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Introduction

Clinically, based on the age at the onset, type, and severity of the symptoms, three types can be distinguished:

  • MADD Type I: Neonatal onset with congenital anomalies

  • MADD Type II: Neonatal onset without congenital anomalies (ethylmalonic-adipic aciduria)

  • MADD Type III: Relatively milder and later onset

Based on the underlying genetic defect (see below), MADD can also be classified as:

  • Glutaric Aciduria Type IIA

  • Glutaric Aciduria Type IIB

  • Glutaric Aciduria Type IIC

However, while the different genotypes are phenotypically non-distinguishable from each other, the residual activity of the affected enzymes (ETFA, ETFB, and ETFDH, see below) seems to correlate with the clinical picture. No activity at all causes congenital anomalies resulting in a MADD Type I disease. Even minimal activity of ETF or ETFDH seems to be sufficient to prevent congenital anomalies giving rise to MADD Type II and even higher activity levels result in Type III.

Incidence

Unknown, although estimates put it in the range of 1 in 20,000 newborns.

Genetic inheritance

MADD is an inborn error in amino- and fatty-acid and choline metabolism with autosomal recessive inheritance that is caused by defects in either one of the electron transfer flavoproteins (ETFA and ETFB) or ETF dehydrogenase (ETFDH, also known as ETF-ubiquinone oxidoreductase). MADD can be caused by defects in any of the three ETF genes with ETFA (Electron Transfer Flavoprotein, Alpha Polypeptide; mapped to chromosome 15q24.2-q24.3), ETFB (Electron Transfer Flavoprotein, Beta Polypeptide; mapped to chromosome 19q13.41), and ETFDH (Electron Transfer Flavoprotein Dehydrogenase; mapped to chromosome 4q32.1) leading to Glutaric Acidemia (GA) IIA, IIB, and IIC, respectively.

Pathophysiology

ETF forms a heterodimer located in the mitochondrial matrix and consists of α- (ETFA) and β-subunits (ETFB) and one flavin adenine dinucleotide (FAD) and one adenosine monophosphate (AMP) per heterodimer as a redox cofactor. ETF receives electrons from β-oxidation of acyl-CoAs. In contrast, ETFDH (ETF-ubiquinone oxidoreductase or ETFC) is a monomer located in the inner mitochondrial membrane and contains one molecule of FAD and 4Fe-4S cluster as redox prosthetic groups. ETFDH transfers electrons from ETF to ubiquinone, which is also located in the inner mitochondrial membrane and is involved in the electron transport chain to produce ATP. Both, ETF and ETFDH are required for the transfer of electrons from several other mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Deficiency of ETF or ETFDH functionally inhibits β-oxidation of acyl-CoA and leads to accumulation of medium- and long-chain fatty acids in tissues and plasma, and urinary excretion of organic acids (eg, isovaleric, isobutyric, glutaric, ethylmalonic, dicarboxylic, and 2-hydroxyglutaric acids).

MADD Type I is characterized by severe hypoketotic (or nonketotic) hypoglycemia, metabolic acidosis, hypotonia, fatty infiltration of the liver, heart, and kidneys resulting in hepatomegaly, heart disease, typical “sweaty feet” odor, and excretion of large amounts of fatty- and amino ...

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