Table 2.

Main causes of diabetes mellitus related to inborn errors of metabolism (IEM)

DISEASES	GENERAL CONTEXT	ENDOCRINE DYSFUNCTION: DIABETES	IEM DIAGNOSIS	TREATMENT
Diabetes likely to signal an IEM: rather insulinopaenic
Hereditary haemochromatosis	Melanodermy Hepatomegaly Rheumatologic involvement Early heart involvement in juvenile forms Complication: cirrhosis and hepatocarcinoma	All types of Diabetes 10% - First insulin resistance - Then insulinopenia Possible inaugural ketoacidosis Hypogonadotropic hypogonadism	Transferrin saturation > 45%, serum ferritin > 200 (F), 300 (M) μg/l HFE gene mutation: HFE-1: 97% in Caucasians HFE-2: hemojuveline and hepcidin HFE-3: transferrin receptor HFE-4: ferroportin (autosomal dominant) Others	Insulin-sensitiser Insulin therapy Phlebotomy
Hereditary acoeruloplasminemia	Adult-onset neurological and psychiatric disease (chorea, cerebellar ataxia, retinal degeneration) Differential diagnosis of high blood ferritin - Normal transferrin saturation Dysmetabolic hepatosiderosis Inherited atransferrinaemia, Gaucher's disease -Increased transferrin saturation Multiple blood transfusions (thalassaemia)	Diabetes mellitus due to iron overload,	Anaemia High serum ferritin Absence of serum coeruloplasmin Coeruloplasmin gene mutations	Insulin therapy Iron chelation
Mitochondrial diseases (respiratory chain defects) MIDD MELAS Kearns-Sayre syndrome DIDMOAD	Deafness, pigmentary retinitis, Neuromuscular symptoms Kidney insufficiency Maternal inheritance	Non-autoimmune diabetes in a lean patient > 30 years, possible inaugural ketoacidosis Thyroid dysfunction More rarely hypoparathyroidism, adrenal insufficiency, hypogonadism, hypopituitarism Possible diabetes insipidus	Blood lactates/pyruvate ratio Blood ßOHbutyrate/acetoacetate ratio CSF lactates- urinary organic acids Plasma amino acids: high alanine and proline Muscle biopsy Mitochondrial DNA study Mitochondrial DNA or WFS1 gene study	Insulin therapy Coenzyme Q10
Channelopathies (ABCC8 gene)	Sometimes childhood fasting hypoglycaemia	Early adult-onset non-autoimmune diabetes	Heterozygous mutation in ABCC8 gene (autosomal dominant)	Sulfonylurea/insulin
Diabetes complicating a previously diagnosed IEM
Glycogen storage disease I and III	Hepatomegaly (I and III) Mild muscular symptoms (Type III) Childhood fasting hypoglycaemia	Progression to adult fasting hypoglycaemia with postprandial hyperglycaemia	Fasting hypoglycaemia Lactic acidosis (preprandial I, postprandial III) Glc-6-P (I) and debranching enzyme (III) genes mutation	Alpha-glucosidase inhibitor and/or Insulin-sensitiser
Alström syndrome	Short stature Renal failure Dilated myocardiopathy Blindness, deafness	Early insulin-resistant diabetes mellitus (82%) Childhood obesity Hypogonadism Hypothyroidism	Major Hypertriglyceridaemia HypoHDLemia ALMS I gene mutation	Insulin-sensitiser Insulin therapy
Cystinosis	early-onset Fanconi syndrome with polyuria and hypophosphatemic rickets then complicated by blindness myopathy, central nervous system impairment- renal insufficiency.	Diabetes mellitus 25% Hypothyroidism 75% Hypogonadism 74% (males) Delayed puberty Growth retardation	Renal tubular Fanconi syndrome (hypokalemia, acidosis, dehydration, kidney loss of phosphate, glucose and amino acids)High leukocyte cystine Cystinosin (CTNS) gene mutatin	Electrolyte/vitamin supplementation Indomethacin Cysteamine
Thiamine-responsive megaloblastic anaemia syndrome	Megaloblastic anaemia Progressive perception deafness in infancy	Thiamine-sensitive diabetes mellitus, frequently insulin-dependent; possible ketoacidosis	SLC19A2 gene inactivation (thiamine transporter THTR1 gene)	B1Vitamin Insulin therapy
Organic aciduria	Cognitive disorders	Transient hyperglycaemic ketoacidosis	Urinary organic acids	Insulin therapy

The other genetic types of diabetes have been ruled out: Down's, Klinefelter, Turner, Friedreich, Huntington, Laurence-Moon-Biedl, Prader-Willi, porphyria, Toni-Debre-Fanconi, cystic fibrosis, Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. Definitions: F: female; M: male; MIDD: Maternal Inherited Diabetes Deafness; MELAS: Myopathy, Encephalopathy, Lactic Acidosis, Stroke; DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness or Wolfram syndrome; Kearns-Sayre syndrome: Starting before 20 years with progressive ophthalmoplegia, retinitis pigmentosa, cardiac conduction disorders and multisystemic injury. Thiamine-responsive megaloblastic anaemia syndrome or Rogers syndrome. CSF: cerebrospinal fluid. G-6-P: Glucose-6-phosphatase.