Niemann-Pick disease

Niemann-Pick disease (pronounced nē′mahn pik) refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases (LSDs). Niemann Pick diseases are classified in a subgroup of LSDs called sphingolipidoses or lipid storage diseases in which harmful quantities of a fatty substances, called lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain.

Symptoms may be related to the organs in which they accumulate. Enlargement of the liver and spleen (heptosplenomegaly) may cause reduced appetite, abdominal distension and pain, and the enlarged spleen may trap platelets and other blood cells, leading to reduced numbers of these cell in the circulation. Storage in specific areas of the nervous system, causes specific symptoms. For example, storage in the cerebellum causes unsteady gait (ataxia), slurring of speech (dysarthria) and incoordinated swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk and face (dystonia) and upper brainstem disease causes impaired voluntary rapid eye movements (supranuclear gaze palsy) and sleep related disorders, including gelastic cataplexy (sudden loss of muscle tone associated with laughter), and sleep inversion (sleepiness during the day and wakefulness at night). More widespread disease involving the cerebral cortex and subcortical structures is responsible for gradual loss of intellectual abilities causing dementia and seizures.

Albert Niemann published the first description of what is now known as Niemann-Pick disease, type A, in 1914 and Ludwig Pick, a German neuropathologist, described the pathology of the disease in a series of papers in the 1930s.

Pick's disease is sometimes confused with Niemann-Pick disease but is a different disease, one of the frontotemporal dementias, described by Arnold Pick.

Genetics

Mutations in the SMPD1 gene cause Niemann-Pick disease types A and B, and mutations in NPC1 and NPC2 cause type C (NPC). Type D was originally separated from type C to delineate a group of otherwise identical patients who shared a common Nova Scotian ancestry. Patients in this group are now known to share a specific mutation in the NPC 1 gene, and NPC is now used to embrace both groups. The terms "Niemann-Pick type I" and "Niemann-Pick type II" were proposed to separate the high and low sphingomyelin forms of the disease in the early 1980s, before the molecular defects were described.

Niemann-Pick disease is inherited in an autosomal recessive pattern, which means both copies, or alleles, of the gene must be mutated (altered in such a way that function is impaired, in contrast to a polymorphism, in which the nucleotide sequence is altered but causes no functional disruption) for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.

Autosomal recessive inheritence

Classification

In 1961, the following classification was introduced:

• type A - classic infantile
• type B - visceral
• type C - subacute/juvenile
• type D - Nova Scotian

Now that the genetics are better understood, the condition can be classified as follows:

• Niemann-Pick disease, SMPD1-associated, which includes types A and B

• Niemann-Pick disease, type C, which includes types C1 and C2. (Type D is caused by the same gene as type C1.)