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There are different types of Niemann-Pick disease but all are rare. There are no statistics for its prevalence in the UK but US statistics state that Niemann-Pick disease (NPD) types A and B occur in 1 in every 250,000 people. Type C affects 1 in 150,000. So, what is this rare disease?
Simply put, Niemann-Pick disease is a group of inherited metabolic disorders with varying severity. It is also known as acid sphingomyelinase deficiency for types A and B. Essentially, a substance called sphingomyelin builds up in the cells’ lysosomes in the liver, spleen, bone marrow, brain and lungs. This causes irreversible neurological damage. This is caused by genetic mutations leading to an acid sphingomyelinase (ASM) deficiency.
Type C NPD is considered to be a separate disease because there is no ASM deficiency and the SMPD1 gene isn’t mutated.
What is Niemann-Pick disease?
With types A and B of NPD, there are mutations in the SMPD1 gene—the sphingomyelin phosphodiesterase 1 gene. This is a neurological condition and the symptoms usually develop in childhood.
Type A becomes apparent during a child’s first few months. By the child’s first birthday, there are usually psychomotor delays and milestone regressions. Children with Niemann-Pick disease generally die in early childhood.
Type B NPD is not as severe as type A and the symptoms don’t show until midway through childhood. Patients with type B present with slowed bone growth, interstitial lung disease (ILD), hepatosplenomegaly (an enlargement of the liver and spleen) and thrombocytopenia (low platelets).
Individuals affected by type C can develop symptoms at any age, though it’s more common to experience them in childhood. These individuals experience ataxia, dysphonia, dysphagia, liver and lung disease and supranuclear gaze palsy (SNGP).
What causes Niemann-Pick disease?
Niemann-Pick types A and B occur due to inheriting a faulty gene mutation of the SMPD1 gene. This causes a decreased level of a substance called acid sphingomyelinase, or ASM. This is an enzyme that is present in cell lysosomes. It converts a substance called sphingomyelin (SM) into phosphocholine and ceramide. The accumulation of SM causes damage to the cells. In total, there are around 180 different SMPD1 genetic mutations that affect ASM activity.
Type C of Niemann-Pick disease is due to pathogenic genetic mutations in either the NPC1 or NPC2 genes. Depending on which is affected, NPD type C is classified further into C1 and C2. Around 95% of people with type C have type C1. There are around 30 sequence alterations in the affected gene.
The NPC1 and NPC2 genes are proteins. These are found in the lysosomes and late endosomes. They aid in the intracellular mobilisation and transport of sterols and cholesterol. When NPC1 and NPC2 are affected, cholesterol can’t get out of the lysosomes, which leads to a build-up. This becomes toxic and causes damage to both individual cells and organs.
Inheritance of NPD
To develop Niemann-Pick disease, you must inherit a copy of the faulty gene from both parents. This is called autosomal recessive inheritance. Other conditions that are autosomal recessive are cystic fibrosis and sickle cell disease.
When both parties in a couple have a copy of the faulty gene, they have a 25% chance (1 in 4) that their child will have Niemann-Pick disease.
As Niemann-Pick disease is so rare, it’s useful to acknowledge similarities with other diseases. NPD is a lysosomal storage disease and one of 70 metabolic disorders that involve lysosomal function. Other similar diseases include Tay-Sachs disease, Gaucher’s disease, Hunter syndrome, Hurler syndrome and Salla disease.
Who does Niemann-Pick disease affect?
There is little data on who is affected by Niemann-Pick disease in the United Kingdom. However, in the US, type 1 and type 2 both affect around 1 in 250,000 people. Of those with Ashkenazi Jewish descent, it affects 1 in 40,000 people. The largest concentrations of Ashkenazi Jews are in the United States (5 to 6 million), followed by Israel with 2.8 million. There are around 260,000 Ashkenazi Jews in the United Kingdom. Ashkenazi Jews also have the highest incidence of colorectal cancer of any other ethnic group.
Niemann-Pick disease type C affects 1 in 150,000 people but people of French-Acadian descent living in Nova Scotia have a higher incidence.
What are the signs and symptoms of Niemann-Pick disease?
You would begin to spot the symptoms of Niemann-Pick type A during the first few months of life, although due to the symptoms being common with a lot of other diseases, diagnosis may take a while. Symptoms begin with slow growth and an enlarged liver and spleen (hepatosplenomegaly) within the first few months.
By the child’s first birthday, you’ll often see a psychomotor retardation. This is characterised by slow movements for things that usually require little thought like hand gestures, walking and picking things up. The child may also display regressions in the developmental milestones that they’ve already achieved. Type A patients also have what is known as a cherry-red spot in their eyes. This is a small, circular red dot in the macula area of the eye.
With type B, you’re most likely to see symptoms midway through childhood and these aren’t as severe. Type B patients will have recurrent lung infections, enlarged liver and spleen, slower bone growth, low platelet level and sometimes (1 in 3) a cherry-red spot in the eye. There will also be neurological symptoms.
The symptoms of type C NPD can occur at any time, but they usually present themselves during childhood. The affected person might experience dystonia (twisting and spasming muscles), dysphonia (a hoarse voice), dysphagia (difficulty swallowing), liver disease, lung disease, ataxia (problems with coordination, balance and speech), and supranuclear gaze palsy (SNGP).
