What Is Pelizaeus-Merzbacher Disease?

In 1885, Pelizaeus was the first to report the pedigree of 5 male children, mainly showing nystagmus, limb paralysis, ataxia, and stunting. Merzbacher re-examined the pedigree reported by Pelizaeus in 1910. At this time, 14 patients were involved and 2 were female patients. It was found that the disease has X-linked recessive genetic characteristics and white matter marrow was found in brain tissue biopsy Sheath is missing, so the disease is named PMD. The pathological manifestation of this disease is that the myelin region and the demyelination region are staggered, showing a tabby-like appearance. Microscopically, Sudan-like substances are deposited in the center of the semiovel, the brain stem, and the cerebellum. PMD is a serious fatal and disabling neurogenetic disease. Patients have a short life span, and severe cases can only survive to a few years old, and even die after birth. Its incidence rate is 1/500 000 to 1/300 000 in the United States. There is still no related incidence research in China. In 2007, the research team conducted the first diagnosis and report of PLP1 gene in a PMD family in China. So far, 76 cases of PMD have been clinically diagnosed, and 60 cases of PLP1 gene mutation analysis have been completed (gene analysis of the remaining patients is ongoing), of which 57 cases have been confirmed. The following will explain the etiology, clinical manifestations, auxiliary examination, diagnosis, differential diagnosis, treatment, prenatal diagnosis and genetic counseling of PMD.

Wang Jingmin	(Associate Researcher)	Pediatrics, Peking University First Hospital
Ji Taoyun	(Attending physician)	Pediatrics, Peking University First Hospital
Jiang Yuwu	(Chief physician)	Pediatrics, Peking University First Hospital

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive genetic disease with diffuse white matter myelin formation disorders. It is a hereditary myelin sheath associated with proteolipid protein 1 (PLP1). Forms a spectrum of disorders. The characteristic pathological change of PMD is that nerve myelin sheath does not form normally, instead of demyelinating changes like other hereditary white matter encephalopathy.

Western Medicine Name

Peme disease

English name

Pelizaeus-Merzbacher disease, PMD

Affiliated Department

Internal Medicine-Neurology

Contagious

Non-contagious

Introduction to Pemay disease

In 1885, Pelizaeus was the first to report the pedigree of 5 male children, mainly showing nystagmus, limb paralysis, ataxia, and stunting. Merzbacher re-examined the pedigree reported by Pelizaeus in 1910. At this time, 14 patients were involved and 2 were female patients. It was found that the disease has X-linked recessive genetic characteristics and white matter marrow was found in brain tissue biopsy. Sheath is missing, so the disease is named PMD. The pathological manifestation of this disease is that the myelin region and the demyelination region are staggered, showing a tabby-like appearance. Microscopically, Sudan-like substances are deposited in the center of the semiovel, the brain stem, and the cerebellum. PMD is a serious fatal and disabling neurogenetic disease. Patients have a short life span, and severe cases can only survive to a few years old, and even die after birth. Its incidence rate is 1/500 000 to 1/300 000 in the United States. There is still no related incidence research in China. In 2007, the research team conducted the first diagnosis and report of PLP1 gene in a PMD family in China, and in 2006 So far, 76 cases of PMD have been clinically diagnosed, and 60 cases of PLP1 gene mutation analysis have been completed (gene analysis of the remaining patients is ongoing), of which 57 cases have been confirmed. The following will explain the etiology, clinical manifestations, auxiliary examination, diagnosis, differential diagnosis, treatment, prenatal diagnosis and genetic counseling of PMD.

The etiology and pathogenesis of Peume's disease

The pathogenic gene of PMD is the proteolipid protein 1 (PLP1) gene located at Xq22.2. The length of the PLP1 gene is about 17 kb, contains 7 exons, and encodes the PLP1 protein containing 276 amino acids and its scissor. Cut the isomer DM20. PLP1 is the main component of the myelin sheath of the central nervous system, accounting for about 50% of the entire myelin protein. Its main function is to compose and stabilize the myelin sheath while playing an important role in the development of oligodendrocyte precursor cells. PLP1 is mainly expressed in oligodendrocytes (OLs). Oligodendrocytes are the main types of glial cells, which are found in the gray and white matter of the central nervous system, especially white matter and oligodendrocytes. The cells are myelin-forming cells, and the normal development of oligodendrocytes provides a guarantee for the integrity of the central nervous system myelin sheath. Myelin sheath is a tubular outer membrane that is wrapped around the axons of nerve cells. There is a Langfie knot on the myelin sheath, which can make nerve impulses jump. The myelin sheath is composed of myelin and has an insulating effect. It has axon protection. The axon conduction velocity is regulated by synaptic diameter, myelin thickness, the number and spatial distribution of Lange's nodules, and the molecular composition of ion channels in the nodule. The myelin can accurately and efficiently transmit neural information and Central information integration plays an extremely important role. Oligodendrocyte / myelin sheath abnormalities can change the stability of axon bundles, thereby affecting the basic electrical conduction pattern of nerve cells, and ultimately affecting normal synaptic transmission. Studies have shown that Plp overexpressing transgenic mice can cause cognitive behavioral damage, which may be related to oligodendrocyte / myelin dysfunction through altered glutamate and dopaminergic signalling. Electrophysiological studies in plasmocyte / myelin abnormal neurons will help understand the molecular axon-myelin interaction mechanism of these signaling pathways.

