Peroxisomal Leukoencephalopathy

 

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Abstract

Peroxisomal leukoencephalopathies include diseases belonging to the Zellweger spectrum and the rhizomelic chondrodysplasia punctata spectrum, as well as some single enzyme defects of peroxisomal β-oxidation. The authors present information on the clinical and diagnostic approach, and the characteristics of brain magnetic resonance imaging (MRI) in these diseases. MRIs of patients belonging to the Zellweger spectrum may show developmental anomalies and regressive changes consisting of abnormal cerebral white matter. Involvement of the central white matter of the cerebellar hemispheres is frequently seen. The leukoencephalopathy is progressive, with or without peripheral nerve involvement, in patients with a prolonged course of the disease. MRI characteristics in the severe phenotype of rhizomelic chondrodysplasia punctata include supratentorial white matter abnormalities, with a parietooccipital predominance. Demyelinative lesions are the hallmark of the cerebral form of X-linked adrenoleukodystrophy and may appear in a similar way in patients with adrenomyeloneuropathy progressing to a cerebral form. The diagnosis of a peroxisomal disorder can be determined by a battery of biochemical assays in blood and/or urine, and should be confirmed in cultured fibroblasts and DNA analysis. Treatment of the peroxisomal leukoencephalopathies is largely symptomatic, except for boys affected by the cerebral form of X-linked adrenoleukodystrophy in whom a bone marrow/hematopoietic stem cell transplant can be lifesaving, at least in the early stages of the disease.

• References

• 1 Gould SJ, Raymond GV, Valle D. The peroxisome biogenesis disorders. In: Scriver CR, Beaudet A, Sly WS, Valle D, , eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001: 3181-3218
  Google Scholar
• 2 Wanders RJA, Barth PG, Heymans HSA. Single peroxisomal enzyme deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, , eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001: 3219-3256
  Google Scholar
• 3 Barkovich AJ, Peck WW. MR of Zellweger syndrome. AJNR Am J Neuroradiol 1997; 18 (6) 1163-1170
  PubMedGoogle Scholar
• 4 Poll-The BT, Gootjes J, Duran M , et al. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet A 2004; 126A (4) 333-338
  CrossrefPubMedGoogle Scholar
• 5 Barth PG, Majoie CBLM, Gootjes J , et al. Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 2004; 62 (3) 439-444
  CrossrefPubMedGoogle Scholar
• 6 Barth PG, Gootjes J, Bode H, Vreken P, Majoie CBLM, Wanders RJA. Late onset white matter disease in peroxisome biogenesis disorder. Neurology 2001; 57 (11) 1949-1955
  CrossrefPubMedGoogle Scholar
• 7 Poll-The BT, Roels F, Ogier H , et al. A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy). Am J Hum Genet 1988; 42 (3) 422-434
  PubMedGoogle Scholar
• 8 Watkins PA, McGuinness MC, Raymond GV , et al. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol 1995; 38 (3) 472-477
  CrossrefPubMedGoogle Scholar
• 9 Ferdinandusse S, Denis S, Mooyer PAW , et al. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ann Neurol 2006; 59 (1) 92-104
  CrossrefPubMedGoogle Scholar
• 10 Soorani-Lunsing RJ, van Spronsen FJ, Stolte-Dijkstra I , et al. Normal very-long-chain fatty acids in peroxisomal D-bifunctional protein deficiency: a diagnostic pitfall. J Inherit Metab Dis 2005; 28 (6) 1172-1174
  CrossrefPubMedGoogle Scholar
• 11 Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 2007; 3 (3) 140-151
  CrossrefPubMedGoogle Scholar
• 12 Dubey P, Fatemi A, Huang HB , et al. Diffusion tensor-based imaging reveals occult abnormalities in adrenomyeloneuropathy. Ann Neurol 2005; 58 (5) 758-766
  CrossrefPubMedGoogle Scholar
• 13 Moser HW, Smith KD, Watkins PA, Powers J, Moser AB. X-linked adrenoleukodystrophy. In: Scriver CR, Beaudet AL, Valle D, Sly WS, , eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001: 3257-3302
  Google Scholar
• 14 White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A 2003; 118A (4) 332-342
  CrossrefPubMedGoogle Scholar
• 15 Braverman N, Chen L, Lin P , et al. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat 2002; 20 (4) 284-297
  CrossrefPubMedGoogle Scholar
• 16 Smeitink JA, Beemer FA, Espeel M , et al. Bone dysplasia associated with phytanic acid accumulation and deficient plasmalogen synthesis: a peroxisomal entity amenable to plasmapheresis. J Inherit Metab Dis 1992; 15 (3) 377-380
  CrossrefPubMedGoogle Scholar
• 17 Barth PG, Wanders RJ, Schutgens RB, Staalman CR. Variant rhizomelic chondrodysplasia punctata (RCDP) with normal plasma phytanic acid: clinico-biochemical delineation of a subtype and complementation studies. Am J Med Genet 1996; 62 (2) 164-168
  CrossrefPubMedGoogle Scholar
• 18 Wanders RJ. Metabolic and molecular basis of peroxisomal disorders: a review. Am J Med Genet A 2004; 126A (4) 355-375
  CrossrefPubMedGoogle Scholar
• 19 Powers JM, Kenjarski TP, Moser AB, Moser HW. Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells. Acta Neuropathol 1999; 98 (2) 129-134
  CrossrefPubMedGoogle Scholar
• 20 Bams-Mengerink AM, Majoie CBLM, Duran M , et al. MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata. Neurology 2006; 66 (6) 798-803 , discussion 789
  CrossrefPubMedGoogle Scholar
• 21 Rosewich H, Waterham HR, Wanders RJ , et al. Pitfall in metabolic screening in a patient with fatal peroxisomal beta-oxidation defect. Neuropediatrics 2006; 37 (2) 95-98
  Article in Thieme ConnectPubMedGoogle Scholar
• 22 Moser AB, Kreiter N, Bezman L , et al. Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999; 45 (1) 100-110
  CrossrefPubMedGoogle Scholar
• 23 Miller WP, Rothman SM, Nascene D , et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood 2011; 118 (7) 1971-1978
  CrossrefPubMedGoogle Scholar
• 24 Aubourg P, Adamsbaum C, Lavallard-Rousseau MC , et al. A two-year trial of oleic and erucic acids (“Lorenzo's oil”) as treatment for adrenomyeloneuropathy. N Engl J Med 1993; 329 (11) 745-752
  CrossrefPubMedGoogle Scholar
• 25 van Geel BM, Assies J, Haverkort EB , et al. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with “Lorenzo's oil.”. J Neurol Neurosurg Psychiatry 1999; 67 (3) 290-299
  CrossrefPubMedGoogle Scholar
• 26 Moser HW, Raymond GV, Lu SE , et al. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo's oil. Arch Neurol 2005; 62 (7) 1073-1080
  CrossrefPubMedGoogle Scholar
• 27 Cartier N, Hacein-Bey-Abina S, Bartholomae CC , et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009; 326 (5954) 818-823
  CrossrefPubMedGoogle Scholar