Pelizaeus-Merzbacher disease is an X-linked recessive hypomyelinative leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (Inoue, 2005).
- ... Pelizaeus-Merzbacher disease is an X-linked recessive hypomyelinative leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (Inoue, 2005). - Genetic Heterogeneity of Hypomyelinating Leukodystrophy Other forms of hypomyelinating leukodystrophy include HLD2 (608804), caused by mutation in the GJC2/GJA12 gene (608803) on chromosome 1q41; HLD3 (260600), caused by mutation in the AIMP1 gene (603605) on chromosome 4q24; HLD4 (612233), caused by mutation in the HSPD1 gene (118190) on chromosome 2q33.1; and HLD5 (610532), caused by mutation in the FAM126A gene (610531) on chromosome 7p15.3; HLD6 (612438), caused by mutation in the TUBB4A gene (602662) on chromosome 19p13; HLD7 (607694), caused by mutation in the POLR3A gene (614258) on chromosome 10q22; HLD8 (614381), caused by mutation in the POLR3B gene (614366) on chromosome 12q23; and Allan-Herndon-Dudley syndrome (AHDS; 300523), caused by mutation in the SLC16A2 gene (300095) on chromosome Xq13.
Tyler (1958) noted that at first, rotary movements of the head and eyes develop but curiously may later disappear. Affected children in these families were sometimes described as 'head nodders' and 'eye waggers.' Spasticity of the legs and ... Tyler (1958) noted that at first, rotary movements of the head and eyes develop but curiously may later disappear. Affected children in these families were sometimes described as 'head nodders' and 'eye waggers.' Spasticity of the legs and later the arms, cerebellar ataxia, dementia, and parkinsonian symptoms are other features developing over the first decade or two of life. Ford (1960) referred to Pelizaeus-Merzbacher disease as the chronic infantile type of diffuse cerebral sclerosis. PMD begins in infancy as early as the eighth day and usually no later than the third month and is very slowly progressive so that the victim may survive to middle age. Initial symptoms are pendular eye movements, head shaking, hypotonia, choreoathetosis, and pyramidal signs. The myelin of the peripheral nervous system is not involved in nerve conduction and velocities are normal. Renier et al. (1981) recognized 3 types of Pelizaeus-Merzbacher disease. (1) The classic type, with onset in infancy and death in late adolescence or young adulthood, is characterized by initial signs of nystagmoid eye movement and jerking and rolling head movements or head tremor. Nystagmus disappears and, as the patient matures, ataxia, spasticity, and involuntary movements become manifest, as well as optic atrophy, microcephaly, and subnormal somatic development. (2) The connatal type shows rapid progression and is fatal in infancy or childhood. (3) The transitional form is intermediate. Stridor in early life is a manifestation in some cases of PMD. A possible relation of the X-linked laryngeal abductor paralysis with mental deficiency (308850) to the connatal form was proposed. Kaye et al. (1994) reported 2 brothers who demonstrated neonatal hypotonia and hyporeflexia and were found to have mutations in the PLP1 gene. The authors suggested that peripheral nervous system myelin may be affected in PMD, yielding a clinical picture suggestive of spinal muscular atrophy. One of the patients of Pelizaeus (1885) lived to 52 years of age, and in the family reported by Tyler (1958) an affected male was still living at age 51. Johnson et al. (1991) studied a 5-generation family in which 6 persons had PMD type I. One patient was 45 years old at the time of report. 'Wavering eyes' and 'floppy head' were noted at the age of a few weeks as the first sign. Hanefeld et al. (2005) performed quantitative proton magnetic resonance spectroscopy (MRS) on 5 children with genetically confirmed PMD. Compared to age-matched controls, affected white matter in PMD patients resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate, glutamine, myoinositol, and creatine and phosphocreatine. The concentration of choline-containing compounds was reduced. The findings were consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia, suggestive of dys- and hypomyelination. Stevenson et al. (2009) reported follow-up of a 2-generation African American family with X-linked spastic paraplegia, originally reported by Arena et al. (1992). Arena et al. (1992) described 5 affected males who had severe mental retardation, lower limb spasticity and atrophy, absent or dysarthric speech, and impaired ambulation requiring wheelchairs from childhood. Other features included nystagmus, dystonic posturing, and ataxia. Brain imaging studies showed macrogyria, lack of myelination, and increased paramagnetic signal suggestive