Metachromatic leukodystrophy in children

Introduction to children with metachromatic leukodystrophy Leukodystrophy, also known as leukodystrophy, is a group of progressive hereditary sphingomyelin metabolic disorders that primarily invade myelins heath metabolism. This group of diseases includes globoid cell leukocystosis (GLD), metachromatic leukodystrophy (MLD), adrenalleukodystrophy (ALD), Pelizaeus-Merzbacher disease, central nervous system spongiform degeneration and Alexander is sick. Metachromatic leukodystrophy (MLD), also known as sulfatidelipidosis, is also a brain lipid deposition disease caused by myelin lipid metabolism disorder, characterized by accumulation of cerebroside sulfate in the body. For autosomal recessive inheritance, the disease gene is located at 22q14. Due to the lack of arylsulfatase A (ASA), sulphur fats are deposited in the white matter. The sick children gradually develop walking difficulties after 1 to 2 years of age. With limb weakness, ataxia or limb rigidity, progressive dementia, optic atrophy, deep sacral reflex disappearance, prolonged nerve conduction time and increased cerebrospinal fluid protein, etc., a small number of 3 to 10 years old (juvenile) or adult onset ( Adult type). Diagnosis by leukocyte sulfatase A activity is reduced by <40 nmol/(h·ml) or genetic diagnosis. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: optic atrophy, ataxia

Pediatric metachromatic leukodystrophy etiology

Genetic factors (95%):

Metachromatic leukodystrophy is an autosomal recessive hereditary disease, which is a poor myelination caused by defects in arylsulfatase A.

Other factors (5%):

Certain environmental factors lead to genetic mutations during the embryonic period.

Pathogenesis

1. Pathogenesis The disease is caused by the MLD mutation of the gene encoding lysine aryl sulphatase A (ASA). MLD is located at 22q13.31, and its mutation types are more; : Patients with type I mutations are unable to produce viable ASA, and no ASA activity can be measured in cultured cells; patients with type A mutations can synthesize a small amount of viable ASA, and the phenotype of the patient depends on the type of gene mutation: I Homozygous homozygous mutants or those with two different type I mutations are clinically characterized as late infants; those with type I and type A mutations are cyan and juvenile; and when both mutations are type A, then Presented as an adult type, a small number of patients with this disease, especially adolescents, are not caused by MLD mutations, and their ASA activity is normal. This is due to the lack of a lysosomal protein, ceramide sulfate activator (SAP1). As a result, these patients are also known as "activating factor-deficient metachromatic leukodystrophy."

2. Pathological changes ASA defects caused by MLD mutations prevent galactocerebrosyl sulphate (cerebate) from being normally hydrolyzed in lysosomes and accumulating in the white matter of nerve tissue, especially in oligodendrocytes and Schwann. In cells, due to its cytotoxic effects, it leads to demyelinating diseases of the nervous system, which are extensive in scope, involving the brain, cerebellum, brainstem, spinal cord and peripheral nerves; renal tubular epithelial cells, liver Kupffer cells, bile duct epithelial cells, etc. There is a large amount of brain sulphur deposition; brain sulphur accumulation accumulated in the epithelial cells of the gallbladder mucosa can cause papilloma lesions, and the sections of the diseased tissue can be detected by cresyl violet or toluidine blue. Red or slightly brown sediments (the control blue-nuclear nuclei are "metachromatic"); electron microscopy shows that laminin is deposited in lysosomes.

Pediatric metachromatic leukodystrophy prevention

To do genetic disease prevention, heterozygous can be detected by enzyme assay, and the activity of arylsulfatase A in amniotic fluid cells or villous cells can be measured. As a prenatal diagnosis of high-risk pregnancy late infants and juveniles, take corrective measures. Measures to prevent the disease from happening.

Pediatric metachromatic leukodystrophy complications Complications optic atrophy ataxia

Insufficient mentality, language disappearance, optic atrophy, late brain destructive position, convulsions, death from secondary infections, late-onset learning or work performance decline, behavioral abnormalities, cognitive impairment, and ataxia.

Pediatric metachromatic leukodystrophy symptoms common symptoms white matter is less gait abnormal tachycardia response dull white matter sparse sputum reflex abnormal convulsion on light reflex dull secondary infection to brain rigidity

MLD can be divided into late infant, juvenile and adult.

