Niemann-Pick Disease

What Causes Niemann-Pick Disease?

NPC is caused by abnormal changes (mutations) in one of two different genes called the NPC1 and NPC2 genes. These genes carry instructions for producing proteins crucial in the movement of cholesterol and fatty acids (lipids) within cells. The mutations impair protein production and, consequently, the normal movement of lipids inside cells.

The dysfunction interferes with normal cell processes that require lipids, and it also results in an accumulation of excess lipids inside cells. The accumulation damages cells, and they eventually die, resulting in the symptoms of NPC.

Is Niemann-Pick Disease Hereditary?

NPC is an inherited disorder. The disorder-causing gene mutations are inherited in an autosomal recessive pattern. This means that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop NPC but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with NPC with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

How Is Niemann-Pick Disease Detected?

In some cases of infantile-onset NPC, liver or spleen enlargement may be the only early symptom, and other symptoms may not appear until years later. In some cases, these symptoms may be detectable via ultrasound exams before birth.

In older children, adolescents, and adults, early signs may be neurological symptoms that look like either typical clumsiness or psychiatric issues such as:

• Learning disabilities
• Behavioral problems
• Language impairment
• Difficulty with writing or drawing
• Attention-deficit/hyperactivity disorder (ADHD)
• Problems with organization or planning

How Is Niemann-Pick Disease Diagnosed?

A doctor may suspect NPC if a patient presents multiple symptoms such as liver disease, enlarged spleen, and neurological symptoms. The diagnostic process usually includes:

• Physical exams
• Neurological exams
• Magnetic resonance imaging (MRI) to look for brain damage characteristic of NPC. This exam may be routine in the early stages of the disorder.
• Eye exams to look for the eye-control problems typical of NPC
• Genetic testing to look for the gene mutations that cause NPC

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Niemann-Pick Disease Treated?

NPC has no cure. In some less severe cases, treatment with the drug miglustat produced improvement in neurological symptoms. Other treatment options aim to prevent complications and improve quality of life. Common treatments include:

• Feeding assistance, including a feeding tube
• Anti-seizure medications
• Medications to improve poor muscle tone
• Antipsychotic and antidepressant medications to treat psychiatric symptoms
• Melatonin or sedatives to treat sleep disturbances
• Monitoring for complications such as lung infections
• Physical therapy
• Speech therapy
• Occupational therapy

How Does Niemann-Pick Disease Progress?

When it develops early, NPC can sometimes cause fatal complications within the first few months after birth. More commonly, symptoms appear in childhood or later and worsen gradually over a period of years. Complications often become life-threatening by adolescence or early adulthood. Long-term impacts of NPC can include:

• Liver disease
• Lung disease
• Severe eye-movement problems
• Hearing impairment
• Loss of speech skills
• Swallowing difficulties that can cause choking or lung infections
• Seizures
• Memory loss
• Dementia

How Is Niemann-Pick Disease Prevented?

There is no known way to prevent NPC when the disorder-causing gene mutations are present. Therefore, parents with a family history of the disorder or who have had another child with NPC are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Niemann-Pick Disease Caregiver Tips

Caregivers for children or adults who are experiencing symptoms of NPC should keep these tips in mind:

• Learn as much as you can about the disorder. NPC is a widely variable disorder, and no one experiences it precisely the same way as anyone else. Become familiar with how NPC affects your child or loved one so you can be the best possible caregiver.
• Be prepared to be an educator. NPC is not a well-known disorder even among many medical professionals. You will have to educate people about the disease to ensure that your child gets the best medical treatment and support from important people in their lives.
• Find support from other NPC families. The National Niemann-Pick Disease Foundation provides resources for families living with the disorder, including connections to online support groups.

Many people with NPC also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with NPC:

• Many people with NPC also suffer from depression.
• People with NPC often exhibit psychotic symptoms consistent with schizophrenia.
• NPC has also been associated with autism, attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD).

Niemann-Pick Disease Brain Science

Scientists don’t understand precisely how NPC1 and NPC2 proteins function within cells. However, it is clear that the proteins play a role in transporting some types of molecules within cells; when the proteins are not produced in adequate amounts, these molecules accumulate abnormally inside cells.

In the brain, the problematic substances appear to be cholesterol and compounds called glycosphingolipids, comprised of fatty acids and carbohydrates. The accumulation of these substances causes damage to brain cells that progressively worsens and causes the neurological symptoms of NPC.

Because NPC impairs the processing of cholesterol within nerve cells in the brain and not in the bloodstream, a diet low in cholesterol does not affect the disorder.

