- Amy T Waldman, MD
Amy T Waldman, MD
- Assistant Professor of Child Neurology
- Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine
- Section Editors
- Francisco Gonzalez-Scarano, MD
Francisco Gonzalez-Scarano, MD
- Section Editor — Multiple Sclerosis, Neurovirology & NeuroAIDS
- John P. Howe, III, MD, Distinguished Chair in Health Policy
- The University of Texas Health Science Center at San Antonio
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
In 1885, Friedrich Pelizaeus first identified a genetic disorder causing spasticity and developmental delay [1,2]. Twenty-five years later, Ludwig Merzbacher further described the neuropathology of 12 affected individuals related to the proband [3-6]. Together, Pelizaeus and Merzbacher identified the X-linked inheritance, the neonatal features, and the hypomyelination of the central nervous system that characterize the disease.
Pelizaeus-Merzbacher disease (PMD; MIM 312080) is classified as a dysmyelinating disorder, in which normal myelination never occurs, as opposed to a demyelinating disorder, in which normal myelin is later destroyed [7,8].
It is now recognized that PMD and subtype called X-linked spastic paraplegia type 2 (SPG2; MIM 312920) are caused by mutations of the gene for proteolipid protein (PLP1; MIM 300401) .
This topic will review the pathogenesis, clinical features, and diagnosis of PMD and related disorders.
Mutations of the proteolipid protein 1 gene (PLP1) result in a range of phenotypes that form a clinical spectrum, from the more severe Pelizaeus-Merzbacher disease (PMD) at one end, to the relatively mild X-linked spastic paraplegia 2 (SPG2) at the other . Over 160 mutations of the PLP1 gene, which is located on the long arm of the X chromosome (Xq22.2), have been identified in PMD .
- Pelizaeus F. Uber eine eigenthümliche form spastischer Lähmung mit cerebralerscheinungen auf hereditärer Grundlage (Multiple Sklerose). Arch Psychiatr Nervenkr 1885; 16:698.
- Osaka H, Kawanishi C, Inoue K, et al. Pelizaeus-Merzbacher disease: three novel mutations and implication for locus heterogeneity. Ann Neurol 1999; 45:59.
- Merzbacher L. Eine eigenartige familiar-hereditäre Erkrankungsform (Aplasia axialis extra-corticalis congenital). Z Ges Neurol Psych 1910; 3:1.
- Hodes ME, Pratt VM, Dlouhy SR. Genetics of Pelizaeus-Merzbacher disease. Dev Neurosci 1993; 15:383.
- Hudson LD. Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 2003; 18:616.
- Garbern JY. Leukodystrophies. In: Neurogenetics: Clinical and Scientific Advances, Lynch DR (Ed), Taylor and Francis, New York 2005. p.469.
- Takanashi J, Sugita K, Tanabe Y, et al. MR-revealed myelination in the cerebral corticospinal tract as a marker for Pelizaeus-Merzbacher's disease with proteolipid protein gene duplication. AJNR Am J Neuroradiol 1999; 20:1822.
- Gencic S, Abuelo D, Ambler M, Hudson LD. Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein. Am J Hum Genet 1989; 45:435.
- Garbern JY, Hobson GM. PLP1-Related Disorders. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1182/ (Accessed on June 04, 2012).
- Stecca B, Southwood CM, Gragerov A, et al. The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin. J Neurosci 2000; 20:4002.
- Wang PJ, Hwu WL, Lee WT, et al. Duplication of proteolipid protein gene: a possible major cause of Pelizaeus-Merzbacher disease. Pediatr Neurol 1997; 17:125.
- Inoue K, Osaka H, Kawanishi C, et al. Mutations in the proteolipid protein gene in Japanese families with Pelizaeus-Merzbacher disease. Neurology 1997; 48:283.
- Schiffmann R, Boespflüg-Tanguy O. An update on the leukodsytrophies. Curr Opin Neurol 2001; 14:789.
- Gudz TI, Schneider TE, Haas TA, Macklin WB. Myelin proteolipid protein forms a complex with integrins and may participate in integrin receptor signaling in oligodendrocytes. J Neurosci 2002; 22:7398.
- Mimault C, Giraud G, Courtois V, et al. 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. The Clinical European Network on Brain Dysmyelinating Disease. Am J Hum Genet 1999; 65:360.
- Garbern JY. Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis. Cell Mol Life Sci 2007; 64:50.
