Introduction
Pey disease(Pelizaeus-Merzbacher disease, PMD) is a rare X-linked recessive genetic disorder of diffuse white matter myelination, a proteolipid protein (PLP1)-associated hereditary myelination disorder One of the spectrum. The characteristic pathological change of PMD is that the myelin sheath cannot form normally, but not the demyelination of other hereditary leukoencephalopathy.
Disease profile
In 1885, Pelizaeus was the first to report the family of five male children, mainly nystagmus, limb paralysis, ataxia, and stunting. In 1910, Merzbacher again studied the family reported by Pelizaeus. At this time, there were 14 patients and 2 female patients. The disease was found to have X-linked recessive genetic features and white matter pulp was found in brain biopsy. The disease is missing, so the disease is named PMD. The pathological manifestation of this disease is that the myelin sheath area and the demyelinating area are interlaced, showing a tiger-like appearance. Under the microscope, the Sudan-like substance is deposited in the center of the semi-oval, brain stem and cerebellum. PMD is a serious lethal, disabling neurogenetic disease with a short life span. In severe cases, it can only survive to a few years old and even die after birth. Its incidence rate is 1/500 000-1/300 000 in the United States. There is still no relevant incidence study in China. In 2007, the research team first diagnosed and reported 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 (the remaining patients are undergoing genetic analysis), of which 57 cases were confirmed by gene. The following will be explained from the etiology, clinical manifestations, auxiliary examination, diagnosis, differential diagnosis, treatment, prenatal diagnosis and genetic counseling of PMD.
Etiology and pathogenesis
The pathogenic gene of PMD is the proteolipid protein 1 (PLP1) gene located in Xq22.2. The PLP1 gene is about 17 kb in length and contains 7 exons. It encodes a PLP1 protein containing 276 amino acids and its scissor. The isomer DM20 was cleaved. PLP1 is the main component of the central nervous system myelin, accounting for about 50% of the entire myelin protein. Its main function is to constitute and stabilize myelin while playing an important role in the development of oligodendrocyte precursor cells. PLP1 is mainly expressed in oligodendrocytes (OL). Oligodendrocytes are the main type of glial cells, which are distributed in the gray matter and white matter of the central nervous system, especially white matter. The cells are myelin-forming cells, and the normal development of oligodendrocytes provides a guarantee for the integrity of the central nervous system myelin. The myelin sheath is a tubular outer membrane wrapped around the axons of nerve cells. The myelin sheath has a Langer's knot, which can transmit nerve impulses. The myelin sheath is composed of myelin and has an insulating effect, which can increase the conduction speed of nerve impulses. With axonal protection, the axonal conduction velocity is regulated by the synaptic diameter, the thickness of the myelin sheath, the number and spatial distribution of the Langer's knot, and the molecular composition of the ion channel in the internode region. The myelin is accurately and efficiently transmitted in the neural information. Central information integration plays an extremely important role. Abnormal glial cells/myelin abnormalities can alter the stability of axonal bundles, thereby affecting the basic electrical conduction patterns of nerve cells, ultimately affecting normal synaptic transmission. Studies have shown that Plp overexpression in transgenic mice can cause cognitive impairment, possibly associated with oligodendrocyte/myelin dysfunction by altering glutamatergic and dopaminergic signaling-induced neurological loop abnormalities, in less acne Electrophysiological studies in cytoplasmic/myelin abnormalities in neurons will help to understand the mechanism of molecular interactions in axons-myelin in these signaling pathways.
Defective PLP1 gene can overexpress PLP1 protein (PLP1 gene duplication mutation), decreased expression or abnormal intracellular distribution (PLP1 gene point mutation) and PLP1 deletion, which can lead to oligodendrocyte/myelin dysfunction, resulting in Abnormal myelination and/or oligodendrocyte death, resulting in a lack or reduction of myelin in a wide range of white matter regions. Different mutation types of the PLP1 gene cause differences in clinical phenotypes through different cellular and molecular mechanisms.
Clinical manifestation
Typical clinical manifestations of PMD are nystagmus, low muscle tone, ataxia, and progressive motor dysfunction. In the process of disease development, most children gradually progress gradually, and then the development of mental motor development gradually declines, and motor dysfunction is more significant than mental retardation. PMD is one of the PLP1-related diseases, and the PLP1-related disease is a spectrum of continuous disease from heavy to light, classified into 6 types according to the clinical manifestations from heavy to light and onset age (Table 1): congenital PMD (connatal PMD), classic PMD (classic PMD), a transitional form, no PLP1 null syndrome, complicated spastic paraplegia and uncomplicated Spastic paraplegia).
