Molecular Genetics of Hereditary Spastic Paraplegias

Abstract

Hereditary spastic paraplegias (HSPs) are a group of single‐gene disorders in which the axons of the corticospinal tract either fail to develop normally or undergo progressive degeneration. The main clinical feature of all HSPs is a bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities, which occurs in relative isolation in pure or uncomplicated HSPs (PHSPs) or in combination with other features in complicated HSPs (CHSPs). So far, about 40 different chromosomal HSP loci have been identified by genetic linkage analysis and an increasing number of gene mutations are being identified, representing one of the most significant examples of genetic heterogeneity. Autosomal and X‐linked patterns of inheritance, both dominant and recessive, have been described. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis.

Key Concepts:

  • Hereditary spastic paraplegias (HSP) are a group of single‐gene disorders characterized by bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities (pure or uncomplicated HSPs).

  • The phenotype can be complicated by additional features (complicated HSPs).

  • HSPs affect 1/10 000 individuals.

  • Pathogenesis depends on abnormalities in intracellular trafficking, trasnsport and endocytosis, neural cell recognition and signalling, myelination and mitochondrial proteins.

  • About 40 different chromosomal loci and 20 genes have been identified indicating the extraordinarly strong genetic heterogeneity.

  • Patterns of inheritance include autosomal and X‐linked, both recessive and dominant.

  • Mutations in Spastin (SPG4) account for approximately 40% of autosomal dominant HSPs, and more then any other HSP defect. Autosomal recessive HSP account for approximately 15–20% of all types of HSPs.

  • Genotype–phenotype correlation and penetrance can be extremely variable even among the same family and/or gene defect.

  • Genetic counselling is particularly challenging because of genetic heterogeneity and should take in consideration pattern of inheritance, geographical epidemiology and clinical evaluation with a multidisciplinary approach.

  • To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.

Keywords: hereditary spastic paraplegia; spastic gait; linkage analysis; genetic heterogeneity; corticospinal tract

Figure 1.

Main cellular‐end neuron‐specific processes implicated in HSP pathogenesis. locus/gene/protein are shown. When locus and gene have the same name only the gene name is indicated. www.drugabuse.gov/JSP/MOD3/page3.html.

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References

Abdallat A, Davis SM and Farrage J (1980) Disordered pigmentation, spastic paraparesis and peripheral neuropathy in three siblings: a new neurocutaneous syndrome. Journal of Neurology, Neurosurgery, and Psychiatry 43: 962–966.

Allan W, Herndon CN and Dudley FC (1944) Some examples of the inheritance of mental deficiency: apparently sex‐linked idiocy and microcephaly. American Journal of Mental Deficiency 48: 325–334.

Antinolo G, Nieto M and Borrego S (1992) Familial spastic paraplegia with neuropathy and poikiloderma. A new syndrome? Clinical Genetics 41: 281–284.

Arnoldi A, Tonelli A and Crippa F (2008) A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Human Mutation 29: 522–531.

Ashley‐Koch A, Bonner ER and Gaskell PC (2001) Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia. Neurogenetics 3: 91–97.

Badhwar A, Jansen AN, Andermann F, Pandolfo M and Andermann E (2004) Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene. Movement Disorders 19(12): 1424–1431.

Bahemuka M and Brown JD (1982) Heredofamilial syndrome of spastic paraplegia, dysarthria and cutaneous lesions in live siblings. Developmental Medicine and Child Neurology 24: 519–524.

Blumen SC, Bevan S, Abu‐Mouch S et al. (2003) A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24‐q32. Annals of Neurology 54: 796–803.

Bonneau D, Rozet JM and Bulteau C (1993) X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. Journal of Medicinal Genetics 30: 381–384.

Bouslam N, Benomar A and Azzedine H (2005) Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Annals of Neurology. 57: 567–571.

Bross P, Li Z and Hansen J (2007) Single nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease causing potential. Journal of Human Genetics 52: 56–65.

