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GLUT1 Deficiency and Other Glucose Transporter Diseases

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GLUT1 Deficiency and Other Glucose Transporter Diseases European Journal of Endocrinology (2004) 150 627–633 ISSN 0804-4643 REVIEW GLUT1 deficiency and other glucose transporter diseases Juan M Pascual, Dong Wang, Beatriz Lecumberri1, Hong Yang, Xia Mao, Ru Yang and Darryl C De Vivo Colleen Giblin Laboratories, Neurological Institute of New York, College of Physicians and Surgeons, Columbia University, New York City, NY, USA and 1Departmento de Endocrinologı´a, Clı´nica Puerta de Hierro, Facultad de Medicina, Universidad Auto´noma de Madrid, Madrid, Spain (Correspondence should be addressed to D C De Vivo; Email: [email protected]) Abstract We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi–Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transpor- ters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification. European Journal of Endocrinology 150 627–633 Introduction that facilitated the diffusion of glucose across the epi- dermis cell membrane (5). Later, Birnbaum et al. Transport of water-soluble molecules across tissue bar- made similar observations in the rat brain, and the riers has attracted increasing interest since 1952 (1), two groups proceeded to clone and sequence the gene when Widdas proposed that the transport of glucose encoding the GLUT1 protein (Fig. 1) (6). Since 1985, across the erythrocyte membrane required a carrier additional proteins have been identified that are respon- mechanism to facilitate diffusion. Today, it is established sible for the facilitated diffusion of hexoses across tissue that transport and uptake of glucose can be rate-limit- barriers (7). These GLUT genes are a subset of genes ing in cells subject to large metabolic demands, as within a large superfamily of transport facilitators. manifested by several disease states involving transport This superfamily of transport facilitators is designated loss of function. In recent decades, two major families of SLC2A for solute carrier 2A, according to the HUGO glucose transporters have been discovered (2, 3). Gene Nomenclature Committee (8–10). GLUT6 was One major family are the concentrative Naþ/glucose identified as a pseudogene, and GLUT7, initially transporters (SGLT), otherwise known as active cotran- reported to encode a microsomal transporter, later sporters or symporters. These symporters are energized was shown to be a cloning artifact (11). These earlier by Hþ or Naþ gradients. Three types of concentrative missteps have been corrected as new information has Naþ/glucose transporters have been identified: SGLT1, emerged. The current understanding of this GLUT SGLT2 and SGLT3. SGLT1 (locus 22q13.1) is respon- gene family has been reviewed recently (2, 7, 12). sible for glucose absorption from the intestinal tract. The GLUT family includes 12 SLC2A genes, numbered SGLT2 (locus 16p11.2, also designated SLC5A2), 1-12, encoding 12 GLUT proteins. A thirteenth together with SGLT1, is responsible for glucose absorp- member of the GLUT family is the myoinositol transpor- tion in the renal tubules. SGLT2 is also localized to a ter, HMIT1. GLUT1 is highly expressed in erythrocytes lesser degree in ileum. SGLT3 (locus 22q12.2-q12.3) and brain, GLUT2 is associated with Fanconi–Bickel is localized to the plasma membrane of enteric neurons syndrome and is discussed in more detail below, and skeletal muscle, and is incapable of functioning as GLUT3 maintains the supply of glucose across the neur- a homo-oligomer (4). onal plasma membrane, GLUT4 is the insulin-regulated The other major family of glucose transporters is the glucose transporter of adipose tissues, heart muscles GLUT gene family. These transporters facilitate passive and skeletal muscles that is responsible for insulin- diffusion of glucose across tissue barriers by energy- regulated glucose transport, GLUT5 is highly expressed independent stereo-specific mechanisms. In the mid- in intestine, testis and kidney, and GLUT7 expression 1980s, Mueckler and colleagues discovered a protein currently is unknown. The GLUT7 gene is contiguous q 2004 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 10:35:30PM via free access 628 J M Pascual and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 150 Figure 1 The predicted GLUT1 model. The 12 transmembrane domains are shown in boxes. Solid bars indicate the location of introns in the GLUT1 gene. to the GLUT5 gene on chromosome 