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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     
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
  1. 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.