Scientific Background
Autosomal recessive inherited conditions of fatty acid oxidation include carnitine cycle defects, medium-chain, long-chain 3-hydroxy and very long-chain acyl CoA dehydrogenase deficiency (MCADD, LCHADD, VLCADD). Multiple acyl-CoA dehydrogenase deficiency (MADD), a condition of electron transfer, is also included. MCADD, LCHADD and VLCADD are part of newborn screening, while MADD is currently not included in Germany.
Congenital conditions of mitochondrial fatty acid oxidation or electron transfer, manifest themselves particularly during periods of fasting. MCADD, LCHADD, VLCADD or MADD are seen in most patients from infancy to early childhood and can include symptoms such as vomiting, lethargy, muscular hypotension and hypoglycemia. Cardiac involvement is common. Acute episodes associated with MCADD, LCHADD or VLCADD can be triggered by fasting or by illnesses such as viral infections. This disease spectrum is sometimes confused with Reye syndrome, a serious illness that can develop in children when they are exposed to viral infections such as chickenpox or influenza. Most cases of Reye syndrome are related to the use of aspirin during a viral infection.
Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
MCADD is an autosomal recessive inherited disorder of the ß-oxidation of fatty acids. A study of over 930,000 newborns in the United States found an incidence of 1:15,000 and previous estimates for the Caucasian population are in the same range. It is probably the most common of all fatty acid metabolism disorders. The disease is characterized by intolerance to periods of fasting. Homozygous carriers often become ill in infancy after periods of fasting due to viral infections. They typically suffer from repeated vomiting, hypoketotic hypoglycemia, and are lethargic, which varies in severity up to coma. In rare cases, the disease can lead to sudden infant death. A biochemical diagnosis can be made by analyzing acetylcarnithine in the blood. Today, MCADD is usually detected by tandem mass spectrometry during neonatal screening.
MCADD is caused by pathogenic variants in the medium-chain acyl-CoA dehydrogenase gene (ACADM). The most common causative variant is in exon 11 and leads to a substitution of lysine with glutamic acid at amino acid position 329 in the protein. It is detectable in about 90% of alleles of patients with MCADD. In most patients, this variant is homozygous, while in about 1/5 of the patients it is combined heterozygous with another variant. Patients with MCADD have a very good prognosis if fasting is strictly avoided by having regular meals.
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)
Autosomal recessive inherited LCHADD is caused by an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme in the trifunctional protein complex (TFP). TFP is a heterooctamer consisting of 4 alpha and 4 beta subunits, which catalyzes three steps in the mitochondrial beta-oxidation of fatty acids. The enzyme deficiency is caused by pathogenic variants in the HADHA and HADHB genes, which code for the alpha and beta subunits of the TFP. Most patients of European origin carry the variant c.1528G>C [p.(Glu510Gln)] in exon 15 in homozygous form, which is located on the catalytic site of the LCHAD domain of the TFP alpha-subunit.
The prevalence in newborns is approximately 1:170,000. The prognosis has improved with early detection and current treatment methods, and patients with LCHADD now reach adulthood more often. Treatment involves adjusting dietary fat intake with a reduction in long-chain fatty acids.
Very long chain acyl-CoA dehydrogenase deficiency (VLCADD)
The ACADVL gene codes for the enzyme very long-chain acyl-CoA dehydrogenase, which is necessary for the metabolism of very long-chain fatty acids (e.g., the oleic acid in olive oil). Without sufficient amounts of this enzyme, the very long-chain fatty acids are not properly metabolized and consequently not converted into energy. This can lead to the characteristic signs and symptoms of the disease, such as lethargy and hypoglycemia. The very long-chain fatty acids or their metabolites, which are only partially broken down, can accumulate in tissues such as the heart, liver and muscles, causing damage.
Clinically, VLCADD is very heterogeneous, but can be divided into three forms. In the severe infantile form, which has an onset between the neonatal period and the first year of life, the high mortality rate is often caused by hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy and cardiac arrhythmia. Hypoketotic hypoglycemia is also the leading symptom of the moderately severe infantile/infantile form, which has an age of onset between the early neonatal period and early childhood. The late-onset myopathic form manifests in older children from 10 years of age and young adults, and only the muscles are affected. Symptoms of myopathic VLCADD are myalgia, rhabdomyolysis, stress intolerance or myoglobinuria. Periods of fasting, physical strain, stress, and cold or heat are triggering factors and should be avoided.
Although VLACDD can be lethal, the prognosis has improved for all phenotypes as newborn screening has led to improved treatment outcomes. Milder forms have a much more favorable prognosis if the treatment plans are adhered to. In Germany, the prevalence of VLCADD is about 1:50,000.
Multiple acyl-CoA dehydrogenase deficiency (MADD) / glutaric aciduria type IIA, IIB, IIC
Glutaraciduria type II is caused by pathogenic variants in the ETFA (type IIA), ETFB (type IIB) and ETFDH (type IIC) genes, which code for the alpha and beta subunits of the electron transfer flavoprotein (ETF) and the ETF coenzyme Q oxidoreductase. A functional disturbance of one of these two flavoproteins leads to impaired fatty acid oxidation. Patients with MADD can be divided clinically into three broad forms:
- Neonatal onset with congenital anomalies. Often premature births with severe non-ketotic hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis within the first 24 hours of life, as well as facultative malformations (dysplastic kidneys with multiple cysts, brain malformations), facial dysmorphia (deep-seated, backward rotated ears, high forehead, hypoplastic midface), prominent calcaneus, and abnormalities of the external genitals. The patients usually die in the first week of life.
- Neonatal onset without congenital anomalies. Onset is usually in the first two days of life with hypotonia, hypoketotic hypoglycemia, hepatomegaly, metabolic acidosis and leukencephalopathy. Most patients die within the first week of life; those patients who live to be several months old usually die of severe cardiomyopathy.
- Mild and/or late-onset MADD. These patients have a more favorable prognosis and show a broad clinical spectrum of disease that is characterized in the first months of life by intermittent episodes of vomiting, metabolic ketoacidosis, and hypoketotic hypoglycemia, with or without cardiac involvement, and in adolescents and adults by acute Reye-like disease with ketoacidosis and lipid storage myopathy. The latter often respond to riboflavin and have a better prognosis. Treatment involves carbohydrate-rich nutrition and ß-hydroxybutyrate in crises.
References
Janeiro et al. 2019, Eur J Pediatr. 178:387 / Vishwanath 2016, Ann Neurosci 23:51 / Lee et Scaglia 2015, Inborn errors of metabolism, Oxford University Press / Polinati et al. 2015, Invest Ophthalmol Vis Sci 56:3371 / Matern et al. 2015, GeneReviews® [Internet], https://www.ncbi.nlm.nih.gov/books/NBK1424/ / Hoffmann et al. 2014, Pädiatrie: Grundlagen und Praxis 4. Auflage Band 1, Springer Verlag Berlin Heidelberg
