Online Mendelian Inheritance in Man (OMIM) (original) (raw)

TEXT

A number sign (#) is used with this entry because spastic paraplegia-5A (SPG5A) is caused by homozygous or compound heterozygous mutation in the CYP7B1 gene (603711) on chromosome 8q12.

Description

Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by Arnoldi et al., 2012).

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.

Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia

Autosomal recessive forms of SPG include SPG7 (607259), caused by mutation in the paraplegin gene (602783) on chromosome 16q24; SPG9B (616586), caused by mutation in the ALDH18A1 gene (138250) on 10q24; SPG11 (604360), caused by mutation in the spatacsin gene (610844) on 15q21; SPG15 (270700), caused by mutation in the ZFYVE26 gene (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 16q23; SPG39 (612020), caused by mutation in the PNPLA6 gene (603197) on 19p13; SPG43 (615043), caused by mutation in the C19ORF12 gene (614297) on 19q12; SPG44 (613206), caused by mutation in the GJC2 gene (608803) on 1q42; SPG45 (613162), caused by mutation in the NT5C2 gene (600417) on 10q24; SPG46 (614409), caused by mutation in the GBA2 gene (609471) on 9p13; SPG48 (613647), caused by mutation in the KIAA0415 gene (613653) on 7p22; SPG50 (612936), caused by mutation in the AP4M1 gene (602296) on 7q22; SPG51 (613744), caused by mutation in the AP4E1 gene (607244) on 15q21; SPG52 (614067), caused by mutation in the AP4S1 gene (607243) on 14q12; SPG53 (614898), caused by mutation in the VPS37A gene (609927) on 8p22; SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on 8p11; SPG55 (615035), caused by mutation in the MTRFR gene on 12q24; SPG56 (615030), caused by mutation in the CYP2U1 gene (610670) on 4q25; SPG57 (615658), caused by mutation in the TFG gene (602498) on 3q12; SPG61 (615685), caused by mutation in the ARL6IP1 gene (607669) on 1p12; SPG62 (615681), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (615686), caused by mutation in the AMPD2 gene (102771) on 1p13; SPG64 (615683), caused by mutation in the ENTPD1 gene (601752) on 10q24; SPG72 (615625), caused by mutation in the REEP2 gene (609347) on 5q31; SPG74 (616451), caused by mutation in the IBA57 gene (615316) on 1q42; SPG75 (616680), caused by mutation in the MAG gene (159460) on 19q13; SPG76 (616907), caused by mutation in the CAPN1 gene (114220) on 11q13; SPG77 (617046), caused by mutation in the FARS2 gene (611592) on 6p25; SPG78 (617225), caused by mutation in the ATP13A2 gene (610513) on 1p36; SPG79 (615491), caused by mutation in the UCHL1 gene (191342) on 4p13; SPG81 (618768), caused by mutation in the SELENOI gene (607915) on 2p23; SPG82 (618770), caused by mutation in the PCYT2 gene (602679) on 17q25; SPG83 (619027), caused by mutation in the HPDL gene (618994) on 1p34; SPG84 (619621), caused by mutation in the PI4KA gene (600286) on 22q11; SPG85 (619686), caused by mutation in the RNF170 gene (614649) on 8p11; SPG86 (619735), caused by mutation in the ABHD16A gene (142620) on 6p21; SPG87 (619966), caused by mutation in the TMEM63C gene (619953) on 14q24; SPG89 (620379), caused by mutation in the AMFR gene (603243) on 16q13; SPG90B (620417), caused by mutation in the SPTSSA gene (613540) on 14q13; SPG92 (620911), caused by mutation in the FICD gene (620875) on chromosome 12q23; and SPG93 (620938), caused by mutation in the NFU1 gene (608100) on chromosome 2p13.

Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; 605229), 13q14 (SPG24; 607584), 6q (SPG25; 608220), and 10q22 (SPG27; 609041).

A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; 615031).

Clinical Features

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). Features included 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 hyperintensities 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.

