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A full-term female baby born with an Apgar score of 10 exhibited a continual decrease in blood glucose and acid-base imbalance until she died at 40 h postpartum despite emergency rescue efforts. Autopsy showed a highly oedematous brain and a swollen liver. The cells of the myocardium, liver and kidney exhibited extensive microscopic vacuolar degeneration. The cardiac muscle and liver and kidney tissues were positive for Sudan III staining. Tandem mass spectrometry analysis revealed that the deceased was deficient in free carnitine, accompanied by an increase in multiple acylcarnitines. Genetic testing showed the parents of the deceased to be ETFDH mutation carriers, and the deceased carried a complex heterozygous mutation in ETFDH. Therefore, based on the results of autopsy, specific staining, genetic metabolic disease testing and genetic testing, we speculated that glutaric aciduria type IIc was the cause of death.

Disorders of amino acid metabolism lead to accumulations of amino acids that lead to toxicity to the developing central nervous system. Others are neuropharmacologic toxins. Phenylketonuria and disorders of biopterin metabolism cause hyperphenylalaninemic toxicity. Tyrosinemia leads to hepatic and renal disease. Organic acidemias such as propionic and methylmalonic lead to ketoacidosis. Glutaric aciduria type I leads to neurodegeneration, and macrocephaly. Maple Syrup urine disease leads to neonatal opisthotonus and seizures.

Objective Glutaric aciduria type 1 is a rare disease, with the estimated prevalence about 1 in 100,000 newborns. GCDH gene mutation can lead to glutaric acid and 3- OH glutaric acid accumulation, with clinical manifestation of neuronal damage, brain atrophy, microencephalic macrocephaly, decreased coordination of swallowing, poor muscle coordination, spasticity, and severe dystonic movement disorder. Case report A 22-year-old female, Gravida 4 Para 2, is pregnancy at 13 weeks of gestational age. Her first child is normal, however, the second child was diagnosed as glutaric aciduria type I after birth. She came to our hospital for prenatal genetic counselling of her fetus at 13 weeks of gestational age. We performed GCDH gene mutation analysis of maternal blood showed IVS 3 + 1 G > A heterozygous mutation, GCDH gene mutation analysis of paternal blood showed c. 1240 G > A heterozygous mutation, and the second child has compound heterozygous IVS 3 + 1 G > A and c. 1240 G > A mutations. Later, we performed amniocentesis at 16 weeks of gestational age for chromosome study and GCDH gene mutation analysis for the fetus. The fetal chromosome study showed normal karyotype, however, GCDH gene mutation analysis showed compound heterozygous IVS 3 + 1 G > A and c. 1240 G > A mutations. The couple decided to termination of pregnancy thereafter. Conclusion Glutaric acidemia type 1 is an autosomal recessive disorder because of pathogenic mutations in the GCDH gene. Early diagnosis and therapy of glutaric acidemia type 1 can reduce the risk of neuronal damage and acute dystonia. We report a case of prenatal diagnosis of fetal glutaric aciduria type 1 with rare compound heterozygous GCDH gene mutation at IVS 3 + 1 G > A and c. 1240 G > A mutations, which provide better genetic counselling for the couples.

Glutaric aciduria type I (GA-I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of l -lysine, l -hydroxylysine and l -tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine in body tissues. Neuropathophysiologic concepts involve disturbance of brain energy metabolism and neurotransmission. Untreated patients are at increased risk for striatal damage and consequent severe neurologic disease. Metabolic treatment is effective and improves neurologic outcome in early diagnosed individuals. Extrastriatal abnormalities frequently occur in all GA-I patients. Bilateral temporal fluid collections, most likely due to frontotemporal hypoplasia, are a characteristic neuroradiologic finding and have been classified (but rarely verified) as bilateral arachnoid cysts (AC). However, the true risk for development of bilateral AC in GA-I is still unknown.

Glutaric Aciduria type I (GA-I) is a rare organic acidemia, caused by mutations in the GCDH gene, and characterized by encephalopathic crises with neurological sequelae. We report herein a patient with GA-I who presented with severe acute renal failure requiring dialysis, following an acute diarrheal illness. Histopathological evaluation demonstrated acute tubular necrosis, and molecular diagnosis revealed the patient to be homozygous for a previously unreported mutation, p.E64D. As renal impairment is not part of the clinical spectrum typical to GA-I, possible associations of renal failure and the underlying inborn error of metabolism are discussed, including recent advancements made in the understanding of the renal transport of glutaric acid and its derivatives during metabolic disturbance in GA-I.

Glutaric aciduria type I (GA-1) results from an inherited defect in a common step of lysine, hydroxylysine and tryptophan metabolism. This defect is associated with an age-dependent susceptibility to encephalopathy commonly preceded by non-specific childhood illnesses or fasting. The brain injury that develops with encephalopathic crisis in GA-1 is anatomically and symptomatically similar to Huntington’s disease, affecting the striatum. The mechanism of injury remains poorly understood. Recently, an animal model of GA-1 encephalopathy was developed by providing GA-1 mice with added dietary lysine. This model shows age-dependent susceptibility similar to the human disease. Enhanced lysine accumulation and utilization in the immature brain correlates with increased glutaric acid levels and age-dependent susceptibility. Neurotransmitter and Krebs cycle intermediate depletion in this model represent novel findings toward uncovering the mechanism of neuronal injury. Additionally this mouse model is responsive to glucose analogous to human GA-1 and provides insight toward the mechanism of this effect. Together these findings led to a new treatment strategy of competing with brain lysine uptake that shows promising results. This research serves as a model for understanding blood brain barrier amino acid transport at critical stages of development and may help advance understanding of brain injury and development of treatments in other IEMs including urea cycle disorders.

Publisher Summary The inherited disorders of mitochondrial β-oxidation are a complex group of disorders. The criteria for the diagnosis of primary carnitine deficiency is proposed as (1) severe reduction of plasma or tissue-carnitine levels, (2) evidence that low carnitine levels impair fatty-acid oxidation, (3) correction of the disorder when carnitine levels are restored towards normal, and (4) absence of other primary defects in fatty-acid oxidation. Those associated with hypoglycemia can be distinguished from other causes of hypoglycemia by simple tests such as the measurement of the major metabolic fuels. However, the availability of sophisticated analytical methods such as tandem-mass spectrometry and gas chromatography–mass spectrometry has allowed the detection of disease-specific metabolites and patterns of metabolites in body fluids and tissue preparations. For some of the disorders direct enzyme measurement is necessary for precise diagnosis, supplemented by investigations at the gene level. Some of the mitochondrial β-oxidation disorders, however, are intractable to treatment such as the severe neonatal forms of glutaric aciduria type II.

We have analyzed the myocardial lipids of an infant with glutaric aciduria type II (GAII) who died from sudden cardiac failure and of five infants who died suddenly from indeterminate causes (sudden infant death syndrome, SIDS). Histology of the SIDS hearts was normal, but there was marked fatty deposition in the GAII heart. Fatty acid composition of myocardial lipids was determined by thin-layer chromatography-gas-liquid chromatography. Total lipid was elevated 20-fold in the GAII heart. Of total fatty acids, 75% was derived from phospholipids in SIDS heart and 89% from neutral lipids in GAII heart. Increased levels of free oleic acid and a 6-fold elevation in the (n-6)/(n-3) fatty acid ratio in phospholipid were noted in GAII heart compared to SIDS hearts.