Blood Biomarkers Are Specific for Fatal Genetic Disorder

A simple blood test can help diagnose the rare progressive neurodegenerative disorder Niemann-Pick type C 1 (NPC1) disease.

NPC 1 disease is characterized by accumulation of cholesterol in the endolysosomes and by measuring these metabolites in plasma a definitive diagnosis of the disease can be made. Endolysosomes are the products of the fusion of an endosome and a lysosome during endocytosis.

In a collaborative study carried out at the Washington University School of Medicine (St. Louis, MO, USA), scientists evaluated the level of these oxidized forms of cholesterol in human plasma and tissue and animal models.

Nonenzymatically formed cholesterol oxidation products were increased in the plasma of all human NPC1 subjects studied and delineated an oxysterol profile specific for NPC1 disease. The oxysterol profile also correlated with the age of disease onset and disease severity. They further showed that the plasma oxysterol markers decreased in response to an established therapeutic intervention in the NPC1 feline model. The oxysterol profiles were obtained using gas chromatography and mass spectrometry (GC/MS) techniques.

Although no group that scientists screened had levels of the two key markers as high as the NPC patients, the markers were significantly increased in parents and siblings of NPC patients. Many of these family members have one mutated NPC gene and are carriers of the disease. In NPC patients, two oxidized forms of cholesterol were present at levels 9 to 10 times higher than normal. The same markers were not elevated in healthy children and adults or in persons with elevated cholesterol levels, heart disease, diabetes or other forms of lysosomal storage disorders.

NPC typically manifests in childhood with a variety of symptoms including problems walking, slurring of speech and difficulty swallowing. In later stages, it immobilizes patients, causing seizures, dementia, and death. NPC belongs to a class of inherited diseases known as lysosomal storage disorders. The disorder breaks down the cell's normal patterns for handling cholesterol, leading it to accumulate in lysosomes, the cellular organelles, which contain acid hydrolase enzymes that break up waste materials and cellular debris.

Daniel S. Ory, M.D., one of the senior authors, said, "This is an important step forward both in terms of making a definitive diagnosis much easier and in terms of providing us with a way to quickly assess the effectiveness of experimental treatments."

The study was published November 3, 2010 in the journal Science Translational Medicine.

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