Arnoldi et al. (2012) reported 2 adult sisters of Italian descent with pure SPG5A. Despite having the same genotype (see 603711.0009), the patients had marked variation in disease severity. One sister had onset at age 10 years of severe lower limb spasticity and developed mild sensory disturbances in the lower limbs, whereas the other had onset of mild spasticity at age 30 years. Brain MRI of both sisters showed similar diffuse white matter abnormalities. Functional studies of the variants were not performed.

Inheritance

The transmission pattern of spastic paraplegia in the families reported by Hentati et al. (1994) was consistent with autosomal recessive inheritance.

Mapping

Hentati et al. (1994) did genetic linkage analysis in 5 Tunisian families with 'pure' autosomal recessive familial spastic paraplegia. In 4 of the 5 families, tight linkage of the disease locus to 5 chromosome markers was established. Exclusion of linkage in the fifth family demonstrated genetic heterogeneity. Crossovers mapped the disease locus to a site between PLAT (173370) and D8S279, a 32.2-cM region containing 2 of the loci that were linked without crossovers, D8S166 and D8S260. 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. (The disorder in the family that was unlinked to chromosome 8 was earlier designated in OMIM as SPG5B.)

By linkage analysis of a consanguineous English family with autosomal recessive SPG, Wilkinson et al. (2003) identified linkage to SPG5A (maximum multipoint lod score of 4.84). The locus was refined to a 23.6-cM interval between markers D8S1833 and D8S285 on chromosome 8q11.1-q21.2. No evidence of oxidative phosphorylation defects was found in muscle biopsies from 2 affected individuals.

Linkage analysis of 4 Italian families with autosomal recessive SPG enabled Muglia et al. (2004) to further refine the candidate SPG5A locus to an 11-cM region on 8q between markers D8S285 and D8S544 (maximum 2-point lod score of 3.99 at marker D8S260). Sequence analysis excluded mutations in the TOX (606863), SDCBP (602217), RAB2 (179509), CA8 (114815), and PENK (131330) genes.

Molecular Genetics

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.

In 4 of 105 Italian probands with pure or complicated hereditary spastic paraplegia, Arnoldi et al. (2012) identified biallelic mutations in the CYP7B1 gene (see, e.g., 603711.0009 and 603711.0010). Two patients had a pure form of the disorder, and 2 had a complicated form with nystagmus, dysarthria, and sensorineural hearing loss in one and cataract and mild cognitive impairment in the other. All 4 patients had white matter abnormalities on brain MRI. Functional analysis of the variants was not performed.

Associations Pending Confirmation

For discussion of a possible association between autosomal recessive spastic paraplegia and biallelic variation in the SPTAN1 gene, see 182810.0010-182810.0012.

