb weakness, and stiffness, with no involvement of the upper limbs or sensory functions. Upon examination, he was found to have spastic paraparesis, hyperreflexia, clonus of both ankle and knee jerks, and upgoing plantar reflexes, with normal nerve conduction studies. His 34-year old brother also showed similar features and symptoms, and both were diagnosed with HSP. Eighteen months after this diagnosis, the patient was readmitted following ascending paresthesia of all limbs, and increasing muscle weakness of the lower limbs. Both upper and lower limbs showed flaccid weakness. There was total areflexia of all four limbs and plantar reflexes were absent. Conduction studies revealed absence of H reflex bilaterally, prolongation of terminal motor latencies and F-wave latencies, and slowing of motor conduction of all tested nerves. The results were suggestive of Guillain Barre syndrome, which was confirmed by nerve biopsy. The condition responded very well to intravenous immunoglobulin.

Tunisia

Hentati et al. (1994) studied five Tunisian families with 'pure' autosomal recessive HSP. Linkage analysis in four of these families showed a tight linkage between the disorder and markers on chromosome 8 (D8S260, D8S166, D8S285, PLAT, and D8S279). As PLAT and D8S166 had been mapped to 8p12 and 8cen-q13, respectively, Hentati et al. (1994) gave the paracentric region of chromosome 8 as the likely location of the SPG5A locus. However, the fifth family did not show any linkage to the markers, indicating genetic heterogeneity. Later, Tsaousidou et al. (2008) identified homozygous mutations in the the cytochrome P450-7B1 (CYP7B1) gene in some of the families reported by Hentati et al. (1994). The findings indicated a primary metabolic route for the modification of neurosteroids in the brain and a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease.

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