Other symptoms reported in patients include executive dysfunction, memory loss, delusions, paranoia, hallucinations, dysarthria (slurred speech), gait impairment, balance problems, hearing loss and falls.
Other possible symptoms are:
- Decreased diffusion capacity (how well the lungs transfer oxygen and carbon dioxide between the blood and the air)
- Interstitial lung disease (scarring of the tissues)
- High cholesterol
- Impaired growth of the long bones
- Slower bone mineralisation
- Coxa Vara – a hip deformity that leads to a shorter leg and a limp
- Corneal opacity
- Peripheral neuropathy (damage to the nerves)
Living with Niemann-Pick disease
Patients and their caregivers will face challenges navigating everyday life. There will be a financial implication on parents of children with the disease as they are forced to navigate appointments and time off work.
There are also difficulties associated with having a rare disease in that there is very little support available, and the condition is not well understood or well-known.
Children will have learning challenges and behavioural problems like anger. For children diagnosed later, it can be difficult to ascertain when symptoms initially began as many are subtle and non-specific. There are also misdiagnoses like schizophrenia.
Even those who aren’t as severely affected will often withdraw from studies or struggle to keep working. This can be as a result of difficulties interacting with others or for other behavioural problems.
Niemann-Picks has a variable impact on those affected, but it is almost always profound. Combined motor function impairment, cognitive difficulties and psychosocial problems make it difficult to be independent.
Life is also difficult for their caregivers, who are almost always parents. This is due to the progressive disease symptoms as well as the fact there are few treatment options available. Since NPD is hereditary, there are families where more than one child is affected by the disease, which compounds things further for parents. There are parallels for parents of children with other rare diseases in terms of the impact on the caregiver. This is due to the huge range of symptoms (physical and emotional) and the demands the disease places on loved ones.
How is Niemann-Pick disease diagnosed?
Given the huge range of symptoms and the many overlaps with other conditions, it can be difficult to get a diagnosis of Niemann-Pick disease. Clinicians do have tools that help them to identify the signs and symptoms but there needs to be suspicion of the condition before these will be used. The tools include:
There are also biomarkers than can be tested. These include bile acids and lysoSM-509. However, there are no biomarkers that will tell you of any CNS (central nervous system) manifestations or whether there has been disease progression.
The difficulty in diagnosing NPC (Niemann-Pick type C) means that there are often years of delays in receiving a diagnosis. On average, this is just over 4 years.
How is Niemann-Pick disease treated?
The treatment prescribed for individuals with Niemann-Pick disease will depend on the type and symptoms. The majority of infants diagnosed with type A will only live to around four years old but most die younger. There is very little medical professionals can do other than manage difficult symptoms with palliative care.
For those with type B, survival is possible until adolescence or even early adulthood. There are often problems with complications, however, that make life very difficult in the latter stages of the disease. This includes problems due to having an enlarged spleen or liver and respiratory failure.
Individuals with type C NPD can have a longer lifespan but the disease is still fatal. The life expectancy of someone with type C will be determined by the age at onset of symptoms. If the symptoms appear early and in infancy, the child will be unlikely to reach age five. However, if symptoms aren’t present until after the age of five, the individual could live until around age 20.
Therapies for NPD
In May 2022, the European Medicines Agency (EMA) recommended to the EU to grant marketing authorisation for Xenpozyme. This is a treatment for those with types A and B. This is the first specific treatment and is an enzyme replacement therapy. It is designed to replace the defective or deficient enzyme ASM so as to reduce the accumulation of fat within cells and relieve disease symptoms. This would be administered every two weeks intravenously.
The recommendations were based on positive results coming from three clinical trials. These showed the drug improved lung function and reduced the size of the liver and spleen.
Support for Niemann-Pick disease
Living with or supporting someone with Niemann-Pick disease can be lonely. This is because the disease is so rare. However, there is a UK-based charity called Niemann-Pick UK (NPUK), which offers care and support to those with the disease and their families. This charitable organisation is dedicated to making a positive difference to those affected by raising awareness, providing emotional and practical support through their helpline (0191 415 0693) and facilitating research.
NPUK has funded research projects at the University of Oxford, University College London (UCL) and Cardiff University. The University of Oxford research is into type C and there are 10 people working on the research in different aspects of the disease. University College London (UCL) is working on gene therapy to try and treat Niemann-Pick disease. The University of Cardiff is working on looking at the differences between types A and B, and type C, to work on treatments for the disease.
The US is home to the National Niemann-Pick Disease Foundation (NNPDF), which is a similar charitable organisation offering patient and family support services as well as research.
The NHS also has a support group called the Niemann-Pick Disease Group (UK), which is based in Washington, Tyne and Wear, but there is a 24-hour helpline too.
Final thoughts on Niemann-Pick disease
This rare and little-understood disease (or group of diseases) is severe and life-limiting. Though the prevalence is low, the profound effects on a person’s life are huge. The challenges of an NPD diagnosis extend beyond the physical symptoms and encompass the emotional and financial toll on the individual and their loved ones. As research is ongoing and medicines are being trialled and released, there is hope that one day an NPD diagnosis won’t be a death sentence.