Cambi F, Tang XM and Cordray P (1996) Refined genetic mapping and proteolipid protein mutation analysis in X‐linked pure hereditary spastic paraplegia. Neurology 46(4): 1112–1117.

Casari G, De Fusco M and Ciarmatori S (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear‐encoded mitochondrial metalloprotease. Cell 93(6): 973–983.

Casari G and Rugarli E (2001) Molecular basis of inherited spastic paraplegias. Current Opinion in Genetics & Development 11(3): 336–342.

Ciccarelli FD, Proukakis C and Patel H (2003) The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics 81(4): 437–441.

Costeff H, Gadoth N and Apter N (1989) A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology 39: 595–597.

Crippa F, Panzeri C and Martinuzzi A (2006) Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Archives of Neurology 63: 750–755.

Crosby AH and Proukakis C (2002) Is the transportation highway the right road for hereditary spastic paraplegia? American Journal of Human Genetics 71(5): 1009–1016.

Cross HE and McKusick VA (1967a) The Mast syndrome: a recessively inherited form of presenile dementia with motor disturbances. Archives of Neurology 16: 1–13.

Cross HE and McKusick VA (1967b) The Troyer syndrome: a recessive form of spastic paraplegia with distal muscle wasting. Archives of Neurology 16: 473–485.

Dahme M, Bartsch U and Martini R (1997) Disruption of the mouse L1 gene leads to malformations of the nervous system. Nature Genetics 17(3): 346–349.

Dautigny A, Mattei MG, Morello D et al. (1986) The structural gene coding for myelin‐associated proteolipid protein is mutated in jimpy mice. Nature 321(6073): 867–869.

Depienne C, Fedirko E and Forlani S (2007) Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia. Journal of Medicinal Genetics 44: 281–284.

Dick KJ, Al‐Mjeni R and Baskir W (2008) A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21‐q23. Neurology 22, 71(4): 248–252.

Dumitrescu AM, Liao XH and Best TB (2004) A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. American Journal of Human Genetics 74: 168–175.

Edgar JM, Mclaughlin M and Yool D (2004) Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. Journal of Cell Biology 166(1): 121–131.

Errico A, Claudiani P and D'Addio M (2004) Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon. Human Molecular Genetics 13(18): 2121–2132.

Evans K, Keller C and Pavur K (2006) Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance. Proceedings of the National Academy of Sciences of the USA 103(28): 10666–10671.

Eymard‐Pierre E, Lesca G and Dollet S (2002) Infantile‐onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. American Journal of Human Genetics 71(3): 518–527.

Farag TI, El‐Badramany MH and Al‐Sharkawy S (1994) Troyer syndrome: report of the first ‘non‐Amish’ sibship and review. American Journal of Medicinal Genetics 53: 383–385.

Fink JK (2003a) Advances in the hereditary spastic paraplegias. Experimental Neurology 2003(suppl. 1): S106–S110.

Fink JK (2003b) Hereditary spastic paraplegia: nine genes and counting. Archives of Neurology 60: 1045–1049.

Fink JK (2008) Hereditary spastic paraplegia overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2009. Available at http://www.genetests.org.

Fink JK and Rainier S (2004) Hereditary spastic paraplegia: spastin phenotype and function. Archives of Neurology 61(6): 830–833.

Fransen E, Lemmon V and Van Camp G (1995) CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. European Journal of Human Genetics 3: 273–284.

Fransen E, Van Camp G and Vits L (1997) L1‐associated diseases: clinical geneticists divide, molecular geneticists unite. Human Molecular Genetics 6(10): 1625–1632.

Fujii K, Sadoshima S and Kusuda K (1986) Two siblings with familial spastic paraplegia associated with decreased levels of factor XII. Rinshō Shinkeigaku 26: 851–855.

Gilman S and Horenstein S (1964) Familial amyotrophic dystonic paraplegia. Brain 87: 51–66.

Gros‐Louis F, Meijer IA and Hand CK (2003) An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Annals of Neurology 53(1): 144–145.

Gupta S and Knowlton AA (2002) Cytosolic heat shock protein 60, hypoxia, and apoptosis. Circulation 106(21): 2727–2733.

