| disease | Niemann-Pick Disease |
| alias | NPD, Sphingomyelin Deposition Abdominal Mass Disease |
Niemann-Pick disease (NPD), also known as sphingomyelin lipidosis, is a congenital glycolipid metabolic disorder. It is characterized by the presence of large amounts of foam cells containing sphingomyelin in the mononuclear phagocyte system and nervous system. It is less common than Gaucher disease. It is an autosomal recessive genetic disorder, with a higher incidence among Jewish populations, reaching as high as 1 in 25,000. Currently, there are at least five known types.
bubble_chart Pathogenesis
This disease is caused by a deficiency of sphingomyelinase, leading to a disorder in sphingomyelin metabolism. This results in the accumulation of the latter in the mononuclear phagocyte system, causing hepatosplenomegaly and degenerative changes in the central nervous system.
Sphingomyelin is formed by the linkage of N-acylsphingosine with a molecule of phosphocholine at the C1 position. Sphingomyelin is derived from various cell membranes and erythrocyte stroma. It is engulfed by macrophages during the aging process of cell metabolism.
The activity of this enzyme is highest in the normal liver, and it is also abundant in the liver, kidney, brain, and small intestine. In patients with this disease, the enzyme activity in tissues such as the liver and spleen is reduced to below 50%.
In 1914, Niëmann reported a case where the patient died at 18 months of age. In 1934, it was discovered that this condition is a type of sphingolipid storage disease, and it was not until 1966 that it was recognized to be caused by a deficiency of sphingomyelinase. The lack of this enzyme leads to systemic sphingomyelin metabolism disorder, with sphingomyelin depositing in the mononuclear phagocyte system and neural tissue cells.
bubble_chart Clinical ManifestationsIt is commonly seen in infants under 2 years old and can also occur in the neonatal period.
1. Acute neurological type (Type A or infantile type): This is the typical Niemann-Pick disease (accounting for 85%), mostly occurring within 3 to 6 months after birth, with a few cases occurring within weeks after birth or after 1 year of age. Initial symptoms include loss of appetite, vomiting, feeding difficulties, extreme emaciation, dry skin with a waxy yellow appearance, progressive decline in intelligence and motor skills, low muscle tone, flaccid paralysis, eventually leading to idiocy. Half of the cases have cherry-red spots in the fundus, blindness, jaundice accompanied by hepatosplenomegaly. Anemia and cachexia are common, and most patients die before the age of 4 due to infections. The skin often shows small yellow xanthoma-like rashes and deafness. The accumulation of sphingomyelin is 20 to 60 times the normal level, and enzyme activity is 5 to 10% of normal, with the lowest being less than 1%.
2. Non-neurological type (Type B or visceral type): This type occurs in infants, young children, or during childhood, with a slow progression of the disease and prominent hepatosplenomegaly. Intelligence is normal, and there are no neurological symptoms. Patients can survive into adulthood. The accumulation of sphingomyelin is 3 to 20 times the normal level, and enzyme activity is 5 to 20% of normal, with the lowest being similar to Type A.
3. Juvenile type (Type C, chronic neurological type): This type is more common in children, with a few cases occurring in young children or adolescents. Development after birth is mostly normal, with a few cases showing early jaundice. Hepatosplenomegaly is often the first symptom, and neurological symptoms usually appear between 5 to 7 years of age (but can also appear earlier or as late as adolescence). Symptoms include intellectual decline, language disorders, learning difficulties, emotional instability, unsteady gait, ataxia, tremor, increased muscle tone and tendon reflexes, seizures, dementia, and cherry-red spots or supranuclear vertical ophthalmoplegia in the fundus. Patients can live to 5 to 20 years old, with some living up to 30 years. The accumulation of sphingomyelin is 8 times the normal level, and enzyme activity can be up to 50% of normal, or close to or at normal levels.
5. Adult type: This type occurs in adults, with normal intelligence, no neurological symptoms, and varying degrees of hepatosplenomegaly. Patients can survive for a long time. The accumulation of sphingomyelin is 4 to 6 times the normal level, and enzyme activity is normal.
bubble_chart Auxiliary Examination
1. Blood Picture: Hemoglobin is normal or shows grade I anemia; leukopenia is evident when splenomegaly is present. Monocytes and lymphocytes often exhibit characteristic vacuoles, about 8 to 10 in number, which are of diagnostic value. Under electron microscopy, these vacuoles are filled with lipid-laden lysosomes. Platelet count is normal, but decreases in advanced stages with splenomegaly and significant bone marrow invasion. Patients' leukocytes lack sphingomyelinase activity.
