SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1

REVIEW ARTICLE Inborn errors of associated with hyperglycaemic ketoacidosis and 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)  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; ; 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 , , INTRODUCTION , 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 , and 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 , 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 , organelles like , 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 disorders of , , organic (hyperglycaemia) and deficiency of secreted acid, carbohydrate, protein glycosylation as well by the 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 (, , maple syrup disorders. Among the most frequent disorders disease etc.), urea cycle defects, sugar associated with IEM are DM, followed by intolerances (hereditary fructose intolerance, hypogonadism and 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, 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

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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 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 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 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 that have shown toxic substances in the pancreas, which impairs to interfere with insulin regulation in IEM are the structure normal functionality leading to either by accumulation of a toxic substance in insulinopenia and diabetes. the pancreas gland ruining the structure and normal functionality, as in hemochromatosis Propionic acidemia (PA) (iron accumulation), cystinosis ( accumulation), organic acidemia (organic acid It is one of the organic acids disorders and accumulations); or by disturbing the energy odd-chain fatty acid metabolism, which was source needed for the hormone synthesis as in initially described by Childs and Nyhan et al. respiratory chain disorders [Maternally inherited in 1961 [13,14]. It is inherited in an autosomal diabetes and deafness (MIDD), Mitochondrial recessive pattern. Initially, was named ketotic myopathy, , lactic acidosis and hyperglycaemia because of its characteristic -like episodes (MELAS), Kearns-Sayre of high level in plasma and urine [14]. syndrome and diabetes insipidus, diabetes Hsia et al., 1969 described deficient oxidation mellitus with optic atrophy and deafness of propionate while Gompertz et al., 1970 (DIDMOAD) syndrome or the hormone release demonstrated enzyme deficiency in hepatocytes, as in Rogers syndrome] causing DM due to then, in leukocytes of affected individuals [15– under production of insulin [7]. 17]. The PA term was used after illustration of

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Table 1 - Summary of IEM diseases associated with DM. IEM Associated General Impaired gene classification mechanism mutation IEM disease Prevalence Diabetes characteristic Metal HAMP, Hemochroma- 1:200 T1DM (due to reduced B intoxication HFE, HFE2, tosis to cell mass) and T2DM (due Iron storage SLC40A1 1:400 to insulin resistance and and TFR2 liver cirrhosis) with possible inaugural ketoacidosis Metal CP Aceruloplas- 1:2,000,000 DM (both T1D and T2D) intoxication minemia due to similar mechanism Iron storage (as above; in hemochromatosis) Cellular intoxication Organic acid MUT, Methylmalonic 1: 50,000 to Transient hyperglycaemic intoxication MMAA, aciduria 1:250,000 ketoacidosis Abnormal MMAB, Propionic metabolism MMADHC, aciduria of organic MCEE, Isovaleric acids ACSF3, IVD aciduria ACAT1 and β-ketothiolase HLCS deficiency HCSD Mitochon- MT-TL1, MIDD & 1:4,000 Non-autoimmune diabetes drial energy MT-TK, MELAS, to with possible inaugural defect MT-TE, Wolfram 1:500,000 ketoacidosis and diabetes Energy Deficient WFS1 and syndrome insipidus defect energy CISD2 production in respiratory chain Lysosomal CTNS Cystinosis 1:100,000 DM disorder to (Due to defective insulin Cystine in 1:200,000 expression because of lysosomes abnormal tRNAs or DNA mutations) Congenital PMM2 Congenital 1:20,000 DM or hyperinsulinemic Complex disorders of disorders of hypoglycaemia (due to molecules glycosylation glycosylation defect in B cell function and defect type Ia to some extend associated liver fibrosis) Transporter SLC19A2 Rogers 30 families Thiamine-sensitive DM defect syndrome world wide with possible ketoacidosis Defective ATP (Thiamine-sensi- production in β tive megaloblas- cells tic anaemia)