of iron deposition. Stevenson et al. (2009) identified a hemizygous mutation in the PLP1 gene (D58Y; 300401.0027) in all affected individuals, confirming that the disorder was in fact PMD. Stevenson et al. (2009) noted that, although altered signals in the basal ganglia and thalamus are not specific for iron deposition, MRI findings suggestive of iron deposition in the basal ganglia have been reported in other patients with PMD. - Carrier Females Some heterozygous females have manifestations of the disorder. The brain of such a female in the family reported by Merzbacher (1909) was studied by Spielmeyer (cited by Tyler, 1958) with demonstration of changes. In a large family in which PMD was segregating (reported by Zeman et al., 1964) and linked to a mutation in PLP by Trofatter et al. (1989), Hodes et al. (1995) observed a heterozygous female infant with typical neurologic signs and with magnetic resonance imaging (MRI) of the brain and brain auditory evoked response consistent with the diagnosis of PMD. The mother and grandmother, who were likewise heterozygous for the leu14-to-pro mutation (300401.0003), were neurologically normal and showed normal MRIs of the brain. Warshawsky et al. (2005) reported a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and CSF immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis (MS; 126200). She and her son, who died at age 10 years of an unknown congenital neurodevelopmental disorder, were found to have a mutation in the PLP1 gene, confirming a diagnosis of Pelizaeus-Merzbacher disease. Warshawsky et al. (2005) noted that the finding of an affected mother of a severely affected boy with PMD was contrary to the current belief that mothers of severely affected sons are asymptomatic as adults. Carrier females with the submicroscopic duplication in the PLP gene that causes PMD are usually asymptomatic. Inoue et al. (2001) described 2 unrelated female patients who presented with mild PMD or spastic paraplegia. In 1 patient, clinical features as well as cranial magnetic resonance imaging and brainstem auditory evoked potential results improved dramatically over a 10-year period. The other patient, who presented with spastic diplegia and was initially diagnosed with cerebral palsy, also showed clinical improvement. Interphase fluorescence in situ hybridization analyses identified a PLP gene duplication in both patients. The same analyses in family members indicated that the duplication in both patients occurred as a de novo event. Neither skewing of X inactivation in the peripheral lymphocytes nor PLP gene coding alterations were identified in either patient. These findings indicated that females with a PLP gene duplication can occasionally manifest an early-onset neurologic phenotype. Inoue et al. (2001) hypothesized that the remarkable clinical improvement was a result of myelin compensation by oligodendrocytes expressing 1 copy of the PLP gene secondary to selection for a favorable X-inactivation pattern. These findings indicated plasticity of oligodendrocytes in the formation of central nervous system myelin and suggested a potential role for stem cell transplantation therapies. Using clinical data compiled from a chart review at Wayne State University comprising 40 pedigrees with PMD including 55 males and 56 carrier females, Hurst et al. (2006) investigated neurologic symptoms in carrier females. They categorized patients according to disease severity and type of genetic lesion within the PLP1 gene and then analyzed the clinical data using nonparametric t tests and analyses of variance. Hurst et al. (2006) concluded that their analyses formally demonstrated the link between mild disease in males and symptoms in carrier female relatives. Conversely, mutations causing severe disease in males rarely caused clinical signs in carrier females. The greatest risk of disease in females was found for nonsense/indel or null mutations. Missense mutations carried moderate risk. The lowest risk, which represents the bulk of families with PMD, was associated with PLP1 gene duplications. Hurst et al. (2006) concluded that effective genetic counseling of PMD and spastic paraplegia carrier females must include an assessment of disease severity in affected male relatives. Marble et al. (2007) reported 2 brothers with classic PMD resulting from a truncating mutation in the PLP1 gene. Three carrier females in the family developed clumsiness, excessive falling, and gait disturbances in the fourth decade of life. Other clinical findings included hyperreflexia, wide-based gait, tremor, and extensor plantar responses. There was also mild cognitive deterioration. X-inactivation studies showed mild skewing (85:15) only in 1 of the carriers.
Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in ... Cailloux et al. (2000) investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by PCR amplification and sequencing of the 7 coding regions and splice sites of the PLP1 gene. Abnormalities were identified in 29 (56%) of the PMD and 4 (14%) of the SPG cases. Of the 33 mutations detected, 23 were missense mutations, 3 were deletion/insertions with frameshifts, and 7 were splice site mutations. Clinical severity was found to be correlated with the nature of the mutation. The severe forms of PMD were most frequently associated with missense mutations in exons 2 and 4, leading to amino acid changes at positions highly conserved in other DM proteins. The mild forms of PMD were frequently caused by mutations, resulting in the production of truncated proteins or by missense mutations. The mutations mostly affected exon 5, leading to the substitution of amino acids only partly conserved in the extracytoplasmic C-D loop. SPG was associated with splice site mutations or changes in the PLP-specific B-C loop. Regis et al. (2008) found no association between clinical disease severity and size of PLP1 duplications among 5 unrelated PMD patients with PLP1 duplications ranging in size from 167-195 kb to 580-700 kb.
Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of ... Cremers et al. (1987) found an insertional translocation into the proximal long arm of the X chromosome in a boy who showed findings typical of PMD at autopsy. Duplication of Xq21-q22 was identified using a large number of X-specific and several X-Y-specific probes. There appeared to be 2 intact copies of the PLP gene (300401) present. The duplication was apparently due to a de novo mutation, because the mother had a normal female karyotype. In a patient with the classic form of PMD, Gencic et al. (1989) described a missense mutation in exon 5 of the PLP gene (300401.0001). Hodes et al. (1993) found that about 30% of patients with the diagnosis of Pelizaeus-Merzbacher disease had a mutation in the coding portion of the proteolipid protein gene. Although the mutations were generally recessive, some mutations were frequently expressed in females. Mimault et al. (1999) investigated 82 strictly selected sporadic cases of PMD and found PLP mutations in 77%. Complete PLP gene duplication was the most frequent abnormality (62%), whereas point mutations in coding or splice site regions of the gene were involved less frequently (38%). In the same report in which they described mutations in the PLP gene in Pelizaeus-Merzbacher disease, Hudson et al. (1989) studied a 6-generation family originally described by Watanabe et al. (1973) and further characterized by Wilkus and Farrell (1976). More than 23 males were affected with a disorder fitting the textbook description of Pelizaeus-Merzbacher disease, both clinically and genetically; however, curious pathologic changes had been noted in a 3-month-old affected infant: apparently normal myelin was present but to a considerable extent the myelin sheaths were organized into ball-like structures in the oligodendrocyte perikarya and terminal processes (Watanabe et al., 1973). Hudson et al. (1989) reported that the PLP gene from this pedigree was unaltered for over 4 kb of coding and noncoding sequence, that Southern blot hybridization failed to reveal any differences from the normal gene, and that a detailed restriction map of a phage lambda genomic clone from 1 patient, containing exons 1-7, also failed to uncover any differences from the normal gene. On the basis of these findings, Hudson et al. (1989) proposed that in addition to the PLP locus another locus on the X chromosome affects myelination. However, Garbern (2004) provided information that affected members of the family described by Watanabe et al. (1973) and by Wilkus and Farrell (1976) were found to have a duplication of the PLP1 (300401.0021) gene and therefore represent bona fide cases of Pelizaeus-Merzbacher disease.
In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) ... In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births.