Synonyms include: sphingomyelin lipidosis, sphingomyelinase deficiency.

Niemann-Pick disease (NP disease) is an inherited group of conditions in which sphingolipids accumulate in cells, especially reticuloendothelial cells, throughout the body. NP disease is part of a group of metabolic diseases classified as lysosomal storage disorders. ^1,2 Other lysosomal storage disorders are Gauchers disease, Tay-Sachs disease and Beta Hex deficiency (Sandhoff disease).

Classification

There are three different types of NP disease, labelled A to C.

• Type A is the acute neuronopathic form.
• Type B is the visceral form.
• Type C is the chronic neuronopathic form. There are two subtypes, C1 and C2, which are phenotypically similar.

Types D-E have also been listed previously, but now belong under types B or C (see appendix below).

Classification is based on clinical and pathological features. Niemann-Pick 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).

There are many different gene mutations which can cause each type of NP disease. This means that there is a spectrum of disease severity and individual cases differ.

Epidemiology

• In the general population the condition is very rare.
• The inheritance pattern is autosomal recessive.
• Type A accounts for the majority of cases and is more common in the Ashkenazi Jewish population.

Pathophysiology²

In types A and B, there is deficient sphingomyelinase activity (more so in type A). The sphingomyelin accumulates in the reticulo-endothelial system. In type A, it also accumulates in the nervous system. The mechanism by which types A and B differ is not known.

In type C, there is accumulation of unesterified cholesterol in cells.

'Foam cells' may be seen on histology of bone marrow.

Clinical features, diagnosis and management

Type A (NPA)¹

Epidemiology

In the general population, NPA is extremely rare (estimated as around 1:10 million). In the Ashkenazi Jewish population, the incidence is around 1:40,000.

Clinical features

NPA presents in the first few months of life with the following features:

• Feeding difficulties
• Prolonged jaundice
• Failure to thrive
• Progressive increase in abdominal girth over 3-6 months
• Regression of early motor skills
• A 'cherry red spot' of the macula
• Usually, progressive deterioration and death by age 2-5 years

Diagnosis

• The level of acid sphingomyelinase activity in white blood cells or cultured cells is diagnostic. This test does not identify carriers.
• DNA testing:²
  • This is possible for NP disease types A and B, because the SMPD1 gene (for the deficient enzyme) has been mapped and many of its mutations have been identified. A specialist centre is required for testing.
  • This test is particularly useful in the Ashkenazi Jewish population, where known mutations account for most cases, and in the Maghreb Northern African population, where a single mutation accounts for virtually all cases.
  • In other populations, the mutations must first be identified in each family before DNA testing can be performed.

Management

There is no specific treatment, and management is symptomatic.

Type B (NPB)¹

Clinical features³

Type B has similar biochemical abnormalities to type A, but is clinically much less severe. Quality of life was only mildly reduced in one study.³ Patients usually live into adulthood. Clinical features are:

• Hepatosplenomegaly - a common presenting feature. May present as abdominal enlargement in early childhood.
• About 10% have some degree of neurological involvement.
• Bone and haematological involvement:
  • Limb and joint pain.
  • Growth delay in adolescence.
  • Thrombocytopaenia and bleeding.
• Respiratory complications:
  • Chest infections.
  • Dyspnoea.
  • A restrictive lung disease pattern is common.
  • There may be radiological features of interstitial lung disease.⁴
• Abnormal lipid profile including raised LDL, VLDL and triglycerides.
• Splenomegaly correlated with most aspects of disease in one study.³

Diagnosis

• The level of acid sphingomyelinase activity in white blood cells or cultured cells is diagnostic (as with NPA). Again, this test does not identify carriers.
• DNA testing is possible, as the relevant gene has been mapped.

Treatment

• Currently, there is no specific treatment.
• Monitoring for complications, and treatment of these where feasible.
• Enzyme replacement may be possible in future.⁵
• Bone marrow (or stem cell) transplantation has been tried in a few cases.

Type C (NPC)¹

Epidemiology

• NPC affects all races but is very rare.
• Incidence is estimated as 1 in 150,000 births. In the general population about 1 in 400 are carriers.

Clinical features

• Age of onset varies, from in utero to adulthood. Possibly, adult onset NPC is under-diagnosed or mis-diagnosed, and may be more common than previously realised.
• NPC symptoms and severity vary greatly between individuals. Clinical features include:
  • Neonatal jaundice.
  • Hepatosplenomegaly.
  • Vertical supranuclear gaze palsy (inability to move the eyes up and down):
    • This is highly suggestive of NPC. Parents may notice it when their child walks up and down stairs, or watches TV while sitting on the floor. The child tilts their head instead of moving their eyes.
  • Ataxia and tremor.
  • Dystonia.
  • Dysarthria.
  • Learning difficulties and progressive intellectual decline - which may be misdiagnosed as other forms of dementia in adulthood.
  • Cataplexy (sudden loss of muscle tone which may lead to falls, without loss of consciousness).
  • Seizures.
  • Psychiatric symptoms are reported in some adult cases e.g. schizophrenia-like features, paranoid illness, depression and behaviour disturbances.⁶
• The prognosis varies between individuals. NPC generally progresses over years or decades, with progressive neurological and psychiatric deterioration.⁶ It remains a fatal disease, with the age of death varying between infancy and adulthood in the sixth decade.⁷
• A detailed review of adult onset NPC is available.⁶
• NPC may present in utero with splenomegaly, hepatomegaly, ascites or other abnormalities.⁸
• A few cases of NPC without neurological involvement have been described.⁹

Diagnosis

• Skin biopsy cells are cultured and tested (this takes about 12 weeks) for:
  • staining with filipin to show the lipid filled lysosomes.
  • the rate of cholesterol esterification.
• Blood tests: chitotriosidase levels are raised in most (but not all) NPC patients.

Management

• Treatment is mainly symptomatic.
• Possible treatments are:
  • A trial of dietary pectin, which is reported to activate sphingomyelinase and to reduce LDL and sphingomyelin concentrations.²
  • Cholesterol-lowering agents may reduce hepatic storage of lipid, but do not affect the progression of neurological disease.
  • Clinical trials are currently evaluating Miglustat, a small iminosugar which inhibits an early step in glycosphingolipid synthesis. Miglustat crosses the blood-brain barrier, so is a potential therapy for neurological disease. Results so far suggest possible benefit.^10,11

Differential diagnosis

• Other lipid storage diseases including Tay-Sachs disease.
• Adult NPC can mimic dementia and psychiatric illness, delaying the diagnosis.⁶

Prevention¹

• 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 Ashkenazi Jews and North African Maghrebs (as above).² Awareness of NPA is relevant to these populations.

Appendix - further notes on classification

• Types D ('Nova Scotia variant') and E ('adult form') were previously listed, but are now known to belong under type C.¹
• Type F is listed in some literature, ¹² and is sometimes mentioned as featuring sea-blue histiocyte disease.² However, sea-blue histiocytosis can be a morphological finding secondary to NP disease. Sea-blue histiocytosis is associated both with acquired conditions of increased cellular turnover, and with inborn errors of lipid metabolism.¹³

History

Albert Niemann graduated in medicine from Strasbourg in 1903. His great interest was metabolic disease.¹⁴ Ludwig Pick obtained his doctorate at Leipzig in 1893 and became eminent in pathology. In 1926 he demonstrated that Niemann-Pick disease is distinct from Gaucher's disease.¹⁵