Niemaoh-Pickdisease (NPD), also known as sphingomyelin deposition disease, is a group of lysosomal storage diseases with abnormal lipid metabolism. Niemaoh-Pick disease (neurosphingolipid storage disease) is caused by abnormal neurosphingolipid metabolism due to mutations in genes such as sphingomyelin phosphodiesterase, resulting in the accumulation of excess lipids in the liver, kidneys, spleen, bone marrow, and brain of patients, and causing lesions in these organs. Niemannpick’s disease (neurosphingolipid storage disease) is autosomal recessive.
Niemannpick’s disease is characterized by a large number of foamy cells containing neurospherin in all mononuclear macrophages and in the nervous system. There are at least five types.
I. Clinical manifestations
Most commonly seen in infants and children under 2 years of age, but also in the neonatal period.
Acute neurological type (type A or infantile type): typical of Niemann-Pick (85% of cases), mostly within 3-6 months after birth, with a few onset a few weeks after birth or after 1 year of age. Initially, loss of appetite, vomiting, feeding difficulties, extreme emaciation, dry waxy skin, progressive mental and motor decompensation, hypotonia and floppy paralysis, eventually becoming an idiot, half of them have cherryred spot of the fundus, blindness, jaundice with hepatosplenomegaly. Anemia, cachexia, and death before 4 years of age due to infection. The skin often has a small yellow verrucous rash and deafness. Neurospherin accumulation is 20-60 times normal, and enzyme activity is 5-10% of normal, with a minimum of <1%.
Non-neurological type (type B or visceral type): infantile or childhood onset of open door, slow progression of disease, prominent hepatosplenomegaly. Normal intelligence, no neurological symptoms. SM accumulation is 3-20 times higher than normal, enzyme activity is 5-20% of normal, low as in type A.
Juvenile type (C chronic neurological type): mostly seen in children, a few young children or adolescents. Postnatal development is mostly normal, and a few have early jaundice. Hepatosplenomegaly is often the first sign, and neurological symptoms appear mostly at the age of 5 to 7 years (or earlier or later in adolescence). Mental retardation, language disorders, learning difficulties, emotional changes, unstable gait, ataxia, tremor, hypertonia and tendon reflexes, convulsions, dementia, and cherry erythema or supranuclear vertical oculomotor paresis are seen in the fundus. SM accumulation is 8 times higher than normal, and enzyme activity is up to 50% of normal, or near normal or normal.
Nova-scotia (type D): slower clinical course than juvenile type, with marked jaundice, hepatosplenomegaly and neurological symptoms, most deaths occur at school age, with reduced enzyme activity.
Adult type: Adult onset, normal intelligence, no neurological symptoms, varying degrees of hepatosplenomegaly. SM accumulation is 4-6 times normal and enzyme activity is normal.
II. Auxiliary examination
1. Blood picture: normal hemoglobin or mild anemia; leukocytopenia when hypersplenism is apparent. Monocytes and lymphocytes often show characteristic vacuoles, about 8 to 10, which have diagnostic value. These vacuoles are lipid-filled lysosomes on electron microscopy. The platelet count is normal, with advanced hypersplenism and decreased time to significant bone marrow invasion. Lack of neurophospholipase activity in the patient’s leukocytes.
2. Bone marrow picture: contains typical nisus-picocytes, often called foam cells, with nuclei 20-100 μm in diameter; small, round or ovoid nuclei, usually single, but may also have double nuclei; abundant cytoplasm, filled with round drop-shaped clear vesicles, resembling mulberry or foam. The electron microscopy showed that the vesicles were surrounded by a partial membrane layer structure. Examination of unstained specimens with a bitemporal microscope showed small bubble-like cells in the cytoplasm, unlike Gaucher cells. Under polarized light, the vesicles are birefringent; under ultraviolet light, the fluorescence is greenish-yellowish. Biochemical characteristics PAS reaction is weakly positive, the wall of the vesicles in the cytoplasm is positive, the center of the vesicles is negative; acid phosphatase, alkaline phosphatase, Sudan black are negative reaction.