Hanein S, Durr A and Ribai P (2007) A novel locus for autosomal dominant ‘uncomplicated’ hereditary spastic paraplegia maps to chromosome 8p21.1‐q13.3. Human Genetics 122: 261–273.

Hanein S, Martin E and Boukhris A (2008) Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal‐recessive spastic paraplegia, including Kjellin syndrome. American Journal of Human Genetics 82: 992–1002.

Hansen JJ, Durr A and Cournu‐Rebeix I (2002) Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. American Journal of Human Genetics 70(5): 1328–1332.

Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1(8334): 1151–1155.

Hazan J, Fonknechten N, Mavel D et al. (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genetics 23(3): 296–303.

Hedera P, Rainier S, Alvarado D et al. (1999) Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. American Journal of Human Genetics 64(2): 563–569.

Heijbel J and Jagell S (1981) Spastic paraplegia, glaucoma and mental retardation – in three siblings. A new genetic syndrome. Hereditas 94: 203–207.

Hentati A, Pericak‐Vance MA and Hung WY (1994) Linkage of ‘pure’ autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Human Molecular Genetics 3: 1263–1264.

Hodgkinson CA, Bohlega S and Abu‐Amero SN (2002) A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 59: 1905–1909.

Holzbaur EL (2004) Motor neurons rely on motor proteins. Trends in Cell Biology 14(5): 233–240.

Hudson LD, Berndt JA and Puckett C (1987) Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proceedings of the National Academy of Sciences of the USA 84(5): 1454–1458.

Hughes CA, Byrne PC, Webb S et al. (2001) SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q. Neurology 56: 1230–1233.

Inoue K, Osaka H and Kawanishi C (1997) Mutations in the proteolipid protein gene in Japanese families with Pelizaeus‐Merzbacher disease. Neurology 48(1): 283–285.

Joshita Y, Yamamoto Y and Satoh Y (1982) Two siblings of familial spastic paraplegia with retinal pigment degeneration (sine pigment). Rinshō Shinkeigaku 22: 789–794.

Jouet M, Rosenthal A and Armstrong G (1994) X‐linked spastic paraplegia (SPG1), MASA syndrome and X‐linked hydrocephalus result from mutations in the L1 gene. Nature Genetics 7(3): 402–407.

Kenwrick S, Watkins A and De Angelis E (2000) Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Human Molecular Genetics 9(6): 879–886.

Klebe S, Azzedine H and Durr A (2006) Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain 129: 1456–1462.

Lesca G, Eymard‐Pierre E and Santorelli FM (2003) Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. Neurology 60(4): 674–682.

Lison M, Kornbrut B and Feinstein A (1981) Progressive spastic paraparesis, vitiligo, premature graying, and distinct facial appearance: a new genetic syndrome in 3 sibs. American Journal of Medicinal Genetics 9: 351–357.

Lo Nigro C, Cusano R, Scaranari M et al. (2000) A refined physical and transcriptional map of the SPG9 locus on 10q23.3‐q24.2. European Journal of Human Genetics 8(10): 777–782.

Macedo‐Souza LI, Kok F and Santos S (2005) Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Annals of Neurology 57: 730–737.

Mannan AU, Krawen P and Sauter SM (2006) ZFYVE27 (SPG33), a novel spastin‐binding protein, is mutated in hereditary spastic paraplegia. American Journal of Human Genetics 79: 351–357.

McDermott C, White K and Bushby K (2000) Hereditary spastic paraparesis: a review of new developments. Journal of Neurology, Neurosurgery, and Psychiatry 69(2): 150–160.

McDermott CJ, Grierson AJ and Wood JD (2003) Hereditary spastic paraparesis: disrupted intracellular transport associated with spastin mutation. Annals of Neurology 54(6): 748–759.

Meierkord H, Nurnberg P and Mainz A (1997) ‘Complicated’ autosomal dominant familial spastic paraplegia is genetically distinct from ‘pure’ forms. Archives of Neurology 54: 379–384.

