Cause

In 1997 medical researchers funded by the Parseghian Foundation identified the location of a gene called NPC1 that is abnormal in patients with Niemann-Pick Type C disease. The NPC1 gene is on chromosome 18 and is normally present in two copies in each cell of the body. However, alterations or mutations in this gene cause about 95 percent of cases of NPC disease. In a second smaller group of patients with NPC, alternations in NPC1 do not cause the disease. Researchers suspect a second gene, called NPC2, may be responsible. Niemann-Pick Type C disease is known as an autosomal recessive inherited condition. This means that each parent of an affected child has one functional NPC1 gene, plus one non-functional NPC1 (or more rarely, NPC2) gene. These parents are called carriers, or heterozygotes, and exhibit no signs or symptoms of the disease. Affected children inherit two non-functional NP-C genes from their parents. In each pregnancy of a carrier couple, there is a one in four (25 percent) chance that they will both pass their non-functional NPC genes to a child who would then be affected. There is a one in two (50 percent) chance that only one of them would pass a non-functional gene. The child would then be a carrier like the parents. There is a 25 percent chance that both functional genes would be passed and the child would be neither a carrier nor affected with the disease.

Signs and symptoms

NPC is a variable condition. This means that it can begin to affect individuals before birth or may not become evident until adulthood.

The classic form of the disease accounts for 50 to 60 percent of all cases. In this form, prenatal development and early childhood are usually normal, although jaundice may be present at or shortly after birth. Concern about behavioral problems may develop upon entry into school. The child will progressively develop loss of intellectual function, clumsiness, and difficulty with upward and downward eye movements.

In childhood, spleen or liver enlargement may be noted. Difficulties with speech (such as slurring), problems with swallowing, and in some cases, seizures may occur. Psychiatric disturbances may develop. Other symptoms may include sudden loss of muscle strength, which may vary from head nodding to complete collapse, abnormal posturing of the limbs, and lung complications.

Death from complications of the disease usually occurs in the teenage years or early adulthood. It is important to note that the early symptoms of NPC may vary significantly in childhood. Among the other symptoms children may experience are:

• Liver failure without neurologic symptoms
• Jaundice at birth
• Early development of neurological problems
• Low muscle tone
• Delayed motor development beginning before age 2
• Progressive liver failure starting in infancy
• Early lung involvement without neurologic disease
• Seizures

Late occurring cases typically have a less dramatic onset of symptoms. In these children and young adults, intellectual and psychiatric symptoms are the most significant.

Diagnosis & Testing

Due to the wide variability of early symptoms of NPC, clinical diagnosis of the condition may be difficult. Physicians who suspect this diagnosis may proceed to specialized testing based on the presence of several symptoms.

Recent advances in mass spectrometry-based biomarker discovery have led to identification of several sensitive biomarkers for diagnosis of NPC. These markers include cholestane-3β,5α,6β-triol (C-triol) (1, 2), N-palmitoyl-O-phosphocholineserine (PPCS, also known as lysoSM-509) (3, 4), and N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (bile acid B) (5). The C-triol or “oxysterol” test is the most widely used and validated biochemical test for NPC, offered by >50 laboratories worldwide. In the US, this test is available through the Mayo Clinic Biochemical Genetics Laboratory. The glycinated bile acid test, a newer biomarker, is the most specific of the NPC biomarkers and is offered free of charge as a CLIA test through the Washington University Metabolomics Core. Biomarker testing has emerged as the principal, first-line diagnostic for NPC because it is rapid, low-cost and non-invasive..

With the identification of NPC1 and NPC2 gene, it is now possible to identify changes in this gene. These changes, called mutations, affect how this gene works. Genetic testing for NPC is offered in the US through GeneDx (Gaithersburg, MD) and Mayo Clinic Molecular Genetics Laboratory. In most cases, positive genetic testing results, or positive biomarker testing results combined with molecular genetic analysis, are sufficient to diagnose NPC.

To learn more about testing, please contact your physician or:

Dr. Marc Patterson, Mayo Clinic

Dr. Denny Porter, NIH

Dr. Elizabeth Berry-Kravis, Rush University

Treatment

MIPLYFFA is the first FDA-approved treatment for Niemann-Pick disease type C. Miplyffa is indicated for use in combination with miglustat for the treatment of neurological manifestations of NPC in adult and pediatric patients 2 years of age and older. Learn more about Miplyffa

*Please note that Miglustat is approved in most European countries, Canada and Japan as a stand-alone therapy

AQNEURSA™ (levacetylleucine) is indicated for the treatment of neurological manifestations of NPC in adults and pediatric patients weighing ≥15 kg. Aqneursa is the only FDA-approved stand-alone therapy for the treatment of NPC, demonstrating significant improvements in neurological symptoms and functional benefits that could be seen within 12 weeks in adult and pediatric patients.

Additionally, there are multiple clinical trials ongoing throughout the world and some medications can be obtained through expanded access programs. For a list of clinical trials for NPC disease visit the National Library of Medicine

ZAVESCA

A drug trial has been concluded with Zavesca (OGT 918 or Miglustat) with NPC patients. This compound proved to be effective in NP-C mice in a research project funded by the Ara Parseghian Medical Research Foundation in slowing the progression of the disease. It has shown some positive benefits with some NPC children and adults.

The Phase 1-2 trial was conducted with NPC patients in the UK and the United States. There was an adult and a pediatric trial.

If you have questions about the trial, the results or about the drug Zavesca, please contact Dr. Marc Patterson at Mayo Clinic in Rochester, MN who was the trial coordinator: Patterson.marc@mayo.edu or Dr. J.E. Wraith in Manchester, UK.

Zavesca (Miglustat) has not been FDA approved for NPC patients. It has however, been approved for use with another disease. Consequently, Zavesca (Miglustat) is being taken by a number of NPC patients off label, depending of whether or not their insurance companies will cover the cost as it is very expensive.

Learn more about Zavesca (miglustat) by visiting https://www.zavesca.com/ In addition, you can read more NPC patient treatment outcomes in the following publication from Orphanet Journal of Rare Diseases.

VTS-270

Non-clinical studies and a Phase 1 clinical trial suggest that intrathecal (IT) administration of VTS-270 in participants with neurologic manifestations of NPC1 disease showed the potential to slow the rate of progression of their neurologic disease. However, in a phase 2b/3 trial VTS-270 did not show a statistically significant separation from placebo.

Currently, Mandos Health is continuing the development and Expanded Access Program for VTS-270 in hopes to gather more data for an approval.

Contact Dr. Elizabeth Berry-Kravis at elizabeth_berry-kravis@rush.edu or Mandos Health at this LINK https://mandoshealth.com/contact