Speedy diagnosis is critical. Too much ammonia in the blood, a product of protein breakdown, provides a key clue. The child likely has been stricken with an inborn error of metabolism, a recessive genetic disorder that interferes with the normal digestion of food. Among the most common are the methylmalonic acidemias (MMA), affecting between one in 50,000 and 80,000 babies born in the United States. Babies that survive — and some do not — often suffer brain damage or at least cognitive impairment.
Among MMA patients who participated in a recent study at the National Institutes of Health, doctors found that more than one in 10 of patients had either lethargy, failure to thrive or a seizure disorder and one in four suffered from recurrent vomiting. But for doctors treating such patients — usually with a low-protein diet and nutritional supplements — detection is just the beginning. They must also assess effects on the brain in the long term.
Researchers at NIH's National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH) conducted the largest effort to date to define the cognitive impact of this metabolic condition. Their six-year study of 43 MMA patients — from ages two to 35 — assessed neurocognitive performance of patients using standardized tests. Their study found distinct cognitive impairment patterns that correspond with the disorder. It is published in the May 21, 2012, early online issue of Pediatrics.
"We've known that our MMA patients face varying degrees of cognitive impairment," said co-author Charles P. Venditti, M.D., Ph.D., investigator in NHGRI's Genetics and Molecular Biology Branch. "We set out to learn as much as possible about specific neurocognitive outcomes so that we can better advise parents and help our patients negotiate the learning disabilities that may accompany this biochemical condition."
MMA can have several different causes, mainly inherited and all involving loss of function of a metabolic pathway that keeps methylmalonic acid in check. In the study, the researchers differentiated among five groups of patients — those diagnosed by prenatal or newborn screening, by testing within 30 days (early onset) or by testing afterwards (late onset); and those with MMA caused by different types of enzyme problems. Their testing measured verbal comprehension, perceptual reasoning and organization, memory and processing speed, as well as full-scale intelligence quotient.
The researchers first studied a subset of patients from all MMA subtypes to assess whether intelligence quotient scores changed or were stable across multiple years. They repeated the tests at one- to four-year intervals as many as four times. On average, patients did not show any change in any of the specific cognitive tests. But those patients in the early onset MMA category showed lower and more variable cognitive functioning.
At the time of their diagnosis, more than half of the patients in the study had an excess of ammonia in the blood that can injure the brain. The study showed that this condition correlated to lower measures of intelligence quotient, verbal comprehension and perceptual reasoning and organization. The study also found an association with patients who had seizures and cognitive function impairment.
The researchers were surprised to find that the MMA patients in their study posted a lower than expected score for processing speed, which involves fluently performing simple tasks. Patients with mild to moderate intellectual disability, which describes most MMA patients, have otherwise achieved higher scores in this test compared to the other cognitive tests. The fact that MMA patients have lower processing speed scores may have to do with the toxic effects of MMA on the part of the brain called the basal ganglia, according to the researchers.
"Our research establishes a valuable reference set and framework for future investigations of MMA," said Dr. Venditti. "Newborn screening for MMA and continued monitoring of learning disabilities are key to the care of patients with this condition."
Joseph Snow, Ph.D., NIMH staff scientist and co-author on the study, said, "The great value of this research is in providing reasonable expectations to the clinician, researcher, and families regarding the neurologic and cognitive functioning of affected individuals going forward."
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Last Updated: May 29, 2012