Defects in the PLP1 gene can cause overexpression of the PLP1 protein (repeated mutations in the PLP1 gene), decreased expression or abnormal intracellular distribution (point mutations in the PLP1 gene), and deletion of PLP1, all of which can lead to abnormal oligodendrocyte / myelin function, leading to Myelin formation is abnormal and / or oligodendrocytes die, resulting in a lack or reduction of myelin in a wide range of white matter regions. Different types of PLP1 gene mutations cause different clinical phenotypes through different cellular and molecular mechanisms.

Clinical manifestations of Pemy's disease

The typical clinical manifestations of PMD are nystagmus, hypotonia, ataxia, and progressive motor dysfunction. During the development of the disease, most children can gradually improve initially, and then gradually develop mental and motor development, and motor dysfunction is more significant than mental retardation. PMD belongs to one of PLP1-related diseases. PLP1-related diseases are a continuous spectrum of diseases from severe to light. They are divided into 6 types according to the clinical manifestations from severe to mild and the age of onset (Table 1): congenital type PMD (connatal PMD), classic PMD (classic PMD), a transitional form, PLP1 null syndrome, complex spastic paraplegia, and uncomplicated spastic paraplegia).

PMD Congenital PMD

Congenital PMD develops at birth with severe clinical symptoms. Appeared as pendulum-like nystagmus, low muscle tone, difficulty swallowing, wheezing, and some children may have seizures. Cognitive function is severely impaired, and language expression is severely affected, but nonverbal communication is possible, and some children may understand the language. Cannot walk alone during development. As the disease progresses, the limbs gradually become convulsed. Most die in childhood, and a few survive longer, but generally do not exceed 30 years of age.

PMD Pepe disease classic PMD

Classic PMD is the PMD described by Pelizaeus and Merzbacher, and it is also the most common one. More than a few months after birth, no later than 5 years old. Early manifestations include nystagmus and low muscle tone. Before 10 years of age, motor function can slowly improve, and free limb movement and walking ability can be obtained, and then gradually regress. As the disease progresses, nystagmus can disappear, and then motor development disorders such as staggering gait, ataxia, quadriplegia, etc. May be associated with cognitive impairment and extrapyramidal abnormalities. Most patients die at the age of 30 to 70 years.

PMD Peme disease intermediate PMD

The clinical manifestations of the intermediate type are between the congenital type and the classic type.

PLP1 Pemme disease without PLP1 syndrome

This type is special and has no nystagmus. Development is usually normal within one year of age, and onset occurs between the ages of one and five. It is mainly manifested as mild spastic paralysis of the extremities, ataxia, mild to moderate cognitive impairment, and certain language functions can be obtained. More than regression after puberty, some children may have mild peripheral nerve symptoms. Life span is mostly 50 to 70 years.

Complex spastic paraplegia

Most of the children develop normally within 1 year of age, and more than 1 to 5 years of age onset. Mainly manifested as nystagmus, ataxia, progressive weakness and cramps in the lower limbs, autonomic dysfunction (such as bladder spasm), no or slight cognitive impairment, and multiple language functions. Life span is mostly 40 to 70 years.

Simple spastic paraplegia

This type is the lightest type. The child usually develops normally within 1 year of age, and the onset of the disease occurs at the age of 1 to 5 years. Symptoms can also occur at the age of 30 to 40 years. The main manifestations are progressive progressive weakness and spasms of the lower limbs, and autonomic dysfunction (such as bladder spasms). However, the patient had no nystagmus and impaired cognitive function. Life is normal.

