Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease (PMD) is an X-linked neurological disorder primarily affecting males, characterized by a mutation or duplication of the proteolipid protein gene (PLP1) that results in dysmyelination—an inadequate formation of the myelin sheath that insulates nerve cells. This condition occurs in approximately 1 in every 200,000 to 500,000 male newborns and is inherited from carrier mothers. The absence of myelin leads to various neurological and motor dysfunctions, with symptoms often beginning in infancy, such as involuntary eye movements (nystagmus), hypotonia, and developmental delays.
Diagnosis of PMD is achieved through DNA testing, which confirms mutations in the PLP1 gene. While there is currently no cure or effective treatment available, symptomatic management options exist to address muscle stiffness and seizures. Research into cell-based therapies is ongoing, with aims to restore myelin production. Prognosis varies widely, with some individuals living into adulthood, while others may have a significantly reduced lifespan. Genetic counseling is recommended for families with a history of PMD to understand the risks and implications of the disorder.
Pelizaeus-Merzbacher disease
ALSO KNOWN AS: Pelizaeus Merzbacher brain sclerosis; sudanophilic leukodystrophy; Cockayne-Pelizaeus-Merzbacher disease; PMD
DEFINITION Pelizaeus-Merzbacher disease (PMD) is an X-linked neurological disorder caused by mutation or duplication of the proteolipid protein gene (PLP1) and characterized by dysmyelination, resulting in permanent hypomyelination or lack of the myelin sheath, the fatty covering of nerve cells.
Risk Factors
PMD occurs in 1 out of every 200,000 to 500,000 male newborns in the United States. It is an X-linked disorder, predominantly affecting males who inherit it from their mothers, who are carriers. The condition rarely affects females. For females who carry the PLP1 gene, there is a 50 percent risk of passing it on with every pregnancy—sons have a 50 percent chance of inheriting the gene and having PMD, while daughters are at a 50 percent risk of being carriers. Genetic counseling and in utero testing are advised for those with a family history.
Etiology and Genetics
PMD is one of the leukodystrophies, a group of inherited and progressive metabolic diseases affecting myelination of the nervous system and the development of white matter in the brain. Each disorder has a separate gene abnormality that affects a different enzyme (protein). In PMD, the defect is in the PLP1 gene, caused by a point mutation (substitution of a single AT or GC base), which results in misfolding of the proteolipid protein 1 and DM20 protein, or a duplication of the entire gene, causing overexpression of the protein. These mutant proteins are toxic to the oligodendrocyte cells that make myelin.
Myelin constitutes the myelin sheath, which is a fatty covering surrounding axons in the central and peripheral nervous systems and acts as an electrical insulator, allowing impulses to be transmitted quickly along the nerve cells. Without myelin, impulses leak out and nerves cannot function normally. Normal myelination is a step-by-step, ordered process that begins at about five months gestation and continues until a child is two to three years old. In PMD, myelin simply never develops, resulting in permanent hypomyelination and axonal degeneration, primarily in the subcortical region of the cerebrum, cerebellum, and/or brain stem. This prevents impulses from being transmitted from neuron to neuron and causes a range of neurological and motor dysfunctions. It is now known that duplication of the PLP1 gene accounts for 50 to 75 percent of PMD cases.
The gene encoding the PLP protein is located on the long arm of the X chromosome at band Xq22 and is about 17 kilobases in size, consisting of seven exons and six introns. Two transcript variants encoding distinct isoforms (Isoform 1 and Isoform DM-20) have been identified. The normal PLP protein is a four-transmembrane domain structure that correlates well with one exon of the gene, except at the C terminal end, and binds strongly to other copies of itself.
Many mutations in the PLP1 gene have been reported. Molecular analysis of the gene revealed a variety of mutations, deletions, and duplications, including two mutations in the 5 untranslated region, missense mutations in exon 2, and an A-to-T transition in exon 4 leading to an Asp-to-Val substitution at residue 202. Exonic mutations tend to be more severe than simple point mutations. Forms of the disorder include the classical X-linked PMD, a severe acute infantile (connatal) PMD, and an autosomal dominant late-onset PMD.
Symptoms
Symptoms of PMD are typically progressive and can appear in the first year of life. In the case of connatal PMD, symptoms can begin in infancy. The first symptom in infants is usually involuntary oscillatory movements of the eyes (nystagmus) and may be concomitant with labored and noisy breathing (stridor) and lack of muscle tone/floppiness (hypotonia). Involuntary muscle spasms (spasticity) and associated muscle and joint stiffness develop. With time, other symptoms become evident, such as impaired ability to coordinate movement (ataxia), developmental delays, loss of motor function and head/trunk control, and deterioration of intellectual abilities.
Screening and Diagnosis
DNA-based testing can be used to diagnose PMD in symptomatic patients, as well as in utero, and to determine carrier status in family members. Identification of pathologic mutations and copies of the PLP1 gene is the definitive test, using sequence analysis and quantitative polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) methods, respectively. Pathological signs of dysmyelination can be examined using magnetic resonance imaging (MRI), once a child is one to two years old when white matter pathways in the brain are maturing and hypomyelination can be detected.
Treatment and Therapy
PMD cannot be cured and there is no effective treatment. Currently, treatment is symptomatic and supportive, but medications are available to alleviate stiffness or spasticity and to control seizures. Cell-based therapies are being investigated, including transplantation of a functioning neuregulin gene into unmyelinated nerve cells, which may reprogram cells to produce myelin; the use of human adult-derived glial progenitor cells as vectors; and RNA-suppressive therapy using antisense oligonucleotides.
Prevention and Outcomes
There are no means of preventing PMD, but genetic counseling and testing is available for couples who have the PLP1 gene mutation. The prognosis for patients with PMD varies by the severity of mutation and form of PMD, with survival as short as early childhood and as long as into the sixties.
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