Niemann-Pick's Disease

Synonyms include: NPD, Crocker's syndrome, Crocker-Farber syndrome, essential lipoid histiocytosis, phosphatidolipoidosis, phosphatidosis sphingomyelin lipidosis, sphingomyelin/cholesterol lipidosis, sphingomyelinosis, sphingomyelin reticuloendotheliosis

This is an autosomal recessive group of diseases in which sphingolipids accumulate in cells, especially reticuloendothelial cells, throughout the body. It is named after Albert Niemann and Ludwig Pick. There are 6 different types labelled A to F, although types E and F are not well characterised. In addition there are a few other less well recognised variations.

• Type A is the acute neuronopathic form.¹
• Type B is the visceral form²
• Type C is the chronic neuronopathic form. There are two subtypes. Niemann-Pick disease type C1³ and Niemann-Pick disease type C2⁴ are phenotypically similar.
• Type D is the same as type C1 and is also called the Nova Scotia variant.³
• Type E is the adult form and appears to be a variant of type B.²
• Type F is called sea-blue histiocyte disease and appears to be a rare variation of type B.⁵

Classification is based on clinical and pathological features. Niemann-Pick disease can also be classified into those with deficiency of acid sphingomyelinase activity, as in types A and B, and those with defective intracellular processing and transporting of LDL cholesterol as in type C. In types A and B sphingomyelin accumulates in cells but in type C it is cholesterol. As is so often the case in deficiency diseases, the deficiency is relative rather than absolute and the degree of deficiency will determine the speed of onset and presentation.

• In the general population the condition is very rare but 1 in 75 Ashkenazi Jews is a carrier.
• Type A accounts for about 85% of cases.
• The sex incidence is equal.
• For a child to be affected both parents must be carriers. The risk to subsequent children is 1 in 2 of being a carrier and 1 in 4 of being affected.
• Consanguineous marriage, especially amongst Ashkenazi Jews is a risk factor.

In both types A and B there is deposition of lipids in the reticuloendothelial system and visceral organs. In type A there is a progressive neurodegenerative pattern in infancy. In type B the nervous system is not involved.

Type A

Type A starts in the first few months of life and has the following features:

• Feeding difficulties
• Progressive increase in abdominal girth over 3 to 6 months
• Regression of early motor skills
• Rapid deterioration and death by age 2 to 3 years

Type B

Type B has similar biochemical abnormalities but is clinically more variable:

• There may be abdominal enlargement in early childhood
• Respiratory infections
• There are no neurological abnormalities

Abnormalities of respiratory function are usual but correlate poorly with radiological abnormality.⁶

Type C

Type C can strike from early infancy to adulthood but usually first manifests in school age children:

• Unsteady gait, clumsy, difficulty walking
• Slurred, irregular, dysarthric speech
• Palsy of the vertical gaze is an important diagnostic feature in type C
• Learning difficulties with progressive mental decline
• Sudden loss of muscular power can cause falls
• Tremor and ataxia
• Epilepsy

Type D is the same as type C1. Type C1 accounts for 95% of cases.⁷

There may be some similarity between the pathogenesis of Niemann-Pick type C disease and Alzheimer's disease.⁸

Type E

Type E patients are adults with moderate hepatosplenomegaly and some increase in sphingomyelin in the liver, spleen, and bone marrow.

Type F

Type F is characterised by childhood onset of splenomegaly, lack of neurological involvement, and diminished sphingomyelinase activity.⁹

Physical examination varies according to type and may reveal all or some of the following features:

• Examination of the eye is very important. A cherry-red macular spot is characteristic of type A. There may also be a brown discoloration of the anterior lens capsule and corneal opacity. These features together can be diagnostic.¹⁰
• Spasticity with myoclonic jerks and ataxia
• Hepatosplenomegaly with jaundice, ascites and features of hepatic failure
• Growth retardation
• Nodular xanthoma on the skin

Investigations may show anaemia, easy bruising and foam cells in the bone marrow. There may be pulmonary interstitial infiltrations and evidence of coronary artery disease.

This is between other lipid storage diseases including Tay-Sachs disease.

• Types A and B are diagnosed by measuring the levels of acid sphingomyelinase activity. It is not reliable to identify carriers.
• Gene testing is feasible as the SMPD1 gene, which codes for acid sphingomyelinase, has been mapped to band 11p15, and many of its mutations have been identified. In Ashkenazi Jews this accounts for 92% of mutations and all the Maghreb Northern African population. In other populations it may be necessary to identify the gene first.
• Types C and D are initially diagnosed by obtaining a skin biopsy sample, growing the fibroblasts in vitro, and then studying their ability to transport and store cholesterol.
• Types E and F are rare and diagnosis is not well established.

• There is no effective treatment in type A.
• Bone marrow transplantation has been attempted in type B with some encouraging results. Liver transplantation has also been used.¹¹
• Types C and D are usually given a low cholesterol diet. Cholesterol lowering drugs improve the hepatic storage component but have no effect on the brain.
• Enzyme replacement therapy may be a possibility in the future.

• Type A die in infancy.
• Type B live longer but the pulmonary disease may necessitate oxygen.
• In type C prognosis is more variable, often with death between infancy and adulthood. It is still a fatal disease. However, it has been found in adult neurology clinics.⁷ There is progressive neurological and psychiatric deterioration.¹²

Parents can be offered genetic counselling. Chorionic villous sampling with a view to TOP is feasible.¹³

Albert Niemann was born in 1880, the son of a famous operatic tenor. He graduated in medicine from Strasbourg in 1903. His great interest was metabolic disease but his career was curtailed when he died in 1921 at the age of 41.¹⁴

Ludwig Pick was born in 1863, the son of a successful businessman. He obtained his doctorate at Leipzig in 1893 and became eminent in pathology. In 1926 he demonstrated that Niemann-Pick disease is distinct from Gaucher's disease. He served with distinction in the German army during the First World War but was later evicted from his home by the Nazis and imprisoned in the Theresienstadt Concentration Camp where he died in 1944 at the age of 76 years.¹⁵