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).

Pathophysiology
Niemann-Pick diseases are genetic diseases primarily afflicting Ashkenazi Jews, which are classified in a subgroup of LSDs called sphingolipidoses or lipid storage disorders in which harmful quantities of fatty substances, or lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain. In the classic infantile type A variant, a missense mutation causes complete deficiency of sphingomyelinase. Sphingomyelin is a component of cell membrane including the organellar membrane and so the enzyme deficiency blocks degradation of lipid, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 microns in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Histology demonstrates lipid laden macrophages in the marrow, as well as "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, imparting a foamy appearance to the cytoplasm.

Presentation & Symptoms
Symptoms are related to the organs in which they accumulate. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension and pain as well as thrombocytopenia secondary to splenomegaly.

Sphingomyelin accumulation in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria) and discoordinated swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk and face (dystonia) and upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures is responsible for gradual loss of intellectual abilities causing dementia and seizures.

Sleep related disorders are also seen, including gelastic cataplexy (sudden loss of muscle tone associated with laughter), and sleep inversion (sleepiness during the day and wakefulness at night).

Treatment
Treatments for Niemann-Pick disease are limited with care being mostly supportive. Anecdotally, organ transplant has been attempted with limited success. Future prospects include enzyme replacement and gene therapy. Bone marrow transplant has been attempted for Type B. Supportive care through nutrition, medication, physical therapy and being followed by specialists can help with quality of life.

In January 2009, Actelion announced that the drug Zavesca (Miglustat) had been approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann-Pick type C disease (NPC). The drug is available to patients in the United States on an experimental basis. In addition, researchers at the University of Texas Southwestern Medical School found that when Niemann Pick type C mice were injected with CYCLO (2-hydroxypropyl-β-cyclodextrin or HPBCD), when they were 7 days old, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life occurred. These results suggest that 2-hydroxypropyl-β-cyclodextrin acutely reverses the storage defect seen in Niemann-Pick type C disease.

In April 2009, a promising development in treatment of Niemann Pick type C was announced. The U.S. Food and Drug Administration granted special permission under its "compassionate use" program for 5 year old identical twins, Addison and Cassidy Hempel of Reno, Nevada, to receive intravenous infusions of 2-hydroxypropyl-β-cyclodextrin. The twins are the first in the United States to receive experimental treatment with this sugar compound and are currently undergoing treatment at Renown Regional Medical Center in Reno.

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

Genetics
Mutations in the SMPD1 gene cause Niemann-Pick disease types A and B, and mutations in NPC1 and NPC2 cause Niemann-Pick disease, type C (NPC). Type D was originally separated from Type C to delineate a group of patients with otherwise identical disorders 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.

Classification
In 1961, the following classification was introduced:


 * Niemann-Pick disease type A: classic infantile
 * Niemann-Pick disease type B: visceral
 * Niemann-Pick disease, type C: subacute/juvenile
 * Niemann-Pick disease 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.)