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R
ikke Katrine Jentoft Olsen, MD, of Aarhus
University, Denmark, explained that MADD
is a rare inborn error of metabolism that may
result in a favorable outcome when treated with
high doses of riboflavin.
Patients with MADD fall into three broad clinical
phenotypes:
1. Neonatal onset with congenital anomalies.
Affected neonates are often premature, pre-
senting with severe nonketotic hypoglycemia,
hypotonia, hepatomegaly and severe meta-
bolic acidosis within the first 24 h of life. They
usually harbor dysplastic kidneys with multiple
cysts and may also exhibit facial dysmorphism
(low-set ears, high forehead, hypertelorism,
and hypoplastic midface); rocker-bottom feet;
and anomalies of external genitalia. Death
usually occurs within the first week of life.
2. Neonatal onset without anomalies (together
called MADD-severe). These patients usually
present within the first 24–48 h of life with
hypotonia, tachypnea, hepatomegaly, meta-
bolic acidosis, and hypoketotic hypoglycemia.
Most die during the first week(s) of life but
some have survived for several months, usu-
ally dying of severe cardiomyopathy.
3. Mild and/or late-onset (MADD-mild). MADD-
mild patients show a broad clinical spectrum
of disease. Onset of intermittent episodes of
vomiting, metabolic acidosis, and hypoketotic
hypoglycemia (with or without cardiac involve-
ment) can occur during the first few months
of life up to adolescent/adult presentation
with acute Reye-like illness with ketoacido-
sis and lipid storage myopathy. The latter
often respond to pharmacological doses of
riboflavin.
Newborn Screening
Programs Should Be
Aware of a Rare SNP in
the Placental Riboflavin
Transporter Gene
Newborn screening programs should be aware of a rare single-
nucleotide polymorphism in the placental riboflavin transporter
gene that causes transient multiple Acyl-CoA dehydrogenation
deficiency (MADD).
The birth prevalence of MADD is estimated at
one in 200,000 individuals, but great variation
is seen between countries/ethnicities. The inci-
dence appears to be considerably rarer in Asian
populations.
Though many individuals who harbor a defective
AMPD gene are asymptomatic, others may suffer
from symptoms such as exercise intolerance, mus-
cle pain, and muscle cramping.
It is important for patients with MADD to maintain
strength and fitness without exercising or working
to exhaustion. Learning this balance can be difficult.
Symptomatic relief of the effects of MADD can be
achieved by administering oral ribose 10 g per 100
pounds (0.2 g per kilogram) of body weight per day,
and exercise modulation as appropriate.
Taken hourly, ribose provides a direct but limited
source of cellular energy. Patients with myoade-
nylate deaminase deficiency do not retain ribose
during heavy exercise, so supplementation
may be required to rebuild levels of adenosine
triphosphate.
Creatine monohydrate may also be helpful, as it
provides an alternative source of energy for anaer-
obic muscle tissue and was found to be helpful for
other, unrelated muscular myopathies.
Potential complications of MADD include:
Increased risk that a statin will cause myopathy
Malignant hyperthermia from anesthesia, with
permanent muscle damage. Patients with MADD
PRACTICEUPDATE CONFERENCE SERIES • ICIEM 2017
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