Genetics of Hereditary Spastic Paraplegias

ABSTRACT

Hereditary spastic paraplegias (HSPs) are clinically and genetically highly heterogeneous. The key symptom of spastic paraparesis of lower limbs can be complicated by a variety of signs and symptoms including cognitive impairment, optic atrophy, cerebellar ataxia, peripheral nerve involvement, or seizures. At least 48 loci have been identified, termed SPG1–SPG48. Ten genes for autosomal dominant HSP are currently known, SPG4 being by far the most common subtype accounting for ∼50% of cases. SPG3 is especially common in young-onset cases. Autosomal recessive HSP seems to be even more heterogeneous. The known 12 autosomal recessive HSP genes collectively explain about one third of cases only. The most common causes for pure autosomal recessive HSP are SPG7 and SPG5. Mental retardation and thin corpus callosum on magnetic resonance imaging point toward SPG11 and SPG15. The authors provide an overview on clinical, neurophysiologic, and neuroradiologic characteristics of the more common HSP subtypes. More details are given in the tables for quick reference, and a genetic testing strategy is proposed.

KEYWORDS

Hereditary spastic paraplegia - phenotype - genetic testing

REFERENCES

• 1 Deluca G C, Ebers G C, Esiri M M. The extent of axonal loss in the long tracts in hereditary spastic paraplegia.  Neuropathol Appl Neurobiol. 2004;  30 (6) 576-584
• 2 Braschinsky M, Luus S M, Gross-Paju K, Haldre S. The prevalence of hereditary spastic paraplegia and the occurrence of SPG4 mutations in Estonia.  Neuroepidemiology. 2009;  32 (2) 89-93
• 3 Erichsen A K, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen C M. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study.  Brain. 2009;  132 (Pt 6) 1577-1588
• 4 Harding A E. Classification of the hereditary ataxias and paraplegias.  Lancet. 1983;  1 (8334) 1151-1155
• 5 Kenwrick S, Ionasescu V, Ionasescu G et al.. Linkage studies of X-linked recessive spastic paraplegia using DNA probes.  Hum Genet. 1986;  73 (3) 264-266
• 6 Blackstone C, O'Kane C J, Reid E. Hereditary spastic paraplegias: membrane traffic and the motor pathway.  Nat Rev Neurosci. 2011;  12 (1) 31-42
• 7 Fonknechten N, Mavel D, Byrne P et al.. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.  Hum Mol Genet. 2000;  9 (4) 637-644
• 8 Sauter S, Miterski B, Klimpe S et al.. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia.  Hum Mutat. 2002;  20 (2) 127-132
• 9 Alvarez V, Sánchez-Ferrero E, Beetz C Group for the Study of the Genetics of Spastic Paraplegia et al. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.  BMC Neurol. 2010;  10 89
• 10 Depienne C, Tallaksen C, Lephay J Y et al.. Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases.  J Med Genet. 2006;  43 (3) 259-265
• 11 Magariello A, Muglia M, Patitucci A et al.. Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia.  J Neurol Sci. 2010;  288 (1-2) 96-100
• 12 Beetz C, Nygren A O, Schickel J et al.. High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia.  Neurology. 2006;  67 (11) 1926-1930
• 13 Depienne C, Fedirko E, Forlani S et al.. Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia.  J Med Genet. 2007;  44 (4) 281-284
• 14 McDermott C J, Burness C E, Kirby J UK and Irish HSP Consortium et al. Clinical features of hereditary spastic paraplegia due to spastin mutation.  Neurology. 2006;  67 (1) 45-51
• 15 Schulte T, Miterski B, Börnke C, Przuntek H, Epplen J T, Schöls L. Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia.  Neurology. 2003;  60 (9) 1529-1532
• 16 McMonagle P, Byrne P, Hutchinson M. Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia.  Neurology. 2004;  62 (3) 407-410
