Niemann-Pick Disease

Niemann-Pick disease is a group of rare inherited conditions that affect how the body breaks down and uses fats inside cells. When these fats build up in organs like the brain, liver, spleen, and lungs, cells stop working properly and eventually die, leading to serious health problems that worsen over time.

Table of contents

• What is Niemann-Pick disease?
• Types of Niemann-Pick disease
• What causes Niemann-Pick disease
• Symptoms and signs
• How doctors diagnose the disease
• Treatment options
• Life expectancy and outlook

What is Niemann-Pick disease?

Niemann-Pick disease is a group of rare inherited conditions that belong to a category called lysosomal storage diseases, which means they affect how the body stores and processes fats^[1]. In a healthy body, lipids (fatty materials such as cholesterol, oils, and waxes) are normally broken down into smaller pieces to provide energy^[5]. However, in people with Niemann-Pick disease, harmful amounts of these fats accumulate in cells throughout the body, particularly in organs like the brain, liver, spleen, lungs, and bone marrow^[1].

Because of this buildup, cells cannot work as they should, and over time they die^[1]. The disease mainly affects children, though symptoms can appear at different ages depending on the type^[1]. Niemann-Pick disease can affect all segments of the population, with cases reported in North America, South America, Europe, Africa, Asia, and Australia^[4].

acid sphingomyelinase deficiency, Juvenile dystonic lipidosis

Types of Niemann-Pick disease

There are three main types of Niemann-Pick disease, called A, B, and C. Each type affects different organs and appears at different ages, with symptoms that vary in severity^[1].

Type A is the most severe form of the disease and usually begins within the first few months of life^[1]. Infants with Type A show symptoms early, including progressive weakness, enlarged liver and spleen, swollen lymph nodes, and serious brain damage by six months of age^[5]. This type is seen primarily in families of Ashkenazi Jewish (Eastern European Jewish) descent^[5][6]. Children with Type A rarely live beyond 18 months^[5].

Type B is less severe than Type A and symptoms may not appear for years^[1]. Type B usually occurs in the pre-teen years, with symptoms that include loss of muscle control during movement, problems with nerves in the arms and legs, enlarged liver and spleen, and breathing difficulties^[5]. The brain is generally not affected in Type B^[5]. People with this type may live comparatively longer than those with Type A, though they may require extra oxygen due to lung problems^[5].

Type C is now considered a separate disease from Types A and B because it involves different genetic problems^[3]. Type C may appear early in life or develop during the teenage or adult years^[5]. It is caused by a lack of certain proteins called NPC1 or NPC2 that help transport fats within cells^[5]. Type C is most common among Puerto Ricans of Spanish descent^[6]. People with Type C may have extensive brain damage that causes an inability to look up and down, difficulty walking and swallowing, and progressive loss of vision and hearing^[5]. There may also be moderate enlargement of the spleen and liver^[5]. In about 50% of adult patients with Type C, the disease can appear without or with minimal liver or spleen enlargement^[2].

A condition called Type D was originally identified as a separate type to describe a group of patients with otherwise identical symptoms who shared a common Nova Scotian ancestry. However, patients in this group are now known to share a specific mutation in the NPC1 gene, so Type D is now classified together with Type C^[3].

What causes Niemann-Pick disease

Niemann-Pick disease is caused by mutations (changes) in specific genes that are inherited from parents^[3]. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have mutations for the disease to develop^[2][3]. This means that both parents must be carriers of the mutated gene, even if they themselves do not have the disease.

Types A and B are caused by mutations in the SMPD1 gene^[3]. This gene normally produces an enzyme called acid sphingomyelinase (ASM), which breaks down a fatty substance called sphingomyelin found in every cell of the body^[2]. When the SMPD1 gene is mutated, there is very low or deficient activity of this enzyme, causing sphingomyelin and its related fats to accumulate in cells, mainly in specialized immune cells called macrophages^[2]. These fat-laden cells then deposit in various organs, causing them to enlarge and malfunction.

Type C is caused by mutations in either the NPC1 or NPC2 genes^[3][5]. These genes produce proteins used to transport lipids, particularly cholesterol, within cells^[3]. When these proteins don’t work properly, the body cannot properly break down cholesterol and other fats, leading to too much cholesterol in the liver and spleen and too much of other fats in the brain^[6].

Most often, the parents of a child with Niemann-Pick disease are carriers of the mutated gene but do not have symptoms themselves^[3].

• Brain
• Liver
• Spleen
• Lungs
• Bone marrow
• Nerves

Symptoms and signs

The symptoms of Niemann-Pick disease vary widely depending on the type of disease and how severe it is^[1]. Symptoms relate to worsening function of the nerves, brain, and other organs over time^[1].

Common symptoms affecting movement and muscles include loss of muscle control, such as clumsiness and problems walking; muscle weakness and floppiness; and stiff and awkward movements^[1]. Many people experience ataxia, which means lack of muscle control during voluntary movements such as walking^[5].

Vision and eye problems are also common, including vision loss and eye movements that cannot be controlled^[1]. A characteristic sign is the inability to look up and down, called vertical supranuclear gaze palsy^[2]. Some people may develop clouding of the cornea and a characteristic cherry-red spot around the center of the retina^[5].

Neurological symptoms include problems with learning and memory that get worse over time, slurred speech (called dysarthria), difficulty swallowing (called dysphagia), and problems sleeping^[1][2]. Brain degeneration and increased sensitivity to touch may also occur^[5]. Some people experience seizures^[10].

