Pediatric Examination and Board Review (144 page)

TABLE 84-1
Inborn Errors of Metabolism and Characteristic Laboratory Findings

Abbreviations: IVA, isovaleric acidemia; LCHAD, long chain hydroxyacyl CoA dehydrogenase; MCAD, medium chain acyl CoA dehydrogenase; MCD, multiple carboxylase deficiency; MMA, methylmalonic acidemia; OTC, ornithine transcarbamylase deficiency; PA, propionic acidemia; VLCAD, very long chain acyl CoA dehydrogenase.

4.
(C)
MCAD is the most common of the fatty acid oxidation disorders, which are characterized by nonketotic hypoglycemia, with mild acidosis. Other findings may include elevated liver transaminases, mild elevation of lactate, hepatomegaly, elevated creatine phosphokinase (CPK), carnitine deficiency, and evidence of medium chain dicarboxylic aciduria on urine organic acid or acylcarnitine analysis (
Table 84-1
). Hyperinsulinism typically presents at an earlier age with nonketotic hypoglycemia, no acidosis or liver abnormalities, and hypoglycemia that occurs after a short fast. Salicylate poisoning is characterized by an elevated anion gap acidosis. Galactosemia typically has more abnormal liver function tests with conjugated hyperbilirubinemia. Physiologic ketotic hypoglycemia is accompanied by significant ketosis.

5.
(E)
The risk for hypoglycemia in fatty acid oxidation disorders is highest after a prolonged fast, especially during times of intercurrent viral illness. The symptoms of diaphoresis, lethargy, vomiting, and signs of hypoglycemia are nonspecific and not specific for an underlying disease. A family history of SIDS should raise the suspicion for an inherited inborn error of metabolism. Many metabolic conditions go unrecognized at the time of presentation and are diagnosed as SIDS or Reye syndrome.

6.
(B)
With few exceptions, inborn errors of metabolism, including fatty acid oxidation defects, are inherited in an autosomal recessive pattern. Therefore, the parents of the affected child should be counseled that there is a 25% risk of recurrence for the condition with each additional pregnancy, and unaffected children are at two-thirds risk of being carriers. There are several conditions (Hunter syndrome, ornithine transcarbamylase deficiency, and Lesch-Nyhan syndrome) associated with Xlinked inheritance patterns, where boys are typically affected and females may be asymptomatic carriers, but because of X-inactivation patterns, girls may be mildly to severely affected as well.

7.
(B)
There are several types of glycogen storage disorders, and they can present with different clinical features. It is difficult to differentiate among them on a purely clinical basis. These disorders result in hypoglycemia because of the inability to break down stored glycogen, with the resulting medical problems listed in the question. Insulin-induced hypoglycemia would not result in lipid abnormalities or hepatomegaly, it and would give nonketotic hypoglycemia. GH deficiency will have growth retardation and hypoglycemia but may be associated with micropenis and does not have the lipid abnormalities or hepatomegaly. Fatty acid oxidation defects were discussed above.

8.
(E)
Galactosemia is an inborn error of carbohydrate metabolism that results from deficiency of galactose-1-phosphate uridyl transferase and is part of most newborn screening programs. Manifestations (
Table 84-1
) usually appear within days of the initiation of milk feedings and may have onset before newborn screen results. Any newborn patient with liver dysfunction including cirrhosis, hepatomegaly, cataracts, renal Fanconi syndrome (renal tubular glycosuria, generalized aminoaciduria, proteinuria), presence of urine reducing substance, and especially
E coli
sepsis should be considered for possible galactosemia.

9.
(D)
Treatment of galactosemia involves restriction of galactose in the diet, mostly by exclusion of milk and its products. The earlier the treatment is initiated, the better the long-term prognosis. Despite treatment, milder manifestations may be present, especially problems in school even with normal IQ levels. Close follow-up of growth and development is indicated. Liver failure may be present in the initial presentation of galactosemia but typically resolves with treatment and is not a long-term sequela.

10.
(D)
It is important to understand the NBS in your state. At the present time there is not a standard set of diseases for which all states screen. All of the states in the continental United States screen for galactosemia. It is also important to understand how the state-specific screening test works to interpret the result correctly. If a child is not given lactose-containing milk before the screen, there may not be a buildup of galactose and galactose-1-phosphate so the NBS will not be abnormal.