• 17 Tallaksen C M, Guichart-Gomez E, Verpillat P et al.. Subtle cognitive impairment but no dementia in patients with spastin mutations.  Arch Neurol. 2003;  60 (8) 1113-1118
• 18 Ribaï P, Depienne C, Fedirko E et al.. Mental deficiency in three families with SPG4 spastic paraplegia.  Eur J Hum Genet. 2008;  16 (1) 97-104
• 19 McMonagle P, Hutchinson M, Lawlor B. Hereditary spastic paraparesis and psychosis.  Eur J Neurol. 2006;  13 (8) 874-879
• 20 Nielsen J E, Johnsen B, Koefoed P et al.. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation.  Eur J Neurol. 2004;  11 (12) 817-824
• 21 Salameh J S, Shenoy A M, David W S. Novel SPG3A and SPG4 mutations in two patients with Silver syndrome.  J Clin Neuromuscul Dis. 2009;  11 (1) 57-59
• 22 Orlacchio A, Kawarai T, Gaudiello F et al.. Clinical and genetic study of a large SPG4 Italian family.  Mov Disord. 2005;  20 (8) 1055-1059
• 23 Dürr A, Camuzat A, Colin E et al.. Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.  Arch Neurol. 2004;  61 (12) 1867-1872
• 24 Rainier S, Sher C, Reish O, Thomas D, Fink J K. De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.  Arch Neurol. 2006;  63 (3) 445-447
• 25 Smith B N, Bevan S, Vance C et al.. Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype.  Clin Genet. 2009;  75 (5) 485-489
• 26 Sauter S M, Engel W, Neumann L M, Kunze J, Neesen J. Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus.  Hum Mutat. 2004;  23 (1) 98
• 27 McCorquodale III D S, Ozomaro U, Huang J et al.. Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia.  Clin Genet. 2011;  79 (6) 523-530
• 28 Fusco C, Frattini D, Farnetti E et al.. Hereditary spastic paraplegia and axonal motor neuropathy caused by a novel SPG3A de novo mutation.  Brain Dev. 2010;  32 (7) 592-594
• 29 Ivanova N, Claeys K G, Deconinck T et al.. Hereditary spastic paraplegia 3A associated with axonal neuropathy.  Arch Neurol. 2007;  64 (5) 706-713
• 30 Scarano V, Mancini P, Criscuolo C et al.. The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy.  J Neurol. 2005;  252 (8) 901-903
• 31 Guelly C, Zhu P P, Leonardis L et al.. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I.  Am J Hum Genet. 2011;  88 (1) 99-105
• 32 Namekawa M, Ribai P, Nelson I et al.. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.  Neurology. 2006;  66 (1) 112-114
• 33 Reid E, Kloos M, Ashley-Koch A et al.. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).  Am J Hum Genet. 2002;  71 (5) 1189-1194
• 34 Crimella C, Baschirotto C, Arnoldi A et al.. Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2.  Clin Genet. 2011;  May 30 [Epub ahead of print]
• 35 Goizet C, Boukhris A, Mundwiller E et al.. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10.  Hum Mutat. 2009;  30 (2) E376-E385
• 36 Schüle R, Kremer B P, Kassubek J et al.. SPG10 is a rare cause of spastic paraplegia in European families.  J Neurol Neurosurg Psychiatry. 2008;  79 (5) 584-587
• 37 Windpassinger C, Auer-Grumbach M, Irobi J et al.. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.  Nat Genet. 2004;  36 (3) 271-276
• 38 Auer-Grumbach M, Schlotter-Weigel B, Lochmüller H Austrian Peripheral Neuropathy Study Group et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.  Ann Neurol. 2005;  57 (3) 415-424
• 39 Irobi J, Van den Bergh P, Merlini L et al.. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V.  Brain. 2004;  127 (Pt 9) 2124-2130
• 40 Beetz C, Schüle R, Deconinck T et al.. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.  Brain. 2008;  131 (Pt 4) 1078-1086
• 41 Goizet C, Depienne C, Benard G et al.. REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.  Hum Mutat. 2011;  32 (10) 1118-1127