Congenital PMD
Congenital PMD is onset at birth and has serious clinical symptoms. It is characterized by pendulum-like nystagmus, low muscle tone, difficulty swallowing, and wheezing. Some children may have seizures. Cognitive function is severely impaired, language expression is severely affected, but non-verbal communication is possible, and some children have the possibility to understand language. You cannot walk alone during the entire development process. As the disease progresses, the limbs gradually become paralyzed. Most of them die during childhood, and a few survive longer, but generally do not exceed 30 years of age.
Classic PMD
The classic PMD is the PMD described by Pelizaeus and Merzbacher and is the most common one. More than a few months after birth, no later than 5 years old. Early manifestations of nystagmus and low muscle tone. Before the age of 10, the motor function can be slowly improved, and the free movement and walking ability of the upper limb can be obtained. Then, the gradual retreat can be repeated. As the disease progresses, the nystagmus can disappear, and then the motor developmental disorders such as gait, ataxia, quadriplegic, etc. Can be associated with cognitive impairment and extrapyramidal abnormalities. Most patients die between 30 and 70 years of age.
Intermediate PMD
The clinical manifestations of the intermediate type range between congenital and classic.
No PLP1 syndrome
This type is special and has no nystagmus. It develops normally within 1 year old and starts from 1 to 5 years old. Mainly manifested as mild quadriplegic spasm, ataxia, mild to moderate cognitive impairment, a certain language function, more than a retrograde after puberty, some children may be accompanied by mild peripheral nerve symptoms. The life expectancy is 50 to 70 years old.
Complex spastic paraplegia
The child develops normally within 1 year of age and is more than 1 to 5 years old. Mainly manifested as nystagmus, ataxia, progressive weakness and paralysis of the lower extremities, autonomic dysfunction (such as bladder spasm), no or slight cognitive impairment, language function. Life expectancy is 40 to 70 years old.
Simple type paraplegia
This type is the lightest type. The child usually develops normally within 1 year of age, and begins to develop from 1 to 5 years old. It can also develop symptoms from 30 to 40 years old. Mainly manifested as progressive lower extremity progressive weakness and paralysis, autonomic dysfunction (such as bladder spasm). However, the patient had no nystagmus and impaired cognitive function. Life expectancy is normal.
Table 1 PLP1 related diseases clinical classification phenotype age of onset nervous system performance walking language death age congenital PMD neonatal period after birth, ocular tremor, swallowing weakness, wheezing, low muscle tone, severe paralysis/without convulsions, Cognitive impairment never
No, there may be non-verbal communication and language understanding baby up to 30 years old classic PMD within 5 years old
Two months after birth, nystagmus, initial muscle tone, spasm paraplegia, ataxia, gait instability with or without dystonia, hand and foot hyperactivity disorder, cognitive impairment assisted walking, child/pubertal loss Walking function can usually occur 30 to 70 years old without PLP1 syndrome within 5 years of no nystagmus, mild spastic paraplegia, ataxia, peripheral neuropathy, mild to moderate cognitive impairment
Yes, usually puberty worsening 50~70 years old complex SPG within 25 years old
Ocular tremor, ataxia, autonomic dysfunction*, spastic gait, mild or no cognitive impairment
Will be 40 to 70 years old, pure SPG2 is usually less than 5 years old, can also be 30 to 40 years old
Autonomic dysfunction*, spastic gait, and no cognitive impairment will be normal
Note: The clinical manifestation of intermediate PMD is between congenital and classic PMD; * sacral bladder assisted examination
Head NMR image
Magnetic resonance imaging, MRI, PMD imaging is mainly characterized by myelin dysplasia or complete absence of myelin. Skull MRI can show myelination abnormalities, mainly in white matter T2-weighted images and Flair-like diffuse high signals. This test is important for the diagnosis of PMD. Because the first and second years after birth are important periods of myelination of the white matter, the MRI manifestation of the skull is relatively small. However, due to the myelination of the posterior limb, corpus callosum and visual radiation zone of the normal 3 months baby, these early abnormalities are important for the diagnosis of PMD. As the age of PMD children gradually increases, the development of white matter is extremely backward. The MRI of the head is manifested as neonatal white matter. The T1-weighted white matter changes are often not obvious. The T2-weighted white matter is almost all high signal. As the disease progresses, the white matter volume shrinks, showing thinning of the corpus callosum, enlargement of the ventricles, and cortical invagination. Children with spastic paraplegia have a milder white matter abnormality than PMD, and their head MRI T2-weighted images can be expressed as flaky high signals.
Nuclear magnetic resonance spectroscopy
Magnetic resonance spectrum, MRS, choline complex (choline) includes glycerophosphorylcholine, phosphatidylcholine, phosphorylcholine, etc., and is an important component of cell membrane phospholipid metabolism. When the cell membrane breaks down, the Cho level rises. Because PMD is a myelin-forming disorder, the level of Cho is not high, which is significant compared with white matter demyelinating diseases. Bonavita et al reported no decrease in N-acetylaspartate (NAA) levels in PLP1 syndrome. Conversely, NAA levels are elevated in children with repeated mutations in the PLP1 gene, which is easily confused with Canavan's disease.
