Partial N-acetyl glutamate synthase deficiency presenting as postpartum hyperammonemia: Diagnosis and subsequent pregnancy management.

N-acetyl glutamate synthase (NAGS) deficiency (OMIM #: 237310) is a rare urea cycle disorder that usually presents early in life with hyperammonemia. NAGS catalyzes the synthesis of N-acetyl glutamate (NAG) which functions as an activator of the carbamoyl phosphate synthetase-1 mediated conversion of ammonia to carbamoyl phosphate. The absence of NAG results in a proximal urea cycle disorder which can result in severe neurologic sequelae secondary to hyperammonemia and even death. Unlike the other urea cycle disorders, a specific pharmacological treatment for NAGS deficiency exists in the form of carglumic acid, an analog of NAG. Here we present a 29-year-old previously healthy female who presented with hyperammonemia and obtundation just after the birth of her first child. Exome sequencing revealed two novel variants in the NAGS gene, and plasma metabolomics revealed extremely low levels of NAG. Carglumic acid treatment led to prompt resolution of her biochemical abnormalities and symptoms. She tolerated two subsequent pregnancies, 2 years and 6 years after her initial presentation, while taking carglumic acid, and breastfed her third child, all without complications in the mother or children. This case report emphasizes the importance of considering urea cycle disorders in previously-healthy adults presenting with neurological symptoms during periods of metabolic stress, including the postpartum period. It also highlights the efficacious and safe use of carglumic acid during pregnancy and while breastfeeding.

Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol-cytochrome c reductase, are particularly rare in humans. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Implementation and obstacles of pharmacogenetics in clinical practice: An international survey.

AIMS: Eight years ago, a paper-based survey was administered during the World Pharma 2010 meeting, asking about the challenges of implementing pharmacogenetics (PGx) in clinical practice. The data collected at the time gave an idea about the progress of this implementation and what still needs to be done. Since then, although there have been major initiatives to push PGx forward, PGx clinical implementation may still be facing different challenges in different parts of the world. Our aim was therefore to distribute a follow-up international survey in electronic format to elucidate an overview on the current stage of implementation, acceptance and challenges of PGx in academic institutions around the world. METHODS: This is an online anonymous LimeSurvey-based study launched on 11 November 2018. Survey questions were adapted from the initially published manuscript in 2010. An extensive web search for worldwide scientists potentially involved in PGx research resulted in a total of 1973 names. Countries were grouped based on the Human Development Index. RESULTS: There were 204 respondents from 43 countries. Despite the wide availability of PGx tests, the consistently positive attitude towards their applications and advances in the field, progress of the clinical implementation of PGx still faces many challenges all around the globe. CONCLUSIONS: Clinical implementation of PGx started over a decade ago but there is a gap in progress around the globe and discrepancies between the challenges reported by different countries, despite some challenges being universal. Further studies on ways to overcome these challenges are warranted.