The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Inheritance is most often autosomal dominant ... The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Inheritance is most often autosomal dominant (see 182600), but X-linked (see 303350) and autosomal recessive forms also occur. Autosomal recessive forms of SPG include SPG7 (607259), caused by mutation in the paraplegin gene (602783) on chromosome 16q24; SPG11 (604360), caused by mutation in the spatacsin gene (610844) on 15q21; SPG15 (270700), caused by mutation in the ZFYVE26 (612012) on 14q24; SPG18 (611225), caused by mutation in the ERLIN2 gene (611605) on 8p11; SPG20 (275900), caused by mutation in the spartin gene (607111) on 13q12; SPG21 (248900), caused by mutation in the maspardin gene (608181) on 15q21; SPG26 (609195), caused by mutation in the B4GALNT1 gene (601873) on 12q13; SPG28 (609340), caused by mutation in the DDHD1 gene (614603) on 14q22; SPG30 (610357), caused by mutation in the KIF1A gene (601255) on 2q37; SPG35 (612319), caused by mutation in the FA2H gene (611026) on chromosome 16q23; SPG39 (612020), caused by mutation in the PNPLA6 gene (603197) on 19p13.3; SPG44 (613206), caused by mutation in the GJC2 gene (608803) on 1q41-q42; SPG46 (614409), caused by mutation in the GBA2 gene (609471) on 9p13; SPG48 (613647), caused by mutation in the KIAA0415 gene (613653) on 7p22.1; SPG49 (615031) caused by mutation in the TECPR2 gene (615000) on 14q32; SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on 8p11; SPG55 (615035), caused by mutation in the C12ORF65 gene on 12q24; and SPG56 (615030), caused by mutation in the CYP2U1 gene (610670) on 4q25. Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; 605229), 13q14 (SPG24; 607584), 6q (SPG25; 608220), 10q22 (SPG27; 609041), 19p13.11-q12 (SPG43; 615043), and 10q24.3-q25.1 (SPG45; 613162).
Recessive cases of SPG were described by Freud (1893) and by Jones (1907). Bell and Carmichael (1939) found probable recessive inheritance in 49 of 74 pedigrees. Allport (1971) briefly described 4 of 8 sibs with spastic paraparesis and ... Recessive cases of SPG were described by Freud (1893) and by Jones (1907). Bell and Carmichael (1939) found probable recessive inheritance in 49 of 74 pedigrees. Allport (1971) briefly described 4 of 8 sibs with spastic paraparesis and mental retardation. In an inbred kindred from rural Louisiana, Rothschild et al. (1979) reported nonataxic spastic paraplegia of late onset (in the 20s or later). Present also were dysarthria, impaired vibratory sense in the legs, impaired function of cranial nerves IX, X and XII, and, by special testing, impaired visual pathways and vibratory sense in the arms. Six living patients in 4 sibships from consanguineous parents were studied. Ten deceased family members reportedly had the same disorder. Wilkinson et al. (2003) reported a large consanguineous English family in which 6 sibs were affected with uncomplicated autosomal recessive SPG. The phenotype was characterized by severe lower limb spasticity, variable lower limb weakness, hyperreflexia, posterior column sensory impairment, and bladder dysfunction; age at onset ranged from 8 to 40 years. Goizet et al. (2009) reported 6 unrelated families with SPG5A and 3 patients with sporadic occurrence of SPG5A. The patients were from France, Portugal, Tunisia, and Algeria. Age at onset ranged from 4 to 47 years (mean of 16.4), and all presented with gait difficulties. All developed moderate to severe spastic paraplegia of the lower extremities after a mean disease duration of 28.3 years. Eleven (69%) of 16 patients had a severe handicap, with 6 (38%) being wheelchair-bound, and 15 of 16 had distal sensory impairment. Other features included bladder dysfunction (63%) and pes cavus (44%). Most had a pure form of the disorder, but some showed cerebellar signs of mild upper limb dysmetria and saccadic pursuit, or cerebral atrophy. Three patients from 2 families had white matter hyperintensitites on brain MRI. Biancheri et al. (2009) reported 2 Italian brothers with SPG5A confirmed by genetic analysis (G57R; 603711.0003). The 20-year-old proband had a history of delayed walking, difficulty walking and running in childhood, and worsening of the disorder in his teens. Physical examination showed spastic paraparesis, but he could walk unaided. Mild urinary urgency was present. Brain MRI showed white matter changes in the supra and infratentorial compartment as well as spinal cord thinning, without signal abnormalities. His affected brother lost the ability to walk independently at age 19, and brain MRI showed similar, but milder, white matter changes. These were the first reports of white matter changes in SPG5A. Biancheri et al. (2009) noted that the CYP7B1 gene is involved in cholesterol and neurosteroid metabolism in the brain, which could be related to the white matter changes.
In affected individuals of 5 families with autosomal recessive SPG5A, Tsaousidou et al. (2008) identified homozygous mutations in the CYP7B1 gene (603711.0002-603711.0005). Some of the families had previously been reported by Wilkinson et al. (2003) and Hentati et ... In affected individuals of 5 families with autosomal recessive SPG5A, Tsaousidou et al. (2008) identified homozygous mutations in the CYP7B1 gene (603711.0002-603711.0005). Some of the families had previously been reported by Wilkinson et al. (2003) and 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. Biancheri et al. (2009) identified a mutation in the CYP7B1 gene (G57R; 603711.0003) in 1 (8%) of 12 families with autosomal recessive SPG, suggesting that it is a relatively uncommon cause of the disorder. Goizet et al. (2009) identified 8 different mutations, including 6 novel mutations, in the CYP7B1 gene (see, e.g., 603711.0007 and 603711.0008) in 6 (7.3%) of 82 unrelated kindreds with autosomal recessive SPG and in 3 (3.3%) of 90 individuals with sporadic SPG.