Niemann-Pick Disease Research

Title: Combined Intrathecal and Intravenous VTS-270 Therapy for Liver and Neurological Disease Associated With Niemann-Pick Disease, Type C1

Stage: Recruiting

Principal investigator: Forbes D Porter, MD  

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Bethesda, MD

Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. NPC results from mutation of either the NPC1 (approximately 95% of cases) or NPC2 genes. Biochemically, NPC is characterized by the endolysosomal storage of unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. Individuals with NPC demonstrate progressive cerebellar ataxia and dementia. Acute cholestatic liver disease is frequently observed in the neonatal/infantile period but subsequently resolves. However, chronic, sub-clinical liver disease persists. Intrathecal 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD, VTS-270) has proven effective in reducing signs and prolonging life in NPC1 animal models, and Phase 1/2a data support efficacy in NPC1 patients. Parenteral administration of VTS-270 has also been shown to effectively treat liver disease in the NPC1 category.

In this Phase 1/2a, open-label, randomized, parallel dose, single-center study, we will examine whether VTS-270 can be used to treat chronic subacute liver disease in NPC1 patients. Our primary objective is to determine the safety and tolerability of intravenous VTS-270 in NPC1 disease. Secondary objectives will be to evaluate the efficacy of VTS-270 to reduce plasma cholestane-3beta,5alpha,6beta-triol, an NPC1-specific pharmacodynamic biomarker, and to normalize the degree of liver injury. Exploratory testing will include lipid and protein biomarkers. This study will evaluate three dose levels (500, 1000, and 1500 mg/kg) administered monthly for twelve months. Safety will be assessed by adverse event recording, clinical laboratory testing, and physical examination. Clinical efficacy will be evaluated by assessing liver chemistries, liver size determination, and liver STIFFNESS changes. Biochemical efficacy will be assessed by measurement of plasma cholestane-3beta,5alpha,6beta-triol, and other biomarkers.

Title: Phase 3 Study to Evaluate Intravenous Trappsol(R) Cyclo(TM) in Pediatric and Adult Patients With Niemann-Pick Disease Type C1 (TransportNPC)

Stage: Recruiting

Principal investigator:  Ozlem Goker-Alpan, MD  

Lysosomal and Rare Disorders Research & Treatment Center, Inc.

Fairfax, VA

The TransportNPC study is a prospective, randomized, double-blind, placebo-controlled therapeutic study for 93 patients aged three and older with a confirmed diagnosis of NPC1. The objective of this study is to evaluate the safety, tolerability, and efficacy of a 2000 mg/kg dose of Trappsol Cyclo (hydroxypropyl beta-cyclodextrin) administered intravenously by slow infusion every two weeks in addition to standard of care as compared to placebo and standard of care. Standard of care may include Miglustat or leucine products that are not currently under investigation as a therapeutic. Patients will be randomized to receive Trappsol Cyclo or placebo at a 2:1 ratio. The study duration is 96 weeks, with an unblinded interim analysis at 48 weeks. An open-label extension of up to 96 weeks follows the interventional study. Patients whose disease progression worsens by two levels in the Clinical Global Impression of Severity scale over 12 weeks, starting at week 36, may be moved to open-label treatment. Efficacy will be measured at week 48 and week 96 by a composite score of major disease features. A sub-study will be conducted in countries following EMA guidance for up to 12 patients age 0 – 3 years who may be asymptomatic. Outcomes for the sub-study are safety, clinical, and caregiver impression of disease.

Title: Evaluation of Biochemical Markers and Clinical Investigation of Niemann-Pick Disease, Type C

Stage: Recruiting

Principal investigator: Forbes D Porter, MD  

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Bethesda, MD

Niemann-Pick Type C disease (NPC) is an autosomal recessive, lysosomal storage disorder characterized by the accumulation of cholesterol and gangliosides. NPC is a rare (estimated prevalence of 1:120,000-150,000) neurodegenerative disorder with a wide clinical spectrum and a variable age of onset. Classically, children with NPC demonstrate neurological dysfunction with cerebellar ataxia, dysarthria, seizures, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and progressive dementia. In general, adolescent and adult-onset forms have a more insidious onset and slower progression.

There is no effective treatment for NPC, and it is a lethal disorder. A major impediment to the testing of therapeutic interventions is the lack of well-defined outcome measures. The purpose of this protocol is to obtain both baseline and rate of progression data on clinical and biochemical markers that may later be used as an outcome measure in a clinical trial.