Niemann-Pick disease in children

　　This condition is a congenital abnormality of glycolipid metabolism, characterized by a large number of foam cells containing sphingomyelin in the reticuloendothelial system throughout the body. This condition is an autosomal recessive genetic disease, with about 1/3 of the cases having a clear family history. Due to the lack of sphingomyelin, there is a disorder in sphingomyelin metabolism, causing the imbalance of lipids and coenzymes, leading to excessive deposition of lipids in the body. In the reticuloendothelial system, there is liver and spleen enlargement, and degenerative changes in the central nervous system. Sphingomyelin is formed by the connection of N-acyl nitramine with one molecule of phosphatidylcholine at the C1 position. Sphingomyelinase is derived from various cell membranes and red blood cell matrices, which is hydrolyzed into N-acyl sphingosine and phosphatidylcholine by macrophages after being engulfed during the process of cell metabolism and aging. The activity of this enzyme is highest in normal liver, while it is reduced to below 50% in the spleen, kidneys, brain, and small intestine. This syndrome is divided into 6 types, with types A, B, and C being the main types in childhood.

　　Types A and B are caused by mutations in the ASM gene, leading to reduced ASM activity and accumulation of sphingomyelin and other lipids in the mononuclear phagocyte system. The ASM gene is fixed at 11p15.1 to p15.4, and 12 mutation types have been identified. Type C is characterized by a defect in the transport of exogenous cholesterol into cells and accumulation of unesterified cholesterol in lysosomes, with the molecular defect of this type still unclear. Accumulations in the liver and spleen tissues of patients, in addition to unesterified cholesterol, include sphingomyelin, phospholipids, and glycolipids, while the accumulations in the brain tissue are only glycolipids. ASM activity in leukocytes is normal, and partial sphingomyelinase deficiency may be present in cultured cells, indicating secondary to the accumulation of cholesterol in lysosomes. Foamy cells and blue sclerotic cells are visible in many tissues. These cells are not specific to Type C and may be absent in cases without organomegaly. Specific inclusions can be seen in skin and conjunctival biopsies.

　　In addition to marked dementia (cognitive impairment), common complications in these children include aphasia, depression, and secondary infections such as pulmonary and urinary tract infections. Hepatosplenomegaly, chronic lung disease, pulmonary heart disease, seizures, and growth and development delays can lead to liver cirrhosis, liver failure, portal hypertension, and ascites. Psychiatric disorders may occur during adolescence.

　　Infantile Niemann-Pick disease is more common in young children, characterized by hepatosplenomegaly, cherry-red spots in the fundus of the eyes, and large foamy cells in bone marrow aspirates. The specific clinical manifestations of the disease are as follows:

　　1. Type A

　　Hepatosplenomegaly appears within the first 6 months of birth, followed by rapid progression of central nervous system degeneration. Early neurological manifestations include hypotonia and muscle weakness, reflected in feeding difficulties, lymphadenopathy, pulmonary infiltration, yellow-brown skin, and seizures. Half of the children have cherry-red spots in the macula of the fundus, with growth and development delays and respiratory complications, and most die between 2 and 3 years of age, with acid sphingomyelinase activity below 5% of normal values.

　　2. Type B

　　The most common type is less severe than Type A, with hepatosplenomegaly and abdominal distension in early childhood. Severe cases may lead to liver cirrhosis, portal hypertension, and ascites. Splenomegaly can progress to hypersplenism, with decreased blood cells, and partial or total splenectomy may be required. In mild cases, splenomegaly may not be discovered until adulthood. Diffuse reticulonodular infiltrates can be seen on the patient's X-ray chest film, which may lead to chronic lung disease and pulmonary heart disease. Most patients do not have neurological involvement and have normal intelligence, although there are individual reports of intellectual disability. Life expectancy can reach adulthood, with acid sphingomyelinase activity at 5% to 10% of normal values.

　　3. C type

　　Clinical manifestations are diverse, with typical manifestations including varying degrees of hepatosplenomegaly, vertical nuclear ophthalmoplegia, and slow progression of central nervous system degeneration (progressive ataxia, dystonia, and dementia) in childhood. Vertical nuclear ophthalmoplegia is a sign of brainstem involvement in the nervous system and is a characteristic sign. Children may show abnormal behavior when they are in kindergarten and primary school, often considered clumsy, and gradually become demented, dysphonia, language difficulties, and drooling. Dystonia first appears in abnormal posture of hands and feet when walking or running, unstable gait, prone to falls, and gradually becomes systemic, often accompanied by seizures, and mental disorders may occur during adolescence.

