Before deciding to screen for a disorder, state heath departments consider the severity and treatability of the condition, as well as the test's accuracy and cost. During the 198Os, a fourth class of dis- eases that includes sickle-cell anemia was added to the test panels, or groups of tests. The justification was looser than for the previous three disorders because sickle-cell conditions do not have a decisive therapy. For this reason California was slow to order a sickle-cell test.
It held off until 1990. Five states have still not committed to it.
Now it's a little more than a decade later, and tandem mass spectrometry has brought a sea change in California's newborn screening program. Jayson's son Austen passed the standard battery of four tests within days. It would take a few more weeks to complete the tandem mass spectrometry tests.
The basic technique of tandem mass spectrometry is more than a century old, but it was adapted to newborn screening about a decade ago by North Carolina and Pennsylvania. The device, which costs about $300,000, identifies a range of biochemicals in blood.
First, molecules are extracted from the blood sample and converted to a stream of electrically charged ions. The spectrometry is called tandem because the machine analyzes the sample twice in rapid succession, once when the molecules are whole and again after they've been fragmented. The machine sorts the particles by weight, and a computer displays the results as a spectrum of peaks.
A peak that is abnormally high or low is the fingerprint of a biochemical disorder. Tandem mass spec is not a DNA test; it searches for genetic flaws the old-fashioned way, by inference. The machine measures the chemical products of the genes, or more often, the lack of a product, which may cause another chemical to peak. Usually the doctor will try to confirm a positive result with newer DNA methodology, going straight to the source of the problem.
In October, a small plastic tray, its top sealed with aluminum foil like a miniature TV dinner, was positioned for analysis in the Berkeley lab. The tray held wells of separate samples from 85 children. One was Austen Muelder's. A thin needle descended from the head of the machine's "auto-sampler" and pierced the foil above one of the samples. A drop of liquid was withdrawn and injected into the machine, where it was gasified, ionized, and analyzed for several dozen of its components. Then the auto-sampler moved to the next sample.
Given the rarity of the conditions under scrutiny, it is a safe statistical bet that 84 of the 85 samples in this particular run produced no unusual spectra. But Austen's readout showed a peak that was 20 times higher than normal for a fatty acid called C-8. A spike at C-8 indicates something called medium-chain acyl-CoA dehydrogenase deficiency, which mercifully can be shortened to the acronym MCADD.
Here is a genetic disease that was unknown, or at least undescribed, a generation ago, although surely it had killed many children before then. MCADD is a recessive disorder. Jayson carries a gene for the condition, and the same flawed DNA is carried by his wife, Angela. Each one is a healthy carrier, but their baby combines the two defective genes.
MCADD refers to an enzyme that helps the body metabolize fat. If it's absent, fatty acids build up in the bloodstream and in the liver. Also, the body is under stress for lack of an energy source. Glucose, a form of sugar, can be drawn on instead of fat, but if glucose is expended because, say, the baby misses one or more feedings, then deadly shock can occur.
A baby gets a cold, fusses, won't eat, and the next thing the bewildered parents know is that their child is in a coma. About one-third of undiagnosed children die. Most who don't are severely damaged. Paradoxically, the simple preventive treatment for such a dangerous illness is a regular schedule of feedings with a low-fat formula. If an MCADD child doesn't eat, for whatever reason, the parents know to take him or her to the emergency room for intravenous glucose.
Once Austen's metabolic spike was detected, the response by health authorities was swift. The next morning the Genetic Disease Branch placed phone calls, unsuccessfully to the Muelders and to their pediatrician. A fax was sent to the pediatrician's office in the afternoon. The state also alerted the clinic for genetics and metabolic disease at UCLA, which was the nearest clinic to the Muelders.
Later that same afternoon, Erica Chang, the nurse coordinator at the UCLA clinic, reached Angela on the phone. She was deliberately vague about the diagnosis until it could be confirmed. "I didn't want to scare them;' Chang says.
Stunned, "like being kicked in the teeth;' Jayson spent the weekend searching the Internet for information about MCADD. Angela was in tears. Linda Fernandez calmed the young parents by reminding them that "Austen looks perfectly healthy. Obviously, he's not going to die overnight." In fact, the baby was not in danger as long as he continued to eat normally.
By the end of Monday, following workups and counseling at the clinic, Jayson, Angela, and Linda felt reassured about Austen and very grateful for the warning, never mind its late- ness."They firid out about other disorders when your baby is in the hospital dying," says Angela. "So I feel really lucky."
California is neither the most advanced nor the most laggard state when it comes to public-health protection, but because it is the most populous, its policies have great clout nationally. The program that caught Austen Muelder's disease is still preliminary: There is no guarantee that tandem mass spec will be made available to all of the 540,000 babies born each year in the state. Tandem mass spec now screens less than half of the babies born in the United States.
Parents' groups and the doctors who treat metabolic disorders have lobbied for expanded newborn testing across the country, and no doubt they would have won their argument by now if the disorders that the new technology detects were more prevalent.
"These are stunningly rare diseases," says Michael Watson, executive director of the American College of Medical Genetics. For example, phenylketonuria affects about one infant in 16,000, while MCADD affects about one in 12,000. Galactosemia is even rarer, affecting one in 53,000 infants. A condition called maple syrup urine disorder, which tandem mass spec can flag, has an incidence of about one in 183,000 births.