Meijer IA, Cossette P and Roussel J (2004) A novel locus for pure recessive hereditary spastic paraplegia maps to 10q22.1‐10q24.1. Annals of Neurology 56: 579–558.

Namekawa M, Ribai P and Nelson I (2006) SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology 66: 112–114.

Neuhauser G, Wiffler C and Opitz JM (1976) Familial spastic paraplegia with distal muscle wasting in the Old Order Amish; atypical Troyer syndrome or “new” syndrome. Clinical Genetics 9: 315–323.

Orlacchio A, Kawarai T and Gaudiello F (2005) New locus for hereditary spastic paraplegia maps to chromosome 1p31.1‐1p21.1. Annals of Neurology 58: 423–429.

Orlacchio A, Kawarai T and Rogaeva E (2002) Clinical and genetic study of a large Italian family linked to SPG12 locus. Neurology 59: 1395–1401.

Orlacchio A, Kawarai T and Totaro A (2004) Hereditary spastic paraplegia: clinical genetic study of 15 families. Archives of Neurology 61: 849–855.

Orlacchio A, Patrono C and Gaudiello F (2008) Silver syndrome variant of hereditary spastic paraplegia: a locus to 4p and allelism with SPG4. Neurology 70(21): 1959–1966.

Orso G, Martinuzzi A and Rossetto MG (2005) Disease‐related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. Journal of Clinical Investigation 115(11): 3026–3034.

Paisan‐Ruiz C, Nath P, Wood NW, Singleton A and Houlden H (2008) Clinical heterogeneity and genotype‐phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11). European Journal of Neurology 15(10): 1065–1070.

Panza E, Pippucci T, Cusano R et al. (2008) Refinement of the SPG9 locus on chromosome 10q23.3‐24.2 and exclusion of candidate genes. European Journal of Neurology 15(5): 520–524.

Patel H, Cross H and Proukakis C (2002) SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nature Genetics 31(4): 347–348.

Pirozzi M, Quattrini A and Andolfi G (2006) Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia. Journal of Clinical Investigation 116(1): 202–208.

Prasad AN, Breen JC, Ampola MG and Bosman NP (1997) Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review. Journal of Child Neurology 12(5): 301–309.

Rainier S, Bui M and Mark E (2008) Neuropathy target esterase gene mutations cause motor neuron disease. American Journal of Human Genetics 82: 780–785.

Rainier S, Chai JH, Tokarz D, Nicholls RD and Fink JK (2003) NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). American Journal of Human Genetics 73(4): 967–971.

Rainier S, Sher C and Reish O (2006) De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. Archives of Neurology 63: 445–447.

Refsum S and Skillicorn SA (1954) Amyotrophic familial spastic paraplegia. Neurology 4: 40–47.

Reid E (2003a) Many pathways lead to hereditary spastic paraplegia. Lancet Neurology 2(4): 210.

Reid E (2003b) Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias. Journal of Medicinal Genetics 40(2): 81–86.

Reid E, Dearlove AM and Osborn O (2000) A locus for autosomal dominant ‘pure’ hereditary spastic paraplegia maps to chromosome 19q13. American Journal of Human Genetics 66: 728–732.

Reid E, Dearlove AM, Whiteford ML, Rhodes M and Rubinsztein DC (1999) Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity. Neurology 53(8): 1844–1849.

Reid E, Kloos M and Ashley‐Koch A (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). American Journal of Human Genetics 71(5): 1189–1194.

Ribai P, Stevanin G and Bouslam N (2006) A new phenotype linked to SPG27 and refinement of the critical region on chromosome. Journal of Neurology 253(6): 714–719.

Rogaeva Z, Bergeron C, Sato C et al. (2003) PS1 Alzheimer's disease family with spastic paraplegia: the search for a gene modifier. Neurology 61(7): 1005–1007.

Sack GH, Huether CA and Garg N (1978) Familial spastic paraplegia‐clinical and pathologic studies in a large kindred. Johns Hopkins Medical Journal 143: 117–121.