1p36.2 and the nonmanifesting carriers, speaking to the autosomal GLUT7 protein has a high degree of similarity (58% recessive pattern of inheritance of this disease. Many identical amino acids) compared with the fructose- patients are the product of consanguineous parents, specific GLUT5 protein. The GLUT5 protein is known emphasizing this concept. to be present in brain microglia, although its function in these cells remains unclear. Fanconi–Bickel syndrome Glucose-galactose malabsorption (OMIM 227810) syndrome (OMIM 606824) The Fanconi–Bickel syndrome was first described in The glucose-galactose malabsorption syndrome was 1949 (15) and originally named hepatorenal glyco- described in 1962 (13, 14). Both reports, one from genosis with renal Fanconi syndrome. This first patient Sweden and the other from France, described a familial presented at age 6 months with failure to thrive, poly- entity of early onset characterized by watery acid diar- dipsia and constipation. Later in childhood, he devel- rhea and life-threatening dehydration. The symptoms oped osteopenia, short stature, hepatomegaly and typically begin before the fourth day of life and respond tubular nephropathy. The nephropathy was associated to the elimination of glucose and galactose in the feed- with glycosuria, phosphaturia, aminoaciduria and ings, although they may recur later in life upon re- intermittent proteinuria. These urinary metabolites exposure to these monosaccharides. The diagnosis of were accompanied by hypophosphatemia and hyper- the disease can be readily confirmed by oral adminis- uricemia. The liver was infiltrated with glycogen and tration of glucose or galactose (2 g/kg) followed by fat. Distinctively, ketotic hypoglycemia was evident pre- lactic acid determination in breath. Fermentation of prandially, and hyperglycemia was evident postpran- the heavy monosaccharide contents of the bowel dially. This distinctive feature is the result of the lumen causes the increase in acidity, while water drag multifunctional role of GLUT2 in the pancreas and accounts for the osmotic diarrhea. All studied patients the liver. These patients may exhibit intestinal malab- carry mutations in their Sglt1 genes, while parents are sorption and diarrhea. www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 10:35:30PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2004) 150 Disorders of glucose transport 629 A mutation in the GLUT2 gene was identified in the Apgar scores are normal. The earliest epileptic events original case by Santer et al. (16). Most patients with include apneic episodes and episodic eye movements the Fanconi–Bickel syndrome are homozygous for the simulating opsoclonus. The infantile seizures are clini- disease-related mutations consistent with an autosomal cally fragmented. The frequency of clinical seizures recessive pattern of inheritance. Some patients have varies considerably from one patient to another. Some been shown to be compound heterozygotes (17). have daily seizures whereas others have only occasional seizures separated by days, weeks or months. As a rule, the clinical seizures respond poorly to antiepileptic De Vivo disease (GLUT1DS) drugs, and disappear rapidly after patients begin a keto- (OMIM 606777) genic diet. These patients suffer other paroxysmal events, and it GLUT1DS was first described in 1991 (18). Since that remains unclear whether these events are epileptic or time, approximately 100 patients have been identified nonepileptic nosologically. Paroxysmal events include in the USA and elsewhere throughout the world intermittent ataxia, confusion, lethargy or somnolence, (2, 19–21). The clinical syndrome, in and of itself, alternating hemiparesis, abnormalities of movement or argues forcefully for the concept that glucose transport posture, total body paralysis, sleep disturbances and across the blood–brain barrier (BBB) is an important recurrent headaches. The frequency of the neurologic rate-limiting event and contributes, in ways not yet symptoms fluctuates unpredictably and may be influ- fully understood, to impaired early brain growth and enced by environmental factors such as fasting or fati- functional development. The clinical signature of gue (23). The patients have degrees of speech and GLUT1DS is the presence of hypoglycorrhachia and language impairment. Varying degrees of cognitive low cerebrospinal fluid (CSF) lactate concentration in impairment have been described, ranging from learn- the absence of hypoglycemia.
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