defective gene from both parents. The parents are said
to be carriers of the disease because they can transmit
it to their children without being affected by it them-
selves. With each pregnancy, the two carrier parents
have a 1:4 chance that the baby will have MSUD. The
chances are 2 in 4 that the child will be a carrier, and
1 in 4 that the child will neither have MSUD nor be a
carrier. MSUD is a rare disorder in most ethnic
groups, affecting one child in 180,000 in the general
North American population and about one in 185,000
children worldwide. Among the Old Order Amish and
the Mennonites in Pennsylvania, however, the rate is
much higher, affecting one child in every 176 live
births. As a result, Pennsylvania was the first state to
mandate screening of newborns for MSUD.
SYMPTOMS AND DIAGNOSIS.The symptoms of
MSUD vary in severity and time of onset, depending
on the subtype of MSUD. As of 2007, researchers
distinguish 5 subtypes, defined by the amount and
type of enzyme activity present in the body:
Classic MSUD: This is the most common subtype of
the disease, with less than 2% of BCKD enzyme
activity present. Newborns show symptoms within
the first 4 to 7 days of life, including poor feeding,
poor weight gain, recurrent vomiting, high-pitched
crying, seizures caused by swelling of the brain, and
alternating rigidity and softness of the muscles. The
baby may make repetitious gestures resembling the
movements of fencing or bicycling. The baby’s urine
develops a characteristic odor of maple syrup as soon
as the other symptoms develop. If untreated, a child
with classic MSUD will eventually stop breathing
and die.
Intermediate MSUD: A rare form of the disease that
differs from the classic form chiefly in a slightly
higher amount of BCKD enzyme activity in the
patient’s body, about 3 to 8 percent. Treatment and
management is similar to that of classic MSUD.
Only 20 patients have been reported with this
subtype.
Intermittent MSUD: The second most common
form of MSUD, with enzyme activity between 8
and 15% of normal. Children with intermittent
MSUD may not show any signs of the disorder
until they are 12 to 24 months of age, usually in
response to an illness or a rapid increase in protein
intake. During episodes of illness or other metabolic
stress, the child may develop seizures or other signs
of metabolic stress. Children or adolescents with this
form of MSUD are at risk of developmental delays,
including mental retardation, as well as metabolic
crises.
Thiamine-responsive MSUD: A rare form of the
disease, in which the level of enzyme activity in the
child’s body is increased by giving doses of thiamine
hydrochloride.
E3-deficient MSUD: A very rare variant of the dis-
ease, reported in only 10 patients as of 2007. These
patients suffer from deficiencies in two other enzyme
complexes as well as a lack of BCKD.
Early diagnosis of MSUD is essential to prevent
neurological damage and death in infancy. Some
states, but not all, have mandatory screening pro-
grams for MSUD. Classic MSUD can be diagnosed
in many cases before the physical symptoms appear by
swabbing the baby’s ear canal within 12 to 24 hours of
birth and testing the cerumen (ear wax) for the odor of
maple syrup. A child suspected of having MSUD
should be given a blood test without delay. The
blood test used to confirm the diagnosis is the BCAA
analysis, which examines the levels of the 20 amino
acids in the baby’s blood and their relationship to one
another. The doctor can also order molecular genetic
testing or tests that measure the levels of organic acids
in the baby’s urine. Prenatal diagnosis of MSUD can
be performed by mutation analysis or by measuring
the concentrations of BCAAs in the amniotic fluid
that surrounds the baby inside the mother’s womb.
TREATMENT.The first step in treatment of classic
MSUD is prompt reduction of the levels of BCAAs in
the body tissues of the affected child, particularly the
level of leucine, which is the most toxic of the three
BCAAs. In the 1960s and 1970s, dialysis was the
method most commonly used to lower the BCAA
levels rapidly. As of 2007, however, the preferred
method involves administration of special intravenous
solutions of amino acids that do not contain BCAAs,
with glucose (sugar) added to meet the body’s energy
needs. In some cases insulin is added to the solution.
These infusions lower the BCAA levels by enabling the
child’s body to use the excess BCAAs to synthesize
proteins.
Lifelong therapy of MSUD has two mainstays:
strict adherence to a diet based on restriction of the
patient’s leucine intake; and aggressive treatment of
acute episodes, which can be triggered by surgery,
infectious diseases, or emotional stress. These episodes
are characterized by vomiting, diarrhea, sleepiness,
irritability, staggering, slurred speech, hallucinations,
and unusual breathing patterns. In many cases, put-
ting the child on a ‘‘sick day’’ dietary regimen and
immediate notification of the child’s doctor will pre-
vent the need for hospitalization. If the child cannot
keep food down, hospitalization with intravenous
feeding or dialysis may be necessary. PreventingMaple syrup urine disease