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Inborn Errors of Metabolism Associated with Hyperglycaemic Ketoacidosis and Diabetes Mellitus: Narrative Review Majid Alfadhel* (1,2), Amir Babiker (2,3)

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Inborn Errors of Metabolism Associated with Hyperglycaemic Ketoacidosis and Diabetes Mellitus: Narrative Review Majid Alfadhel* (1,2), Amir Babiker (2,3) SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 REVIEW ARTICLE Inborn errors of metabolism associated with hyperglycaemic ketoacidosis and diabetes mellitus: narrative review Majid Alfadhel* (1,2), Amir Babiker (2,3) (1) Genetics Division, Department of Paediatrics, King Abdullah Specialized Children’s Hospital, Riyadh, Saudi Arabia (2) King Abdullah International Medical Research Centre and King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs, King Abdulaziz Medical City, Riyadh, Saudi Arabia (3) Endocrinology Division, Department of Paediatrics, King Abdullah Specialized Children’s Hospital, Riyadh, Saudi Arabia ABSTRACT megaloblastic anaemia) and congenital disorders of glycosylation type Ia. Clinical approach will Inborn errors of metabolism (IEM) are help in ready diagnosis and treatment for IEM heterogeneous group of disorders that might disorders in early detection of diabetes. In this present in the clinics or emergency departments in review, we will discuss the differential diagnosis, different phenotypes, and one of these is a diabetes clinical features and diagnostic approaches of scenario. Diabetes is the most common endocrine IEM presenting as hyperglycaemic ketoacidosis disorder among children. The mechanism of how and diabetes. IEM could lead to diabetes is unclear; however, the postulated pathogenesis consists of three KEYWORDS: mechanisms: 1) accumulation of toxic substance Aceruloplasminemia; Congenital disorders in the gland, ruining structure and normal of glycosylation; Cystinosis; Diabetes functionality, 2) disturbing energy availability mellitus; Hemochromatosis; Inborn errors required for hormone synthesis and 3) defect of of metabolism; Mitochondrial disorders; complex molecules. The differential diagnosis of Organic aciduria; Rogers syndrome. IEM associated with hyperglycaemic ketoacidosis and diabetes include: organic acidemias specifically propionic acidemia, methylmalonic acidemia, INTRODUCTION isovaleric acidemia, hereditary hemochromatosis, Inborn errors are genetic disorders affecting aceruloplasminemia, holocarboxylase synthetase the biochemical processes of the cells. Most deficiency, β-ketothiolase deficiency and finally, inborn errors of metabolism (IEM) are caused cystinosis, Rogers syndrome (thiamine-responsive Correspondence to: How to cite this article: Majid Alfadhel Alfadhel M, Babiker A. Inborn errors of Division of Genetics, Department of Paediatrics, metabolism associated with hyperglycaemic King Saud bin Abdulaziz University for Health ketoacidosis and diabetes mellitus: narrative Sciences, King Abdulaziz Medical City, Riyadh, review. Sudan J Paediatr. 2018;18(1):10–23. Saudi Arabia https://doi.org/10.24911/SJP.2018.1.3 Email: [email protected] Received: 27 April 2018 | Accepted: 29 May 2018 10 http://www.sudanjp.org https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 by enzymes defects, which result in insufficient brain or other tissues. These disorders can be or absent end products. In many cases, the sub divided into mitochondrial and cytoplasmic accumulation of toxic substances generated energy deficiencies. Mitochondrial defects along the processes causes serious consequences lead to congenital lactic acidemia (Krebs cycle [1]. Garrod et al. in the year 1909 were the first enzymes) and mitochondrial respirator chain to report on genetic and biochemical natures disorders (respiratory chain, impaired synthesis of albinism, cystinuria and alkaptonuria by of coenzyme Q10) are the most severe and developing a concept of chemical individuality. untreatable. Cytoplasmic disorders are less Different classes of IEM’s have been expanding severe and treatable such as defects in glycolysis, into huge diversity of biochemical disorders glycogen metabolism and gluconeogenesis and that fall into IEM category. The online resource hyperinsulinism. Symptoms of disorders involving of metabolic and molecular bases of inherited energy metabolism include hypoglycaemia, diseases describes more than 90 chapters hyperlactatemia, severe generalised hypotonia, discussing such disorders related to IEMs [2]. hepatomegaly, cardiomyopathy, failure to thrive, myopathy, sudden death in infancy and impaired The classification of IEM is challenging. Several brain development. classifications currently exist. The favourable classification is to small molecules diseases such C. Disorders involving complex molecules: as carbohydrate, protein, lipid and nucleic acids are related to synthesis or catabolism of cellular and large molecules diseases such as