Saito H, Kubota M and Roberts RW (2004) RTP family members induce functional expression of mammalian odorant receptors. Cell 119(5): 679–691.

Saugier‐Veber P, Munnich A and Bonneau D (1994) X‐linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus. Nature Genetics 6: 257–262.

Serena M, Rizzuto N and Moretto G (1990) Familial spastic paraplegia with peroneal amyotrophy. A family with hypersensitivity to pyrexia. Italian Journal of Neurological Sciences 11: 583–588.

Seri M, Cusano R and Forabosco P (1999) Genetic mapping to 10q23.3‐q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts, gastroesophageal reflux, and spastic paraparesis with amyotrophy. American Journal of Human Genetics 64: 586–593.

Silver JR (1966) Familial spastic paraplegia with amyotrophy of the hands. Annals of Human Genetics 30: 69–75.

Simpson MA, Cross H and Proukakis C (2003) Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. American Journal of Human Genetics 73(5): 1147–1156.

Slavotinek AM, Pike M and Mills K (1996) Cataracts, motor system disorder, short stature, learning difficulties, and skeletal abnormalities: a new syndrome? American Journal of Human Genetics 62: 42–47.

Soderblom C and Blackstone C (2006) Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacological Therapy 109(1–2): 42–56.

Steinmuller R, Lantigua‐Cruz A and Garcia‐Garcia R (1997) Evidence of a third locus in X‐linked recessive spastic paraplegia. Human Genetics 100: 287–289.

Stevanin G, Paternotte C and Coutinho P (2007a) A new locus for autosomal recessive spastic paraplegia (SPG32) on chromosome 14q12‐q21. Neurology 68: 1837–1840.

Stevanin G, Santorelli FM and Azzedine H (2007b) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nature Genetics 39: 366–372.

Svenson IK, Ashley‐Koch AE and Gaskell PC (2001) Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. American Journal of Human Genetics 68: 1077–1085.

Svenson IK, Kloos MT and Gaskell PC (2004) Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. Neurogenetics 5: 157–164.

Tamagaki A, Shima M and Tomita R (2000) Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. American Journal of Human Genetics 94: 5–8.

Thomas PK, Misra VP and King RH (1994) Autosomal recessive hereditary sensory neuropathy with spastic paraplegia. Brain 117(Pt 4): 651–659.

Trotta N, Orso G and Rossetto MG (2004) The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Current Biology 14(13): 1135–1147.

Uyama E, Teramoto H and Hashimoto Y (1988) Two siblings of familial spastic paraplegia with cutis verticis gyrata and mental retardation. Rinshō Shinkeigaku 28: 97–101.

Valente EM, Brancati F and Caputo V (2002) Novel locus for autosomal dominant pure hereditary spastic paraplegia (SPG19) maps to chromosome 9q33‐q34. Annals of Neurology 51: 681–685.

Vazza G, Zortea M and Boaretto F (2000) A new locus for autosomal recessive spastic paraplegia associated with mental retardation and distal motor neuropathy, SPG14, maps to chromosome 3q27‐q28. American Journal of Human Genetics 67: 504–509.

Wilkinson PA, Simpson MA and Bastaki L (2005) A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1‐12q14. Journal of Medicinal Genetics 42: 80–82.

Windpassinger C, Auer‐Grumbach M and Irobi J (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature Genetics 36: 271–276.

Winner B, Uyanik G, Gross C et al. (2004) Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Archives of Neurology 61: 117–121.

Zhao X, Alvarado D, Rainier S et al. (2001) Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nature Genetics 29(3): 326–331.

Zortea M, Vettori A and Trevisan CP (2002) Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3‐q24.1. Journal of Medicinal Genetics 39: 387–390.

Zuchner S, Wang G and Tran‐Viet KN (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. American Journal of Human Genetics 79: 365–369.

Further Reading

OMIM, On‐line Mendelian Inheritance in Men http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM&itool=toolbar

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Novelli, Giuseppe, and Contino, Gianmarco(Sep 2009) Molecular Genetics of Hereditary Spastic Paraplegias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021451]