- Inoue K, Osaka H, Imaizumi K, et al. Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol 1999; 45:624.
- Benarroch EE. Lipid rafts, protein scaffolds, and neurologic disease. Neurology 2007; 69:1635.
- Southwood C, Gow A. Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene. Microsc Res Tech 2001; 52:700.
- Gow A, Lazzarini RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 1996; 13:422.
- Gow A, Southwood CM, Lazzarini RA. Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease. J Cell Biol 1998; 140:925.
- Bonkowsky JL, Nelson C, Kingston JL, et al. The burden of inherited leukodystrophies in children. Neurology 2010; 75:718.
- Heim P, Claussen M, Hoffmann B, et al. Leukodystrophy incidence in Germany. Am J Med Genet 1997; 71:475.
- Boulloche J, Aicardi J. Pelizaeus-Merzbacher disease: clinical and nosological study. J Child Neurol 1986; 1:233.
- Cailloux F, Gauthier-Barichard F, Mimault C, et al. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur J Hum Genet 2000; 8:837.
- 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; 125:551.
- Hurst S, Garbern J, Trepanier A, Gow A. Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease. Genet Med 2006; 8:371.
- Sivakumar K, Sambuughin N, Selenge B, et al. Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol 1999; 45:680.
- Barkovich AJ. Magnetic resonance techniques in the assessment of myelin and myelination. J Inherit Metab Dis 2005; 28:311.
- van der Knaap MS, Valk J. Pelizaeus-Merzbacher disease and X-linked spastic paraplegia type 2. In: Magnetic Resonance of Myelination and Myelin Disorders, 3rd ed, Springer, New York 1999. p.276.
- Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72:750.
- Nezu A, Kimura S, Takeshita S, et al. An MRI and MRS study of Pelizaeus-Merzbacher disease. Pediatr Neurol 1998; 18:334.
- Cambi F, Tartaglino L, Lublin F, McCarren D. X-linked pure familial spastic paraparesis. Characterization of a large kindred with magnetic resonance imaging studies. Arch Neurol 1995; 52:665.
- Hodes ME, Zimmerman AW, Aydanian A, et al. Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet 1999; 82:132.
- Bonavita S, Schiffmann R, Moore DF, et al. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56:785.
- 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; 34:127.
- Takanashi J, Inoue K, Tomita M, et al. Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication. Neurology 2002; 58:237.
- Hanefeld FA, Brockmann K, Pouwels PJ, et al. Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination. Neurology 2005; 65:701.
- Garbern J, Cambi F, Shy M, Kamholz J. The molecular pathogenesis of Pelizaeus-Merzbacher disease. Arch Neurol 1999; 56:1210.
- Inoue K, Kanai M, Tanabe Y, et al. Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease. Prenat Diagn 2001; 21:1133.
- Regis S, Filocamo M, Mazzotti R, et al. Prenatal diagnosis of Pelizaeus-Merzbacher disease: detection of proteolipid protein gene duplication by quantitative fluorescent multiplex PCR. Prenat Diagn 2001; 21:668.
- Garbern J, Hobson G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat Diagn 2002; 22:1033.
- Hobson GM, Davis AP, Stowell NC, et al. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 2000; 55:1089.
- 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; 75:251.
- Wolf NI, Cundall M, Rutland P, et al. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 2007; 8:39.
- Orthmann-Murphy JL, Enriquez AD, Abrams CK, Scherer SS. Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 2007; 34:629.
- Henneke M, Combes P, Diekmann S, et al. GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology 2008; 70:748.
- Meyer E, Kurian MA, Morgan NV, et al. Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease. Mol Genet Metab 2011; 104:637.
- Combes P, Kammoun N, Monnier A, et al. Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. Ann Neurol 2012; 71:146.
- Osaka H, Hamanoue H, Yamamoto R, et al. Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease. Ann Neurol 2010; 68:250.
- Vaurs-Barrière C, Deville M, Sarret C, et al. Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects. Ann Neurol 2009; 65:114.
- Heuer H, Visser TJ. Minireview: Pathophysiological importance of thyroid hormone transporters. Endocrinology 2009; 150:1078.
- Wilson MG, Towner JW, Forsman I, Siris E. Syndromes associated with deletion of the long arm of chromosome 18[del(18q)]. Am J Med Genet 1979; 3:155.
- Loevner LA, Shapiro RM, Grossman RI, et al. White matter changes associated with deletions of the long arm of chromosome 18 (18q- syndrome): a dysmyelinating disorder? AJNR Am J Neuroradiol 1996; 17:1843.