• 42 Tsaousidou M K, Ouahchi K, Warner T T et al.. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration.  Am J Hum Genet. 2008;  82 (2) 510-515
• 43 Arnoldi A, Crimella C, Tenderini E et al.. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations.  Clin Genet. 2011;  January 10 [Epub ahead of print]
• 44 Goizet C, Boukhris A, Durr A et al.. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.  Brain. 2009;  132 (Pt 6) 1589-1600
• 45 Schlipf N A, Schüle R, Klimpe S et al.. Amplicon-based high-throughput pooled sequencing identifies mutations in CYP7B1 and SPG7 in sporadic spastic paraplegia patients.  Clin Genet. 2011;  80 (2) 148-160
• 46 Schüle R, Brandt E, Karle K N et al.. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia.  Neurogenetics. 2009;  10 (2) 97-104
• 47 Manganelli F, Pisciotta C, Dubbioso R et al.. Electrophysiological characterisation in hereditary spastic paraplegia type 5.  Clin Neurophysiol. 2011;  122 (4) 819-822
• 48 Casari G, De Fusco M, Ciarmatori S et al.. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease.  Cell. 1998;  93 (6) 973-983
• 49 Wilkinson P A, Crosby A H, Turner C et al.. A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.  Brain. 2004;  127 (Pt 5) 973-980
• 50 Elleuch N, Depienne C, Benomar A et al.. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.  Neurology. 2006;  66 (5) 654-659
• 51 Brugman F, Scheffer H, Wokke J H et al.. Paraplegin mutations in sporadic adult-onset upper motor neuron syndromes.  Neurology. 2008;  71 (19) 1500-1505
• 52 Warnecke T, Duning T, Schirmacher A et al.. A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects.  Mov Disord. 2010;  25 (4) 413-420
• 53 Arnoldi A, Tonelli A, Crippa F et al.. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia.  Hum Mutat. 2008;  29 (4) 522-531
• 54 Di Bella D, Lazzaro F, Brusco A et al.. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.  Nat Genet. 2010;  42 (4) 313-321
• 55 Hehr U, Bauer P, Winner B et al.. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.  Ann Neurol. 2007;  62 (6) 656-665
• 56 Stevanin G, Azzedine H, Denora P SPATAX consortium et al. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.  Brain. 2008;  131 (Pt 3) 772-784
• 57 Orlacchio A, Babalini C, Borreca A et al.. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.  Brain. 2010;  133 (Pt 2) 591-598
• 58 Anheim M, Lagier-Tourenne C, Stevanin G et al.. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism.  J Neurol. 2009;  256 (1) 104-108
• 59 Paisán-Ruiz C, Guevara R, Federoff M et al.. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations.  Mov Disord. 2010;  25 (12) 1791-1800
• 60 Guidubaldi A, Piano C, Santorelli F M et al.. Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive parkinsonism.  Mov Disord. 2011;  26 (3) 553-556
• 61 Kjellin K. Familial spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration.  Arch Neurol. 1959;  1 133-140
• 62 Schüle R, Schlipf N, Synofzik M et al.. Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia.  J Neurol Neurosurg Psychiatry. 2009;  80 (12) 1402-1404
• 63 Goizet C, Boukhris A, Maltete D et al.. SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum.  Neurology. 2009;  73 (14) 1111-1119
• 64 Jouet M, Rosenthal A, Armstrong G et al.. X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.  Nat Genet. 1994;  7 (3) 402-407
• 65 Vos Y J, de Walle H E, Bos K K et al.. Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.  J Med Genet. 2010;  47 (3) 169-175
• 66 Saugier-Veber P, Munnich A, Bonneau D et al.. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus.  Nat Genet. 1994;  6 (3) 257-262
• 67 Sistermans E A, de Coo R F, De Wijs I J, Van Oost B A. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease.  Neurology. 1998;  50 (6) 1749-1754