http://www.sudanjp.org 13 https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 propionyl-CoA carboxylase (PCC) deficiency. therapy consists of lipids (2 grams/kg) and amino PCC is responsible for the conversion of acid free parenteral solution. The latter is suitable propionyl-CoA to methylmalonyl-CoA and for the first 24–48 hours but synthetic protein must its deficiency leads to accumulation of a toxic then be introduced after reduction of substance (propionyl–CoA) in plasma and to <100 µmol/L using commercially available urine [18,19]. Clinically, the patients usually formulas like Propimex® or MMA/PA Anamix in present in the neonatal period between the 3rd addition to natural protein such as any regular milk and 7th day of life with poor feeding, vomiting, formula for infants or food containing protein for lethargy and decreased level of consciousness. children and adults. Initially, starting with 50% of If left untreated, it will lead to progressive natural protein that the individual usually takes encephalopathy and , coma or even at home, then, followed by the full amount and death. Patients may frequently develop metabolic concentration, which are given at home. Calories acidosis with high anion gap, lactic acidosis, source is also essential like prophree or polycose ketonuria, hypoglycaemia, hyperammonaemia as tolerated. Chronic management consists of and cytopenias [20]. Other rare forms include: , metronidazole and , which is late-onset, in which the patient suffers a a co-enzyme for PCC enzyme, in addition, to metabolic crisis only under stress (e.g., illness, nutritional therapy. Dweikat et al., 2011, reported a surgery, fasting) or may have a more slowly 9-month-old Palestinian male who presented with progressive onset with global developmental diabetic ketoacidosis (DKA) [21]. Similarly, Joshi delay, hypotonia, failure to thrive, movement and Phatarpekar, 2011, reported an 11-month-old disorders, protein intolerance or cardiomyopathy. girl diagnosed to have PA appearing as DKA [22]. Isolated cardiomyopathy form can rarely be the presentation without a metabolic decompensation Methylmalonic acidemia (MMA) or neurocognitive complications [20]. Diagnosis Similar to propionicacidemia, MMA is one of can be achieved by the aforementioned clinical organic acids disorders and an odd-chain fatty acid presentation and laboratory findings like increase metabolism disorder. It is inherited in autosomal propionyl carnitine in acylcarnitine profile recessive pattern and was first described by measured by MS/MS (increase C3, C3/C2 ratio), Rosenberg et al., 1968, who also demonstrated and high plasma glycine. Additionally, urine in the same year the metabolic block localisation organic acids measurement shows increased and B12 dependency [23,24]. This is a propionylcarnitine, 3-hydroxypropionate, heterogeneous genetic disorder of methylmalonic methylcitrate and intermediates of the acid and cobalamin metabolism. Different forms pathway: tiglic acid, tiglylglycine, 2-methyl- of isolated methylmalonic aciduria are identified. 3-hydroxybutyrate, 3-hydroxybutyrate and They are classified according to in vitro propionylglycine. Enzyme assay of PCC in complementation groups of cells, which include lymphocytes or cultured skin fibroblasts and the following: DNA molecular testing of PCCA or PCCB genes confirm the diagnosis. Treatment of PA consists of • Methylmalonyl-CoA mutase complete acute life-saving management during metabolic or partial deficiency (mut0 enzymatic or crises; summarised as basic life support, high mut¯ enzymatic subtype, respectively). caloric intake (Intravenous fluids of 10% • Cobalamin and its cofactors synthesis Dextrose and Normal saline 1½ maintenance) and and transport; adenosyl-cobalamin (cblA, carnitine as chelating agent for propionyl–CoA, cblB or cblD variant 2 type). which forms propionylcarnitine and excreted in • Methylmalonyl-CoA epimerase the urine. Moreover, Metronidazole that helps in deficiency. reducing product of propionate by bacterial gut Clinically, the patient presentation is similar to metabolism, scavengers such PA, usually in the neonatal period between the as carglumic acid and sodium benzoate can be 3rd and 7th day of life with poor feeding, lethargy, used. If not responding, dialysis by continuous vomiting and decreased level of consciousness, veno-venous hemodiafiltration. Nutritional

