CC BY 4.0 · Arq Neuropsiquiatr 2023; 81(11): 1000-1007
DOI: 10.1055/s-0043-1777005
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Movement disorders in hereditary spastic paraplegias

Distúrbios de movimento em paraplegia espástica hereditária
1   Universidade Federal de São Paulo, Departamento de Neurologia, São Paulo SP, Brazil.
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2   Universidade Federal de Juiz de Fora, Hospital Universitário, Departamento de Clínica Médica, Serviço de Neurologia, Juiz de Fora MG, Brazil.
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1   Universidade Federal de São Paulo, Departamento de Neurologia, São Paulo SP, Brazil.
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3   Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências Comportamental, Ribeirão Preto SP, Brazil.
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4   Universidade Federal da Paraíba, Departamento de Medicina Interna, Serviço de Neurologia, João Pessoa PB, Brazil.
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5   Universidade Federal do Ceará, Departamento de Medicina Clínica, Divisão de Neurologia, Fortaleza CE, Brazil.
6   Universidade Estadual do Ceará, Centro de Ciências da Saúde, Fortaleza CE, Brazil.
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7   Universidade Estadual de Campinas, Departamento de Neurologia, Campinas SP, Brazil.
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3   Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências Comportamental, Ribeirão Preto SP, Brazil.
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8   Universidade Federal do Paraná, Curitiba PR, Brazil.
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1   Universidade Federal de São Paulo, Departamento de Neurologia, São Paulo SP, Brazil.
› Author Affiliations

Abstract

Background Hereditary or familial spastic paraplegias (SPG) comprise a group of genetically and phenotypically heterogeneous diseases characterized by progressive degeneration of the corticospinal tracts. The complicated forms evolve with other various neurological signs and symptoms, including movement disorders and ataxia.

Objective To summarize the clinical descriptions of SPG that manifest with movement disorders or ataxias to assist the clinician in the task of diagnosing these diseases.

Methods We conducted a narrative review of the literature, including case reports, case series, review articles and observational studies published in English until December 2022.

Results Juvenile or early-onset parkinsonism with variable levodopa-responsiveness have been reported, mainly in SPG7 and SPG11. Dystonia can be observed in patients with SPG7, SPG11, SPG22, SPG26, SPG35, SPG48, SPG49, SPG58, SPG64 and SPG76. Tremor is not a frequent finding in patients with SPG, but it is described in different types of SPG, including SPG7, SPG9, SPG11, SPG15, and SPG76. Myoclonus is rarely described in SPG, affecting patients with SPG4, SPG7, SPG35, SPG48, and SPOAN (spastic paraplegia, optic atrophy, and neuropathy). SPG4, SPG6, SPG10, SPG27, SPG30 and SPG31 may rarely present with ataxia with cerebellar atrophy. And autosomal recessive SPG such as SPG7 and SPG11 can also present with ataxia.

Conclusion Patients with SPG may present with different forms of movement disorders such as parkinsonism, dystonia, tremor, myoclonus and ataxia. The specific movement disorder in the clinical manifestation of a patient with SPG may be a clinical clue for the diagnosis.

Resumo

Antecedentes As paraplegias espásticas hereditárias ou familiares (SPG) compreendem um grupo de doenças geneticamente e fenotipicamente heterogêneas caracterizadas por degeneração progressiva dos tratos corticospinais. As formas complicadas evoluem com vários outros sinais e sintomas neurológicos, incluindo distúrbios do movimento e ataxia.

Objetivo Resumir as descrições clínicas de SPG que se manifestam com distúrbios do movimento ou ataxias para auxiliar o clínico na tarefa de diagnosticar essas doenças.

Métodos Realizamos uma revisão da literatura, incluindo relatos de casos, séries de casos, artigos de revisão e estudos observacionais publicados em inglês até dezembro de 2022.