- Häusler M, Anhuf D, Schüler H, et al. White-matter disease in 18q deletion (18q-) syndrome: magnetic resonance spectroscopy indicates demyelination or increased myelin turnover rather than dysmyelination. Neuroradiology 2005; 47:83.
- Lancaster JL, Cody JD, Andrews T, et al. Myelination in children with partial deletions of chromosome 18q. AJNR Am J Neuroradiol 2005; 26:447.
- van der Knaap MS, Naidu S, Pouwels PJ, et al. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. AJNR Am J Neuroradiol 2002; 23:1466.
- van der Knaap MS, Linnankivi T, Paetau A, et al. Hypomyelination with atrophy of the basal ganglia and cerebellum: follow-up and pathology. Neurology 2007; 69:166.
- Zara F, Biancheri R, Bruno C, et al. Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nat Genet 2006; 38:1111.
- Biancheri R, Zara F, Bruno C, et al. Phenotypic characterization of hypomyelination and congenital cataract. Ann Neurol 2007; 62:121.
- Daoud H, Tétreault M, Gibson W, et al. Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J Med Genet 2013; 50:194.
- Wolf NI, Harting I, Boltshauser E, et al. Leukoencephalopathy with ataxia, hypodontia, and hypomyelination. Neurology 2005; 64:1461.
- Timmons M, Tsokos M, Asab MA, et al. Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 2006; 67:2066.
- Jauhari P, Sahu JK, Singhi P, et al. An Indian boy with a novel leukodystrophy: 4H syndrome. J Child Neurol 2014; 29:135.
- Orcesi S, Tonduti D, Uggetti C, et al. New case of 4H syndrome and a review of the literature. Pediatr Neurol 2010; 42:359.
- Atrouni S, Darazé A, Tamraz J, et al. Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity? Am J Med Genet A 2003; 118A:76.
- Wolf NI, Harting I, Innes AM, et al. Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy. Neuropediatrics 2007; 38:64.
- Bernard G, Thiffault I, Tetreault M, et al. Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31. Neurogenetics 2010; 11:457.
- Sasaki M, Takanashi J, Tada H, et al. Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. Brain Dev 2009; 31:582.
- Bernard G, Vanderver A. Pol III-related leukodystrophies. GeneReviews 2012. www.ncbi.nlm.nih.gov/books/NBK99167/ (Accessed on January 21, 2014).
- La Piana R, Tonduti D, Gordish Dressman H, et al. Brain magnetic resonance imaging (MRI) pattern recognition in Pol III-related leukodystrophies. J Child Neurol 2014; 29:214.
- Aula P, Autio S, Raivio KO, et al. "Salla disease": a new lysosomal storage disorder. Arch Neurol 1979; 36:88.
- Haataja L, Parkkola R, Sonninen P, et al. Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder. Neuropediatrics 1994; 25:238.
- Schleutker J, Leppänen P, Månsson JE, et al. Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15. Am J Hum Genet 1995; 57:893.
- Sonninen P, Autti T, Varho T, et al. Brain involvement in Salla disease. AJNR Am J Neuroradiol 1999; 20:433.
- Varho TT, Alajoki LE, Posti KM, et al. Phenotypic spectrum of Salla disease, a free sialic acid storage disorder. Pediatr Neurol 2002; 26:267.
- Battistella PA, Peserico A. Central nervous system dysmyelination in PIBI(D)S syndrome: a further case. Childs Nerv Syst 1996; 12:110.
- Yoon HK, Sargent MA, Prendiville JS, Poskitt KJ. Cerebellar and cerebral atrophy in trichothiodystrophy. Pediatr Radiol 2005; 35:1019.
- van der Knaap MS, Smit LM, Barth PG, et al. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities. Ann Neurol 1997; 42:50.
- Role of PLP1
- - Duplications
- - Missense mutations
- - Other mutations
- - Null mutations
- CLINICAL FEATURES
- Connatal PMD
- Classic PMD
- Transitional form
- X-linked spastic paraplegia type 2
- PLP1 null syndrome
- Carrier females
- Genetic testing
- DIFFERENTIAL DIAGNOSIS
- Pelizaeus-Merzbacher-like disease
- Hypomyelinating leukodystrophies
- Other leukodystrophies
- Hereditary spastic paraplegia
- SUMMARY AND RECOMMENDATIONS