Synonyms: these include sphingomyelin lipidosis, sphingomyelinase deficiency
Niemann-Pick disease (NP disease) is a group of genetic conditions inherited in an autosomal recessive pattern. It involves the accumulation of sphingolipids in cells throughout the body, particularly 'reticuloendothelial' cells (the mononuclear phagocyte system). NP disease is part of a group of metabolic diseases classified as lysosomal storage disorders. Other lysosomal storage disorders are Gaucher's disease, Tay-Sachs disease and Beta Hex deficiency (Sandhoff's disease).
Classification is based on clinical and pathological features. NP disease can also be classified into those with deficiency of acid sphingomyelinase activity (types A and B) and those with defective intracellular processing and transporting of LDL cholesterol (type C).
Acid sphingomyelinase deficiency is a rare autosomal recessive inborn error of metabolism that leads to the accumulation of sphingomyelin in cells and tissues. Two distinct subtypes have been described on the basis of their phenotypes (NP types A and B - NPA and NPB). However it now seems that there is a disease spectrum related to the amount of enzyme activity, where some patients may be described as having A/B variant, falling in the middle of the spectrum and exhibiting neurological problems which may become more apparent over time. The enzyme deficiency for both NPA and NPB arises from mutations in a gene on chromosome 11.
NP disease type C (NPC) is a very rare genetic disorder arising from neuronal accumulation of glycosphingolipids, causing structural and functional damage in cells and tissues. There are two subtypes, NPC1 and NPC2, which are phenotypically similar.
Niemann-Pick disease type A (NPA)
- NPA has an Ashkenazi Jewish predilection, with an estimated incidence of 1:40,000. It is extremely rare in the general population with an estimated incidence of around 1:10 million.
- A build-up of sphingomyelin occurs in the liver, spleen, lungs and brain, leading to severe neurodegenerative disease of infancy.
- Presentation is usually in the first few months of life. Symptoms include progressive regression of early motor skills, failure to thrive, hepatosplenomegaly, cherry-red spot on the macula, feeding difficulties and prolonged jaundice.
- There is progressive loss of early motor skills, and usually a very rapid decline leading to death by 2-5 years of age.
- NPA is diagnosed by measuring the level of acid sphingomyelinase in white blood cells and is usually confirmed by DNA sequencing to identify mutations.
- A build-up of sphingomyelin mainly occurs in the liver, spleen and lungs.
- The incidence of NPB is estimated at 1:250,000 in the general population.
- NPB is characterised by hepatosplenomegaly, thrombocytopenia, interstitial lung disease and dyslipidaemia with most patients having little or no neurological involvement.
- It usually presents with splenomegaly, first noted in childhood.
- Other features include hepatosplenomegaly, bone and haematological involvement, limb and joint pain, growth delay in adolescence, thrombocytopenia and bleeding, respiratory or cardiac complications and abnormal lipid profile including raised LDL, VLDL and triglycerides.
- There may be radiological features of interstitial lung disease.
- Progressive neurological disease occurs in fewer than 10% of cases.
- NPB is diagnosed by measuring the level of acid sphingomyelinase in the white blood cells and is usually confirmed by DNA sequencing to identify mutations.
Niemann-Pick type A/B variant
Some patients with acid sphingomyelinase deficiency may be described as having A/B variant, falling in the middle of the spectrum and exhibiting neurological problems which may become more apparent over time. Patients with A/B variant may present with disease symptoms of NPA/NPB, ranging from severe to moderate, neurological difficulties, cognitive impairment and ataxia.
- NPC is a lysosomal storage disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and other tissues.
- Autosomal recessive inheritance. NPC1 and NPC2 are caused by different gene mutations. Approximately 95% are NPC1 (gene located on chromosome 18) and 5% are NPC2 (gene located on chromosome 14).
- The incidence is estimated as 1:120,000. However, NPC may be more common than previously realised, as awareness and diagnosis have increased in recent years. Adult-onset NPC in particular may be under-diagnosed.
- Symptoms and severity of NPC can vary greatly and tend to depend on the patient’s age at onset:
- Neonates and infants: fetal ascites, liver disease with jaundice, hepatosplenomegaly, hypotonia and delayed developmental milestones.
- Children: vertical supranuclear gaze palsy, progressive ataxia, dysarthria, dystonia, seizures, cataplexy, liver or spleen enlargement and cognitive impairment.
- Adolescents and adults: psychiatric illness (depression or schizophrenia-like illness), dementia and progressive neurological deterioration. Vertical supranuclear gaze palsy may be present.
- NPC2: extensive pulmonary infiltration with foam cells, delayed psychomotor development and respiratory failure, with death in early childhood.
- NPC may present in utero with splenomegaly, hepatomegaly, ascites or other abnormalities.
- Plasma biomarkers (eg, cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites) appear to be rapid, cost-effective and efficient tests for first screening.
- However, specificity of the biomarkers is currently under investigation and other conditions have been shown to also result in elevations of these biomarkers.
- Identifying two alleles with NPC1 or NPC2 disease-causing mutations will confirm the diagnosis of NPC. Genomic DNA sequencing has become easier, faster and cheaper. However, molecular genetic testing also has its limitations, particularly with unidentified mutations and the classification of new variants.
- Prenatal diagnosis of NPC is currently achieved by mutation analysis.
- The filipin test has been extensively used and was considered the gold standard until recently. Filipin is a fluorescent polyene antibiotic, which
specifically binds to cholesterol but not to esterified sterols. The test uses cultivated skin fibroblasts for filipin staining and fluorescence
- Usually patients with NPC die prematurely. However, the prognosis varies between individuals.The prognosis correlates with the age at the onset of neurological signs - patients with early onset tend to progress faster.
- NPC generally causes progressive neurological and psychiatric deterioration. The age of death varies between infancy and the sixth decade of life.
- A few cases of NPC without neurological involvement have been described.[10, 11]
- Other lipid storage diseases, including Tay-Sachs disease.
- Adult NPC can mimic dementia and psychiatric illness, delaying the diagnosis.
- There is no specific treatment for NPA or NPB.
- Miglustat has been shown to decelerate neurological regression for people with NPC. Miglustat is a small iminosugar which inhibits an early step in glycosphingolipid synthesis; it crosses the blood-brain barrier, hence is suitable for use in neurological disease.
- A combination of lipid-lowering drugs (statin, cholestyramine and nicotinic acid) has been shown to be the most effective at treating lipid abnormalities.
- Other treatment is symptomatic depending on symptoms - for example (after exclusion of any other underlying cause for the presenting symptoms):
- Cataplexy - tricyclic antidepressants or CNS stimulants.
- Seizures - anticonvulsant drugs.
- Dystonia and tremor - anticholinergic drugs; botulinum toxin in selected cases.
- Insomnia - melatonin; referral to a sleep specialist.
- Dysphagia - adjustment of diet, monitoring for risk of aspiration, gastrostomy tube. Patients with NPC become malnourished as dysphagia progresses.
- Drooling - small doses of oral atropine, or parotid/and submandibular glandular injections of botulinum toxin.
- Gastro-intestinal problems - treat symptomatically - eg, laxatives, loperamide.
- Behavioural problems - multidisciplinary treatment.
- Families can be offered genetic counselling.
- Prenatal diagnosis is feasible in many cases. This is generally accurate for types A and B but more difficult for type C.
- Carrier testing is usually only possible once there is an affected person in the family, when the gene mutation can be identified. The exception is the known mutations of the NPA gene in certain communities - eg, Ashkenazi Jews. Awareness of NPA is relevant to these populations.
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