Resultados O parkinsonismo juvenil ou de início precoce com resposta variável à levodopa foi relatado principalmente em SPG7 e SPG11. A distonia pode ser observada em pacientes com SPG7, SPG11, SPG22, SPG26, SPG35, SPG48, SPG49, SPG58, SPG64 e SPG76. O tremor não é um achado frequente em pacientes com SPG, mas é descrito em diferentes tipos de SPG, incluindo SPG7, SPG9, SPG11, SPG15 e SPG76. A mioclonia é raramente descrita em SPG, afetando pacientes com SPG4, SPG7, SPG35, SPG48 e SPOAN (paraplegia espástica, atrofia óptica e neuropatia). SPG4, SPG6, SPG10, SPG27, SPG30 e SPG31 podem raramente apresentar ataxia com atrofia cerebelar. E SPG autossômico recessivo, como SPG7 e SPG11, também pode apresentar ataxia.

Conclusão Indivíduos com SPG podem apresentar diferentes formas de distúrbios do movimento, como parkinsonismo, distonia, tremor, mioclonia e ataxia. O distúrbio específico do movimento na manifestação clínica de um paciente com SPG pode ser uma pista clínica para o diagnóstico.

Authors' Contributions

JLP, TCV: conceptualization, data curation, investigation, supervision, validation, visualization, writing-original draft, writing-review, and editing; FMMA, ATM, PBN, MCFJ: data curation, investigation, writing-original draft; VT, HAGT, OGPB: conceptualization, data curation, writing-original draft, writing-review, and editing; JLP, TCV: these authors have equally contributed.




