Niemann-Pick disease type C1

Alternate names

Niemann-Pick disease, type C; NPC1; Niemann-Pick disease with cholesterol esterification block; Niemann-Pick disease, subacute juvenile form; Niemann-Pick disease, chronic neuronopathic form; Neurovisceral storage disease with vertical supranuclear ophthalmoplegia

Definition

Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.

Epidemiology

Combined, Niemann-Pick disease types C1 and C2 are estimated to affect 1 in 150,000 individuals; however, type C1 is by far the more common type, accounting for 95 percent of cases.

Cause

• Mutations in NPC1 gene cause Niemann-Pick disease type C1.
• The proteins produced from these genes are involved in the movement of lipids within cells.

Gene mutations

• Mutations in these genes lead to a shortage of functional protein, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells.
• Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired.
• The accumulation of lipids as well as the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease types C1 and C2.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• The signs and symptoms of Niemann-Pick disease types C1 and C2 are very similar; these types differ only in their genetic cause.
• Niemann-Pick disease types C1 and C2 usually become apparent in childhood, although signs and symptoms can develop at any time. People with these types usually develop difficulty coordinating movements (ataxia), an inability to move the eyes vertically (vertical supranuclear gaze palsy), poor muscle tone (dystonia), severe liver disease, and interstitial lung disease.
• Individuals with Niemann-Pick disease types C1 and C2 have problems with speech and swallowing that worsen over time, eventually interfering with feeding. Affected individuals often experience progressive decline in intellectual function and about one-third have seizures. People with these types may survive into adulthood.

Diagnosis

Assay of oxysterols has largely replaced skin biopsy (see Clinical Description), and is now regarded as both a robust screening test and a first-line diagnostic test for NPC. The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic variants in either NPC1 or NPC2 identified by molecular genetic testing.

Treatment

• No curative therapy for NPC exists. Supportive therapy is provided by specialists from multiple disciplines including among others: neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and medical genetics.
• Treatment with miglustat, approved for the management of neurologic manifestations of NPC in several countries but not the United States, has increased survival by five years from date of diagnosis or approximately ten years from onset of neurologic manifestations.[1].

NIH genetic and rare disease info

• NIH info on Niemann-Pick disease type C1

Niemann-Pick disease type C1 is a rare disease.