• 68 Plecko B, Stöckler-Ipsiroglu S, Gruber S et al.. Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype.  Neuropediatrics. 2003;  34 (3) 127-136
• 69 Cailloux F, Gauthier-Barichard F, Mimault C Clinical European Network on Brain Dysmyelinating Disease et al. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations.  Eur J Hum Genet. 2000;  8 (11) 837-845
• 70 Seal R L, Gordon S M, Lush M J, Wright M W, Bruford E A. genenames.org: the HGNC resources in 2011.  Nucleic Acids Res. 2011;  39 (Database issue) D514-D519
• 71 Engert J C, Bérubé P, Mercier J et al.. ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.  Nat Genet. 2000;  24 (2) 120-125
• 72 Zhao X, Alvarado D, Rainier S et al.. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.  Nat Genet. 2001;  29 (3) 326-331
• 73 Hazan J, Fonknechten N, Mavel D et al.. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia.  Nat Genet. 1999;  23 (3) 296-303
• 74 Rainier S, Chai J H, Tokarz D, Nicholls R D, Fink J K. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6).  Am J Hum Genet. 2003;  73 (4) 967-971
• 75 Valdmanis P N, Meijer I A, Reynolds A et al.. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia.  Am J Hum Genet. 2007;  80 (1) 152-161
• 76 Hansen J J, Dürr A, Cournu-Rebeix I et al.. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60.  Am J Hum Genet. 2002;  70 (5) 1328-1332
• 77 Alazami A M, Adly N, Al Dhalaan H, Alkuraya F S. A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18).  Neurogenetics. 2011;  12 (4) 333-336
• 78 Yıldırım Y, Orhan E K, Iseri S A et al.. A frameshift mutation of ERLIN2 in recessive intellectual disability, motor dysfunction and multiple joint contractures.  Hum Mol Genet. 2011;  20 (10) 1886-1892
• 79 Züchner S, Wang G, Tran-Viet K N et al.. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.  Am J Hum Genet. 2006;  79 (2) 365-369
• 80 Lin P, Li J, Liu Q et al.. A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42).  Am J Hum Genet. 2008;  83 (6) 752-759
• 81 Stevanin G, Santorelli F M, Azzedine H et al.. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.  Nat Genet. 2007;  39 (3) 366-372
• 82 Hanein S, Martin E, Boukhris A et al.. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.  Am J Hum Genet. 2008;  82 (4) 992-1002
• 83 Patel H, Cross H, Proukakis C et al.. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.  Nat Genet. 2002;  31 (4) 347-348
• 84 Simpson M A, Cross H, Proukakis C et al.. Maspardin is mutated in MAST syndrome, a complicated form of hereditary spastic paraplegia associated with dementia.  Am J Hum Genet. 2003;  73 (5) 1147-1156
• 85 Dick K J, Eckhardt M, Paisán-Ruiz C et al.. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).  Hum Mutat. 2010;  31 (4) E1251-E1260
• 86 Rainier S, Bui M, Mark E et al.. Neuropathy target esterase gene mutations cause motor neuron disease.  Am J Hum Genet. 2008;  82 (3) 780-785
• 87 Orthmann-Murphy J L, Salsano E, Abrams C K et al.. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.  Brain. 2009;  132 (Pt 2) 426-438
• 88 Słabicki M, Theis M, Krastev D B et al.. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.  PLoS Biol. 2010;  8 (6) e1000408
• 89 Eymard-Pierre E, Lesca G, Dollet S et al.. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene.  Am J Hum Genet. 2002;  71 (3) 518-527
• 90 Bohan T P, Azizi P. Allan-Herndon-Dudley syndrome: should the locus for this hereditary spastic paraplegia be designated SPG 22?.  Arch Neurol. 2004;  61 (9) 1470-1471, author reply 1471
• 91 Montenegro G, Rebelo A D, Conell J et al.. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.  J Clin Invest. 2012;  122 (2) In press