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A Term Newborn with Respiratory Distress, Acidosis, and Hypoglycemia.

Clinical History and Background

A term newborn developed respiratory distress shortly after birth. The pregnancy was notable for intrauterine growth restriction and oligohydramnios. Fetal ultrasound performed at 30-weeks gestation showed enlarged kidneys and an echogenic focus in the left cardiac ventricle. On day 2 of life, the child was admitted with metabolic acidosis (total C[O.sub.2] = 12 mmol/L; reference interval: 18-28 mmol/L), hypoglycemia (plasma glucose = 38 mg/dL; reference interval: 63-90 mg/dL), hyperbilirubinemia (direct bilirubin = 0.5 mg/dL; reference interval: <0.3 mg/dL) and hyperammonemia (plasma ammonia = 230 [micro]mol/L; reference interval: <100 [micro]mol/L). Urine was negative for ketones by dipstick. Physical examination showed an infant with growth restriction and facial dysmorphism with midface hypoplasia, broad nasal root, and flat philtrum. Additionally, a strong odor, described as "sweaty feet" was noted. A urine sample was collected for organic acid analysis using GC-MS. The chromatogram is shown in Fig. 1.

Diagnosis and Summary

This infant has an autosomal recessive disorder described as multiple acyl-CoA dehydrogenase deficiency (MADD).3 The underlying defect is a deficiency of 2 flavoproteins: electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETF-QO). Several dehydrogenases transfer electrons to ETF, which transfer to ETF-QO and ultimately to coenzyme Q within the respiratory chain. MADD is classified into 3 groups based on clinical phenotype: (a) neonatal form with congenital anomalies; (b) neonatal form without anomalies; and (c) mild form characterized by ethylmalonicadipic aciduria. This report describes a neonatal presentation with congenital anomalies, metabolic acidosis, and hypoketotic hypoglycemia.

The phenotype is caused by impaired activities of several dehydrogenases involved in the oxidation of fatty acids and several amino acids. Metabolic acidosis is a key feature due to the production of lactic and glutaric acids, and hypoketotic hypoglycemia due to impaired [beta]-oxidation and ketogenesis. The organic acid chromatogram (Fig. 1) is notable for lactic and glutaric acid peaks, secondary to diminished perfusion and defective glutaryl-CoA dehydrogenase activities, respectively. MADD was initially referred to as glutaric aciduria type II (GA II) to distinguish it from glutaric aciduria type I (GA I). In contrast to GA I, MADD is associated with 2-hydroxyglutaric acid production, caused by defective D-2-hydroxyglutaric acid dehydrogenase (D-2-HGDH) activity (1).

Ethylmalonic acid is observed due to defective butyryl-CoA dehydrogenase activity. This results in the accumulation of butyryl-CoA, which is converted to ethylmalonyl-CoA (by propionyl-CoA carboxylase) and hydrolyzed to ethylmalonic acid. The presence of a [C.sub.6]-[C.sub.10] dicarboxylic aciduria (adipic, sebacic, and suberic acids) is also prominent due to increased [omega]-oxidation of fatty acids. Defects in isovaleryl-CoA, 2 methylbutyryl-CoA, and hexanoyl-CoA dehydrogenases cause accumulation of their respective CoA esters, which conjugate with glycine to form

isovalerylglycine, 2-methylbutyrylglycine, and hexanoylglycine, respectively (Fig. 2). The production of isovaleric acid is occasionally observed, causing the strong odor. In this case, 4-hydroxyphenolic acids (4-hydroxyphenyllactic and 4-hydroxyphenylpyruvic acids) were also present, reflecting hepatic dysfunction.

Despite the provision of bicarbonate boluses, the acidosis was unresponsive and the child died of cardio-pulmonary complications on day 3 of life. The major findings at autopsy included growth restriction, cardiomegaly, pulmonary hypoplasia with hyaline membrane formation, and renal cystic dysplasia (primarily at the microscopic level). The findings in the brain included focal minimal parasagittal and parietal pachygyria, glioneuronal heterotopias, neuronal migrational abnormalities, hypomyelination of central white matter, and mineralizing lenticulostriate vasculopathy with focal gliosis in basal ganglia and thalamus. Extensive cytoplasmic lipid (confirmed by oil red O stains of cryostat sections) was present in cardiomyocytes, skeletal muscle cells, hepatocytes, and renal proximal tubular epithelial cells.

MADD is detected in newborn screening by increased C4, C5, C5-DC, C6, C8, C12, C14, and C16 acylcarnitines (see abbreviation list) on tandem mass spectrometry. In this case, newborn screening results were unavailable at the time of presentation. MADD may be caused by mutations in the electron transfer flavoprotein alpha subunit (ETFA), [4] electron transfer flavoprotein beta subunit (ETFB), or electron transfer flavoprotein dehydrogenase (ETFDH) genes. In this case, molecular analysis demonstrated 2 disease-causing mutations in the ETFDH gene, c.121C>T and c.1647_1648delCT. The early-presenting form of MADD is a devastating disorder with extremely poor outcomes and no available treatment.

Reproduced with permission from Roy Peake, PhD.

Author Contributions: AH authors confirmed they have contributed to the intellectual content of this paper and have met the following3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis 2012;35: 571-87.

Roy W.A. Peake [1] * and Harry P.W. Kozakewich [2]

Departments of [1] Laboratory Medicine and [2] Pathology, Boston Children's Hospital, Boston, MA.

* Address correspondence to this author at: Boston Children's Hospital, 300 Longwood Ave., Boston, MA02115. E-mail

Received September 20,2016; accepted October 18,2016.

DOI: 10.1373/clinchem.2016.267328

[3] Nonstandard abbreviations: MADD, multiple acyl-CoA dehydrogenase deficiency; ETF, electron transfer flavoprotein; ETF:QO, ETF dehydrogenase; GA II, glutaric aciduria type II; GAI, glutaric aciduria type I; D-2-HGDH, D-2-hydroxyglutaric acid dehydrogenase; C4, butyrylcarnitine; C5, 2-methylbutyrylcarnitine; C5-DC, glutarylcarnitine; C6, hexanoylcarnitine; C8, octanoylcarnitine; C12, dodecanoylcarnitine; C14, myristoylcarnitine; C16, palmitoylcarnitine.

[4] Human genes: ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETFDH, electron transfer flavoprotein dehydrogenase.

Caption: Fig. 1. Organic acid analysis of patient urine by use of GC-MS. Urine organic acids were extracted into ethyl acetate/ether and converted to trimethylsilyl derivatives prior to analysis using a GC 6890N/MS 5975 system equipped with a DB-1 column (Agilent). IS, internal standard.

Caption: Fig. 2. Some of the defective pathways in multiple acyl-CoA dehydrogenase deficiency. VLCAD, very-long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; SCADD, short-chain acyl-CoA dehydrogenase; TCA, tricarboxylic acid.
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Title Annotation:the Clinical Chemist: Genetic Metabolic Series
Author:Peake, Roy W.A.; Kozakewich, Harry P.W.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Feb 1, 2017
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