JULY, 2021 A three-week-old female infant is brought to the emergency department for poor feeding and tachypnea. Physical examination reveals a nondysmorphic infant with nasal flaring diffuse rales on lung examination, a quiet precordium and mild hepatomegaly. Chest radiography demonstrates cardiomegaly and pulmonary edema. Echocardiography shows hypertrophic cardiomyopathy and pericardial effusion with no structural defects. Electrocardiography demonstrates increased voltages throughout. Laboratory results are as follows: Laboratory Test
Result
Complete blood cell count
Normal
C-reactive protein
Normal
Blood cultures
No growth at 48 hours
Comprehensive metabolic panel
Normal with the following exceptions;
Blood glucose
-35 mg/dL (1.9 mmol/L)
Aspartate aminotransferase
-125 U/L
Alanine aminotransferase
-150 U/L
Urinalysis
Negative, no ketones noted
Newborn screening
Elevated C14:1 of > 1 mmol/L
Urine organic acids
Increased dicarboxylic acids
Of the following, this infant’s MOST likely diagnosis is A. Barth syndrome B. α-galactosidase A deficiency C. Pompe disease D. very long-chain acyl-coenzyme A dehydrogenase deficiency Answer: D The neonate in the vignette has very long-chain acylcoenzyme A dehydrogenase (VLCAD) deficiency and autosomal recessive inborn error of metabolism that can present in one of three scenarios. This neonate has a subtype that manifests with severe early-onset cardiac failure that can progress to multiorgan failure. Cardiac findings include hypertrophic or dilated cardiomyopathy, arrhythmias and pericardial effusion. Affected neonates and infants will have hypotonia and hepatomegaly. Laboratory findings include hypoketotic hypoglycemia, hepatic dysfunction, elevated creatine kinase and increased dicarboxylic acids on urine organic acid analysis. Acylcarnitine analysis, an appropriate second-tier test, would reveal elevated C14:1, C14L2, XC14 and C12:1 metabolites. This disorder is typically detected via newborn screening with elevated C14:1 of more than 1 mmol/L: screening is performed because early intervention and treatment will improve morbidity and mortality in affected children.
A second type of VLCAD is the hepatic or hypoketotic hypoglycemic form. This type presents in early childhood with hypotonia and hepatomegaly but typically lacks cardiomyopathy. The third type has an even later onset, manifesting with episodic myopathy and intermittent rhabdomyolysis typically provoked by muscle cramps, pain, or exercise. The diagnosis of VLCAD is confirmed with an acylcarnitine analysis and identification of biallelic pathogenic gene mutations in ACADVL. In affected children having episodes of acute illness, management requires the administration of intravenous glucose as an energy source to stimulate insulin secretion and suppress lipolysis, as well as careful monitoring for and management of arrhythmias and rhabdomyolysis. Avoidance of triggers such as fasting, dehydration and long-chain fats is important for preventing metabolic decompensation; therefore, patients are maintained on a low-fat high-carbohydrate diet with supplementation of medium-chain triglyceride oil and frequent regular feeding. Fats are an important source of energy and serve as the principal fuel source rather than glucose for the heart and skeletal muscle during exercise. Many tissues prefer to use fatty acids for energy, thus allowing the brain to selectively use glucose. Hepatic fatty acid oxidation disorders commonly lead to hypoketotic hypoglycemia, hepatomegaly, hepatic dysfunction, myopathy, rhabdomyolysis and encephalopathy. Other fatty acid oxidation disorders include, but are not limited to, carnitine palmitlyltransferase (CPT) I deficiency, CPT II deficiency, medium-chain acyl-CoA dehydrogenase deficiency, shortchain acyl-CoA dehydrogenase deficiency and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Most fatty acid oxidation disorders have been associated with significant morbidity and mortality; however, because many of these disorders are now detected via newborn screening, their outcomes have improved with early treatment, dietary interventions and avoidance of triggers. Barth syndrome is an X-linked recessive mitochondrial disorder arising from TAZ mutations, which presents in affected males with cardiomyopathy, muscular weakness, neutropenia, distinctive facial dysmorphology and impaired growth. Urine organic acids would reveal significantly elevated urinary 3-methaylglutaconic acid and moderately increased urinary 3-methylglutaric acid and 2-ethylhydradrylic acid. α-Galactosidase A deficiency, also known as Fabry disease, is an X-linked disorder that causes increasing lysosomal deposition of globotriaosylceramide in cells. It typically presents with periodic pain crises of the distal extremities, angiokeratomas, sweating dysfunction, corneal/ lenticular opacities and proteinuria. Progressive renal deterioration ultimately leads to end-stage renal disease in untreated affected males in the 3rd to 5th decade of life. Cerebrovascular strokes and heart disease are major causes of morbidity and mortality, typically in adulthood. Pompe disease, an autosomal recessive glycogen storage and lysosomal disorder caused by a deficiency of the acid α-glucosidase enzyme, can present in infancy with cardiomyopathy, left ventricular hypertrophy, hepatomegaly, poor feeding, macroglossia, failure to thrive, muscular weakness and respiratory difficulties. Affected children will have normal cognition. It is detectable on newborn screening; the diagnosis is then confirmed by the detection of reduced acid α-glucosidase enzyme activity or biallelic GAA pathogenic gene mutations. Other laboratory abnormalities include an elevated creatine kinase and abnormal urinary oligosaccharide levels.