Publication History

Received: 21 August 2023

Accepted: 22 September 2023

Article published online:
30 November 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Panza E, Meyyazhagan A, Orlacchio A. Hereditary spastic paraplegia: Genetic heterogeneity and common pathways. Exp Neurol 2022; 357: 114203
  • 2 Kara E, Tucci A, Manzoni C. et al. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain 2016; 139 (Pt 7): 1904-1918
  • 3 Guidubaldi A, Piano C, Santorelli FM. et al. Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early-onset levodopa-responsive Parkinsonism. Mov Disord 2011; 26 (03) 553-556
  • 4 Micheli F, Cersósimo MG, Zúñiga Ramírez C. Hereditary spastic paraplegia associated with dopa-responsive parkinsonism. Mov Disord 2006; 21 (05) 716-717
  • 5 De la Casa-Fages B, Fernández-Eulate G, Gamez J. et al. Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism. Mov Disord 2019; 34 (10) 1547-1561
  • 6 Varghaei P, Estiar MA, Ashtiani S. et al. Genetic, structural and clinical analysis of spastic paraplegia 4. Parkinsonism Relat Disord 2022; 98: 62-69
  • 7 Hsu SL, Hsueh HW, Chen SY. et al. Clinical and genetic characterization of hereditary spastic paraplegia type 3A in Taiwan. Parkinsonism Relat Disord 2021; 87: 87-91
  • 8 Albin RL, Koeppe RA, Rainier S, Fink JK. Normal dopaminergic nigrostriatal innervation in SPG3A hereditary spastic paraplegia. J Neurogenet 2008; 22 (04) 289-294
  • 9 Rossi S, Rubegni A, Riso V. et al. Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network. Neurol Genet 2022; 8 (02) e664
  • 10 Coarelli G, Schule R, van de Warrenburg BPC. et al. Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7. . Neurology 2019; 92 (23) e2679-e2690
  • 11 Pedroso JL, Vale TC, Bueno FL. et al. SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit. Parkinsonism Relat Disord 2018; 47: 88-90
  • 12 Bhattacharjee S, Noushad M, Sadler M. Early Onset Degenerative Parkinsonism - Consider SPG7 Mutation. Neurol India 2021; 69 (04) 1051-1052
  • 13 Anheim M, Lagier-Tourenne C, Stevanin G. et al. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism. J Neurol 2009; 256 (01) 104-108
  • 14 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
  • 15 Park S, Kim AR, Kim NKD, Park WY, Kim JS, Oh E. Lighthouse in the open sea of spastic ataxia; what are the features that should not be missed in SPG11?. Parkinsonism Relat Disord 2021; 91: 181-183
  • 16 de Bot ST, Willemsen MA, Vermeer S, Kremer HP, van de Warrenburg BP. Reviewing the genetic causes of spastic-ataxias. Neurology 2012; 79 (14) 1507-1514
  • 17 Hehr U, Bauer P, Winner B. et al. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann Neurol 2007; 62 (06) 656-665
  • 18 Faber I, Martinez ARM, Martins Jr CR. et al. SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response. Mov Disord 2018; 33 (10) 1650-1656
  • 19 Servelhere KR, Rezende TJR, de Lima FD. et al. Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes. Mov Disord 2021; 36 (07) 1644-1653
  • 20 Faber I, Martinez ARM, de Rezende TJR. et al. SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage. Neuroimage Clin 2018; 19: 848-857
  • 21 Mori S, Honda H, Hamasaki H. et al. Transactivation response DNA-binding protein of 43 kDa proteinopathy and lysosomal abnormalities in spastic paraplegia type 11. Neuropathology 2021; 41 (04) 253-265
  • 22 Pensato V, Castellotti B, Gellera C. et al. Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48. Brain 2014; 137 (Pt 7): 1907-1920
  • 23 Mallaret M, Lagha-Boukbiza O, Biskup S. et al. SPG15: a cause of juvenile atypical levodopa responsive parkinsonism. J Neurol 2014; 261 (02) 435-437
  • 24 Schicks J, Synofzik M, Pétursson H. et al. Atypical juvenile parkinsonism in a consanguineous SPG15 family. Mov Disord 2011; 26 (03) 564-566
  • 25 Elleuch N, Bouslam N, Hanein S. et al. Refinement of the SPG15 candidate interval and phenotypic heterogeneity in three large Arab families. Neurogenetics 2007; 8 (04) 307-315
  • 26 Hirst J, Edgar JR, Esteves T. et al. Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet 2015; 24 (17) 4984-4996
  • 27 Schaefer SM, Szekely AM, Moeller JJ, Tinaz S. Hereditary spastic paraplegia presenting as limb dystonia with a rare SPG7 mutation. Neurol Clin Pract 2018; 8 (06) e49-e50
  • 28 Campins-Romeu M, Baviera-Muñoz R, Sastre-Bataller I, Bataller L, Jaijo T, Martínez-Torres I. Hereditary Spastic Paraplegia 7 Presenting as Multifocal Dystonia with Prominent Cranio-Cervical Involvement. Mov Disord Clin Pract (Hoboken) 2021; 8 (06) 966-968
  • 29 Wijemanne S, Shulman JM, Jimenez-Shahed J, Curry D, Jankovic J. SPG11 Mutations Associated With a Complex Phenotype Resembling Dopa-Responsive Dystonia. Mov Disord Clin Pract (Hoboken) 2015; 2 (02) 149-154
  • 30 Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004; 74 (01) 168-175
  • 31 Boukhris A, Schule R, Loureiro JL. et al. Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 2013; 93 (01) 118-123
  • 32 Dick KJ, Eckhardt M, Paisán-Ruiz C. et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat 2010; 31 (04) E1251-E1260
