Niemann-Pick disease type C (ORPHA:646)
A rare 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
Prevalence at birth of Niemann-Pick disease type C (NPDC) ranges between 1/45,000-286,000 worldwide.
Clinical description
The clinical onset and presentation is heterogeneous. NPDC is classically a neurovisceral condition with hepatosplenomegaly usually preceding the neurological symptoms, occurring in infancy or childhood but possibly occurring much later. Some patients exhibit lung disease early on and a small subset of patients can develop rapidly deteriorating hepatic or respiratory failure in early infancy. Neurological onset varies between early infancy to adulthood. Typically, neurologic involvement is progressive and consists mainly of dystonia, cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. VSGP and cataplexy (with or without narcolepsy) are characteristic. Psychiatric disturbances are frequent in late-onset patients.
Etiology
Most patients (95%) have mutations in the NPC1 gene (localized to 18q11.2), which encodes a membrane glycoprotein. The remainder have mutations in the NPC2 gene (localized to 14q24.3 ), which encodes a soluble lysosomal protein that binds cholesterol. The loss of function of those proteins blocks cholesterol egress from lysosomes leading to accumulation of lipid membrane components (unesterified cholesterol, glucosylceramide, and gangliosides) in the late endosomal/lysosomal compartment of the cell.
Diagnostic methods
The diagnosis of NPDC must be confirmed by mutation analysis and, if necessary, filipin test (based on the reaction of unesterified cholesterol with fluorescent antibiotic filipin). Several biomarkers are used alone or in combination as a first-line test to screen for NPDC: oxysterols (cholestane-3β, 5α, 6β-triol); lyso-SM-509 and lyso-sphingomyelin. Foam cells and sea-blue histiocytes are usually present in the bone marrow.
Differential diagnosis
In the first 2 years of life, NPDC must be differentiated from Niemann-Pick types A and B, Wolman disease, Gaucher disease type II/III, idiopathic neonatal hepatitis, and other causes of cholestatic jaundice. In older children and adults, neurodegenerative disorders such as mitochondrial diseases, Wilson disease, late-onset lysosomal storage diseases, Friedreich Ataxia, progressive supranuclear palsy, Huntington disease, Alzheimer disease, Pick disease, frontotemporal dementias, amyotrophic lateral sclerosis, primary psychiatric illnesses must be ruled out. Acquired conditions such as pineal region or midbrain tumors, attention-deficit disorder, learning disabilities, absence seizures, other dementia illnesses, HIV encephalopathy, sleep disorders, and syncope also should also be included in the differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis of NPDC should be offered to couples at risk. Molecular genetic analysis is the preferred strategy.
Genetic counseling
NPDC is an autosomal recessive disease. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management of NPDC remains largely symptomatic. Treatment with an iminosugar inhibitor of glucosylceramide synthase (miglustat) was approved for the management of neurologic manifestations of NPDC in several countries. There are presently some therapies under investigation, including 2-hydroxypropyl-beta-cyclodextrin and arimoclomol.
Prognosis
Lifespan varies from a few days (in case of fetal hydrops) to a few decades. Death in early infancy can be due to either liver failure or severe pulmonary insufficiency (usually before 3-6 months). Early infantile, severe, neurological onset is often fatal between 3-5 years of age, late-infantile neurologic onset typically between 7-12, and juvenile neurologic onset between adolescence and 30 years of age.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Ekaterina ZAKHAROVA