National Human Genome Research Institute (NHGRI) researchers participating in an international study with colleagues at the University of Colorado in Denver, McGill University in Montreal, Canada, and University Children's Hospital in Zurich, Switzerland have described a new disease involving a defect in the body's ability to process vitamin B12, or cobalamin. The rare inherited disorder, which has been found only in boys, can cause severe neurological symptoms, including developmental delay, epilepsy and brain malformations.
Newborns are screened for cobalamin metabolic defects but the new disorder had not previously been distinguished from a related condition, known as cobalamin C deficiency, or cblC. With their discovery, published Sept. 5, 2013 in the American Journal of Human Genetics [cell.com], the researchers located a gene alteration on the X chromosome that regulates expression of a critical enzyme in the metabolism of cobalamin. The new disorder is called cobalamin X deficiency (cblX).
"CblX is a new class of metabolic error that derives from transcriptional dysregulation," said co-author Charles Venditti, M.D., Ph.D., investigator in NHGRI's Genetic and Molecular Biology Branch. "This mechanism has not been observed in any other inborn error of metabolism."
The researchers identified male patients with symptoms similar to cblC, but whose screening did not detect alterations in the gene associated with that condition. By sequencing the whole exome of one of these patients, they found an alteration of a different gene on the X chromosome. Whole-exome sequencing gives detail about the 1-2 percent of the genome that contains protein-coding genes. They subsequently screened 17 others and found that 13 additional patients had alterations affecting the same gene as the first patient.
The gene, called HCFC1, plays a role in regulation, turning on the expression of the gene and enzyme associated with cblC. Alterations in HCFC1 cause reduced expression of that enzyme. HCFC1, unlike other genes associated with cobalamin disorders, does not encode an enzyme in the cobalamin pathway. By regulating expression rather than encoding an enzyme, it affects cobalamin metabolism nonetheless.
"This discovery has very important genetic counseling implications for families because the gene is on the X chromosome, unlike all other cobalamin genes," says study co-author Jennifer Sloan, Ph.D., an NHGRI certified genetic counselor and researcher. "Males are affected with cblX because they have only one copy of the X chromosome. Females are less likely to be affected because they have two X chromosomes and one normally functioning copy of the HCFC1 gene."
Dr. Sloan explained that females that carry an HCFC1 alteration have a 50 percent chance of passing the alteration on to each of their male children, causing cblX. All other cobalamin disorders such as cblC are inherited in a different way, called autosomal recessive inheritance, where both parents are carriers and there is a 25 percent chance of recurrence in a sibling of either gender. "Genetic testing is critical in this group of disorders so we can determine the chance that a cobalamin disorder will happen again in the family," she said.
Max Watson from Denver, Colo., is a boy whose exome sequencing pointed to the tell-tale gene alteration. He was seen both at the National Institutes of Health and at the University of Colorado School of Medicine where researchers performed the exome sequencing part of the study. The 9-year-old uses a specialized wheelchair and devices to help him stand and move to a bed. He is unable to be in a classroom, but is enrolled in school, engaging with classmates via live Internet. The discovery of the cause of his condition is not likely to help with the challenges this disease poses for him and that he and his family meet daily.
"We're pretty realistic about all of this," said Max's mother, Deana. "The whole reason we have from the beginning agreed to any sort of studies is that maybe someday, with Max's findings, another family won't be in this situation. We're OK with that and proud Max is playing a part with that."
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Posted: September 9, 2013