PracticeUpdate: Conference Series - The Best of ICIEM 2017

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).

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.

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: Ÿ Ÿ Increased risk that a statin will cause myopathy Ÿ Ÿ Malignant hyperthermia from anesthesia, with permanent muscle damage. Patients with MADD

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PRACTICEUPDATE CONFERENCE SERIES • ICIEM 2017