- NPC is caused by mutations in either the NPC1 (95% of cases) or NPC2gene.
- The proteins encoded by these genes are involved in the trafficking of lipids and other large molecules within cells.
- More than 400 mutations have been identified in NPC1 and more than 20 have been identified in NPC2.
- NPC is inherited in an autosomal recessive manner, meaning that both parents must carry a mutation.
- The mutations result in intracellular accumulation of complex lipid compounds, causing an inflammatory response and increased cell death in multiple organs and tissues across the lifespan.
- The disease can present at any stage of life and can strike unexpectedly with highly variable and insidious symptomatology.
NPC can present at any stage of life with a diverse group of symptoms and variable speed and patterns of progression. It is often categorized by age of neurological onset:
- Early infantile (onset before age 2)
- Late infantile (onset between age 2 and 6)
- Juvenile (onset between age 6 and 15)
- Adult onset (onset after age 15)
Although the expression and progressions of the disease is unique for each individual. In general, earlier onset of disease is associated with more rapid progression and greater severity.
- Many patients present an enlarged spleen, jaundice, and/or liver issues or failure at birth, but these symptoms may not be recognized as signs of NPC.
- Eye movement problems are often one of the earliest symptoms of NPC.
- Neurological involvement results in ambulation and walking difficulties, cognitive impairment, swallowing difficulties, vertical supranuclear gaze palsy (VSGP), seizures, and cataplexy.
- Visceral organs such as the spleen, liver, kidneys and lungs may be damaged throughout the course of disease.
- Adolescent- and adult-onset NPC onset can include mental illnesses such as psychosis and bipolar disorder, which can be among the most problematic symptoms of the disease.
The high variability and lack of specificity of most signs and symptoms of NPC, combined with the fact that most clinicians will have little or no experience with the disease leads to substantial diagnostic delays, misdiagnoses, delayed intervention, and high levels of frustration and stress among families and caregivers. The average delay in diagnosis is about five years according to several care centers, by which time the nervous system may be severely damaged. There is a growing effort in the community to promote newborn screening for NPC, which holds the promise for earlier diagnosis in future patients.
Assay of oxysterols is now regarded as both a robust screening test and a first-line diagnostic test for NPC. These results are needed to identify the classic and other forms of NPC and to eliminate other possible causes of the symptoms.
Genetic testing will confirm a potential diagnosis. Traditional sequencing methods along with targeted gene and multigene panels including NPC1 and NPC2, with complete exons and exon–intron boundaries, can be used to screen clinical patient groups with an increased risk of NPC.
Contact Marc Patterson at the Mayo Clinic or Denny Porter at the NIH for recommendations.
There are no FDA-approved biomarkers or clinical outcome measures for NPC. However, a clinical severity scale was published and used to characterize and quantify disease progression.
Clinical signs and symptoms in nine major:
- Eye movement
- Fine motor
And eight minor:
- Auditory brainstem response
- Gelastic cataplexy
- Respiratory problems