lysosomes, organelles like lysosome, peroxisome and mitochondria, peroxisomes and cytoplasm [3]. mitochondria. Another classification is based on the affected Diabetes mellitus (DM) is one of the metabolic metabolic process or enzymes involved in endocrine disorders which has main characteristic generating toxic substances such as the individual of elevated levels of glucose in blood disorders of amino acid, urea cycle, organic (hyperglycaemia) and deficiency of insulin secreted acid, carbohydrate, protein glycosylation as well by the pancreas inside the human body [5]. as lysosomal and peroxisomal disorders and The number of people with diabetes has increased mitochondrial diseases. from 108 million in 1980 to 422 million in 2014. Based on pathophysiology, perspective IEMs are The world prevalence of diabetes among adults divided into three sub groups, i.e., disorders that over 18 years of age has risen from 4.7% in 1980 cause intoxication, disorders of energy metabolism to 8.5% in 2014 [6]. There are three major types of and disorders of complex molecules [4]. diabetes: type 1 diabetes (T1DM), type 2 diabetes (T2DM) and gestational diabetes [6]. A. Intoxication causing disorders: can lead to acute or progressive intoxication, which A single IEM could present as hyperglycaemic involves IEMs such as amino acid metabolism ketoacidosis and may display several endocrine (phenylketonuria, homocystinuria, maple syrup disorders. Among the most frequent disorders urine disease etc.), urea cycle defects, sugar associated with IEM are DM, followed by intolerances (hereditary fructose intolerance, hypogonadism and thyroid dysfunction [7]. galactosemia), organic acidurias, metal T1DM is an autoimmune disease. It is caused intoxication and phorphyrias. All of these by autoimmune destruction of insulin- diseases share similar clinical features such as producing beta cells of the pancreas, which vomiting, coma, liver failure and thromboembolic leads to lack of insulin resulting in an increase complications in acute phase, developmental of glucose levels in blood and urine. Disorders delay and failure to thrive, in chronic stage. requiring anabolism and prevention of protein B. Disorders involving energy metabolism: are degradation represent a threat by accumulating usually related to deficiency of energy production toxic metabolites that can affect the pancreas or utilisation in liver, muscle, myocardium, leading to or complicating non-autoimmune http://www.sudanjp.org 11 https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 T1DM. In addition, disorders requiring SUMMARY OF INBORN ERRORS glucose stabilisation, glycogen degradation OF METABOLISM (IEM) DISEASES and gluconeogenesis can cause hypoglycaemia ASSOCIATED WITH DIABETES complicating the management of T1DM. In addition to insulinopenia, the dysfunction in MELLITUS liver and muscles in IEMs may lead to insulin resistance and T2DM. Organic aciduria In this review, we will discuss the differential Organic aciduria is a group of disorders caused diagnosis, clinical features and diagnostic by abnormal metabolism of proteins, fats or approaches of IEM presenting as hyperglycaemic carbohydrates which leads to an unexpected ketoacidosis and DM. accumulation of particular acids known as organic acids, and is characterised by noticeable metabolic acidosis with ketosis. Aciduria disorder MECHANISM OF IEM LEADING may be life threatening as such build up causes TO DIABETES MELLITUS severe damage to the tissues and organs. Various genes and huge number of mutations variants Hormones are essential in coordinating are involved in organic aciduria, depending on various functions such as growth, metabolism, the impaired organic acid metabolism. Statistic reproduction and energy equilibrium. studies have shown that 1 in 50,000 to 250,000 Hormonal impairments could contribute to IEM people was diagnosed with this genetic disorder complications. The endocrine coordination also [2,4,8]. However, the prevalence of these has autocrine and paracrine systems and is closely disorders is higher in certain parts of the world connected with central nervous system and such as Saudi Arabia [9,10]. immunology networks through neuromodulators and cytokines. In case of diabetes, insulin Few organic acidemia were reported to present hormone is the major player and insulinopenia is with DM in the form of diabetes ketoacidosis. the main cause of IEM related diabetes, although These include methylmalonic acidemia (MMA), insulin resistance could also be implicated propionic acidemia (PA), isovaleric acidemia (Table 1). Beta cells of the pancreas produce the (IVA), β-ketothiolase deficiency (BKT) and peptide hormone, insulin, which is considered holocarboxylase synthetase deficiency (HCSD) the main anabolic hormone in the body. [11,12]. The mechanism is generally unclear; however, it seems to be due to accumulation of The three known mechanisms
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