Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing

Abstract

BackgroundUrea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile.ResultsWe present data from two major metabolic centres in India, including 123 cases of various UCDs. The majority of them (72/123, 58%) presented in the neonatal period (before 30 days of age) with 88% on or before day 7 of life (classical presentation), and had a high mortality (64/72, 88%). Citrullinemia type 1 was the most common UCD, observed in 61/123 patients. Ornithine transcarbamylase (OTC) deficiency was the next most common, seen in 24 cases. Argininosuccinic aciduria was diagnosed in 20 cases. Deficiencies of arginase, N-acetylglutamate synthase, carbamoyl phosphate synthetase, citrin, and lysinuric protein intolerance were also observed.Molecular genetic analysis revealed two common ASS1 mutations: c.470G > A (p.Arg157His) and c.1168G > A (p.Gly390Arg) (36 of 55 tested patients). In addition, few recurrent point mutations in ASL gene, and a deletion of the whole OTC gene were also noted. A total of 24 novel mutations were observed in the various genes studied. We observed a poor clinical outcome with an overall all time mortality of 63% (70/110 cases with a known follow-up), and disability in 70% (28/40) among the survivors. Prenatal diagnosis was performed in 30 pregnancies in 25 families, including one pre-implantation genetic diagnosis.ConclusionsWe report the occurrence of UCDs in India and the spectrum that may be different from the rest of the world. Citrullinemia type 1 was the most common UCD observed in the cohort. Increasing awareness amongst clinicians will improve outcomes through early diagnosis and timely treatment. Genetic diagnosis in the proband will enable prenatal/pre-implantation diagnosis in subsequent pregnancies.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0908-1) contains supplementary material, which is available to authorized users.

Investigating the Metabolic Model in Preterm Neonates by Tandem Mass Spectrometry: A Cohort Study

“…Low level of Ornithine could reduce the efficiency of urea cycle and cause the accumulation of ammonia. The urea cycle disorders have a wide range of symptoms, including nausea and vomiting, loss of appetite, liver premature, mental retardation, and so on [43][44][45]. The OR = 0.554 of Ornithine indicated preterm neonates might have a low level of Ornithine, which might adversely affect the growth and development.…”

Considering Proximal Urea Cycle Disorders in Expanded Newborn Screening

“…Genetic testing is available in clinical laboratories for suspected PUCD patients and will also be helpful for recurrence-risk assessments for carrier identification, prenatal diagnosis, and genetic counseling [ 15 , 16 ]. Currently molecular sequencing and/or multiplex ligation-dependent probe amplification for deletion and duplication detection will identify most CPS1D and NAGSD but is limited to approximately 80% of the mutations in OTCD [ 15 , 16 , 29 ].…”

“…Measurement of enzyme activity from liver or intestinal mucosa biopsy is recommended if the metabolite pattern or genetic testing is non-informative or inconclusive or may be reserved for research [ 30 ]. While molecular confirmation may not be possible with current technology for less than 20% of OTCD patients [ 6 , 29 ], ongoing research into deep genomic sequencing may resolve this.…”

Identification of rare variants causing urea cycle disorders: A clinical, genetic, and biophysical study

“…With respect to the genetic counselling on future pregnancies of these affected family, what needs attention is that the siblings of I‐1, II‐1, III‐1 and V‐1 will have a 25% risk of being affected, so reproductive options such as prenatal diagnosis or pre‐implantation diagnosis (with in‐vitro fertilization, IVF) are recommended, which also applies to case IV 40,41 . As a matter of fact, families I, III and V have made it clear that IVF approach will be considered.…”