Disorders of Organic Acid and Amino Acid Metabolism

Özand, Pinar; Alessa, Mohammed

doi:10.1007/978-3-642-02202-9_38

Cited by 3 publications

(3 citation statements)

References 119 publications

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“…5 A Textbook of Clinical Pediatrics describes a nine-yearold girl who was diagnosed as a case of homocystinuria found to have bronchiectasis. 6 This is the first case of homocystinuria presenting as bronchiectasis in India. Bronchiectasis develops due to fibrillin degeneration.…”

Section: Discussionmentioning

confidence: 87%

Bronchiectasis in a Marfanoid: Diagnosis Beyond Marfans

Desai¹,

Kalamkar²,

Jm³

2022

The Indian Journal of Chest Diseases and Allied Sciences

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Section: Discussionmentioning

confidence: 87%

Bronchiectasis in a Marfanoid: Diagnosis Beyond Marfans

Desai¹,

Kalamkar²,

Jm³

2022

The Indian Journal of Chest Diseases and Allied Sciences

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“…Organic acidemias (OAs) are a group of metabolic disorders caused by enzymatic deficiencies in the catabolic pathway of branched-chain amino acids, leading to the accumulation of organic acids in body fluids and tissues (2). More than 65 specific organic acids that can affect these pathways have been identified (3). Many enzymes in the converging catabolic pathways are responsible for the characteristic clinical presentations of OAs and other in born errors of metabolism (4).…”

Section: Introductionmentioning

confidence: 99%

Brain Magnetic Resonance Imaging in Organic Acidemias: A Single Center Experience

Ibrahim

Girgis

Nassar

et al. 2023

Pediatric Sciences Journal

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Background: Organic acidemias (OAs) are a group of inherited diseases with a defect of amino acid metabolism, unless treatment is initiated early in life, they cause serious central nervous system (CNS) complications as seizures, encephalopathy and others. Pre-symptomatic diagnosis is achieved within neonatal screening programs, otherwise the diagnosis is delayed and challenging. Aim of work:To search for a specific magnetic resonance imaging (MRI) diagnostic finding common to OAs. Material and Methods: This cross-sectional descriptive study included 42 children with confirmed organic acidemias following up at the Neurometabolic Clinic at Center for Social and Preventive Medicine, Pediatric Hospitals, Cairo University, Egypt. MRI brain scans were performed on a (1.5 T Aera machine). Results:The study included 42 children with a median age of 36 months. Of them 29 (69%) were males and 13 (31%) were females, with male to female ratio of 2.23:1. Glutaric academia type 1 was confirmed in 26 (61.9%) followed by methylmalonic academia in 7 (16.67%), isovaleric academia in 3 (7.14%), propionic academia in 3 (7.14%), pyroglutamic academia in 2 (4.76%) and D2 hydroxy glutaric acidemia in 1 (2.38%). Abnormal signal in basal ganglion was encountered in 20 (47.6%), followed by cortical atrophy in 11 (26.2%), white matter changes in 11 (26.2%), temporal lobe hypovolemia in 10 (23.8%), ventricular dilatation in 6 (16.7%), arachnoid cyst in 4 (9.5%), normal MRI brain in 3 (7.1%) and encephalomalacia in 2 (4.8%). No specific imaging finding was associated with OAs or its type. Conclusion: MRI findings of brain are common but not unique in organic acidemias or its types, but is not sensitive or specific. Normal MRI brain does not exclude the diagnosis of OAs.

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“…In children with tyrosinemia I, one of these herbicides is used therapeutically to inhibit 4-HPPD, thus suppressing formation of the hepatotoxins maleylacetoacetate, fumarylacetoacetate, and their saturated derivatives (11). Introduced in 1992, this agent, 2-(2-nitro-4trifluoromethylbenzoyl)-cyclohexane-1,3-dione or NTBC (Orfadin; Swedish Orphan International AB, Harpenden/United Kingdom), has benefited several hundred tyrosinemia I patients and has changed at least the time frame for liver transplantation, presently still the definitive treatment (12,13). However, until now no specific consideration was given to any inhibitory effect NTBC might exert on other 2-oxoacid-utilizing dioxygenases in humans, or to its mode of binding to 4-HPPD, the basis for its clinical utility.…”

Section: Introductionmentioning

confidence: 99%

Tyrosinemia I, A Model For Human Diseases Mediated By 2‐Oxoacid‐Utilizing Dioxygenases: Hepatotoxin Suppression By NTBC Does Not Normalize Hepatic Collagen Metabolism

Hanauske‐Abel,

Popowicz,

Remotti

et al. 2002

J. pediatr. gastroenterol. nutr.

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ObjectivesMedical treatment of tyrosinemia I relies on the herbicide NTBC [Orfadin™ 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐cyclohexane‐1,3‐dione], an inhibitor of plant and mammalian 2‐oxoacid‐utilizing dioxygenases with a collective catalytic cycle (`HAG' mechanism). We hypothesize that NTBC‐treated tyrosinemia I is a human model for the pathogenic role of two major enzymes in this class, 4‐hydroxyphenylpyruvate dioxygenase (4‐HPPD; EC 1.13.11.27) and prolyl 4‐hydroxylase (P4‐H; E.C. 1.14.11.2), essential for tyrosine and collagen metabolism, respectively.MethodsIn a patient with established tyrosinemia I, we monitored the in vivo activities of 4‐HPPD and P4‐H via five biomarkers before and during NTBC medication. Hypothesis testing at the molecular level was performed by computational modeling of NTBC binding to the crystal structure‐derived active site of 4‐HPPD, and then relating these findings to our experimental results and to known P4‐H data.ResultsNTBC rapidly normalized the biomarkers for 4‐HPPD activity. However, those for P4‐H activity remained uniformly elevated after one hundred days on NTBC, the PIIINP biomarker even increasing above its grossly abnormal, initial level. This selective enzyme inhibition despite a collective catalytic cycle is attributed to the conformation of NTBC, which only fits the active site of 4‐HPPD, as confirmed by its crystal structure.ConclusionsNormalization of hepatic collagen formation, highly desirable in all fibrotic liver diseases, is not achieved by NTBC in tyrosinemia I. By establishing the molecular cause for this failure, our results also establish a rational approach to identify inhibitors that achieve that goal, either by joint 4‐HPPD / P‐4H inhibition, or by inhibition of only P‐4H.

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Disorders of Organic Acid and Amino Acid Metabolism

Cited by 3 publications

References 119 publications

Bronchiectasis in a Marfanoid: Diagnosis Beyond Marfans

Bronchiectasis in a Marfanoid: Diagnosis Beyond Marfans

Brain Magnetic Resonance Imaging in Organic Acidemias: A Single Center Experience

Tyrosinemia I, A Model For Human Diseases Mediated By 2‐Oxoacid‐Utilizing Dioxygenases: Hepatotoxin Suppression By NTBC Does Not Normalize Hepatic Collagen Metabolism

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