OVERVIEW
Multiple acyl-CoA dehydrogenase deficiency (MACD) is an autosomal recessive genetic metabolic disease characterized by hypo- or non-ketotic hypoglycemia and metabolic acidosis. The main pathological changes are fatty degeneration of hepatocytes, renal tubular epithelial cells and cardiomyocytes. Clinical manifestations vary in severity, and some children have a better prognosis if detected at an early stage and treated appropriately.
Etiology
Due to the defective function of electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETF-QO), fatty acid β-oxidation metabolism is impaired, and there is energy deficiency and production of organic acid metabolism toxins, which cause multiple organ damage. organ damage. Hereditary ETF-QO or ETF defects result in glutaric acidemia type II, with ETF-QO defects being prevalent in patients with associated congenital malformations. The degree of enzyme deficiency is less severe in patients with mild or late-onset forms. A minority of patients with glutaric acidemia type II have normal ETF and ETF-QO activity, which may be associated with impaired flavin adenine dinucleotide biosynthesis or transport.
Symptoms
There are three types based on clinical features, namely, neonatal onset with congenital malformations, neonatal onset without congenital malformations, and mild and/or delayed onset. The first two types often have severe multiple acyl-coenzyme A dehydrogenation defects, while the latter have mild multiple acyl-coenzyme A dehydrogenation defects or ethylmalonic acid-adipic aciduria.1. Neonatal-onset with congenital malformations are most often preterm, with onset of the disease in the first few hours to 48 hours of life, with hypotonia, hepatomegaly, severe hypoglycemia, and metabolic acidosis. The children often have a peculiar “sweaty feet” odor similar to that of patients with isovaleric acidemia. Some children may have palpable enlarged kidneys or facial abnormalities (high forehead, low ear position, wide eye spacing, hypoplasia of the lower face, etc.). Most children die within 1 week of spring birth, and in some cases no malformations are seen on physical examination and only renal cysts are found at autopsy. Patients may have bowed feet, anterior abdominal muscle development defects, external genital abnormalities (hypospadias and painful penile erection).2. Neonatal onset without congenital malformationsPatients with neonatal onset of the disease often develop in the first few hours or days of life, with hypotonia, increased respiration, metabolic acidosis, hepatomegaly, hypoglycemia, and “sweaty feet”-like body odor. Some children who receive prompt diagnosis and treatment survive for a long time, but those with severe cardiomyopathy often die within a few months. In a few cases, hypoglycemia occurs in the neonatal period, followed by Reye syndrome-like symptoms, and the patient may survive for a long period of time.3. Patients with late-onset glutaric acidemia type II or ethylmalonic acid-adipic aciduria have a variable clinical picture. Patients may present with intermittent episodes of vomiting, hypoglycemia, and acidosis in the first few weeks of life, or they may be asymptomatic in childhood and develop episodes of vomiting, hypoglycemia, hepatomegaly, and proximal myopathy in adulthood. Other manifestations may include progressive lipid deposition myopathy, carnitine deficiency, or progressive extrapyramidal dyskinesia.
Examination
1. Routine examination In acute stage, there may be severe metabolic acidosis, accompanied by increased anionic intervals, mild to moderate hyperammonemia, severe hypoglycemia, often no ketosis or mild ketoacidosis, increased serum liver enzymes, myokinase, and prolonged prothrombin and partial thromboplastin time in severe patients. Serum lactate is usually increased. Cardiac enlargement is seen on chest X-ray, and hypertrophic cardiomyopathy is seen on ultrasound. Renal cysts can be seen on abdominal ultrasound or CT scan.2. Urinary organic acid analysis A variety of spectral patterns are possible, with increases in volatile short-chain organic acids (e.g., isovaleric acid, isobutyric acid, and 2-methylbutyric acid), glutaric acid, ethylmalonic acid, 3-hydroxyisovaleric acid, 2-hydroxyglutaric acid, 5-hydroxyhexanoic acid, hexanedioic acid, octanedioic acid, sebacic acid, dodecanedioic acid, isovalerylglycine, and 2-methylbutyrylglycine.3,4 Urinary organic acid analysis is usually performed with an increase in the amount of 3-hydroxypropanoic acid. Urine has only small or undetectable amounts of 3-hydroxybutyric acid and acetoacetic acid. In some cases, especially those with only intermittent onset of the disease, urinary organic acid analysis is abnormal only in the acute phase.3. Amino acid analysis reveals total amino acidemia and total amino aciduria, and blood proline and hydroxyproline are markedly elevated in those with neonatal onset of the disease, whereas patients with delayed onset of the disease often have elevated serum and urinary sarcosine.4. Blood Carnitine Spectrum The free carnitine may be normal or reduced, and the free carnitine may be normal or reduced, with acetylcarnitine, isobutyrylcarnitine, isopentanoylcarnitine Acetylcarnitine, acetylcarnitine, butyrylcarnitine, and propionylcarnitine are increased to varying degrees.5. Urinary carnitine profile Urinary esterified carnitine is significantly increased in the acute phase of the disease, and a large amount of acylcarnitine is excreted in the urine after oral leucovorin.6. Genetic analysis Mutations in two alleles encoding the subunits of the ETF-QO, ETFa, and ETFb are diagnostic value.
Diagnosis
The clinical diagnosis of glutaric acidemia type II is difficult and relies on laboratory tests to make a definitive diagnosis.1. Urinary organic acid, blood fatty acid, and blood acylcarnitine profiles are analyzed. Typical organic aciduria can be detected only during episodes of the disease, and may be normal during intervals. Therefore, urine gas chromatography mass spectrometry should be performed as early as possible and repeatedly several times for patients with high suspicion of the disease, and the diagnosis cannot be easily affirmed or denied.2. Muscle or liver pathology, which reveals the accumulation of fat.3. Genetic analysis, which can clarify the diagnosis.
Treatment
Glutaric acidemia type II early-onset patients with vitamin B2 are mostly unresponsive and require a low-fat, low-protein diet and the administration of leucovorin, and oral benzofibrate is effective in some patients. Mild or late-onset patients are mostly vitamin B2 effective and are better treated with oral vitamin B2, leucovorin, and a low-fat diet.
Prognosis
Patients with neonatal onset of the disease have a poor prognosis and most often die in the first few days or months of life, while patients with the vitamin B2-effective form have a favorable prognosis.
Prevention
1. Parents and siblings of patients should undergo genetic analysis, genetic counseling, and prenatal diagnosis through fetal genetic analysis when parents have another child. 2. Newborn screening: some patients can be detected through analysis of amino acid and acylcarnitine profiles of heel blood, and patients with glutaric acidemia II can be detected during asymptomatic period or early stage of the disease, so as to intervene in early stage, to avoid the onset of the disease, to protect the organs, and to reduce the deaths and disabilities.