Niemann-Pick Diseases

What are Niemann-Pick Diseases ?

Niemann-Pick Diseases (NPD) are rare, life-limiting inherited lysosomal storage disorders (LSDs) that can affect both children and adults. There are two distinct diseases classified under Niemann-Pick Diseases :

Both ASMD and Niemann-Pick Disease Type C are considered pan-ethnic diseases, meaning they can occur in all racial and ethnic populations affecting both males and females.

Niemann-Pick diseases, though distinct in their fundamental causes, share similarities in patient presentations, such as varying degrees of lipid storage and foam cell infiltration in tissues. Common clinical features include enlargement of the liver and spleen, lung involvement, and/or central nervous system (CNS) involvement. These similarities led to the diseases being collectively named Niemann-Pick, after the two doctors who described the symptoms in the early 20th century.

In 1958, the disease presentations were classified into types A, B, and C. By 1966, types A and B were identified as deficiencies in the lysosomal enzyme acid sphingomyelinase. In 1997, a genetic link was discovered for most NPC cases, identified as NPC1. Later, another gene, NPC2, was linked to most of the remaining NPC cases.

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Acid Sphingomyelinase
Deficiency (ASMD)

Niemann-Pick disease

Type A, B or A/B (NPA, NPB)

Acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick Disease Type A, B or A/B is a rare, progressive genetic disorder caused by a deficiency of the enzyme acid sphingomyelinase. This enzyme is essential for breaking down a fatty substance called sphingomyelin. When acid sphingomyelinase is deficient, sphingomyelin accumulates in major organs such as the liver, lungs, and spleen, which leads to complications as these organs may not function properly over time.

ASMD is highly variable, with the age of onset, specific symptoms, and severity differing significantly among individuals, even within the same family. The disorder can be viewed as a spectrum of disease. At the severe end of the spectrum is Acute Neurovisceral ASMD/Niemann-Pick Disease Type A, a fatal, progressive neurodegenerative condition which presents in infancy. At the milder end of the disease spectrum is Chronic Visceral ASMD/Niemann-Pick Disease Type B, where affected individuals have minimal or no neurological symptoms and often survive into adulthood. An intermediate form, Chronic Neurovisceral ASMD/Niemann-Pick disease Type A/B, also exists, with neurological symptoms typically appearing later and the condition progressing more slowly than in NPA In all forms of ASMD harmful quantities of a fatty substance known as sphingomyelin build up in the body’s cells and organs – with the key difference being that in NPB/Chronic visceral ASMD this build up occurs mainly in the liver, spleen and lungs, however in NPA/acute neurovisceral ASMD this buildup also occurs in the brain, leading to progressive neurological decline.

ASMD is caused by mutations in the SMPD1 gene and is inherited in an autosomal recessive manner. This means an affected child inherits one defective copy of the gene from each parent. Carriers have one faulty copy of the gene, while affected individuals have two. Carriers typically do not show symptoms. A positive diagnosis of Niemann-Pick Disease in a child indicates that both parents are carriers of a disease-causing mutation in the SMPD1 gene. In each pregnancy of a carrier couple, there is a 1 in 4 (25%) chance that the child will have ASMD/Niemann-Pick Disease A, B, A/B. The incidence of ASMD is estimated to be 1 in 250,000.

Treatment for Acid Sphingomyelinase Deficiency (ASMD) Niemann Pick Disease Type A & B (NPA & NPB)

Currently, there is no cure for ASMD. Enzyme replacement therapy (ERT) (olipudase alfa/xenpozyme™) is a disease modifying treatment for the non neurological option available for some individuals with ASMD in certain countries. This intravenous medication provides a functional enzyme (recombinant acid sphingomyelinase) to reduce the buildup of sphingomyelin caused by ASMD. As a relatively new treatment, it is not yet available in all regions.

It is important to note that this treatment targets the visceral disease (involving the liver, spleen, lungs, and bone marrow) caused by ASMD but has limited ability to cross the blood-brain barrier in order to address neurological involvement in types A and A/B ASMD.

Presently, caring for children with Type A involves managing the various symptoms resulting from the disease, and supportive care including the use of a multidisciplinary team where available.

Ongoing research is exploring other treatment strategies to address the unmet needs in ASMD. Information on current clinical trials can be found at clinicaltrials.gov and on the clinical trials update page on the INPDA website.

In addition to targeted disease modifying treatments, individuals with ASMD may receive treatments aimed at managing specific symptoms they experience, including prescription medications, physiotherapy, occupational therapy, speech-language therapy, and social, educational, and community support.
You can find the Consensus Clinical Management Guidelines for ASMD here.

Niemann-Pick Disease Type C (NPC)

Niemann-Pick disease type C (NPC) is a rare, progressive, and life-limiting genetic disorder characterized by the body’s inability to transport cholesterol and other fatty substances (lipids) inside cells. This leads to the abnormal accumulation of these substances within various tissues, including the brain. The buildup affects many organs and systems, particularly the central nervous system, resulting in progressive intellectual decline, loss of motor skills, seizures, and dementia. Speech may become slurred, and swallowing difficulties can develop.

NPC is highly variable, with the age of onset and specific symptoms differing from person to person, even among family members. The disorder can range from a fatal condition within the first few months after birth (neonatal period) to a late-onset, more slowly progressive disorder that may remain undiagnosed well into adulthood. Most cases are detected during childhood and progress to cause life threatening complications by the second or third decade of life.

NPC is caused by mutations in the NPC1 or NPC2 genes. This genetic condition is inherited in an autosomal recessive pattern, meaning an affected child has received one defective copy of the gene from each parent. Carriers have one faulty copy of the gene, while affected individuals have two. Carriers typically do not show symptoms. A positive diagnosis of NPC in an individual indicates that both parents are carriers of the disease-causing mutation. In each pregnancy of a carrier couple, there is a 25% chance that the child will inherit the mutation from both parents.

The incidence of NPC is widely reported as 1 in 100,000, although recent studies suggest this may be an underestimate.

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