Disorders of Glycerol Metabolism

ABSTRACT

• Glycerol kinase (GK) deficiency (MIM 307030) is an X-linked inborn error of metabolism characterized by hyperglycerolemia and glyceroluria. These individuals may evidence “pseudohypertriglyceridemia” if the laboratory measures triglycerides by quantitation of glycerol released after lipolysis. Glycerol kinase deficiency has been subdivided into three clinical forms according to phenotype: (1) complex glycerol kinase deficiency, which is an Xp21 contiguous gene syndrome involving the GK locus together with the adrenal hypoplasia congenita (AHC) and/or Duchenne muscular dystrophy (DMD) loci; (2) the juvenile form, associated with episodic vomiting, acidemia, and central nervous system depression, as well as hypotonia and a Reye-like illness in certain patients, presenting in the first several years of life; and (3) the benign, or adult, form, detected incidentally with pseudohypertriglyceridemia. The juvenile and benign forms result from isolated GK deficiency.

• The diagnosis of GK deficiency may be confirmed by a decrease in GK enzymatic activity and/or identification of a GK gene mutation or deletion. The enzyme activity may be determined in leukocytes, fibroblasts, liver, and/or transformed lymphoblastoid cell lines. Kidney, small intestine, and adrenal gland are also deficient in GK activity among affected individuals.

• Because of the relatively high frequency of interstitial deletions in this chromosomal region, all patients with DMD and developmental delay should be evaluated for adrenal hypoplasia and insufficiency and for GK deficiency.

• Treatment is most critical for patients with adrenal hypoplasia and insufficiency, since all the deaths seem to have resulted from Addisonian crises. These patients require glucocorticoid and mineralocorticoid treatment. Patients with vomiting, acidemia, and stupor associated with GK deficiency or the glycerol intolerance syndrome may be placed on a low-fat (i.e., glycerol-restricted) diet, but most important is the avoidance of prolonged fasts.

• The gene order surrounding the GK locus is: Xpter– AHC -GK- DMD - ornithine transcarbamylase (OTC)–cen. Human GK cDNAs have been isolated from testis, brain, liver, and adrenal gland, and the deduced amino acid sequences show striking similarities to prokaryotic sequences.

• Patients with the glycerol intolerance syndrome have episodes of sweating, irritability, confusion, marked lethargy, and coma. Hypoglycemia and seizures are variably observed. Episodes can be precipitated by glycerol ingestion or infusion. The patients may outgrow these episodes. Each of the three individuals investigated has a history of prematurity. Measurements of GK activity have been normal. Diminished hepatic fructose 1,6-bisphosphatase activity and increased sensitivity of this enzyme to inhibition by glycerol 3-phosphate have been reported. These observations have prompted speculation that this syndrome may represent an unusual sensitivity to the hypoglycemic effects of glycerol 3-phosphate, possibly due to delayed maturation of enzymes of the glycerol metabolic pathway. Similarity of symptoms to those of the juvenile form of GK deficiency has suggested alternative hypotheses that include abnormal compartmentation of a mutant GK gene with normal enzyme activity or a mutation in the glycerol facilitator gene involved in uptake of glycerol across the cell membrane.

INTRODUCTION AND HISTORICAL PERSPECTIVE

Glycerol (C₃H_...