　　4. Other variants

　　Lethal neonatal liver disease, liver failure, and early progressive nervous system damage in infants, accompanied or without liver involvement, in adults accompanied by mental illness or progressive dementia.

　　This disease is an autosomal recessive inheritance, and in terms of prevention, attention should be paid to prenatal diagnosis and genetic counseling for hereditary diseases. If a child already has the disease, there is a 50% chance that the subsequent fetus may have the disease, so prenatal enzyme activity detection should be performed on the fetus. Determining the enzyme activity of skin fibroblasts can detect hemizygotes of types A and B, and enzyme activity detection of amniotic fluid cells can be used for prenatal diagnosis of types A and B.

　　Niemann-Pick disease is a hereditary metabolic disease caused by the deposition of sphingomyelin and cholesterol in various organs of the body, which is usually diagnosed by laboratory tests and auxiliary examinations.

　　1. Blood picture:Hemoglobin is normal or has mild anemia. When splenic hyperactivity is obvious, there is a decrease in white blood cells, and monocytes and lymphocytes often show characteristic vacuoles, about 8-10 in number, which have diagnostic value. Under an electron microscope, these vacuoles are lysosomes filled with lipids, and the platelet count is normal. In the late stage, there is splenic hyperactivity, and the patient lacks the activity of lysophospholipase in white blood cells.

　　2. Bone marrow:The cells contain typical Niemann-Pick cells, commonly known as foam cells, with a diameter of 20-100μm. The nucleus is small, round or oval, usually single, but can also be binucleated. The cytoplasm is rich and filled with round droplet-like transparent vesicles, resembling mulberry-like or foamy. Under an electron microscope, it shows that there is a partial membranous structure surrounding the vesicles. Phase-contrast microscopy of unstained specimens can show vesicular cytoplasm within the cells, which is different from Gaucher cells. Under polarized light observation, the vesicles show birefringence. Under ultraviolet light, fluorescence appears greenish yellow. Biochemical characteristics include a weak positive PAS reaction, positive vesicle walls in the cytoplasm, and negative in the center of the vesicles. Acid phosphatase, alkaline phosphatase, peroxidase, and Sudan black all show negative reactions.

　　3. Blood biochemistry test:Total cholesterol can increase, and SGPT can slightly increase.

　　4. Urine test: The excretion of neurosphingolipids is significantly increased.

　　5. Liver, spleen, and lymph node biopsy: There are accumulations, sheets, or diffuse infiltration of foam cells containing neurosphingolipids.

　　6. Sialidase activity measurement: White blood cells or the activity of fibroblast sialidase in culture, the activity of each type of enzyme is different, which is the most reliable for diagnosis.

　　7. X-ray examination: No characteristic X-ray findings. In long-term survival cases, due to the massive proliferation of lipophilic tissue cells in the bones, osteoporosis, medullary cavity widening, and thinning of the bone cortex may occur, and focal destructive areas may appear in long bones, but no skeletal enlargement or deformity changes. After infancy, the lung alveoli are infiltrated by lipophilic tissue cells, and the lungs show similar manifestations of histiocytosis X, with granular or reticular infiltration in the lungs. In summary, there is no specificity, and it only provides a basis for auxiliary diagnosis.

　　8. Ultrasound examination: Liver, spleen, and lymph node enlargement can be seen.

　　9. Electroencephalogram: Abnormal brain waves.

　　10. Fundus examination: Cherry red spots can be seen.

　　Early control of diet in the disease has a significant therapeutic effect and can prevent the progression of the disease. Starting from newborns, do not feed milk and foods containing galactose, such as soy milk, sugar, etc., and replace them with cereal, fruit, meat, and egg foods. Starting from 2 months after birth, a low phenylalanine diet is provided, replacing hydrolyzed protein, until around 6 years of age. Parents should also pay attention to limiting copper-containing diets.

　　Niemann-Pick disease type C (NPD) in children currently has no effective curative treatment. The main treatment is supportive and symptomatic, with attention to nutrition and a low-fat diet. Clinical symptoms can be treated symptomatically, and nursing care should be strengthened. Some people have performed liver transplantation surgery on a 7-year-old girl with NPD, which restored liver function, but did not prevent the progression of neurological symptoms.