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Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: A diagnostic approach

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Journal of Inherited Metabolic Disease

Summary

Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammatory, metabolic, infectious diseases) and the so-called ‘hereditary spastic paraparesis’ Although poorly recognized by neurologists, spastic paraparesis is also one of the multiple presentations of inborn errors of metabolism (IEMs) in children and adults. Pyramidal signs are usually included in a diffuse neurological or systemic clinical picture; however, in some cases spastic paraparesis remains the only symptom for years. Since these metabolic causes are often treatable, it is essential to include them in the general diagnostic approach to spastic paraparesis. Here we review IEMs causing paraparesis in adults.

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References

  • Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al (1992) Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy. Neurology 42: 85-1.

    CAS  PubMed  Google Scholar 

  • Bajaj NPS, Waldmann A, Orrell B, Wood NW, Bhatia KP (2002) Familial adult onset of Krabbe’s disease resembling hereditary spastic paraplegia with normal neuroimaging. J Neurol Neurosurg Psychiatry 72: 635-38.

    Article  CAS  PubMed  Google Scholar 

  • Bank WJ, Morrow G 3rd (1972) A familial spinal cord disorder with hyperglycinemia. Arch Neurol 27: 136-44.

    Google Scholar 

  • Barkhof F, Verrips A, Wesseling P, et al (2000) Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 217: 869-76.

    CAS  PubMed  Google Scholar 

  • Baumann N, Masson M, Carreau V, Lefevre M, Herschkowitz N, Turpin JC (1991) Adult forms of metachromatic leukodystrophy: clinical and biochemical approach. Dev Neurosci 13: 211-15.

    Article  CAS  PubMed  Google Scholar 

  • Baykal T, Gokcay G, Gokdemir Y, et al (2005) Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis 28: 903-12.

    Article  CAS  PubMed  Google Scholar 

  • Cowley DM, Bowling FG, McGill JJ, et al (1998) Adult-onset arginase deficiency. J Inherit Metab Dis 21: 677-78.

    Article  CAS  PubMed  Google Scholar 

  • Crombez EA, Cederbaum SD (2005) Hyperargininemia due to liver arginase deficiency. Mol Genet Metab 84: 243-51

    Article  CAS  PubMed  Google Scholar 

  • Depienne C, Tallaksen C, Lephay JY, et al (2006) Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. J Med Genet 43: 259-65.

    Article  CAS  PubMed  Google Scholar 

  • Dinopoulos A, Matsubara Y, Kure S (2005) Atypical variants of non-ketotic hyperglycinemia. Mol Genet Metab 86: 61-9.

    Article  CAS  PubMed  Google Scholar 

  • Farina L, Bizzi A, Finocchiaro G, et al (2000) MR imaging and proton MR spectroscopy in adult Krabbe disease. Am J Neuroradiol 21: 1478-482.

    CAS  PubMed  Google Scholar 

  • Ferdinandusse S, Denis S, Clayton PT, et al (2000) Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24: 188-91.

    Article  CAS  PubMed  Google Scholar 

  • Fink JK (2003) The hereditary spastic paraplegias: nine genes and counting. Arch Neurol 60: 1045-049.

    Article  PubMed  Google Scholar 

  • Fontaine B, Thenin JP, Viader F (2003) Gait disorders with insidious progression in a 60-year old woman. Rev Neurol (Paris) 159: 695-99.

    CAS  Google Scholar 

  • Freeman JM, Finkelstein JD, Mudd SH (1975) Folate-responsive homocystinuria and “schizophrenia” A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med 292: 491-96.

    Article  CAS  PubMed  Google Scholar 

  • Friedman J, Hyland K, Blau N, MacCollin M (2006) Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67: 2032-035.

    Article  PubMed  Google Scholar 

  • Furukawa Y, Graf WD, Wong H, et al (2001) Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations. Neurology 56: 260-63.

    CAS  PubMed  Google Scholar 

  • Hansen FJ, Blau N (2005) Cerebral folate deficiency: life-changing supplementation with folinic acid. Mol Genet Metab 84: 371-73.