14 http://www.sudanjp.org https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 if left untreated, it will lead to progressive heterozygous mutations in MUT gene (p.R694W encephalopathy, seizures, coma or even death. and p.Q476*) [29]. Patients may frequently develop metabolic acidosis with high anion gap, lactic acidosis, Isovaleric acidemia (IVA) ketonuria, hypoglycaemia, hyperammonemia and Similar to PA and MMA, IVA is one of the organic cytopenias [25]. Other forms include the infantile acids, and odd-chain fatty acid metabolism non-B12-responsive form, intermediate B12- disorders, that is inherited in autosomal recessive responsive phenotype and atypical and “benign” pattern. Specifically, it is a disorder of adult MMA. In infantile non-B12-responsive form, metabolism. Historically, it is the first organic patients are usually normal at birth but present with acidemia described in literature by Tanaka poor feeding, lethargy, vomiting, dehydration, et al., 1966, who subsequently described the failure to thrive, hypotonia, hepatomegaly and clinical, biochemical and molecular defects of encephalopathy in the first few weeks to months of this disorder [30–35]. Biochemically, the defect life. The intermediate B12-responsive phenotype is due to deficiency of the enzyme isovaleryl presents later; affected children experience Co-A dehydrogenase, which is responsible of poor appetite, hypotonia, developmental delay, conversion of isovaleryl Co-A to 3-methylcrotonyl failure to thrive and sometimes suffer from Co-A in leucine metabolism. Clinically, the protein aversion and/or decompensation after patients present in a similar way to PA and MMA taking protein. The Atypical and “benign” adult with a common neonatal and late onset forms. MMA form is usually asymptomatic and has a Diagnosis can be achieved by the aforementioned high excretion of methylmalonic acid [25–27]. clinical presentation and laboratory findings like Diagnosis can be achieved by the aforementioned increased isovaleryl carnitine in acylcarnitine clinical presentation and laboratory findings like profile measured by MS/MS (increase C5 level), increase propionyl carnitine in acylcarnitine and high plasma glycine. Additionally, urine profile measured by MS/MS (increase C3, C3/ organic acids test shows increased isovaleric acid, C2 ratio), high plasma glycine and elevated isovalerylglycine and 3-hydroxy isovaleric acid. methylmalonic acid. Additionally, urine Enzyme assay of isovaleryl Co-A dehydrogenase organic acids measurement shows increased in lymphocytes or cultured skin fibroblasts and methylmalonate, 3-hydroxypropionate and DNA molecular testing of IVD gene confirm the methylcitrate. Enzyme assay of methylmalonyl diagnosis. Treatment of IVA consists of acute co-A mutase in lymphocytes or cultured skin lifesaving management during metabolic crises fibroblasts and DNA molecular testing of MMA in exactly the same way we treat PA and MMA. gene panel confirm the diagnosis. Treatment of Chronic management consists of carnitine, MMA consists of acute lifesaving management metronidazole and glycine [36–38]. Hou et al., during metabolic crises in exactly the same way we 1990, described a 3-year-old IVA male patient, who treat the patients with PA. Chronic management presented with DKA, mild psychomotor retardation, consists of Carnitine, metronidazole and vitamin recurrent episodes of acute encephalopathy, B12, which is a for methylmalonyl Co-A and pancytopenia after upper respiratory tract mutase enzyme, in addition, to nutritional therapy. infection. On admission, he had vomiting Importantly, responsiveness should associated with dehydration, acidosis, ketonuria, be determined for all patients by vitamin B12 coma and a pungent odour. Laboratory findings loading test [25–27]. Guven et al., 2012, reported included hyperglycaemia, hyperammonemia, a 13-month-old Turkish girl with MMA, who hyperamylasemia, , neutropenia, presented with DKA [28]. Similarly, Dejkhamron thrombocytopenia and subsequent anaemia [39]. et al., 2016, described a 2-year-old Thai girl who Later, Attia et al., 1996, reported a Saudi child with presented with hyperglycaemia, acidosis and IVA and had DKA [40]. Subsequently, few reports ketosis [29]. She had developmental impairment, confirmed the previous findings of IVA in several optic atrophy, seizures and poor growth, and was children with DKA [41,42]. confirmed to have previously reported compound