Molecular genetic testing
The PLP1 gene has a variety of mutation types. Up to now, human gene mutation databases of PLP1 related diseases have been found, including repeated mutations, point mutations and deletion mutations. Repeat mutations are the most common, accounting for 50% to 70% of the total number of PMD patients, and point mutations account for 10% to 25% of the total number of PMD patients. According to this, in the clinical diagnosis of the disease detection strategy of patients with pem disease, the first detection of PLP1 gene repeat mutation detection, multiplex ligation-dependent probe amplification (MLPA), is developed in recent years. A new technique for qualitative and semi-quantitative analysis of DNA sequences to be tested. The technique is highly efficient and specific, and can detect changes in copy number of 30-48 nucleotide sequences in one reaction, and has been applied to research in various fields and diseases. Used to detect PLP1 gene repeat/deletion mutations in the diagnosis of Pécybee. Results Normal subjects were tested for point mutation using DNA direct sequencing.
For patients with clinically suspected PMD, a PLP1 genetic test is needed to confirm the diagnosis.
Studies have shown a significant correlation between genotype and phenotype in PLP1-related disease lineage: PLP1 gene mutations are most common with repeated mutations, accounting for 50% to 70%, point mutations account for 10% to 25%, and deletion mutations account for only 2 out. PLP1 gene repeat mutations are found in most classical and intermediate PMDs; point mutations have a wide clinical phenotype and can be found in all clinical phenotypes of PLP1-related diseases, but with congenital PMD; and deletion mutations are found in PLP1-free syndrome. Sexual paraplegia type 2. Our team's experimental results of 53 patients with PLP1 gene mutation analysis showed that 71.7% were PLP1 gene repeat mutations, of which the clinical phenotype was 68.4% (26/38) and 26.3% (classical and intermediate PMD, respectively). 12/38); 22.6% were point mutations, of which 41.6% (5/12) were congenital PMD; 5.7% did not find PLP1 gene changes. The latest study also showed that the copy number variation (CNV) fragment size of the X chromosome associated with PLP1 gene mutations in PMD patients is closely related to the clinical phenotype. We applied the gene chip to the above 38 patients with PLP1 gene duplication mutation. A preliminary analysis of the changes in CNV in related 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 by genetic testing in Pediatrics, Peking University First Hospital.
diagnosis
The clinical diagnosis of PMD is mainly based on typical clinical manifestations and cranial imaging studies, and the diagnosis relies on molecular genetics research. Clinically encountered in male children, with nystagmus, mainly manifested as nystagmus, low muscle tone, ataxia and progressive motor dysfunction, head MRI showed T2-weighted diffuse high signal of white matter, consider PMD The possibility of further PLP1 genetic testing should be confirmed.
Differential diagnosis
Identification of PMD and Pei's disease
If there is no abnormality in the PLP1 gene test, the GJA12 gene should be further investigated, especially in women with clinical manifestations of classic PMD.
Pelizaeus-Merzbacher-like disease (PMLD) is a rare autosomal recessive diffuse white matter myelination disorder. Its clinical manifestations are similar to those of PMD patients, hence the name PMLD. The currently known pathogenic gene of PMLD is gapjunction protein alpha 12 (GJA12), also known as GJC2, and other genes can cause clinical manifestations of PMLD. Therefore, the 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, and the gene coding product is gap junction protein 47 (connexin 46.6, Cx47). GJA12 gene mutation can cause severe nerves. Systemic lesions. The pathogenesis of PMLD is unclear. It is currently believed that PMLD-associated GJA12 gene mutations may cause changes in Cx47 expression and interfere with the coupling between astrocytes and oligodendrocytes. The astrocytes and oligodendrocytes are coupled to each other by a gap junction. Different cells express different gap junction proteins. Astrocytes were coupled between Cx43/Cx43 and Cx30/Cx30 channels. Astrocytes/oligodendrocytes are coupled between Cx43/Cx47 and Cx30/Cx32 channels. Immunostained sections showed that Cx47 is expressed in oligodendrocytes and is close to the cell edge. The missense mutation of GJA12 gene leads to the loss of Cx47 function. Therefore, GJA12 gene mutation is considered to affect Cx43/Cx47-mediated A/O coupling. A series of clinical manifestations have emerged. Pediatrics of the First Hospital of Peking University first diagnosed and reported 2 cases of PMLD in China in 2007. The results of genetic analysis showed that one case was a GJA12 gene point mutation, and one case was a frameshift mutation, and it was a parental single parent diploid of chromosome 1. Caused. Up to now, our group has diagnosed 9 patients with PMLD, 4 patients with genetically diagnosed PMLD1, and only 60 patients with internationally confirmed genes.
