Niemann-Pick disease (NPD), also known as sphingomyelin lipidosis, is a congenital glycolipid metabolism disorder. It is characterized by the presence of large numbers of foam cells containing sphingomyelin in the mononuclear phagocyte system and nervous system. It is rarer than Gaucher disease. It is an autosomal recessive genetic disorder, more common among Jewish populations, with an incidence rate as high as 1 in 25,000. Currently, there are at least five known types.

bubble_chart Etiology

This disease is caused by a deficiency of sphingomyelinase, leading to impaired metabolism of sphingomyelin. This results in the accumulation of the latter in the mononuclear-macrophage system, manifesting as 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 originates from various cell membranes and erythrocyte stroma, among others. During the aging process of cellular metabolism, it is phagocytosed by macrophages.

The highest activity of this enzyme is found in the normal liver, and it is also abundant in the liver, kidneys, 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 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, causing sphingomyelin to accumulate in the mononuclear-macrophage system and neural tissue cells.

Most commonly seen in infants under 2 years old, and some may develop symptoms during the neonatal period.

1. Acute neurological type (Type A or infantile type): This is the classic Niemann-Pick disease (accounting for 85% of cases), typically manifesting between 3 to 6 months after birth, with a minority presenting within weeks or after 1 year of age. Initial symptoms include loss of appetite, vomiting, feeding difficulties, extreme emaciation, dry and waxy yellow skin, progressive decline in intellectual and motor functions, low muscle tone (flaccid paralysis), and eventual dementia. Half of the cases exhibit cherry-red spots in the fundus, blindness, jaundice accompanied by hepatosplenomegaly, anemia, and cachexia. Most patients die before the age of 4 due to infections. The skin often develops fine yellowish xanthoma-like rashes, and deafness may occur. Sphingomyelin accumulation is 20–60 times the normal level, with enzyme activity at 5–10% of normal, with the lowest <1%。
2. Non-neurological type (Type B or visceral type): Symptoms appear in infancy or childhood, with a slow disease progression and prominent hepatosplenomegaly. Intelligence remains normal, with no neurological symptoms. Patients may survive into adulthood. Sphingomyelin accumulation is 3–20 times the normal level, with enzyme activity at 5–20% of normal, similar to Type A in severe cases.
3. Juvenile type (Type C or chronic neurological type): Mostly seen in children, with a minority presenting in early childhood or adolescence. Development is typically normal after birth, though some may exhibit early jaundice. Hepatosplenomegaly is often the first symptom, with neurological symptoms (such as intellectual decline, speech impairment, 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) appearing mostly between 5–7 years (though onset may be earlier or delayed until young adulthood). Patients may survive to 5–20 years of age, with some living up to 30 years. Sphingomyelin accumulation is 8 times the normal level, with enzyme activity up to 50% of normal, sometimes near or at normal levels.
4. Nova-Scotia type (Type D): The clinical course is slower than the juvenile type, with prominent jaundice, hepatosplenomegaly, and neurological symptoms. Most patients die during school age, with reduced enzyme activity.
5. Adult type: Onset occurs in adulthood, with normal intelligence, no neurological symptoms, and varying degrees of hepatosplenomegaly. Patients can survive long-term. Sphingomyelin accumulation is 4–6 times the normal level, with normal enzyme activity.

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bubble_chart Diagnosis

1. Hepatosplenomegaly;
2. with or without neurological damage or cherry-red spots in the fundus;
3. peripheral blood stranguria lymphocytes and monocytes with vacuoles in the cytoplasm;
4. foam cells can be found in the bone marrow;
5. X-ray shows foxtail millet-like or reticular infiltration in the lungs;
6. if conditions permit, sphingomyelinase activity can be measured, and sphingomyelin excretion, liver, spleen, or lymph node biopsy can be performed for confirmation.

bubble_chart Treatment Measures

There is no specific treatment, and symptomatic treatment is the main approach, supplemented with a high-fat diet and enhanced nutrition.

1. Antioxidants: 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: Suitable for non-neurological types with splenomegaly and hypersplenism.
3. Embryonic liver transplantation: Successful cases have been reported.

bubble_chart Differentiation

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: Distinctive facial features at birth, including a high forehead, low nasal bridge, and coarse skin. 50% of cases exhibit cherry-red spots in the fundus and vacuoles in lymphocyte cytoplasm. X-rays reveal multiple bone dysplasias, particularly in the vertebrae.
4. Hurler disease (mucopolysaccharidosis type I): Hepatosplenomegaly, intellectual disability, vacuoles in lymphocyte cytoplasm, foam cells in the bone marrow similar to NPD. Cardiac defects, multiple bone dysplasias, no pulmonary infiltration. Increased urinary mucopolysaccharide excretion, special granules in neutrophils. After 6 months, obvious physical and skeletal changes occur, along with visual impairment and corneal clouding.