Pelizaeus-Merzbacher Disease, Pelizaeus-Merzbacher-Like Disease 1, and Related Hypomyelinating Disorders

 

 Buy Article Permissions and Reprints

Abstract

The purpose of this article is to present contemporary information on the clinical and molecular diagnosis and the treatment of Pelizaeus-Merzbacher's disease (PMD) and related leukodystrophies. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. A diffuse pattern of hypomyelination is seen on magnetic resonance imaging (MRI) of PMD/SPG2 patients. A similar constellation of signs and pattern of hypomyelination lead to the autosomal recessive disease called Pelizaeus-Merzbacher-like disease 1 (PMLD1) and the less-severe spastic paraplegia 44 (SPG44), caused by mutations of the gap junction protein, gamma-2 gene (GJC2), formerly known as the gap junction protein, α-12 gene (GJA12). Magnetic resonance spectroscopy (MRS) and brainstem auditory evoked potentials (BAEP) may assist with differential clinical diagnosis of PMD and PMLD1. Supportive therapy for patients with PMD/SPG2 and PMLD1/SPG44 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.

Corresponding Author Statement: MIM numbers refer to entries in Online Mendelian Inheritance in Man available at http://www.ncbi.nlm.nih.gov/omim/.

• References

• 1 Mimault C, Giraud G, Courtois V , et al; The Clinical European Network on Brain Dysmyelinating Disease. Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. Am J Hum Genet 1999; 65 (2) 360-369
  CrossrefPubMedGoogle Scholar
• 2 Woodward KJ, Cundall M, Sperle K , et al. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet 2005; 77 (6) 966-987
  CrossrefPubMedGoogle Scholar
• 3 Lee JA, Inoue K, Cheung SW, Shaw CA, Stankiewicz P, Lupski JR. Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum Mol Genet 2006; 15 (14) 2250-2265
  CrossrefPubMedGoogle Scholar
• 4 Regis S, Biancheri R, Bertini E , et al. Genotype-phenotype correlation in five Pelizaeus-Merzbacher disease patients with PLP1 gene duplications. Clin Genet 2008; 73 (3) 279-287
  CrossrefPubMedGoogle Scholar
• 5 Shimojima K, Inoue T, Hoshino A , et al. Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications. Brain Dev 2010; 32 (3) 171-179
  CrossrefPubMedGoogle Scholar
• 6 Hodes ME, Woodward K, Spinner NB , et al. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome. Am J Hum Genet 2000; 67 (1) 14-22
  CrossrefPubMedGoogle Scholar
• 7 Inoue K, Osaka H, Thurston VC , et al. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am J Hum Genet 2002; 71 (4) 838-853
  CrossrefPubMedGoogle Scholar
• 8 Shy ME, Hobson G, Jain M , et al. Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann Neurol 2003; 53 (3) 354-365
  CrossrefPubMedGoogle Scholar
• 9 Hobson GM, Huang Z, Sperle K , et al. Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Hum Mutat 2006; 27 (1) 69-77
  CrossrefPubMedGoogle Scholar
• 10 Bonnet-Dupeyron MN, Combes P, Santander P, Cailloux F, Boespflug-Tanguy O, Vaurs-Barrière C. PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher disease and SPG2 fibroblasts are associated with different types of mutations. Hum Mutat 2008; 29 (8) 1028-1036
  CrossrefPubMedGoogle Scholar
• 11 Grossi S, Regis S, Biancheri R , et al. Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis 2011; 6: 40
  CrossrefPubMedGoogle Scholar
• 12 Wolf NI, Sistermans EA, Cundall M , et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 2005; 128 (Pt 4) 743-751
  CrossrefPubMedGoogle Scholar
• 13 Combes P, Bonnet-Dupeyron MN, Gauthier-Barichard F , et al. PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1. Neurogenetics 2006; 7 (1) 31-37
