Classification^[1]

There are three different types of NP disease, labelled A to C. The clinical pattern of each type depends on the speed of sphingolipid accumulation and the organs affected:

• Type A (NPA) - sphingolipid accumulation is rapid. Those affected usually die in early childhood.
• Type B (NPB) - the brain is not involved. Those affected usually survive into adolescence or early adulthood; many can lead a full and normal life.
• Type C (NPC) - the severity, age of onset and rate of progression vary greatly between individuals. The brain and other organs are involved, leading to hepatosplenomegaly and progressive intellectual and neurological deterioration.

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.

Classification of NP disease changes with understanding of the condition. Some US researchers are now referring to NPA and NPC as 'acid sphingomyelinase deficiency disease' rather than Niemann-Pick disease, as this more accurately describes the condition; the two types may represent the opposite ends of a spectrum of the same disease.^[1]

Types D ('Nova Scotia variant') and E ('adult form') were previously listed, but are now known to belong under type C.^[1][3]

Epidemiology^[1]

NP disease is rare.

• Type A - in the general population, NPA is extremely rare (estimated as around 1:10 million). It is more common in the Ashkenazi Jewish population in the USA (in which the incidence is around 1:40,000). In the UK there are probably no known cases of NPA.
• Type B - in the UK there are about 25 known cases (giving an population prevalence of about 1:5 million).
• Type C - NPC affects all races but is very rare. Incidence is estimated as 1 in 150,000 births. In the general population about 1 person in 400 is a carrier.

Note that 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 - for example, some cases might be classified as unspecified liver disease or dementia.

Aetiology^[2]

In types A and B, there is deficient sphingomyelinase activity (more so in type A). The sphingomyelin accumulates particularly in the mononuclear phagocyte system (the 'reticuloendothelial' cells). In type A, it also accumulates in the nervous system.

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

Clinical features, diagnosis and management

Type A (NPA)^[1]

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 features^[4]

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.^[4] Patients usually live into adulthood. Clinical features are:

• Hepatosplenomegaly - a common presenting feature. This 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.
  • Thrombocytopenia and bleeding.
• Respiratory complications - these affect most patients at some stage:
  • Chest infections.
  • Dyspnoea.
  • A restrictive lung disease pattern is common.
  • There may be radiological features of interstitial lung disease.^[5]
• Abnormal lipid profile including raised LDL, very low-density lipoprotein (VLDL) and triglycerides.
• Splenomegaly correlated with most aspects of disease in one study.^[4]

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 and many of its mutations identified.

Management

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

Type C (NPC)^[1]

Clinical features^[3]

• Age of onset varies, from in utero to adulthood.
• NPC symptoms and severity vary greatly between individuals. Clinical features include:
  • Neonatal jaundice (NPC is a significant cause of neonatal cholestatic liver disease).
  • 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, eg schizophrenia-like features, paranoid illness, depression and behavioural 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

• Blood tests: chitotriosidase levels are raised in most (but not all) NPC patients.
• Bone marrow biopsy (if appropriate) may show foam cells.
• Skin biopsy cells are cultured and tested (this takes about 12 weeks). The tests involve staining with filipin and testing the rate of cholesterol esterification.

A detailed algorithm for investigation and diagnosis is detailed in recent guidelines.^[3]

Management^[3]

Miglustat:

• This is a new treatment, recently approved. 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. The aim of treatment is to stabilise neurological manifestations.
• Expert guidance on NPC and miglustat suggests:
  • NPC patients with any type of neurological manifestations can be considered for miglustat.
  • For patients without neurological manifestations, but for whom there is a known family history and disease course, consider miglustat treatment starting at or before the anticipated time of neurological symptom onset.
  • Patients with early-infantile onset NPC, and those with severe dementia in the terminal stage of the disease are less likely to benefit from miglustat - treatment decisions should be made on an individual basis.

Other treatment is symptomatic depending on symptoms - for example:

• 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.

Prognosis^[3]

Usually patients with NPC die prematurely. The rate of disease progression varies greatly between individuals. Rarely, patients can survive into the seventh decade of life. Some reported cases have been without neurological abnormalities.

Differential diagnosis

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

Prevention^[1]

• 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.

Research

There is current research aiming to develop recombinant human acid sphingomyelinase for the potential treatment of NP disease types A and B. A phase 1 clinical trial was completed in 2009.^[1] A phase 2 trial is planned.^[10]

History

Albert Niemann graduated in medicine from Strasbourg in 1903. His great interest was metabolic disease.^[11] Ludwig Pick obtained his doctorate at Leipzig in 1893 and became eminent in pathology. In 1926 he demonstrated that NP disease is distinct from Gaucher's disease.^[12]