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Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Among mutations observed [9, 11], F188, a 3-bp inframe deletion in a sequence of four consecutive TTC phenylalanine codons encodes an unstable functionless protein. This mutation was found in nine of ten French-Canadian homozygotes and one heterozygote. E180K encodes a stable properly targeted protein and results from a G to A transition at bp 538. This mutation was found in the patient's Irish-American father, but not in his Japanese mother, who had a terminal microdeletion 13q14. Our patient had a nonsense mutation R179X (Camacho et al., personal communication, 2002). This nonsense mutation p.R179X is commonly found in patients from Japan and the Middle East [10]. In 16 patients from 13 unrelated families with HHH syndrome, 13 different mutations were identified in the SLC25A15 gene, including 11 novel mutations [16]. In a recent summary, 35 different mutations were listed for 77 patients [5].
A pilot study on machine learning approach to delineate metabolic signatures in intellectual disability
Published in International Journal of Developmental Disabilities, 2021
Vidya Nikam, Suvidya Ranade, Naushad Shaik Mohammad, Mohan Kulkarni
In the present study, the technique of tandem mass spectrometry was successfully used to screen the children with the ID for IEM. No classical IEM was detected in 20 individuals screened. However, the comparison of each analyte in ID individuals with controls revealed that proline, phenylalanine, ornithine, and alanine were elevated in the ID group while arginine levels were found to be decreased. Although we have not observed any classical case of hyperprolinemia (OMIM 239500; 239510) presenting with seizures along with ID (Evers et al.2015), proline levels were higher in ID individuals. There are reports on the association of ID and hyperalaninemia associated with Leigh’s syndrome (OMIM 256000) (Tada et al.1973). Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome (OMIM 238970) is one of the commonest disorders associated with ornithine elevation resulting in growth and developmental delays, learning disabilities, periodic confusion, and ataxia (Martinelli et al.2015). High levels of phenylalanine in ID persons substantiate that there could be hydroxylation defects due to tetrahydrobiopterin resulting in low tyrosine levels.
High levels of blood glutamic acid and ornithine in children with intellectual disability
Published in International Journal of Developmental Disabilities, 2022
Muhammad Wasim, Haq Nawaz Khan, Hina Ayesha, Abdul Tawab, Fazal e Habib, Muhammad Rafique Asi, Mazhar Iqbal, Fazli Rabbi Awan
Inborn errors of metabolism (IEMs) are inherited metabolic disorders which may manifest clinical or pathological aspects after birth (van Karnebeek 2018). More than 1000 IEMs have been reported worldwide and many of these are not treatable; however, luckily, about 200 such disorders causing intellectual disability (ID) are potentially treatable, if diagnosed earlier in life (Graham et al.2018, Ferreira et al.2019, Colonetti et al.2018, Ibarra-Gonzalez et al.2017). These IEMs are further categorized in different groups like: Aminoacidopathies, Fatty acid β-oxidation disorders, organic acidemias/acidurias etc. Aminoacidopathies are potentially treatable group of disorders, if diagnosed early in life, because special diets and pharmacological therapies are available (van Karnebeek et al.2014, van Karnebeek and Stockler 2012, Costanzo et al.2017). A total of 13 disorders are included in aminoacidopathies as: Phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), Homocystinuria, Hyperornithinemia–Hyperammonemia–Homocitrullinuria (HHH) syndrome, Ornithine Transcarbamylase (OTC) deficiency etc. (Wasim et al.2018b). Moreover, several aminoacidopathies are related to urea cycle complications, which is an important metabolic pathway in the liver. Urea cycle disorders (UCD) are inherited metabolic disorders with high level of ammonia, glutamine, citrulline and ornithine, and cause significant mortality and morbidity in infants and children (Haberle et al.2012, Bijarnia-Mahay et al.2018). Such disorders go undiagnosed in the developing countries due to lack of awareness in families and general physicians; thus result in severe delay in availing timely treatments, which cause irreversible pathology in patients. Additional factors include inadequate facilities for the diagnosis in the hospitals and research centers in the developing countries like Pakistan. Therefore, a majority of children with such diseases die without receiving any diagnosis.