11.
(C)
The characteristic findings of an organic acidemia (
Table 84-1
) include significant anion gap acidosis, ketosis, variable elevations in lactate and ammonia, neutropenia, and thrombocytopenia. Urine organic acid analysis typically reveals the main anion contributing to the acidosis and the diagnosis. All protein feeds should be stopped and the child should be given liberal amounts of IV glucose while the results of the laboratory tests are pending. IV bicarbonate should be administered and, because of the ongoing organic acid production, the child may require large amounts. Dialysis should be considered for severely acidotic neonates.

12.
(C)
Hyperammonemia is a common finding in many inborn errors of metabolism including organic acidemias and urea cycle defects. Urea cycle defects are characterized by significant hyperammonemia (typically >1000 μmol/L) and respiratory alkalosis in the early presentation, whereas organic acidemias usually have severe metabolic acidosis (
Table 84-1
). Plasma amino acid analysis and urine orotic acid measurement are useful tests in the differentiation of the types of urea cycle defects, which is important to determine therapy. Synthetic liver dysfunction with normal transaminases suggests tyrosinemia. Vomiting, lethargy, and tachypnea, which are nonspecific features, and hepatosplenomegaly with hypercholesterolemia and hypoglycemia are suggestive of a glycogen storage disorder.

13.
(C)
Immediate treatment should include removal of all sources of protein, and in cases of severe hyperammonemia, hemodialysis (as opposed to peritoneal dialysis, continuous arteriovenous hemoperfusion, or exchange transfusion) is the most efficient way to remove the ammonia. Cerebral edema is common in urea cycle defects and should be treated aggressively. Carnitine is useful in the treatment of fatty acid oxidation defects but not in urea cycle defects.

14.
(E)
Tyrosinemia should be considered in any child who presents with liver disease in early infancy and is characterized by elevations of tyrosine and methionine with generalized aminoaciduria (
Table 84-1
). α
₁
-antitrypsin deficiency may present with clinical manifestations similar to neonatal or giant cell hepatitis. Neonatal hemochromatosis is a poorly understood disorder with an associated fulminating course and hepatic and extrahepatic parenchymal iron deposition.

15.
(A)
PKU is an inborn error of phenylalanine (phe) metabolism most often caused by a deficiency of the enzyme phenylalanine hydroxylase, which converts phe into tyrosine. Newborns with PKU have a normal examination, and the diagnosis is not evident until 6-12 months of age when the symptoms of mental retardation, seizures, spasticity, and hypopigmentation are evident. Screening for PKU is a part of all newborn screening programs and has been successful in early disease identification and treatment. This program has virtually eliminated the severe clinical manifestations. PKU is inherited in an autosomal recessive fashion with 25% risk of recurrence for siblings of an affected individual.

16.
(D)
It is common for premature babies who are on TPN at the time of the NBS to have false elevations of some amino acids including phenylalanine. These cases are typically false positives and the child does not have PKU, but additional testing is mandatory for confirmation.

17.
(E)
Treatment of PKU involves dietary restriction of phe and careful monitoring of phe and tyrosine levels. Fruits and vegetables are low in phe; high protein content foods are rich in phe. The use of phe-free formulas is needed throughout life to provide adequate calories and other nutrition.

18.
(C)
Previous treatment recommendations suggested that the PKU diet can be safely discontinued at 5 or 6 years of age. Recent studies have shown there is a uniform and progressive loss of IQ after stopping the diet leading to the current recommendations to continue the diet throughout life. The successful treatment of PKU has allowed affected individuals to become normal functioning adults. Women with PKU are at risk during pregnancy of having children with severe mental retardation as a result of fetal exposure to high phenylalanine levels throughout pregnancy, even though the children do not typically have PKU themselves. Initiation of the diet before conception and continuing throughout pregnancy decreases, but does not eliminate, the potential for retardation, microcephaly, and birth defects.

S
UGGESTED
R
EADING

Burton B. Inborn errors of metabolism in infancy: a guide to diagnosis.
Pediatrics
1998;102:e69.

Nyhan WL, Ozand PT.
Atlas of Metabolic Diseases.
2nd ed. London, United Kingdom: Chapman & Hall Medical; 2005.

CASE 85: A NEONATE WITH A VENTRICULAR SEPTAL DEFECT AND A THIN UPPER LIP