3, plasma cholesterol and total lipids may be elevated, SGPT is mildly elevated.
4, urinary excretion of nerve sphingolipids significantly increased.
5, liver, spleen and lymph node biopsies have mounded, patchy or diffuse foam cell infiltration. Neurosphingomyelin.
6, X-ray examination: no characteristic X-ray manifestations, in long-term survival cases, due to the proliferation of lipid-filled histiocytes in the bone can show osteoporosis, widening of the medullary cavity, thinning of the bone cortex, and even long bones can appear focal areas of destruction, but no skeletal expansion deformity changes. After infancy, the alveoli are infiltrated by lipid-filled histiocytes, and lung manifestations similar to histiocytic hyperplasia X are seen. In short, non-specific, providing only the basis for an auxiliary diagnosis.
7. Determination of leukocyte or cultured fibroblast sphingomyelinase activity, which varies among types of enzymes.
III. Diagnosis
1. hepatosplenomegaly.
2, with or without neurological damage or cherry erythema of the fundus.
3. vacuolation of peripheral blood lymphocytes and monocyte plasma.
4, foam cells can be found in the bone marrow.
5, X-rays of the lungs showing a corn-like or reticular infiltrate.
6, conditions can be made neurosphingolipase activity assay, quiet neurosphingolipid excretion, liver, spleen or lymph node biopsy to confirm. In children with hepatosplenomegaly of unknown origin, the possibility of this disease should be considered, regardless of whether it is accompanied by neurological symptoms, with particular attention to those with recurrent pulmonary infections. The initial diagnosis of type A can be made with hepatosplenomegaly, early neurological symptoms and typical foam cells on bone marrow smear, but the diagnosis is still based on enzyme activity testing. Since sphingomyelinase activity is also low in normal leukocytes, cultured skin fibroblasts are usually used as the test material. The enzymatic substrate of choice is 2-hexadecanoylamino-4-nitrophenylphosphorylcholine. The diagnosis of type A and B patients can be confirmed by DNA analysis; for type C patients, a special method must be used to test the intracellular cholesterol lipidation ability to confirm the diagnosis.
Differential diagnosis
1, Gaucher disease infantile type: predominantly large liver, hypertonia, spasticity, no fundus cherry erythema, no vacuolation of lymphocyte plasma, elevated serum acid phosphatase, Gaucher cells found in the bone marrow.
2, Wolman’s disease: no fundus cherry erythema, X-ray abdominal plain film shows bilateral adrenal enlargement with unchanging shape and diffuse punctate calcification shadow. Lymphocytes with vacuoles in the cytoplasm.
3, GM gangliosidosis type I: born with features of appearance, high forehead, low nasal bridge, coarse skin, 50% of cases have cherry erythema of the fundus and lymphocyte cytoplasm with vacuoles. x-ray shows multiple bone dysplasia, especially vertebrae.
4, Hurler disease (mucopolysaccharide type I): large liver and spleen, poor intelligence, lymphocyte cytoplasm with vacuoles, bone marrow with foam cells, etc. resembling NPD. heart defect, multiple bone dysplasia, no pulmonary infiltration. Increased urinary mucopolysaccharide excretion, neutrophils with special granules. after 6 months, shape, skeletal changes are obvious, vision is diminished, corneal clouding.
V. Treatment
Niemann’s disease (nerve sphingolipid storage disease) currently has no treatment, scientists are further investigation of the biochemical mechanisms and pathology of the disease, hoping to develop bone marrow transplantation, enzyme replacement therapy, gene therapy and other treatment methods.
Antioxidants: Vitamins C and E or butylated stilbene, which can prevent the peroxidation and polyheterogeneity of unsaturated fatty acids contained in neurospherin M and reduce lipofuscin and free radical formation.
Splenectomy: suitable for non-neurological types with hypersplenism.
Embryonic liver transplantation: successful results have been reported.