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Holocarboxylase synthetase deficiency inherited in autosomal recessive manner. It is (HCSD) due to deficiency of mitochondrial β-ketothiolase enzyme, which converts acetoacetyl Co-A to HCSD is one of the biotin responsive disorders. Acetyl Co-A in isoleucine . Alternatively, it is called multiple carboxylase Clinically, bouts of decompensation initially start deficiency. It is inherited in autosomal recessive with tachypnea and vomiting, and followed by pattern and was first described by Roth et al., dehydration and altered level of consciousness. 1980 [43]. In HCSD, the affinity of biotin Biochemically, the patients suffer from severe to apocarboxylases is impaired, which leads metabolic acidosis, ketosis and ketonuria. to reduction in the production of the four Lactate and ammonia levels are normal in holocarboxylases from their corresponding most patients. Diagnosis is achieved through inactive apocarboxylases at physiological biotin elevation of 3-hydroxyisovaleryl carnitine concentrations. These are PCC, 3-methylcrotonyl- (C5) by MS/MS and finding of a significant CoA carboxylase (3-MCC), Pyruvate carboxylase elevation of 2-methylacetoacetate, 2-methyl-3- and acetyl-CoA carboxylase (ACC). Such hydroxybutyric acid and tiglylglycine with high disturbance is responsible for the whole excretion of and dicarboxylic biochemical profile of this disease. Clinically, acids and confirmed by molecular genetic testing the most common form is the neonatal form with of ACAT1 gene. Treatment of acute crises is poor feeding, vomiting, lethargy and decreased typically with high caloric intake by sufficient level of consciousness, if left untreated, will lead glucose infusion and correction of acidosis. to progressive encephalopathy, seizures, coma Chronic management includes avoidance of or even death. Additionally, it is associated with fasting and mild protein restriction. The outcome metabolic acidosis, neurological manifestations of this disorder is usually favourable. Clinical like and skin features of a scaly skin consequences can be prevented by applying the rash that spreads all over the body or may look aforementioned measures [4,48,49]. Ketoacidosis like seborrheic dermatitis or ichthyosis [4,44– is often associated with hypoglycaemia leading 46]. Biochemically, PCC deficiency leads to to endocrine and metabolic disorders of glucose accumulation of propionylcarnitine (C3) detected and glucagon metabolism [50]. by MS/MS in dry blood spot and elevation of propionyl co-A, methylcitrate, 3-hydroxypro Hemochromatosis pionate, propionylglycine, tiglylglycine and propionic acid in urine, while PC and ACC Hereditary hemochromatosis, also known as deficiency lead to high level of lactate and ketosis disorder, is the most frequent IEM, in blood and urine. 3-MCC deficiency leads to observed with 1 in 200 to 400 prevalence [51]. It is high level of Hydroxyisovalerylcarnitine (C5- a condition where the body absorbs excess amount OH) detected by MS/MS in dry blood spots of iron leading to accumulation of this metal, and increased 3-hydroxyisovaleric acid and which usually occurs in skin, heart, pancreas liver 3-methylcrotonylglycine in urine. Diagnosis and joints, and eventually damages these organs. is achieved by molecular confirmation of the The disease phenotype varies according to the biochemical profile through DNA molecular mutations’ penetrance, with possible inaugural testing of HLCS gene. HCSD is one of treatable ketoacidosis and 10% prevalence for diabetes. It IEM and treatment is effective with oral biotin is inherited in autosomal recessive manner and in pharmacologic doses [47]. Hou et al., 2004 genetic studies have linked hemochromatosis reported a 30-month-old female patient who to mutations in several genes, including the presented with the features of DKA, lactic human hemochromatosis protein (HFE), acidemia and moderate hyperammonemia [12]. hepcidin (HAMP), receptor 2 (TFR2), ferroportin (SLC40A1) and hemojuvelin (HFE2). β-ketothiolase deficiency (BKT) Despite the phenotypic and genetic diversity of hereditary hemochromatosis, it is presumed that BKT is one of ketolysis defects. It is specifically the main pathogenic mechanism underlying this a defect of isoleucine metabolism and is