  CrossrefPubMedGoogle Scholar
• 14 Garbern J, Krajewski K. Hobson G, PLP1-related disorders. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle University of Washington: 1993. http://www.ncbi.nlm.nih.gov/books/NBK1182/ . Accessed September 29, 2011
  Google Scholar
• 15 Heim P, Claussen M, Hoffmann B , et al. Leukodystrophy incidence in Germany. Am J Med Genet 1997; 71 (4) 475-478
  CrossrefPubMedGoogle Scholar
• 16 Seeman P, Krsck P, Namestkova K , et al. Pelizaeus-Merzbacher's disease (PMD) - Detection of the most frequent mutation of the proteolipid protein gene in Czech patients and families with the classical form of PMD. Ceska Slovenska Neurol Neurochir 2003; 66: 95-104
  PubMedGoogle Scholar
• 17 Abrams CK, Scherer SS. Gap junctions in inherited human disorders of the central nervous system. Biochim Biophys Acta 2011;
  PubMedGoogle Scholar
• 18 Uhlenberg B, Schuelke M, Rüschendorf F , et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 2004; 75 (2) 251-260
  CrossrefPubMedGoogle Scholar
• 19 Salviati L, Trevisson E, Baldoin MC , et al. A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease. Neurogenetics 2007; 8 (1) 57-60
  CrossrefPubMedGoogle Scholar
• 20 Wolf NI, Cundall M, Rutland P , et al. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 2007; 8 (1) 39-44
  CrossrefPubMedGoogle Scholar
• 21 Bugiani M, Al Shahwan S, Lamantea E , et al. GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006; 67 (2) 273-279
  CrossrefPubMedGoogle Scholar
• 22 Henneke M, Combes P, Diekmann S , et al. GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology 2008; 70 (10) 748-754
  CrossrefPubMedGoogle Scholar
• 23 Wang J, Wang H, Wang Y, Chen T, Wu X, Jiang Y. Two novel gap junction protein alpha 12 gene mutations in two Chinese patients with Pelizaeus-Merzbacher-like disease. Brain Dev 2010; 32 (3) 236-243
  CrossrefPubMedGoogle Scholar
• 24 Combes P, Kammoun N, Monnier A , et al. Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann Neurol 2010; 71 (1) 146-148
  PubMedGoogle Scholar
• 25 Orthmann-Murphy JL, Salsano E, Abrams CK , et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 2009; 132 (Pt 2) 426-438
  PubMedGoogle Scholar
• 26 Ferrell RE, Baty CJ, Kimak MA , et al. GJC2 missense mutations cause human lymphedema. Am J Hum Genet 2010; 86 (6) 943-948
  CrossrefPubMedGoogle Scholar
• 27 Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol 1986; 1 (3) 233-239
  CrossrefPubMedGoogle Scholar
• 28 Hodes ME, Pratt VM, Dlouhy SR. Genetics of Pelizaeus-Merzbacher disease. Dev Neurosci 1993; 15 (6) 383-394
  CrossrefPubMedGoogle Scholar
• 29 Cailloux F, Gauthier-Barichard F, Mimault C , et al; Clinical European Network on Brain Dysmyelinating Disease. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Eur J Hum Genet 2000; 8 (11) 837-845
  CrossrefPubMedGoogle Scholar
• 30 Garbern JY, Yool DA, Moore GJ , et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 2002; 125 (Pt 3) 551-561
  CrossrefPubMedGoogle Scholar
• 31 Sistermans EA, de Coo RF, De Wijs IJ, Van Oost BA. Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease. Neurology 1998; 50 (6) 1749-1754
  CrossrefPubMedGoogle Scholar
• 32 Fattal-Valevski A, DiMaio MS, Hisama FM , et al. Variable expression of a novel PLP1 mutation in members of a family with Pelizaeus-Merzbacher disease. J Child Neurol 2009; 24 (5) 618-624
  CrossrefPubMedGoogle Scholar
• 33 Hurst S, Garbern J, Trepanier A, Gow A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med 2006; 8 (6) 371-378
  CrossrefPubMedGoogle Scholar