  • 33 Hirst J, Madeo M, Smets K. et al. Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48). Neurol Genet 2016; 2 (05) e98
  • 34 Tesson C, Nawara M, Salih MA. et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 2012; 91 (06) 1051-1064
  • 35 Caballero Oteyza A, Battaloğlu E, Ocek L. et al. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology 2014; 82 (22) 2007-2016
  • 36 Calame DG, Herman I, Maroofian R. et al. Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia. Ann Neurol 2022; 92 (02) 304-321
  • 37 Garcia-Berlanga JE, Moscovich M, Palacios IJ, Banegas-Lagos A, Rojas-Martinez A, Martinez-Ramirez D. CAPN1 Variants as Cause of Hereditary Spastic Paraplegia Type 76. Case Rep Neurol Med 2019; 2019: 7615605
  • 38 Odake Y, Koh K, Takiyama Y. et al. Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia. Neurol Genet 2020; 6 (05) e514
  • 39 Kalmár T, Maróti Z, Zimmermann A, Sztriha L. Tremor as an early sign of hereditary spastic paraplegia due to mutations in ALDH18A1. Brain Dev 2021; 43 (01) 144-151
  • 40 Innes EA, Goetti R, Mahant N. et al. SPG11 presenting with dystonic tremor in childhood. Parkinsonism Relat Disord 2022; 99: 76-78
  • 41 Primiano G, Zanni G, Nardella M, Servidei S. Teaching Video NeuroImages: Palatal tremor associated with SPG7 variants. Neurology 2020; 94 (19) e2074-e2075
  • 42 Alecu JE, Saffari A, Jumo H. et al. Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early-onset psychosis. Ann Clin Transl Neurol 2022; 9 (04) 570-576
  • 43 Ersen A, Gençpınar P, Arıcan P. et al. Topiramate-Responsive Tremor in a Novel Pathogenic Variant of SPG15 Patient. Clin Neuropharmacol 2020; 43 (04) 121-122
  • 44 Picillo M, Erro R, Munhoz RP, Fasano A. When shaking during standing points to hereditary spastic paraplegias. Parkinsonism Relat Disord 2018; 46: 92-94
  • 45 Erro R, Cordivari C, Bhatia KP. SPG31 presenting with orthostatic tremor. Eur J Neurol 2014; 21 (04) e34-e35
  • 46 Everett CM, Kara E, Maresh KE, Houlden H. Clinical variability and L-Dopa responsive Parkinsonism in hereditary spastic paraplegia 11. J Neurol 2012; 259 (12) 2726-2728
  • 47 Renvoisé B, Chang J, Singh R. et al. Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11. Ann Clin Transl Neurol 2014; 1 (06) 379-389
  • 48 Paisan-Ruiz C, Nath P, Wood NW, Singleton A, Houlden H. Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11). Eur J Neurol 2008; 15 (10) 1065-1070
  • 49 Messing A. Alexander disease. Handb Clin Neurol 2018; 148: 693-700
  • 50 Elert-Dobkowska E, Stepniak I, Krysa W. et al. Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. J Neurol Sci 2015; 359 (1-2): 35-39
  • 51 Duis J, Dean S, Applegate C. et al. KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. Ann Neurol 2016; 80 (04) 633-637
  • 52 Macedo-Souza LI, Kok F, Santos S. et al. Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Ann Neurol 2005; 57 (05) 730-737
  • 53 Simpson MA, 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 (05) 1147-1156
  • 54 Estiar MA, Leveille E, Spiegelman D. et al. Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype. Mol Genet Genomic Med 2020; 8 (03) e1052
  • 55 Boccone L, Mariotti S, Dessì V, Pruna D, Meloni A, Loudianos G. Allan-Herndon-Dudley syndrome (AHDS) caused by a novel SLC16A2 gene mutation showing severe neurologic features and unexpectedly low TRH-stimulated serum TSH. Eur J Med Genet 2010; 53 (06) 392-395
  • 56 Mulroy E, Magrinelli F, Mohd Fauzi NA, Kutty SK, Latorre A, Bhatia KP. Paroxysmal, exercise-induced, diurnally fluctuating dystonia: Expanding the phenotype of SPG8. Parkinsonism Relat Disord 2021; 85: 26-28
  • 57 Gauthier J, Meijer IA, Lessel D. et al. Recessive mutations in VPS13D cause childhood onset movement disorders. Ann Neurol 2018; 83 (06) 1089-1095
  • 58 Cooper HM, Yang Y, Ylikallio E. et al. ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Hum Mol Genet 2017; 26 (08) 1432-1443
  • 59 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 2012; 81 (02) 150-157
  • 60 Mukai M, Koh K, Ohnuki Y, Nagata E, Takiyama Y, Takizawa S. Novel SPG11 Mutations in a Patient with Symptoms Mimicking Multiple Sclerosis. Intern Med 2018; 57 (21) 3183-3186
  • 61 Pedroso JL, Vale TC, França Junior MC. et al. A Diagnostic Approach to Spastic ataxia Syndromes. Cerebellum 2022; 21 (06) 1073-1084
  • 62 Synofzik M, Schüle R. Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways. Mov Disord 2017; 32 (03) 332-345
  • 63 Nan H, Shiraku H, Mizuno T, Takiyama Y. A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature. BMC Neurol 2021; 21 (01) 439
  • 64 Hedera P, Rainier S, Zhao XP. et al. Spastic paraplegia, ataxia, mental retardation (SPAR): a novel genetic disorder. Neurology 2002; 58 (03) 411-416
  • 65 Yahikozawa H, Yoshida K, Sato S. et al. Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7). Hum Genome Var 2015; 2: 15012
  • 66 Rajakulendran S, Paisán-Ruiz C, Houlden H. Thinning of the corpus callosum and cerebellar atrophy is correlated with phenotypic severity in a family with spastic paraplegia type 11. J Clin Neurol 2011; 7 (02) 102-104