Table 1 Clinical classification of PLP1-related diseases

Phenotype	Age of onset	Nervous system performance	walk	Language	Age of death
Congenital PMD	Neonatal period	Nystagmus, weakness in swallowing, wheezing, low muscle tone, severe spasms with / without convulsions, cognitive impairment found after birth	Never	No, and may have non-verbal communication and language understanding	Babies to 30 years
Classic PMD	Under 5 years old	Nystagmus, initial hypotonia, spastic paraplegia, ataxia, gait instability with / without dystonia, hand and foot dyskinesia, cognitive impairment within two months after birth	Assisted walking, loss of walking in children / puberty	Can usually appear	30 ~ 70 years old
No PLP1 syndrome	Under 5 years old	No nystagmus, mild spastic paraplegia, ataxia, peripheral neuropathy, mild to moderate cognitive impairment	meeting	Yes, usually adolescence worsens	50 ~ 70 years old
Complex SPG2	Under 5 years old	Nystagmus, ataxia, autonomic dysfunction *, spastic gait, mild or no cognitive impairment	meeting	meeting	40 ~ 70 years old
SPG2	Usually under 5 years old, but also 30-40 years old	Autonomic dysfunction *, spastic gait, no cognitive impairment	meeting	meeting	normal

Note: The clinical manifestations of intermediate PMD are between congenital and classic PMD; * spastic bladder

Pey's disease auxiliary examination

MRI of the skull

The main manifestations of magnetic resonance imaging, MRI, and PMD imaging are dysmyelination or complete non-development of the myelin sheath. Skull MRI can show abnormal myelination, which is mainly manifested by diffuse high signal of white matter T2 weighted image and Flair image. This test is of great significance for the diagnosis of PMD. Because the first and second years after birth are important periods for the formation of white matter myelination, the specificity of the head MRI manifestation is relatively small at this time. However, since the inner capsule hindlimb, corpus callosum, and optic radiation area of normal 3-month-old infants have myelin sheath formation, abnormalities in these areas in the early stage are of great significance for the diagnosis of PMD. With the gradual increase in the age of children with PMD, the development of white matter in the brain is extremely backward, and the MRI of the skull shows neonatal white matter. The T1 weighted image of white matter is not usually changed, and the T2 weighted image of white matter is almost all high signal. As the disease progresses, the white matter volume of the brain shrinks, manifested by thinning of the corpus callosum, enlargement of the ventricles and cortical invasion. Children with spastic paraplegia have milder white matter abnormalities than PMD, and their MRI T2-weighted images of the skull can show a patchy high signal.

Nuclear magnetic resonance spectroscopy

Magnetic resonance spectrum (MRS), choline complex (choline, cho) includes glyceryl phosphate choline, phosphatidylcholine, choline phosphate, etc., and is an important component of cell membrane phospholipid metabolism. When cell membranes break down, Cho levels rise. Because PMD is a disorder of myelin formation, Cho levels are not high, and it is of great significance compared with white matter demyelinating disease. Bonavita et al. Reported a decrease in N-acetylaspartate (NAA) levels in patients without PLP1 syndrome. Conversely, NAA levels are increased in children with repeated mutations in the PLP1 gene, which is easily confused with Canavan disease.

Molecular genetic testing for Peper's disease

There are various types of PLP1 gene mutations. To date, 142 PLP1 gene mutations (human gene mutation databases) have been identified, including repetitive, point, and deletion mutations. Repeat mutations are the most common, accounting for 50% to 70% of the total number of patients with PMD, and point mutations account for 10% to 25% of the total number of patients with PMD. According to this, in the clinical diagnosis of patients with Pemei disease, the genetic detection strategy first performs repeated mutation detection of PLP1 gene, and multiplex ligation-dependent probe amplification technology (MLPA) is a kind of target developed in recent years. New technology for qualitative and semi-quantitative analysis of test DNA sequences. This technology is highly efficient and specific, and can detect changes in the copy number of 30-48 nucleotide sequences in one reaction. It has been applied to research in many fields and diseases. It is used to detect PLP1 gene duplication / deletion mutation in the diagnosis of Peyer's disease. Results Normal persons applied direct DNA sequencing to detect point mutations.

For children with clinically suspected PMD, a PLP1 genetic test is required to confirm the diagnosis.

