New and known mutations associated with inborn errors of metabolism in a heterogeneous Middle Eastern population (original) (raw)
Related papers
Genetic Testing and Molecular Biomarkers, 2012
Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders.
Sultan Qaboos University Medical Journal, 2014
Objectives: This study aimed to determine the mutation spectrum and prevalence of inborn errors of metabolism (IEM) among Emiratis. Methods: The reported mutation spectrum included all patients who were diagnosed with IEM (excluding those with lysosomal storage diseases [LSD]) at Tawam Hospital Metabolic Center in Abu Dhabi, United Arab Emirates, between January 1995 and May 2013. Disease prevalence (per 100,000 live births) was estimated from data available for 1995-2011. Results: In 189 patients, 57 distinct IEM were diagnosed, of which 20 (35%) entities were previously reported LSD (65 patients with 39 mutations), with a birth prevalence of 26.87/100,000. This study investigated the remaining 37 (65%) patients with other IEM (124 patients with 62 mutations). Mutation analysis was performed on 108 (87%) of the 124 patients. Five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. The remaining 103 (95%) patients had homozygous mutations. As of this study, 29 (47%) of the mutations have been reported only in Emiratis. Two mutations were found in three tribes (biotinidase deficiency [BTD, c.1330G>C] and phenylketonuria [PAH, c.168+5G>C]). Two mutations were found in two tribes (isovaleric aciduria [IVD, c.1184G>A] and propionic aciduria [PCCB, c.990dupT]). The remaining 58 (94%) mutations were each found in individual tribes. The prevalence was 48.37/100,000. The most prevalent diseases (2.2-4.9/100,000) were biotinidase deficiency; tyrosinemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia, and mitochondrial deoxyribonucleic acid depletion. Conclusion: The IEM birth prevalence (LSD and non-LSD) was 75.24/100,000. These results justify implementing prevention programmes that incorporate genetic counselling and screening.
Frontiers in Genetics, 2022
Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.
Annals of Saudi Medicine, 2010
I nborn errors of metabolism (IEM) can be classified according to the size of accumulated or deficient metabolites into small-molecule disorders such as aminoacidemia, organic acidopathies, urea cycle defect, galactosemia, fatty acid oxidation disorders, and other disorders such as glycogen and lysosomal storage and organelle diseases. 1 Despite an increased understanding of their pathogenesis and prevalence, no uniform consensus on screening for these disorders has been established to date. 2,3 Furthermore, the outcome of these disorders remains highly variable even with early diagnosis. In countries where consanguinity rates are high, offspring can inherit 1/4 to 1/8 of their genes from a common ancestor, leading to an increased incidence of inherited disorders. The inbreeding coefficient factor ranges from 0.
Cureus
Inborn errors of metabolism (IEM) form a large group of genetic diseases involving defects in genes coding for enzymes, receptors, and cofactors in the metabolic pathways of small and large molecules. The present study is the comprehensive data analysis of the tandem mass spectrometry (TMS) and urine metabolic pattern for the diagnosis of IEMs by gas chromatography and mass spectrometry (GC/MS) in samples received for high-risk IEM screening. Methods We conducted a retrospective analysis of children diagnosed with IEMs presenting at the genetic clinic of Mahatma Gandhi Missions (MGM) Medical College, Aurangabad. This article summarizes retrospective data of 40 pediatric cases over a three-year period, diagnosed with small molecule IEM based on the standard testing criteria. Results Out of 40, 17 patients (42.5%) were found to have organic acidemias, four (10%) had fatty acid oxidation defects, six (15%) had disorders of aminoacidopathies, seven (17.5%) had mitochondrial diseases, and three (7.5%) had urea cycle defects. One patient in each group (2.5% each) had carbohydrate metabolism defects, purine metabolic defects, and neurotransmitter metabolic defects. Conclusions This clinico-etiological profile study has thrown light on the clinical features and natural course of many common and rare IEMs, and it may provide clinicians with a deeper understanding of these conditions, allowing for improved early diagnosis and treatment of these diseases. Because of the high degree of consanguinity and marriages in the same community, common as well as many rare inherited metabolic diseases were diagnosed and novel genetic variants were identified.
Inherited metabolic disorders in a cohort of Egyptian children
Egyptian Liver Journal, 2022
Background Inborn errors of metabolism (IEMs) represent a special challenge in pediatric practice. Despite the unquestionable clinical significance of newborn screening, it just offers a snapshot of an extremely minor subgroup of metabolic disorders. So, it is crucial to use multiple techniques for accurate diagnosis of a wider spectrum of IEMs early in infancy to prevent overwhelming irreversible neurological complications in a cohort of high-risk Egyptian pediatrics. This study included four thousand and eighty suspected IEMs patients. They were referred to the Chromatography Unit, Clinical Biochemistry and Molecular Diagnostics Laboratories, National Liver Institute (NLI) for laboratory assessment in the period from March 2016 to November 2020. Separation of amino acids and acylcarnitines using tandem mass spectrometry (LC/MS) and organic acids using gas chromatography mass spectrometry (GC/MS) was done. Results Three hundred and twenty (320/4080, 7.8%) patients were diagnosed wi...
Spectrum of inherited metabolic disorders in Malaysia
Annals of the Academy of Medicine, Singapore, 2008
Issues pertaining to the diagnosis and management of inborn errors of metabolism (IEM) in Malaysia included low awareness of atypical and variable presentations in IEMs leading to delayed diagnosis or treatment, absence of reliable population data on IEMs and involvement of multiple siblings in the same family due to consanguinity. The importance of careful family history taking and genetic counselling are emphasised. Selected testing of ill infants and children for IEM yielded a positive 2% (264/13,500) results for IEMs in Malaysia. Out of the 264 patients, the spectrum of IEMs in Malaysia included organic acidurias (98), aminoacidopathies (78), urea cycle defects (54), neurotransmitter conditions (12) and lysosomal disorders, mainly mucopolysaccharidosis (14). Confirmatory studies of IEMs are an important aspect of management of IEMs. There is a need for more metabolic specialists and funding for diagnosis and treatment of IEMs in Malaysia. Long-term care issues and cost-effective...
Identification of Clinical Variants beyond the Exome in Inborn Errors of Metabolism
International Journal of Molecular Sciences
Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes’ e...
Molecular Genetics and Metabolism Reports, 2020
Traditionally thought of as a pediatric diagnostic and therapeutic dilemma, the diagnostic rate and spectrum of inborn errors of metabolism (IEM) in the adult population is largely unknown. A retrospective chart review of patients seen by the Michigan Medicine Adult Medical Genetics Clinic for clinical evaluation from 2014 to 2018 was conducted. Patients referred for a primary indication possibly consistent with an IEM were considered. Variables included age at genetic evaluation, symptom onset age, sex, clinical course, organ systems involved, developmental history, family history and prior genetic testing. Of patients evaluated during the study period, 112 were referred for an indication possibly consistent with an IEM and underwent a complete biochemical workup with an IEM diagnostic rate of 9.8% achieved. An additional 9.8% were diagnosed with a non-IEM genetic diagnosis. Management changes were implemented in all IEM diagnoses. Metabolic disorders in the adult population are under-recognized and under-diagnosed. This report demonstrates the need for clinicians to consider these diagnoses in adults and either refer to a genetics clinic or initiate a biochemical workup. As advances in diagnosis, treatment, and life expectancy of patients with IEMs increases, recognizing and diagnosing these conditions can significantly impact care.