1. Late-infant late-infant type is most common, normal at birth, 85% can be walked normally before onset, mostly onset at about 2 years old, early gait abnormalities, ataxia, strabismus, low muscle tone, reduced autonomous movement The sputum reflex can not be induced, the nerve conduction velocity is slowed down, the latter is due to the involvement of the peripheral nerve, the mid-term mental decline, the reaction is reduced, the language disappears, the pathological reflex is positive, the gaze is not gaze, the pupil is slow to respond to light, and there may be optic atrophy. In the late stage, the brain was in a tough position, occasionally with seizures, and there was a medullary palsy sign. The course of the disease continued to progress, and more than 4 to 8 years old died of secondary infection.

2. Late-onset (adolescent and adult) The onset age ranges from 3 to 10 years old to adolescence, even adulthood. The clinical manifestations vary. Onset, the progressive walking difficulty is mainly accompanied by a decrease in tendon reflex. Peripheral nerve involvement such as decreased nerve conduction velocity; adolescents or adults with a younger onset of age often have learning or work performance decline, behavioral abnormalities, cognitive disorders, etc., and then there are anaction disorders such as ataxia and pyramidal tract signs. The course of this type is 5 to 10 years.

Examination of children with metachromatic leukodystrophy

1. Determination of urinary brain sulphur lipids MLD patients have a large amount of brain sulphur lipids in the urine, but there may be false negatives, so it should be repeated many times.

2. The activity of aryl sulfate lipase A (ASA) is generally measured by peripheral blood leukocytes or cultured fibroblasts. MLD patients can be measured without enzyme activity.

3. SAP1 determination of clinical MLD symptoms and normal ASA activity, the use of special antibodies to detect SAP1 content.

4. DNA analysis For families with prior probands, family members can be screened and prenatally diagnosed by DNA analysis.

5. Peripheral (sputum) nerve biopsy for individual clinical manifestations and biochemical examinations are not consistent, patients with unclear diagnosis, may consider nerve biopsy, looking for brain sulphur deposits in Schwann cells, to make a clear diagnosis.

6. Other examinations The protein content in the cerebrospinal fluid may be slightly elevated, and may gradually increase with the course of the disease.

7. EEG examination Non-specific EEG abnormalities are more common in the late stage of the disease, with a wide range of slow waves in the middle stage, and extensive EEG abnormalities in the late stage. Spikes are often scattered on the background of 2 to 3 times/s.

8. Electromyography showed prolonged nerve conduction time. Early EMG showed prolonged nerve conduction time and slowed down.

9. Cerebrospinal fluid examination showed further increase in protein in cerebrospinal fluid.

10. Brainstem auditory evoked potential examination is abnormal at an early stage.

11. Brain MRI examination showed that white matter lesions developed from the forehead to the posterior.

Diagnosis and diagnosis of pediatric heterochromatic leukodystrophy

The diagnosis of this disease is based on the test results of ASA activity, but in a few cases with typical symptoms and normal ASA activity, the possibility of activating factor-deficient metachromatic leukodystrophy should be considered, for each confirmed child. A member of the family should be tested for ASA activity to determine heterozygous carriers and patients who are not yet ill, and for future prenatal diagnosis. The ASA activity of heterozygotes is approximately 50% of the normal mean, such as the discovery of a member. The ASA activity is 10% to 15% of normal people. When clinically asymptomatic, except for the pre-onset state, the possibility of ASA pseudo-deficiency should be considered. The ASA pseudo-deficiency is due to the allele of MLD gene. Pd mutations, the carrying rate of Pd in the population is 10%, so it is more likely to appear in the family of MLD patients; homozygous Pd or heterozygous Pd and MLD can make ASA activity at a very low level, easy Misdiagnosed as pre-morbid patients; on the other hand, it is also possible to make MLD misdiagnosis for other neurological diseases with Pd gene and non-MLD. Therefore, cultured fibroblasts should be used as much as possible for family members. Amniotic fluid cells, or the like fluff 14C- sulfatide load test and DNA analysis, may determine whether to carry Pd gene.

This disease must be differentiated from other types of white matter malnutrition, other types of white matter dystrophy without the performance of peripheral nerve involvement, etc., can help identify.

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