16 http://www.sudanjp.org https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 disease is the hepcidin–ferroportin axis abnormal strategy led to marked reduction of the prevalence regulation, leading to a failure in preventing of diabetes related to hemochromatosis from 80% excess iron from entering the circulation [52]. to less than 20% with early detection (1935–2014) Eighty percent of cases have DM and the majority [53,54]. Liver transplantation is only indicated in has liver iron loading and cirrhosis. Post mortem case of end-stage liver disease due to iron overload evaluation reveals severe hemosiderin deposition and cirrhosis [54]. and eventually iron-induced fibrosis of the islets of Langerhans and pancreatic acini [53]. The Aceruloplasminemia diagnosis of hereditary hemochromatosis in Aceruloplasminemia is an autosomal recessive patients with suggestive clinical findings is based disorder. In this disease, iron also gradually on the following: accumulates but in other uncommon sites or • Elevated transferrin-iron saturation at organs especially the brain. The accumulation 45% or more. of iron in the brain results in neurological sequel • Serum concentration exceeding that generally appears in adulthood and worsens the upper limit of normal range (i.e., over time. Statistical studies have shown that >300 ng/mL in men and >200 ng/mL in only 1 in 2,000,000 people were diagnosed women). with this rare genetic disorder [55]. Clinically, • Two pathogenic variants in HFE genetic aceruloplasminemia patients present in triad of testing. retinal degeneration, DM and neurologic disease [56]. They may develop a variety of cognitive Serum ferritin concentration is not specific problems, in addition to the high prevalence of for hemochromatosis, despite its progressive DM (68.5%) due to iron accumulation in beta increase over time in untreated individuals, and pancreas cells [57]. The clinical features of therefore, it cannot be used as a standalone test aceruloplasminemia and phenotypic severity may for identifying the disease [54]. Treatment of vary, as various mutations in (CP) diabetes in hemochromatosis requires insulin, gene have been identified to correlate with this phlebotomies with or without insulin sensitisers. disease [58–61]. Phlebotomy alone would not be sufficient to treat diabetes due to hemochromatosis. This is because CP catalyses iron transport and processing, by of the underlying pathogenesis that includes assisting iron attachment to transferrin, which reduction of B cell mass and increased hepatic and transports it to the red blood cells to support extra hepatic insulin resistance. Established tissue oxygen transportation and supplementation damage resulting in cirrhosis, insulin dependent throughout the human body. Alternative form of diabetes (T1DM) is only partially reversible by CP, known as the glycosylphosphatidylinositol- iron depletion (phlebotomy). Similar to other anchored, which is produced specifically by liver diseases glucose intolerance due to insulin the nerve cells, and is responsible of the iron resistance precedes DM also in hemochromatosis. regulation in the brain tissue. The involvement Insulin resistance is probably caused by alterations of the central nervous system differentiates of insulin or glucose metabolism in the liver and aceruloplasminemia from other acquired and potentially also in extra-hepatic peripheral tissue. inherited iron storage disorders [62–64]. In advanced iron overload, iron accumulation in The biochemical profile of patients with pancreatic B-cells deteriorates pancreatic insulin aceruloplasminemia includes: deficient serum secretion and leads to insulin-dependent DM, CP, low serum iron concentration, low serum which cannot be reversed by iron removal. In concentration, elevated serum ferritin contrast, early alteration of glucose intolerance level, and increased hepatic iron load. The and insulin resistance may partially be improved enzyme activity of plasma CP ferroxidase is not by phlebotomies. Thus, the best strategy should detectable using the technique illustrated by Erel, aim at early diagnosis of hemochromatosis in early 1998 [58,65,66]. MRI features are characterised stages to prevent both mechanisms that lead to DM by low intensities indicating iron accumulation in due to insulin insufficiency or liver cirrhosis. This