• 34 Carvalho C, Bartnik M, Pehlivan D , et al. Evidence for disease penetrance relating to CNV size: Pelizaeus-Merzbacher disease and manifesting carriers with a familial 11 Mb duplication at Xq22. Clin Genet , in press
  PubMedGoogle Scholar
• 35 Nezu A, Kimura S, Takeshita S, Osaka H, Kimura K, Inoue K. An MRI and MRS study of Pelizaeus-Merzbacher disease. Pediatr Neurol 1998; 18 (4) 334-337
  CrossrefPubMedGoogle Scholar
• 36 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Steenweg ME, Vanderver A, Blaser S , et al. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 2010; 133 (10) 2971-2982
  CrossrefPubMedGoogle Scholar
• 38 Barkovich AJ. Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis 2005; 28 (3) 311-343
  CrossrefPubMedGoogle Scholar
• 39 Takanashi J, Inoue K, Tomita M , et al. Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication. Neurology 2002; 58 (2) 237-241
  CrossrefPubMedGoogle Scholar
• 40 Bonavita S, Schiffmann R, Moore DF , et al. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56 (6) 785-788
  CrossrefPubMedGoogle Scholar
• 41 Hobson GM, Huang Z, Sperle K, Stabley DL, Marks HG, Cambi F. A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann Neurol 2002; 52 (4) 477-488
  CrossrefPubMedGoogle Scholar
• 42 Hanefeld FA, Brockmann K, Pouwels PJ, Wilken B, Frahm J, Dechent P. Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 2005; 65 (5) 701-706
  CrossrefPubMedGoogle Scholar
• 43 Henneke M, Gegner S, Hahn A , et al. Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease. Neurology 2010; 74 (22) 1785-1789
  CrossrefPubMedGoogle Scholar
• 44 Verlinsky Y, Rechitsky S, Laziuk K, Librach C, Genovese R, Kuliev A. Preimplantation genetic diagnosis for Pelizaeus-Merzbacher disease with testing for age-related aneuploidies. Reprod Biomed Online 2006; 12 (1) 83-88
  CrossrefPubMedGoogle Scholar
• 45 Welch KO, Marin RS, Pandya A, Arnos KS. Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature. Am J Med Genet A 2007; 143A (14) 1567-1573
  CrossrefPubMedGoogle Scholar
• 46 Feinstein M, Markus B, Noyman I , et al. Pelizaeus-Merzbacher-like disease caused by AIMP1/p43 homozygous mutation. Am J Hum Genet 2010; 87 (6) 820-828
  CrossrefPubMedGoogle Scholar
• 47 Magen D, Georgopoulos C, Bross P , et al. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am J Hum Genet 2008; 83 (1) 30-42
  CrossrefPubMedGoogle Scholar
• 48 Biancheri R, Zara F, Bruno C , et al. Hypomyelination and congenital cataract. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK2587/ . Accessed September 29, 2011
  Google Scholar
• 49 Dempsey MA, Dumitrescu AM. Refetoff S, MCT8 (SLC16A2)-specific thyroid hormone cell transporter deficiency. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK26373/ . Accessed September 29, 2011
  Google Scholar
• 50 Padiath QS, Saigoh K, Schiffmann R , et al. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 2006; 38 (10) 1114-1123
  CrossrefPubMedGoogle Scholar
• 51 Adams D, Gahl WA. Free sialic acid storage disorders. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1470/ . Accessed September 29, 2011
  Google Scholar
• 52 Inoue K, Khajavi M, Ohyama T , et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 2004; 36 (4) 361-369
  CrossrefPubMedGoogle Scholar
• 53 Schrander-Stumpel C, Vos YJ. L1 Syndrome. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1484/ . Accessed September 29, 2011
  Google Scholar
• 54 Fink JK. Hereditary spastic paraplegia overview. In: Pagon R, Bird T, Dolan C, Stephens K, , eds. GeneReviews. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1509/ . Accessed September 29, 2011
  Google Scholar