    Google Scholar 

  • Haworth JC, Dilling LA, Surtees RA, et al (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45: 572-76.

    Article  CAS  PubMed  Google Scholar 

  • Henderson RD, MacMillan JC, Bradfield JM (2003) Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 10: 638-39.

    Article  CAS  PubMed  Google Scholar 

  • Kasim S, Moo LR, Zschocke J, Jinnah HA (2001) Phenylketonuria presenting in adulthood as progressive spastic paraparesis with dementia. J Neurol Neurosurg Psychiatry 71: 795-97.

    Article  CAS  PubMed  Google Scholar 

  • Kong CK, Ko SF, Tong, Lam CV (2001) Atypical presentation of dopa-responsive dystonia: generalized hypotonia and proximal weakness. Neurology 57: 1121-124.

    CAS  PubMed  Google Scholar 

  • McCombe PA, McLaughlin DB, Chalk JB, Brown NN, McGill JJ, Pender MP (1992) Spasticity and white matter abnormalities in adult phenylketonuria. J Neurol Neurosurg Psychiatry 55: 359-61.

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto T, Kanazawa N, Hayakawa C, Tsujino S (2002) A novel mutation, P126R, in a Japanese patient with HHH syndrome. Pediatr Neurol 26: 65-7.

    Article  PubMed  Google Scholar 

  • Moser HW, Mahmood A, Raymond GV (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3: 140-51.

    Article  PubMed  Google Scholar 

  • Nygaard TG, Trugman JM, de Yebenes JG, Fahn S (1990). Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family. Neurology 40: 66-9.

    CAS  PubMed  Google Scholar 

  • Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Supplement 2): S77-3.

    Article  PubMed  Google Scholar 

  • Patel K, Roskrow T, Davis JS, Heckmatt JZ (1995) Dopa responsive dystonia. Arch Dis Child 73: 256-57.

    Article  CAS  PubMed  Google Scholar 

  • Pogson D (1997) Issues for consideration in dihydropteridine reductase (DHPR) deficiency: a variant form of hyperphenylalaninaemia. J Intellect Disabil Res 41: 208-14.

    Article  PubMed  Google Scholar 

  • Powers JM, Rosenblatt DS, Schmidt RE, et al (2001) Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 49: 396-00.

    Article  CAS  PubMed  Google Scholar 

  • Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46: 843-51.

    Article  PubMed  Google Scholar 

  • Ramaekers VT, Brab M, Rau G, Heimann G (1993) Recovery from neurological deficits following biotin treatment in a biotinidase K m variant. Neuropediatrics 24: 98-02.

    Article  CAS  PubMed  Google Scholar 

  • Ramaekers VT, Rothenberg SP, Sequeira JM, et al (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352: 1985-991.

    Article  Google Scholar 

  • Rauschka H, Colsch B, Baumann N, et al (2006) Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology 67: 859-63.

    Article  CAS  PubMed  Google Scholar 

  • Roze E, Gervais D, Demeret S, et al (2003) Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. Arch Neurol 60: 1457-462.

    Article  PubMed  Google Scholar 

  • Rosenblatt D, Fenton WA (2001) Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3897–3933.

    Google Scholar 

  • Salvi FM, Santorelli E, Bertini R, et al (2001) Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology 57: 911-14.

    CAS  PubMed  Google Scholar 

  • Saudubray JM, Sedel F, Walter JH (2006) Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis 29: 261-74.

    Article  PubMed  Google Scholar 

  • Schiller A, Wevers RA, Steenbergen GC, et al (2004) Long-term course of l-dopa-responsive dystonia caused by tyrosine hydroxylase deficiency. Neurology 63: 1524-526.

    CAS  PubMed  Google Scholar 

  • Sedel F, Lyon-Caen O, Saudubray JM (2007) Inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases. Nat Clin Pract Neurol 3: 279-90.

    Article  CAS  PubMed  Google Scholar 

  • Segawa M, Nomura Y, Nishiyama N (2003) Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 54(Supplement 6): S32-5.

