Niemann-Pick Disease

Niemann-Pick (NP) disease is an umbrella term for a group of rare diseases that cause fatty substances (lipids) to build up in different parts of your child’s body. The buildup of these lipids damages different organs and tissues and keeps them from working properly. Symptoms — like lung, liver and neurological problems — gradually get worse over time, leading to life-threatening complications. These diseases often lead to premature death.

Healthcare providers usually diagnose these diseases in infants and children. But symptoms can also appear for the first time in adolescents and adults. Treatments can manage symptoms and, sometimes, prevent the disease from getting worse for a little while. Providers do whatever they can to keep you or your child comfortable and support your family.

Types of Niemann-Pick disease

There are two distinct disorders within the Niemann-Pick umbrella:

• Acid sphingomyelinase deficiency (ASMD), which used to be known as either Niemann-Pick type A if it’s severe/early onset (in infancy), or Niemann-Pick type B if it’s later-onset/chronic
• Niemann-Pick disease type C (NPC)

ASMD and NPC are both examples of inherited metabolic disorders. Specifically, providers classify them as lysosomal disorders. With these disorders, substances that your body normally breaks down (like lipids) build up and become toxic.

ASMD

ASMD occurs when a certain enzyme called acid sphingomyelinase (ASM) isn’t working as expected. Normally, ASM breaks down a lipid called sphingomyelin. But when ASM is “deficient,” or not doing as much as it should, sphingomyelin and other lipids start to build up inside cells. Cells are tiny building blocks that make up all our organs and tissues. As these lipids accumulate, they prevent cells from working normally.

ASMD can affect nearly all the cells in a person’s body. But the disease often has the most severe effect on cells in these areas:

• Central nervous system 
• Liver
• Lungs
• Spleen

ASMD further breaks down into the following types:

• Infantile neurovisceral (also called ASMD type A): This is the most severe form of ASMD. Symptoms begin in early infancy and affect liver, spleen and central nervous system function. The disease progresses (gets worse) quickly and is usually fatal by age 3.
• Chronic neurovisceral (also called ASMD type A/B): This form starts later in infancy or childhood than type A and progresses more slowly. Symptoms affect many areas of your body, including your central nervous system. They can range from mild to severe.
• Chronic visceral (also called ASMD type B): This form can start anywhere from childhood to adulthood. There’s a wide range of symptoms that could get worse over time. This type doesn’t affect your central nervous system.

Experts estimate that ASMD affects anywhere from 1 in 100,000 to 1 in 1,000,000 live births around the world — often quoted as 1 in 250,000. There’s a higher prevalence of ASMD type A among people of Ashkenazi Jewish descent. 

Niemann-Pick disease type C

Niemann-Pick disease type C occurs when certain proteins (NPC1 or NPC2) aren’t working as expected. These proteins help cholesterol and other lipids move from one spot to another within cells. When lipids can’t move properly within cells, they build up in different tissues in your body — including brain tissue.

Providers classify NPC according to the age when symptoms begin. They generally use these five categories:

• Perinatal (sometimes called neonatal): Just before or after birth
• Early infantile: Between 2 months and 2 years of age
• Late infantile: Between 2 years and 6 years of age
• Juvenile: Between 6 years and 15 years of age
• Adolescent/adult: Age 15 or older

Experts estimate that NPC affects at least 1 in 100,000 live births.

Symptoms of Niemann-Pick disease

Symptoms vary based on the type of disease.

Symptoms of ASMD

ASMD symptoms occur on a spectrum from mild to severe. While there’s some overlap between types, type A has the most severe symptoms that are quickly life-threatening.

Type A

ASMD type A (infantile neurovisceral) symptoms appear soon after birth and worsen fast. Infants with this condition typically:

• Cry for long periods of time and have trouble sleeping and feeding
• Develop an enlarged liver and spleen by age 2 to 4 months
• Get sick with respiratory infections often
• Grow more slowly than expected
• Have frequent vomiting
• Have low muscle tone (hypotonia), making their arms and legs seem droopy
• Reach normal developmental milestones for the first 6 months of life but then start losing those skills by around 10 to 12 months

Type A/B and type B

ASMD type A/B (chronic neurovisceral) and ASMD type B (chronic visceral) have a wide range of symptoms. These range from mild to severe and can start any time from early childhood to adulthood.

Possible signs and symptoms include:

• Abnormal blood lipid levels, like low HDL cholesterol and high total cholesterol, LDL, VLDL and triglycerides
• Bone issues like osteopenia, osteoporosis and fractures
• Diarrhea
• Enlarged liver and/or spleen
• Growth delays and possibly delayed puberty
• Headaches
• Interstitial lung disease and related problems like shortness of breath and frequent respiratory infections
• Joint pain
• Liver disease or failure
• Low platelet counts, which can lead to bleeding problems like frequent nosebleeds, excessive bleeding from surgeries and easy bruising
• Low white blood cell counts, which can lead to frequent sickness

Type B doesn’t have neurological symptoms. But type A/B often does. Possible neurological symptoms with type A/B — in addition to some or all of the visceral symptoms mentioned above — include:

• Cognitive decline (dementia)
• Coordination difficulties that lead to uncertain or clumsy movements (ataxia)
• Decreased reflex response (hyporeflexia)
• Delays in reaching developmental milestones (developmental delay)
• Involuntary muscle contractions (spasticity)
• Low muscle tone
• Trouble swallowing (dysphagia)

Symptoms of Niemann-Pick disease type C

Providers often describe NPC symptoms as visceral, neurological or psychiatric:

• Visceral symptoms: These affect internal organs like the liver or spleen. They often begin at a younger age (perinatal or early infantile forms of the disease).
• Neurological symptoms: These symptoms affect brain and nerve function. They can begin at any age, but gradually become more noticeable as a person gets older.
• Psychiatric symptoms: These affect how a person thinks, feels and interacts with the world around them. These symptoms typically occur in adolescents and adults.