http://www.sudanjp.org 17 https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 the brain (namely in thalamus, striatum, dentate most frequently reported mitochondrial disorder nucleus) and liver on both T1 and T2 weighted associated with diabetes is the single mitochondrial images [66]. Iron deposition in visceral organs, transfer RNA (tRNA) genes (MT-TL1, MT-TK and especially the pancreas, liver and heart can be MT-TE). The DNA mutation A3243G (located in found in histopathology studies. The liver usually MT-TL1 gene), found especially in the MIDD and does not show cirrhotic changes. The iron load MELAS syndrome, which accounts for 80%– in the liver is more than that in the brain. Iron 99% of the cases. Another abnormality deposition in beta cells of the pancreas leads to identified within the tRNA gene associated with DM [58,60,66]. The diagnosis is achieved by diabetes is the C12258A mutation. These tRNAs identification of biallelic pathogenic variants in help to assemble proteins involved in oxidative CP gene on molecular genetic testing [58,60,66]. phosphorylation, which is the main energy source The treatment consists of iron chelating for the cells. Furthermore, defectiveness in the medications like desferrioxamine or deferasirox mitochondria might also implicate the beta cells of to lower serum ferritin level, and to decrease the the pancreas, which is responsible of controlling brain and liver iron loads, and accordingly to blood glucose by regulating the expression of prevent progression of neurological features in insulin [69,70]. affected patients with blood haemoglobin level > Additionally, DNA mutations (deletions 9 g/dL. The combination of IV desferrioxamine and duplications) found within complex and fresh-frozen human plasma (FFP) is an rearrangement of gene (WFS1 and CISD2) of effective approach in lowering iron load in the mtDNA was shown to be the causative reasons liver. Repetitive FFP treatment might improve for Wolfram syndrome, which is also known as the neurologic manifestations. agents DIDMOAD. Another mitochondrial disorder like vitamin E may be given with chelation in associated with diabetes, is the Kearns-Sayre addition to to prevent liver and pancreas syndrome, which presents as progressive damages [58,60,66]. external ophthalmoplegia, retinal pigmentary degeneration and heart block. It is caused by a Mitochondrial disorders single yet large DNA deletion (commonly 4,997 Mitochondrial disorders also known as respiratory base pair) resulting in loss of 12 mitochondrial chain disorders, are group of diseases that genes that are important for complex protein mainly affect the mitochondria (energy-making rearrangement and oxidative phosphorylation. organelle) activity, and are characterised by Such deletions of mtDNA indirectly impairs apparent developmental delay, muscle weakness, oxidative phosphorylation, hence, diminishes neurological problem, autistic spectrum, cellular energy production [71,72]. gastrointestinal disorders, impaired vision/hearing, thyroid/adrenal abnormalities, heart/liver/ Cystinosis disease, DM, high risk of infection, autonomic Cystinosis is a rare genetic disorder with 1 in dysfunction and . Mitochondrial 100,000–200,000 of yearly prevalence. Emil disorders could be life threatening as such defects Abderhalden (1877–1950) first described it in may cause severe damage to the organs. Various 1903 [73]. The pathophysiology of cystinosis is genes and huge number of mutation variants deficiency of a cystine carrier in the lysosomal are involved, and statistical studies have shown membrane, which will lead to the accumulation that 1 in 4,000–500,000 people was diagnosed cystine in many organs. It is due to a mutation with these genetic disorders, which accounts in CTNS gene (located on the short arm of for 0.06%–2.8% of diabetes cases with possible chromosome 17p13.2), which encodes the inaugural ketoacidosis and adrenal failure [67]. cystinosin protein (lysosomal cystine transporter) They can be caused by nuclear or mitochondrial [74,75]. Cystine buildup often forms a crystal- DNA mutations. It is not easy to classify the like structure, which typically troubles the eye mitochondrial diseases, as a single syndrome and kidney. More than 80 CTNS mutations were may display wide variants of mutations [68]. The reported to cause cystinosis. Clinically, it has three