Studies have shown that genotypes and phenotypes are significantly related in the PLP1-related disease lineage: PLP1 gene mutations are most commonly repeated mutations, accounting for 50% to 70%, point mutations account for 10% to 25%, and deletion mutations account for only 2 %about. Repeated PLP1 gene mutations are found in most classic and intermediate PMDs; point mutations are widely distributed in clinical phenotypes, and can be found in all clinical phenotypes of PLP1-related diseases, but congenital PMD is more common; deletion mutations are found in patients without PLP1 syndrome and Spastic paraplegia type 2. Our team's experimental results on 53 patients with PMD who completed the PLP1 gene mutation analysis showed that 71.7% were repeated PLP1 gene mutations, of which the clinical phenotypes were classic and intermediate PMD, accounting for 68.4% (26/38) and 26.3% ( 12/38); 22.6% were point mutations, of which 41.6% (5/12) were congenital PMD; 5.7% had no PLP1 gene changes. The latest research also showed that the copy number variation (CNV) fragment size of the X chromosome involved with the PLP1 gene repeated mutation in PMD patients is closely related to the clinical phenotype. We previously applied the gene chip to the 38 patients with the PLP1 gene repeated mutation. Preliminary analysis of CNV changes in the relevant regions also showed that the size and pattern of CNV fragments are closely related to the clinical phenotype. So far, 58 children with PMD have been diagnosed in Pediatrics of Peking University First Hospital through genetic testing.

Peme disease diagnosis

The clinical diagnosis of PMD is mainly based on typical clinical manifestations and skull imaging examinations, and the diagnosis is based on molecular genetic studies. Male patients are clinically diagnosed with nystagmus, which is mainly manifested as nystagmus, hypotonia, ataxia, and progressive motor dysfunction. A MRI of the skull shows a T2 weighted image with diffuse high signal in white matter. PMD must be considered. If possible, further PLP1 genetic tests should be performed to confirm the diagnosis.

Differential diagnosis of Paget's disease

PMD Differentiation of PMD from Peme disease

If there is no abnormality in the PLP1 genetic test, the GJA12 gene should be further investigated, especially for women with clinical manifestations of classic PMD.

Pelizaeus-Merzbacher-like disease (PMLD) is a rare autosomal recessive diffuse white matter myelin formation disorder. Its clinical manifestations are similar to those of patients with PMD, hence the name PMLD. The known pathogenic gene of PMLD is gap junction protein alpha 12 (GJA12), also known as GJC2. There are other genes that can cause clinical manifestations of PMLD. Therefore, PMLD caused by GJA12 / GJC2 is called PMLD1. This gene was identified in 2004 by Uhlenberg et al. The GJA12 gene is about 9.9 kb in length and includes two exons. The coding region is located in exon 2. The gene coding product is gap junction protein 47 (connexin 46.6, Cx47). Mutations in the GJA12 gene can cause severe nerves. Systemic lesions. The pathogenesis of PMLD is unclear. It is currently believed that PMDA-related GJA12 gene mutations may cause changes in Cx47 expression and interfere with the coupling between astrocytes and oligodendrocytes. Astrocytes and oligodendrocytes are coupled to each other through gap junctions. Different cells express different gap junction proteins. Astrocytes are coupled via Cx43 / Cx43 and Cx30 / Cx30 channels. Astrocytes / oligodendrocytes are coupled via Cx43 / Cx47 and Cx30 / Cx32 channels. Immunostaining sections showed that Cx47 was expressed in oligodendrocytes and was close to its cell edges. A missense mutation in the GJA12 gene caused a loss of Cx47 function. Therefore, it is believed that the GJA12 gene mutation affects Cx43 / Cx47-mediated A / O coupling. As a result, a series of clinical manifestations appeared. Pediatrics of Peking University First Hospital was the first to diagnose and report 2 cases of PMLD in China in 2007. The results of genetic analysis showed that 1 case was a point mutation of the GJA12 gene, 1 case was a frameshift mutation, and was a parental diploid diploid of chromosome 1. Caused by. Up to now, the group has clinically diagnosed 9 cases of PMLD patients, 4 cases of genetically confirmed PMLD1 patients, and only over 60 cases have been genetically confirmed internationally.

The clinical manifestations of PMLD and PMD are similar. The skull MRI manifestations are basically the same as PMD and difficult to distinguish, but patients with PMLD have a greater chance of convulsions. PMLD is an autosomal recessive inheritance. There is no significant difference between men and women in the incidence of autosomal recessive inheritance. There is no significant difference in the incidence of men and women. However, PMD is an X-linked recessive inheritance, which is more common in men and more serious. It is difficult to separate these two diseases based on general imaging and biochemical examination. At present, only genetic mutation analysis can be used to confirm the diagnosis. If there is no abnormality in the PLP1 genetic test, the GJA12 / GJC2 gene test should be further investigated, especially for classic clinical manifestations. Female child with PMD.