2. Bone Marrow Picture: Contains typical Niemann-Pick cells, often referred to as foam cells, with nuclear cell diameters ranging from 20 to 100 μm; the nucleus is small, round or oval, usually single, but can be binucleated; the cytoplasm is abundant, filled with round, droplet-like transparent vesicles, resembling mulberry fruit or foam. Electron microscopy shows that the vesicles are partially surrounded by membrane layers. Examination of unstained specimens with phase contrast microscopy reveals small bubbles in the cytoplasm, differing from Gaucher cells. Under polarized light, the vesicles show birefringence; under ultraviolet light, they fluoresce green-yellow. The generation and transformation characteristics show a weakly positive PAS reaction, with the vesicle walls in the cytoplasm being positive and the vesicle contents being heart yin; acid phosphatase, alkaline phosphatase, and Sudan black are all negative.
4. Urinary excretion of sphingomyelin is significantly increased.
5. Liver, spleen, and lymph node biopsies all show clusters, sheets, or diffuse infiltration of foam cells. Sphingomyelin.
6. X-ray Examination: No characteristic X-ray findings are present. In long-term survival cases, due to the proliferation of lipid-laden histiocytes in the bones, osteoporosis, widened medullary cavities, and thinning of the bone cortex may be observed, and even focal destructive areas in long bones may appear, but without skeletal enlargement or deformity. After infancy, alveolar infiltration by lipid-laden histiocytes may show lung manifestations similar to histiocytosis X. In summary, there are no specific findings, only providing auxiliary diagnostic evidence.
7. Measurement of sphingomyelinase activity in leukocytes or cultured fibroblasts shows varying enzyme activities among different types. {|106|}
Diagnostic criteria: ① Hepatosplenomegaly; ② Presence or absence of neurological damage or cherry-red spots in the fundus; ③ Vacuoles in the cytoplasm of peripheral blood lymphocytes and monocytes; ④ Foam cells can be found in the bone marrow; ⑤ X-ray shows miliary or reticular infiltration in the lungs; ⑥ If possible, measure the activity of sphingomyelinase, determine the excretion of sphingomyelin, and confirm through liver, spleen, or lymph node biopsy.
bubble_chart Treatment Measures
There is no specific treatment, and the main approach is symptomatic treatment, supplemented with a lipid-rich diet to enhance nutrition.
1. Antioxidants such as Vitamin C, E, or resveratrol can prevent the peroxidation and polymerization of unsaturated fatty acids in sphingomyelin M, reducing the formation of lipofuscin and free radicals.
2. Splenectomy is suitable for non-neurological types with hypersplenism.
3. Embryonic liver transplantation has been reported to be successful.
1. Gaucher disease infantile type: Mainly characterized by hepatomegaly, hypertonia, spasms, absence of cherry-red spots in the fundus, no vacuoles in lymphocyte cytoplasm, elevated serum acid phosphatase, and the presence of Gaucher cells in the bone marrow.
2. Wolman disease: Absence of cherry-red spots in the fundus, abdominal X-ray shows bilateral adrenal enlargement with unchanged shape and diffuse punctate calcification shadows. Vacuoles are present in lymphocyte cytoplasm.
3. GM1 gangliosidosis type I: Characteristic facial features at birth, including a high forehead, low nasal bridge, and coarse skin. 50% of cases have cherry-red spots in the fundus and vacuoles in lymphocyte cytoplasm. X-ray shows multiple bone dysplasias, especially in the vertebrae.
4. Hurler disease (mucopolysaccharidosis type I): Hepatosplenomegaly, intellectual disability, vacuoles in lymphocyte cytoplasm, and foam cells in the bone marrow similar to NPD. Heart defects, multiple bone dysplasias, and no lung infiltration. Increased urinary excretion of mucopolysaccharides, special granules in neutrophils. After 6 months, significant changes in appearance and skeletal structure, vision deterioration, and corneal clouding.