18 http://www.sudanjp.org https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 phenotypes: first, nephropathic cystinosis, which of Israeli, Arab, Lebanese, Alaskan, Brazil, presents with renal (, Japan, Oman, Tunisia, Italy, Iran, Pakistan, polydipsia, dehydration and acidosis), poor Kashmir, Kurds ethnic, Caucasians and African growth, hypophosphatemic rickets, renal failure Americans. The clinical condition is caused by and accumulation of cystine in almost all organs mutation of SLC19A2 gene (located on the long leading to tissues damage. Additionally, patients arm of chromosome 1q24.2), encoding thiamine suffer from corneal opacity, hypothyroidism, transporter protein (member of the solute carrier DM and hypogonadism. Central nervous system family) responsible for the effective utilisation of manifestations including , gross and fine thiamine molecules in various tissues including motor impairment, hypotonia, speech delay, the pancreatic beta cells [78,79]. idiopathic intracranial hypertension, behavioural Clinically, the patients present with a triad of problems neurocognitive dysfunction and megaloblastic anaemia, progressive sensorineural encephalopathy [73]. The onset of this phenotype hearing loss and DM. Megaloblastic anaemia typically occurs by 6 month of age. The second occurs in the first decade of life. The anaemia phenotype is intermediate cystinosis, which has the resolves with thiamine administration, but the red same clinical findings of nephropathic cystinosis, cells continue to be macrocytic, and anaemia can but onset is at a later age. The third phenotype is recur when treatment is withdrawn. Progressive the non-nephropathic (ocular) cystinosis, which is sensorineural hearing loss manifests early and can clinically presents with resulting from be detected in toddlers. Thiamine treatment may corneal cystine crystal build up [76]. The diagnosis not prevent the irreversible hearing loss. The DM is achieved either by the demonstration of corneal is usually non-type I, with age of onset ranging cystine crystals on slit lamp examination, finding from infancy to adolescence. Thiamine treatment a high cystine concentration in white blood cells may delay the onset of DM in several patients. (WBC) or by the identification of elevated cystine Treatment constitutes of 50–100 mg/day of oral content in cultured fibroblasts or in the placenta thiamine for life [78]. at the time of birth and is confirmed by DNA molecular testing of CTNS gene. Few therapeutic Congenital disorder of glycosylation options are available for cystinosis including supportive treatment, aiming to maintain fluid (CDG) Ia and electrolyte exchange at adequate level and Congenital disorder of glycosylation (CDG) Ia protection of the acid–base balance, prevent is a disorder caused by defect in the synthesis, rickets, ensure appropriate replacement of required assembly or processing of glycans. Glycosylation hormones and provide nutritional support. Other is process of adding glycans or sugars to proteins options include: the use of to deplete (both secreted and membrane-bound) and cystine, renal replacement therapy and renal lipids, which is the most frequent modification transplantation; however, no curative treatment is in proteins. CDG Ia is caused by deficiency in available yet [76]. DM in cystinosis usually occurs Phosphomannomutase 2 (PMM2) gene. There in the second or third decade of life. The risk of are three phenotypes of CDG Ia and are classified DM in cystionosis is approximately 24% [77]. based on the age of onset. The first phenotype is Interestingly, the frequency of DM decreases along the infantile onset and patients usually present with the duration of cysteamine therapy [77]. with multisystem involvement. Historically, the affected infants suffer from cerebellar hypoplasia, Rogers syndrome (Thiamine-responsive global developmental delay, facial dysmorphism megaloblastic anaemia) and impaired subcutaneous fat distribution [80]. However, the clinical phenotype continues to be Rogers syndrome also known as Thiamine- highly variable to include patients with normal responsive megaloblastic anaemia is an extremely cognitive function [81]. Some infants present rare genetic disorder with only 30 families with liver fibrosis and high liver enzymes. worldwide notable to acquire this disease. The Additionally, other features include coagulopathy, case series have only been reported in kinships renal hyperechogenicity, pericardial effusion,

