Table 2 Main causes of diabetes mellitus related to inborn errors of metabolism (IEM)
From: Endocrine manifestations related to inherited metabolic diseases in adults
DISEASES | GENERAL CONTEXT | ENDOCRINE DYSFUNCTION: DIABETES | IEM DIAGNOSIS | TREATMENT |
|---|---|---|---|---|
Diabetes likely to signal an IEM: rather insulinopaenic | Â | Â | Â | Â |
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 | Â | Â | Â | Â |
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 |