Two Uneventful Pregnancies in a Woman with Glutaric Aciduria Type 1

Abstract

Glutaric aciduria type 1 (GA1) is an autosomal recessive rare disorder caused by mutations in the GCDH gene resulting in deficiency of glutaryl-CoA dehydrogenase, leading to accumulation of the amino acids lysine, hydroxylysine and tryptophan and other metabolites. The phenotypic spectrum of disease is broad. Stress caused by infection and fever and possibly pregnancy may lead to worsening of the signs and symptoms, often with uncertain recovery.We describe a case of a female patient with GA1 who had two clinically uneventful pregnancies.At the age of 11 she was diagnosed with GA1 by family screening. The cultured skin fibroblast showed reduced glutaryl-CoA dehydrogenase activity (0.16 mg protein per min).The initial diagnostic urine glutaric acid level for this patient was 1,784 μmol/mmol creatinine. Mutation analysis showed compound heterozygosity for the p.(Gly185Arg), c.553G>A in exon 7 and p.(Arg402Trp), c.1204C.T in exon 11 mutations of the GCDH.Her pregnancy at the age of 23 was complicated by pre-eclampsia and required treatment with beta-blockers. Four years later the second pregnancy was uncomplicated. The management plan during the caesarean section included intravenous dextrose and lipid infusions. The patient rapidly recovered from both surgeries.Both babies have had normal development to date. On newborn screening, plasma acylcarnitine showed a transient increase in glutarylcarnitine, and the urine organic acid analysis showed a trace of 3-hydroxyglutarylcarnitine, likely to be of maternal transfer.The multidisciplinary team, consisting of metabolic, dietetic and obstetric care providers, have responsibility to ensure the risk of acute decompensation in pregnant GA1 women is minimal.

Metabolic Serendipities of Expanded Newborn Screening

“…Maternal GA-1, in contrast to other metabolic disorders, does not seem to affect the health of the fetus, though it is not known if fetal maturation could be influenced by low levels of maternal carnitine [ 15 , 19 ]. The phenotypic spectrum of GA-1 is broad, ranging from severely affected individuals to asymptomatic adults [ 20 , 21 ].…”

Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin‐1‐deficient patients

“…Despite our intensive treatment of episodes of acute RM or at‐risk situations, 3 the mortality rate among patients with lipin‐1 deficiency was high (as emphasized by P7's death in 2016). Most deaths were due to arrhythmia, 3–5 which was probably related to hyperkalaemia and/or cardiac dysfunction. Indeed, lipin‐1 has specific roles in cardiac lipid metabolism 6–8 .…”

“…LPIN1 mutations are associated with a poor prognosis, despite aggressive management in the intensive care unit (ICU). The complications of RM include cardiac arrhythmia (due to hyperkalaemia) and kidney failure 2–5 . The cardiac complications are possibly linked to lipin‐1's specific regulation of the heart's lipid metabolism and contractile function in response to hemodynamic stress 6–8 .…”

Organic Aciduria Disorders in Pregnancy: An Overview of Metabolic Considerations

“…There are no consensus guidelines for dietary management during pregnancy or breastfeeding. The physiological changes of pregnancy and the catabolism associated with labour and delivery can impose the risk of a neurological 'crisis' in GA1 [58]. Therefore, the vulnerable stages of pregnancy may also necessitate this treatment to minimise catabolic stress and prevent neurological crises.…”

“…There are a number of successful pregnancies reported in GA1 [58,60] (Table 6). The outcomes of three pregnancies involving two women who had undiagnosed GA 1 were reported in 2007.…”