http://www.sudanjp.org 19 https://www/sudanjp.com SUDANESE JOURNAL OF PAEDIATRICS 2018; Vol 18, Issue No. 1 hypertrophic cardiomyopathy, nephrotic above tests came unremarkable or inconclusive, syndrome, renal cysts and multiorgan failure. then a whole exome and/or genome sequencing The second phenotype is the late infantile or would be the methods of choice. childhood phenotypes, which are characterised by and intellectual disability. Finally, there is the adult phenotype with intellectual CONCLUSION disability [82]. The endocrine dysfunction is not The current review of covers IEM based on genes unusual and patients could have hyperglycaemia, and variants identified with potential targets hyperprolactinemia, hypothyroidism, insulin of IEM and DM. It also gives insights into the resistance and hyperinsulinemic hypoglycaemia mechanisms leading to diabetes of various [83,84]. The diagnosis is achieved by finding IEM disorders, which elucidates several key abnormal transferrin isoelectric focusing (TIF) pathways and essential enzymes to be targeted for (type I pattern) or a high level of carbohydrate therapeutic interventions. Clinical approach will deficient transferrin and confirmed by the DNA help in ready diagnosis and treatment for IEM molecular testing of PMM2 gene. One patient was disorders at early detection of diabetes. reported with heterozygous mutation in the PMM2 gene (c.470T>C (p. F157S), exon 6) diagnosed with CGD Ia had DM with hepatic dysfunction REFERENCES and hyperinsulinemic hypoglycaemia [82]. 1. Garrod AE, Harris H. Inborn errors of metabolism. Oxford University Press, London; 1963. 2. Scriver CR. The metabolic and molecular bases CLINICAL APPROACH of inherited disease. 8th ed. McGraw-Hill, New York; 2001. The early detection of IEM associated with 3. Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of diabetes leads to an early initiation of therapy; metabolism: the flux from Mendelian to complex thus, prevent death in newborn infants as well diseases. Nat Rev Genet. 2006;7(6):449–60. as disruption of mental or physical health and 4. Fernandes J, Berghe GVD, Saudubray J-M, Walter inadequate growth. Detailed history, including JH, SpringerLink (Online service). Inborn metabolic three-generation family history and physical diseases diagnosis and treatment. 4th, rev. ed. examination are the clue to diagnosis. Presence Springer Medizin Verlag, Berlin, Heidelberg; 2006; of multisystem involvement beside diabetes http://dx.doi.org/10.1007/978-3-540-28785-8 is a red flag for IEM. Screening methods for 5. Maritim AC, Sanders RA, Watkins JB, 3rd. patients presented with diabetes include serum Diabetes, oxidative stress, and : a ammonia and lactate, kinase (CK) level, review. J Biochem Mol Toxicol. 2003;17(1):24–38. acylcarnitine profile measured by MS/MS, plasma 6. Mathers CD, Loncar D. Projections of global aminoacids, urine for organic acids and TIF. The mortality and burden of disease from 2002 to aforementioned tests screen for organic acidemias 2030. PLoS Med. 2006;3(11):e442. and CDG type Ia. hereditary hemochromatosis 7. Vantyghem MC, Dobbelaere D, Mention and aceruloplasminemia could be detected by K, Wemeau JL, Saudubray JM, Douillard C. Endocrine manifestations related to inherited measurements of serum ferritin, transferrin- metabolic diseases in adults. Orphanet J Rare Dis. iron saturation, serum iron, copper and CP. 2012;7:11. Demonstration of cystine crystals in the cornea on 8. Lehnert W, Niederhoff H. Seven years of slit lamp examination or findings of high cystine experience with selective screening for organic concentration in WBC are the clue for cystinosis. acidurias. Eur J Pediatr. 1984;142(3):208–10. These biochemical investigations will tailor the 9. Alfadhel M, Al Othaim A, Al Saif S, Al Mutairi F, appropriate DNA molecular testing for specific Alsayed M, Rahbeeni Z, et al. Expanded newborn genes. Specific clinical pictures, high lactic acid, screening program in Saudi Arabia: incidence CK levels and measurement of respiratory chain of screened disorders. J Paediatr Child Health. enzymology in the muscle and fibroblasts as well 2017;53(6):585–91. as mitochondrial genome sequencing will confirm 10. Alfadhel M, Benmeakel M, Hossain MA, Mutairi the diagnosis of mitochondrial disorders. If the FA, Othaim AA, Alfares AA, et al. Thirteen year

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