Collaborative Database Uses Newborn Blood Spot Screening to Detect Children With Genetic Abnormalities

Jacquelyn K. Beals, PhD

October 26, 2009

October 26, 2009 (Honolulu, Hawaii) — A study investigating the use of a long-term follow-up database of children with inborn errors of metabolism has shown that metabolic practitioners can systematically gather information about outcomes from newborn blood spot screening (NBS) for a collaborative database useful for short-term patient follow-up. The proof-of-principle study also yielded specific information about children with medium-chain acyl CoA dehydrogenase deficiency (MCAD).

The project was an initiative of the Inborn Errors of Metabolism–Information System (IBEM-IS) work group of the Region 4 Genetics Collaborative, the goal of which is to come up with strategies for children with congenital and inherited disorders. Current participants include newborn screening specialists in a 7-state region near the Great Lakes. The results were presented here at the American Society of Human Genetics (ASHG) 59th Annual Meeting.

Their project involved the use of a condition registry as a research platform, explained presenter Susan Berry, MD, from the Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota in Minneapolis. Dr. Berry is an IBEM-IS project coleader for the Region 4 Genetics Collaborative–Priority 2 Workgroup IBEM-IS for Long-Term Follow-Up, Michigan Public Health Institute in Okemos, Michigan.

The collaborative database has the potential to ascertain information about metabolic diseases, overlay research questions, and document interventions that can be assessed with data in the IBEM-IS. The initial project will examine the natural history and short-term outcomes for a specific metabolic condition. A priority has been to encourage registry subjects to consent to follow-up.

The selected disease was MCAD deficiency "because it's among the more common [metabolic diseases]," Dr. Berry told Medscape Pathology. "So we figured we'd get data fast. It is a common disease, and we knew we would be able to get enough cases. . . . It was a proof of principle. Plus, it's a really important disease that has very serious consequences, so we thought it would be informative to the families," said Dr. Berry.

MCAD deficiency is a disorder of fatty acid oxidation resulting from defects in, and reduced activity of, the MCAD enzyme complex that normally oxidizes 6C to 12C fatty acids. A point mutation (985 A>G) in the MCAD gene is present in about 90% of cases. Children with reduced enzyme activity show few problems, but fasting or high energy demands involving fatty acid oxidation lead to fatty acid build-up, hypoglycemia, hyperammonemia, and sometimes death. Among undiagnosed cases, 20% to 25% are fatal, and those surviving severe crises can sustain brain damage.

"The most important [thing] is prevention of fasting, and everyone agrees that you have to do that because you can't generate fuel," said Dr. Berry. "Prevention of fasting is a critical element. But . . . whether you need to supplement with carnitine [is controversial]. . . . Whether you need to restrict fat intake [is also controversial] ," she added.

A clinical indication of MCAD deficiency is the presence of medium-chain acylcarnitines in the blood, and octanoic acid (a C8 fatty acid) accumulates in the blood during metabolic stress. The current study tested the hypotheses that children with the highest C8 values in NBS would be the most symptomatic, and that the highest C8 values would occur in children homozygous for the 985 A>G mutation.

Of 42 newborns whose NBS demonstrated elevated C8 levels, 17 of the 21 with the lower C8 values (0.40–8.69 ng/mL) had 2 mutations, and "5 were 985 A>G homozygotes." Among the 21 patients with the higher C8 values (8.97–38.80 ng/mL), 16 had 2 mutations but "11 were 985 A>G homozygotes." Only 3 patients in the lower C8 group had clinical problems; the others had no abnormal lab results or symptoms. In the higher C8 group, 6 patients had a lab abnormality or symptom, and 3 had both.

The study concluded that the long-term follow-up database was a successful tool for short-term follow-up in these patients. In addition, preliminary indications are that higher C8 values are associated with a greater likelihood of being homozygous 985 A>G, and with being symptomatic or having abnormal lab results during NBS.

"A big lesson we learned from newborn screening is that we really didn't understand the diseases at all based on the symptomatic patients," comoderator Jerry Vockley, MD, PhD, told Medscape Pathology. Dr. Vockley is professor of pediatrics at the University of Pittsburgh School of Medicine, professor of human genetics at the Graduate School of Public Health, and chief of medical genetics at the Children's Hospital of Pittsburgh of UPMC in Pennsylvania.

"When we see the symptomatic patients and we focus on them, we see the most severely affected patients. We're looking at the tip of the iceberg," Dr. Vockley observed. "Once we start identifying everybody with that biochemical abnormality, we start seeing strata of risk, where there are a whole group of individuals who have what looks like a low risk for developing symptoms, as opposed to the inevitable presence of disease."

"There are other factors that determine the severity of disease that we need to sort out," Dr. Vockley added. "The only way we can do that is by these large consortia now that allow us to accumulate hundreds of patients, as opposed to each of us looking at individuals or a handful of patients."

Dr. Berry and Dr. Vockley have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 61. Presented October 22, 2009.

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