Hypoglycemia is defined as a decrease in the blood glucose level or its tissue utilization accompanied by typical signs and symptoms. Based on rate of decline (rapid or slow) in glucose blood levels, symptoms of hypoglycemia are classified mainly in two major categories: adrenergic and neuroglycopenic. Inadequate supply of glucose to the brain and other tissues may have a negative impact on their energy requirements and function.
Whipple triad defines a combination of three criteria used to diagnose hypoglycemia:
The presence of characteristic hypoglycemia symptoms
Low glucose levels and typical symptoms
The resolution of symptoms after the normalization of blood glucose
Hypoglycemia can be inherited as an isolated finding or as one component of a multisystem syndrome. Observed pattern of inheritance includes autosomal dominant, autosomal recessive, and X-linked recessive. See mur_ch57cap1.
Various disorders of excessive or underproduction of glucose have a genetic component. The most common forms of genetic hyperinsulinemia are represented by familial hyperinsulinemia hypoglycemia (FHH) (Table 57-1). Autosomal dominant and recessive forms are identified based on SUR1/Kir6.2 receptor mutations in the different genes that encoded it: ABCC8, KCNJ11. Other rarer genetic causes of hyperinsulinism have been linked to mutations that coded for different enzymes or receptors identified with other subtypes of FHH: GCK, HADH, INSR, GLUD1, SLC16A1.
In 50% of patients with hyperinsulinism, there are no identifiable genetic markers but single-nucleotide polymorphisms (SNPs) were reported in some infants with hypoglycemia.
Beckwith-Wiedemann syndrome is an autosomal dominant condition with variable penetrance and genomic imprinting should be a part of the differential diagnosis of hyperinsulinemia.
Glucose-processing defects (glycogen synthase deficiency, glycogen-storage disease, respiratory chain defects) are mostly manifested during infancy and early childhood. Defects in alternative fuel production (carnitine acyl transferase deficiency, hepatic HMG CoA lyase deficiency, long-chain or medium-chain or variably short-chain acyl-coenzyme A dehydrogenase deficiency) can destabilize the energy balance in the body making it difficult to accommodate a prolonged starvation or acute stress period.
Disorders of glucose underproduction are caused by inadequate glucose stores (prematurity, small for gestational age), glycogen synthase deficiency, glycogen-storage disease, or hormonal abnormalities.
Glycogen synthase deficiency is manifested as fasting hypoglycemia because of the liver’s inability to store glucose, whereas in glycogen-storage disease there are problems with glucose release and gluconeogenesis.
Hormonal deficiencies (partial or complete) are expressed as autosomal recessive or X-linked recessive condition. Some of these hormonal deficiencies may be associated with transient or persistent hypoglycemia.
Table 57-1Genetic Differential Diagnosis |Favorite Table|Download (.pdf) Table 57-1 Genetic Differential Diagnosis
|Syndrome || ||Gene Symbol ||Associated Findings |
|Hyperinsulinemia || |
Hyperinsulinemic hypoglycemia Familial (HHF) 1
Hypoglycemia in the newborn or infant, elevated serum insulin, low serum ketone bodies, hypotonia, poor feeding, apnea, increased glucose response ...
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