REFERENCES

  1. Aagenaes, O.Hereditary spastic paraplegia: a family with ten injured. Acta Psychiat. Scand. 34: 489-494, 1959. [PubMed: 13791321] [Full Text: https://doi.org/10.1111/j.1600-0447.1959.tb07537.x\]
  2. Allport, R. B.Mental retardation and spastic paraparesis in four of eight siblings. (Letter) Lancet 298: 1089 only, 1971. Note: Originally Volume II. [PubMed: 4106928] [Full Text: https://doi.org/10.1016/s0140-6736(71)90402-8\]
  3. Arnoldi, A., Crimella, C., Tenderini, E., Martinuzzi, A., D'Angelo, M. G., Musumeci, O., Toscano, A., Scarlato, M., Fantin, M., Bresolin, N., Bassi, M. T.Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin. Genet. 81: 150-157, 2012. [PubMed: 21214876] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01624.x\]
  4. Bell, J., Carmichael, E. A.On the heredity of ataxia and spastic paraplegia. In: Treasury of Human Inheritance. Vol. 4. Part 3. London: Cambridge Univ. Press (pub.) 1939. Pp. 169-172.
  5. Biancheri, R., Ciccolella, M., Rossi, A., Tessa, A., Cassandrini, D., Minetti, C., Santorelli, F. M.White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1. Neuromusc. Disord. 19: 62-65, 2009. [PubMed: 19187859] [Full Text: https://doi.org/10.1016/j.nmd.2008.10.009\]
  6. Fink, J. K., Heiman-Patterson, T., Bird, T., Cambi, F., Dube, M.-P., Figlewicz, D. A., Haines, J. L., Hentati, A., Pericak-Vance, M. A., Raskind, W., Rouleau, G. A., Siddique, T.Hereditary spastic paraplegia: advances in genetic research. Neurology 46: 1507-1514, 1996. [PubMed: 8649538] [Full Text: https://doi.org/10.1212/wnl.46.6.1507\]
  7. Fink, J. K.Advances in hereditary spastic paraplegia. Curr. Opin. Neurol. 10: 313-318, 1997. [PubMed: 9266155] [Full Text: https://doi.org/10.1097/00019052-199708000-00006\]
  8. Freud, S.Ueber familiaere Formen von cerebralen Diplegien. Neurol. Centrabl. (Mendel) 12: 512-515 and 542-547, 1893.
  9. Goizet, C., Boukhris, A., Durr, A., Beetz, C., Truchetto, J., Tesson, C., Tsaousidou, M., Forlani, S., Guyant-Marechal, L., Fontaine, B., Guimaraes, J., Isidor, B., and 14 others.CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 132: 1589-1600, 2009. [PubMed: 19439420] [Full Text: https://doi.org/10.1093/brain/awp073\]
  10. Hentati, A., Pericak-Vance, M. A., Hung, W.-Y., Belal, S., Laing, N., Boustany, R.-M., Hentati, F., Ben Hamida, M., Siddique, T.Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum. Molec. Genet. 3: 1263-1267, 1994. [PubMed: 7987300] [Full Text: https://doi.org/10.1093/hmg/3.8.1263\]
  11. Holmes, G. L., Shaywitz, B. A.Strumpell's pure familial spastic paraplegia: case study and review of the literature. J. Neurol. Neurosurg. Psychiat. 40: 1003-1008, 1977. [PubMed: 591968] [Full Text: https://doi.org/10.1136/jnnp.40.10.1003\]
  12. Jones, E.Eight cases of hereditary spastic paraplegia. Rev. Neurol. 5: 98-106, 1907.
  13. Muglia, M., Criscuolo, C., Magariello, A., De Michele, G., Scarano, V., D'Adamo, P., Ambrosio, G., Gabriele, A. L., Patitucci, A., Mazzei, R., Conforti, F. L., Sprovieri, T., Morgante, L., Epifanio, A., La Spina, P., Valentino, P., Gasparini, P., Filla, A., Quattrone, A.Narrowing of the critical region in autosomal recessive spastic paraplegia linked to the SPG5 locus. Neurogenetics 5: 49-54, 2004. [PubMed: 14658060] [Full Text: https://doi.org/10.1007/s10048-003-0167-7\]
  14. Rothschild, H., Happel, L., Rampp, D., Hackett, E.Autosomal recessive spastic paraplegia: evidence for demyelination. Clin. Genet. 15: 356-360, 1979. [PubMed: 436332] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb01746.x\]
  15. Skre, H.Hereditary spastic paraplegia in Western Norway. Clin. Genet. 6: 165-183, 1974. [PubMed: 4426134] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb00647.x\]
  16. Tsaousidou, M. K., Ouahchi, K., Warner, T. T., Yang, Y., Simpson, M. A., Laing, N. G., Wilkinson, P. A., Madrid, R. E., Patel, H., Hentati, F., Patton, M. A., Hentati, A., Lamont, P. J., Siddique, T., Crosby, A. H.Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am. J. Hum. Genet. 82: 510-515, 2008. [PubMed: 18252231] [Full Text: https://doi.org/10.1016/j.ajhg.2007.10.001\]
  17. Wilkinson, P. A., Crosby, A. H., Turner, C., Patel, H., Wood, N. W., Schapira, A. H., Warner, T. T.A clinical and genetic study of SPG5A linked to autosomal recessive hereditary spastic paraplegia. Neurology 61: 235-238, 2003. [PubMed: 12874406] [Full Text: https://doi.org/10.1212/01.wnl.0000069920.42968.8d\]