White matter ablation leukoencephalopathy

vanishing white matter disease, VWM, this disease can also be manifested as diffuse involvement of white matter in the brain, but abnormal white matter can appear liquefied, which can be clearly seen in the cerebrospinal fluid signal in Flair. No clinical nystagmus. Instead, the onset of dyskinesia, dyskinesia is more severe than mental retardation, and fever or mild head trauma caused by infection can cause the disease to significantly worsen. There can be ataxia, seizures, and optic nerve atrophy.

Salla Peme disease Salla disease

It is a free sialic acid storage disease caused by the accumulation of N-acetic acid neuraminic acid (NANA) in the lysosome. It can also be clinically manifested as hypotonia, nystagmus and mental retardation. However, epilepsy is more common in this disease than in PMD, and it can have a rough face, hepatosplenomegaly, and enlarged heart. Cranial MRI can show diffuse T2 high signal in heavier children, and it is mainly concentrated around the ventricle in relatively light children. High-performance liquid tandem mass spectrometry can be used to detect the increase of free sialic acid in urine, and the free sialic acid in cultured skin fibroblasts is stored in the lysosome rather than in the cytoplasm or a disease-causing mutation in the SLC17A5 gene can confirm the diagnosis. ^[1]

Pepe disease treatment

At present, there is no satisfactory treatment for Pemei disease and Pemei disease. If pregnant women are suspected of being carriers of PLP1 or GJA12 mutations, genetic counseling and prenatal diagnosis can be performed. However, it is difficult to accurately predict the phenotype of the affected fetus, because family members with the same mutation can have very different phenotypes. With the deepening of stem cell research, some diseases have been treated with stem cell transplantation. Although there are still some key technical issues that have not yet been resolved, I believe that stem cell transplantation for PMD and PMLD will become possible in the near future. ^[2-3]

Prenatal diagnosis and genetic counseling of Pemei disease

Prenatal diagnosis (prenatal diagnosis) is also called intrauterine diagnosis or prenatal diagnosis. It is based on genetic counseling and uses various diagnostic techniques to make intrauterine diagnosis of fetal diseases. In addition to prenatal diagnosis of hereditary diseases, prenatal diagnosis mainly uses genetic testing and imaging studies to make a clear diagnosis of high-risk fetuses, and to achieve fetal selection through selective abortion of affected fetuses, thereby reducing the rate of birth defects. To improve the quality of eugenics and the quality of the population.

Prenatal diagnostic methods are generally divided into two categories, invasive and noninvasive, based on the differences in materials and examination methods. The former mainly includes amniocentesis, villus sampling, cord blood sampling, fetal scope and embryo biopsy. Etc .; the latter includes ultrasound, maternal peripheral serum marker determination, and fetal cell detection. At present, invasive methods are still the main methods in prenatal diagnosis. Amniocentesis and villus sampling are the two most commonly used methods. After the diagnosis of the proband in the family of Pemei disease is clear, the family separation analysis is performed to determine the genetic method in the family, and genetic counseling and prenatal diagnosis can be performed. The proband has a molecular test to confirm the diagnosis, and the mother of the proband After getting pregnant again, sign the informed consent, collect fetal villi or amniotic fluid to extract DNA for prenatal molecular diagnosis, SRY is used for fetal sex identification, and DXS6797, DX6807 and AR are short repeat sequence tags on the X chromosome to check whether there is maternal blood contamination and For the detection of fetal biological parents, genetic diagnosis is performed according to the method used by proband molecular molecular diagnosis.

Genetic counseling is a program that helps people understand and adapt to the effects of genetic factors on disease and its medical, psychological, and family effects. This process includes: assessing the risk of occurrence or recurrence of the disease through the interpretation of family history; education on the genetics, laboratory testing, treatment and prevention of related diseases, and providing a variety of help-related diseases Channels and research directions; counselling promotes informed choice and progressive awareness and acceptance of the disease and its recurrence risk. Genetic counseling is required for those with prenatal diagnostic indications.

With the advancement of modern detection technology and the continuous deepening of understanding of genetic diseases, the role of genetic counseling in public life has become more and more important, especially in recent years, the widespread development of genetic disease screening has made genetic counseling a minority of people from the past. Counseling has become a wider range of consultations related to all genetic diseases now. It is foreseeable that the basic principles of genetic counseling will remain unchanged in the future, but the content of genetic counseling will be continuously updated, and the application fields will become wider and wider. ^[4]