Mental health problems can include depression, paranoia, behavior problems, psychosis with hallucinations and delusions, and attention deficit hyperactivity disorder^[1][10].

Physical symptoms affecting organs include a liver and spleen that become too large (called hepatosplenomegaly), which may cause reduced appetite, abdominal swelling and pain^[3][2]. Enlargement of the spleen may also cause low levels of platelets in the blood, called thrombocytopenia^[3][2]. Repeated infections that cause pneumonia may occur, particularly in Type B^[1]. Some infants may show jaundice at or shortly after birth^[6].

Other symptoms may include hearing loss, being sensitive to touch, problems with feeding and eating, and abnormal posturing of the limbs, trunk, and face called dystonia^[1][3][2]. Sleep-related disorders also occur, such as being sleepy during the day and wakeful at night, and a condition called gelastic cataplexy, where a person suddenly loses muscle tone when laughing^[3].

How doctors diagnose the disease

Diagnosis of Niemann-Pick disease begins with a physical exam, where doctors may find early warning signs such as a liver or spleen that is too large^[7]. Healthcare professionals will talk with you about symptoms and family health history^[7]. Because Niemann-Pick disease is rare and its symptoms can be similar to those of other health conditions, testing is needed to get the right diagnosis^[7].

The diagnostic tests used depend on the type of Niemann-Pick disease suspected. For Type A or B, doctors use blood or a tiny sample of skin to measure how much sphingomyelinase enzyme is in white blood cells^[7]. A bone marrow test can also be done to diagnose Types A and B^[6].

For Type C, doctors use a blood sample to measure levels of a specific type of cholesterol called oxysterol^[7]. In rare cases, a small sample of skin can be used to see how cells move and store cholesterol^[7]. A skin biopsy is usually done to diagnose Type C, where a technician watches how the skin cells grow, move, and store cholesterol^[6].

Other tests may be done, including genetic testing, where DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B, and C^[7]. People who have only one copy of the gene change but do not have the condition are called carriers^[7]. DNA tests can show carriers for all types of Niemann-Pick disease if the gene changes have been identified in the first person in a family to have the condition^[7].

A Magnetic Resonance Imaging (MRI) scan of the brain may show loss of brain cells, though in the early stages of Niemann-Pick disease, an MRI may not show any changes because symptoms usually appear before the loss of brain cells^[7]. MRI can also be used to look at the liver and spleen to see if they are enlarged and to measure their size^[7].

An eye exam may show changes caused by Niemann-Pick disease, and may reveal a characteristic cherry-red spot around the center of the retina^[7].

Other tests that might be done include bone marrow biopsy, liver biopsy (usually not needed), and slit-lamp eye examination^[6].

Treatment options

There is currently no cure for Niemann-Pick disease^[1][5]. Treatment is focused on helping people live with their symptoms and managing complications^[1].

For Type A, there is currently no effective treatment^[5]. Treatment is supportive, focusing on managing symptoms and complications.

For Type B, bone marrow transplantation has been attempted in a few individuals^[5]. In 2022, the FDA approved a medicine called olipudase alfa for enzyme replacement therapy to treat non-central nervous system symptoms of Type B^[6]. This represents the first approved treatment for acid sphingomyelinase deficiency (Types A and B). The development of gene therapies might also be helpful for those with Type B^[5].

For Type C, a medicine called miglustat is available for treating nervous system symptoms^[6]. Miglustat works by limiting the accumulation of certain fats called gangliosides in the brain and is the only medicine approved to treat Type C in many countries^[8]. In 2025, the European Medicines Agency recommended approval of a new treatment called Aqneursa (levacetylleucine) for the treatment of neurological symptoms of Type C in adults and children aged six years and older^[9]. This medicine should be used in combination with miglustat, or as a single therapy in patients where miglustat is not tolerated^[9]. Studies showed that patients treated with Aqneursa demonstrated significant improvement in neurological symptoms compared to those treated with placebo^[9].

Other treatments focus on managing symptoms. Medicines are available to control seizures, help with sleep, and treat depression^[6]. High cholesterol may be managed with a healthy, low-cholesterol diet or medicines, though research does not show that these methods stop the disease from getting worse or change how cells break down cholesterol^[6]. Restricting one’s diet does not prevent the buildup of fats in cells and tissues^[5].

Researchers continue to study additional possible treatments, including gene therapy and other experimental approaches^[6]. Clinical trials are investigating new drugs and treatment strategies^[10].

Life expectancy and outlook

The outlook for people with Niemann-Pick disease varies greatly depending on the type and severity of the condition.

Infants with Type A typically die in infancy^[5]. The disease is usually fatal before the age of three^[2]. Children with this type rarely live beyond 18 months^[5].

Children with Type B may live a comparatively long time, but may require supplemental oxygen because of lung impairment^[5]. Those with Type B have a better chance of surviving into adulthood compared to Type A^[1].

The life expectancy of people with Type C varies considerably: some individuals die in childhood while others who appear to be less severely affected can live into adulthood^[5]. The course of the disease varies highly depending on the age of onset, but most Type C patients are children and many die before the age of 20^[9].

Children with all types of Niemann-Pick disease usually die from infection or progressive neurological loss^[5]. The disease is sometimes fatal and has no known cure^[1].