The clinical manifestations of PMLD and PMD are similar. The MRI of the skull is basically the same as that of PMD. It is difficult to distinguish, but patients with PMLD have a high rate of seizures. PMLD is an autosomal recessive inheritance. There is no significant difference between men and women in autosomal recessive inheritance. There is no significant difference between male and female, but PMD is X-linked recessive inheritance, which is more common in men and more serious. According to the general imaging and biochemical examination, it is difficult to separate the two diseases. At present, it can only rely on gene mutation analysis for diagnosis. If the PLP1 gene test is normal, the GJA12/GJC2 gene test should be further investigated, especially for the clinical manifestation. Female children with PMD.
White matter ablation leukoencephalopathy
Vanishing white matter disease, VWM, can also be manifested as diffuse involvement of white matter in the brain, but abnormal white matter can appear liquefied, and the Flair image can be seen clearly as cerebrospinal fluid signal. There was no nystagmus in clinical manifestations. Instead, the onset of dyskinesia, dyskinesia is more important than mental retardation. Every infection caused by fever or mild head trauma can cause aggravation of the condition, and there may be ataxia,epilepsyAttack and optic atrophy.
Salla disease
It is a free sialic acid storage disease caused by the accumulation of N-acetate neuraminic acid (NANA) in lysosomes. It can also be clinically manifested as hypotonia, nystagmus and mental retardation. However, epilepsy is more common in this disease than PMD, and the disease can have a rough face, large liver and spleen, and enlarged heart. Skull MRI can be characterized by a diffuse T2 high signal in heavier children and mainly around the ventricles in relatively light children. High-performance liquid chromatography-tandem mass spectrometry (ELISA) for the detection of free sialic acid in urine can be diagnosed. Free sialic acid in cultured skin fibroblasts is stored in lysosomes rather than in cytosol or a pathogenic mutation in the SLC17A5 gene can be diagnosed.
treatment
At present, there is no satisfactory treatment for Pei's disease and Pemei's disease. Pregnant women who are suspected to be carriers of the PLP1 or GJA12 mutation can undergo genetic counseling and prenatal diagnosis. However, the phenotype of the affected fetus is difficult to predict accurately because the phenotypes of family members with the same mutation can vary widely. With the deepening of stem cell research, some diseases have been treated with stem cell transplantation. Although there are still some key technical problems that have not yet been resolved, it is believed that the use of stem cell transplantation for the treatment of PMD and PMLD will also be possible in the near future.
Prenatal diagnosis and genetic counseling
Prenatal diagnosis, also known as intrauterine diagnosis or prenatal diagnosis, is based on genetic counseling, using various diagnostic techniques to make intrauterine diagnosis of fetal disease. Prenatal diagnosis, in addition to prenatal diagnosis of hereditary diseases, mainly through genetic testing and imaging examination, a clear diagnosis of high-risk fetuses, through the selective abortion of the fetus to achieve the purpose of fetal selection, thereby reducing the birth defect rate Improve the quality of eugenics and the quality of the population.
Prenatal diagnosis methods are generally divided into two types, invasive and noninvasive, depending on the materials and examination methods. The former mainly includes amniocentesis, villus sampling, cord blood sampling, fetal mirror and embryo biopsy. Etc.; the latter includes ultrasound, parental peripheral serum marker determination and fetal cell detection. At present, invasive methods are still the main methods for prenatal diagnosis, and amniocentesis and villus sampling are the most commonly used. After the diagnosis of the proband in the Pey disease family is clear, the family separation analysis is carried out to determine the genetic pattern in the family, and the genetic counseling and prenatal diagnosis can be performed. The proband is diagnosed by molecular test, and the mother of the proband After re-pregnancy, sign the informed consent form, collect fetal fluff or amniotic fluid to extract DNA for prenatal molecular diagnosis, SRY for fetal sex identification, DXS6797, DX6807 and AR for the short repetitive sequence label on X chromosome for maternal blood contamination and The detection of fetal biology parents is based on the method used by the proband's molecular genetic diagnosis for genetic diagnosis.
Genetic counseling is a program that helps people understand and adapt to the effects of genetic factors on disease and its effects on medicine, psychology, and family. This procedure includes: assessing the incidence of disease or recurrence risk through interpretation of family history; educating genetics, laboratory testing, treatment, and prevention of related diseases, and providing various types of diseases that can be sought for Channels and research directions; counseling 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 deepening of understanding of genetic diseases, the role of genetic counseling in public life is becoming more and more important, especially in recent years, the widespread development of genetic disease screening has made genetic counseling from the past few people. Counseling has become a broader consultation with all genetic diseases. 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 field of application will become more and more extensive.
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