    Article  CAS  PubMed  Google Scholar 

  • Sindern E, Ziemssen F, Ziemssen T, et al (2003) Adult polyglucosan body disease: a postmortem correlation study. Neurology 61: 263-65.

    CAS  PubMed  Google Scholar 

  • Sjaastad O, Berstad J, Gjesdahl P, Gjessing L (1976) Homocarnosinosis. 2. A familial metabolic disorder associated with spastic paraplegia, progressive mental deficiency, and retinal pigmentation. Acta Neurol Scand 53: 275-90.

    Article  CAS  PubMed  Google Scholar 

  • Steiman GS, Yudkoff M, Berman PH, Blazer-Yost B, Segal S (1979) Late-onset nonketotic hyperglycinemia and spinocerebellar degeneration. J Pediatr. 94: 907-11.

    Google Scholar 

  • Stevanin G, Santorelli FM, Azzedine H, et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39: 366-72.

    Article  CAS  PubMed  Google Scholar 

  • Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157: S118–S121.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Yoneda M, Nakajima T, Miyatake T, Owada M (1987) Dihydrobiopterin synthesis defect: an adult with diurnal fluctuation of symptoms. Neurology 37: 519-22.

    CAS  PubMed  Google Scholar 

  • Tokatli A, Coskun T, Ozalp I (1997) Biotinidase deficiency with neurological features resembling multiple sclerosis. J Inherit Metab Dis 20: 707-08.

    Article  CAS  PubMed  Google Scholar 

  • Trivedi JR, Wolfe GI, Nations SP, et al (2003) Adult polyglucosan body disease associated with lewy bodies and tremor. Arch Neurol 60: 764-66.

    Article  PubMed  Google Scholar 

  • Van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV (2001) Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 49: 186-94.

    Article  PubMed  Google Scholar 

  • Verrips A, Nijeholt GJ, Barkhof F, et al (1999) Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 122(Pt 8): 1589-595.

    Article  PubMed  Google Scholar 

  • Verrips A, Hoefsloot LH, Steenbergen GC, et al (2000) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123: 908-19.

    Article  PubMed  Google Scholar 

  • Visy JM, Le Coz P, Chadefaux B (1991) Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurology 41: 1313-315.

    CAS  PubMed  Google Scholar 

  • Weglage J, Oberwittler C, Marquardt T (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23: 83-4.

    Article  CAS  PubMed  Google Scholar 

  • Willemsen MA, IJlst L, Steijlen PM, et al (2001a) Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren–Larsson syndrome. Brain 124: 1426-437.

    Article  CAS  Google Scholar 

  • Willemsen MA, Lutt MA, Steijlen PM, et al (2001b) Clinical and biochemical effects of zileuton in patients with the Sjogren–Larsson syndrome. Eur J Pediatr 160: 711-17.

    CAS  Google Scholar 

  • Wolf B, Pomponio RJ, Norrgard KJ (1998) Delayed-onset profound biotinidase deficiency. J Pediatr 132: 362-65.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Federation of Nervous System Diseases, The Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France

    F. Sedel, B. Fontaine & O. Lyon-Caen

  2. Reference Center for Lysosomal Diseases, The Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France

    F. Sedel

  3. INSERM, UMR 546, The Salpêtrière Hospital, Pierre et Marie Curie University, Paris, France

    B. Fontaine

  4. Department of Pediatrics and Metabolic Diseases, Reference Center for Metabolic Diseases, Necker-enfants malades Hospital, René-Descartes University, Assistance Publique-Hôpitaux de Paris, Paris, France

    J. M. Saudubray

  5. Federation of Nervous System Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651, Paris, Cedex 13, France

    F. Sedel

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  1. F. Sedel
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  2. B. Fontaine
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  3. J. M. Saudubray
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  4. O. Lyon-Caen
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Correspondence to F. Sedel.

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Communicating editor: John Walter

Competing interests: None declared

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Sedel, F., Fontaine, B., Saudubray, J.M. et al. Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: A diagnostic approach. J Inherit Metab Dis 30, 855–864 (2007). https://doi.org/10.1007/s10545-007-0745-1

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  • DOI: https://doi.org/10.1007/s10545-007-0745-1

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