Below are possible symptoms within each category.

Visceral NPC symptoms

• Enlarged liver and spleen (hepatosplenomegaly)
• Growth that’s slower than expected
• Jaundice that lasts longer than expected

Neurological NPC symptoms

• Abnormal walking pattern (gait disturbance)
• Challenges with fine motor skills
• Clumsiness or frequent falls
• Coordination difficulties and involuntary muscle movements (dystonia) that get worse over time
• Developmental delay
• Difficulty with language and learning
• Difficulty moving eyes up and down (vertical supranuclear gaze palsy, or VSGP)
• Low muscle tone
• Seizures
• Sudden muscle weakness when laughing (gelastic cataplexy)
• Trouble speaking (dysarthria) and/or swallowing

Psychiatric NPC symptoms

• Delusions
• Depression
• Hallucinations (auditory and/or visual)

Complications of Niemann-Pick disease

The most common complications and causes of death vary by disease.

ASMD:

• Respiratory failure
• Liver failure

NPC:

• Aspiration pneumonia
• Respiratory failure
• Seizures that treatment can’t control

Niemann-Pick disease causes

Gene variations cause ASMD and Niemann-Pick disease type C. The specific genes that are changed vary by disease.

Genetics of ASMD

Changes to the SMPD1 gene cause ASMD. This gene tells your body how to make the ASM enzyme that breaks down certain lipids. Researchers have found over 250 different SMPD1 variants (changed versions of a gene) that cause ASMD. That’s why people with ASMD have such a wide range of symptoms and severity levels. It depends on the specific variant they inherit and how it affects ASM function.

These gene variations pass down within biological families. This means parents can pass a gene variant down to their biological children. ASMD follows an autosomal recessive pattern of inheritance. You need to receive two copies of the changed gene (one from each parent) to develop the disease. If you receive just one copy, you’re a carrier but won’t have symptoms.

Full siblings of someone with ASMD are expected to have a 25% chance of having ASMD, as well.

Genetics of NPC

Changes to the NPC1 gene or NPC2 gene cause Niemann-Pick disease type C. These genes tell your body how to make certain proteins (NPC1 and NPC2) that help cholesterol and other lipids move within cells. A change to either gene causes lipids to build up in body tissues.

NPC also follows an autosomal recessive pattern of inheritance. But carriers may have some mild symptoms of NPC themselves. Siblings of someone with NPC have a 25% chance of also having it.

How is Niemann-Pick disease diagnosed?

ASMD and NPC are rare diseases that can be challenging for providers to diagnose. This is especially true when symptoms start later in life. In general, providers use a person’s symptoms, medical history and test results to reach a diagnosis.

Usually, red flags pop up that make a provider first suspect a possible Niemann-Pick diagnosis. For example, your child might have a certain combination of symptoms typical of NPC. Or routine lab or imaging testing might show common features of ASMD (like low platelets, high blood lipids or increased liver and spleen size).

If providers suspect ASMD or NPC, they’ll do specific tests to confirm a diagnosis. These might include:

• Blood tests to look for signs of either disease
• Genetic testing to identify gene variants

What are available treatments for Niemann-Pick disease?

There’s no cure for ASMD or NPC. But in many cases, medications, therapies and other treatments can help your child manage symptoms and function at their best.

Medications for ASMD

Olipudase alfa (Xenpozyme®), a type of enzyme replacement therapy, is currently the only treatment that directly targets the cause of ASMD. Providers give your child medicine through an IV. This medicine provides your child with functional ASM enzymes to replace the ones that aren’t working right. This treatment can help:

• Improve lung function
• Reduce liver and spleen size
• Support normal platelet counts and blood lipid levels
• Support growth (in children)

Enzyme replacement therapy doesn’t improve symptoms related to central nervous system function.

Medications for NPC

With NPC, providers focus on treating the neurological symptoms. These symptoms typically get worse over time. Certain medications may slow down this process. Your child’s care team may prescribe one or more of the following:

• Miglustat (Zavesca®)
• Arimoclomol (Miplyffa™)
• Levacetylleucine (Aqneursa™)

Providers may also prescribe specific medications to help with delusions, depression, hallucinations, muscle weakness or seizures.

Therapies and other treatments

Your child’s care team may recommend therapies or other treatments. These vary according to the type of disease your child has and how it affects their body. Possibilities include:

• Changes to what your child eats to help with swallowing difficulties
• Feeding tube placement to help your child get enough nutrients and lower the risk of aspiration
• Liver transplant
• Physical therapy, occupational therapy and/or speech therapy to address neurological symptoms
• Spleen removal (providers prefer partial to total removal whenever possible to lessen complications)
• Therapy to manage mental health conditions
• Treatments for lung disease, like oxygen therapy

What is the life expectancy of someone with Niemann-Pick disease?

Your child’s care team can give you the most accurate sense of what you might expect. Life expectancy varies widely and depends on:

• The type of Niemann-Pick disease
• The age when symptoms begin
• Which organs are affected
• Which complications arise

In general:

• ASMD type A is the most severe and usually fatal by age 3.
• Some people with ASMD type B have the same life expectancy as someone without the disease.
• Life expectancy with Niemann-Pick disease type C can range from several days to several decades. Many people experience life-threatening complications by their teens or 20s.