Ren´e Santer, Jörg Klepper
“Disorders of glucose transport” in this chapter refers to congenital defects of membrane proteins that are able to transfer glucose and other monosac- charides from one side to the other of the hydrophobic bilayer of a cellular membrane. Each type of monosaccharide transporter has its characteristic substrate specificity, and this, together with the tissue-specific expression of these proteins, explains the complex clinical picture and the involvement of more than one organ system in some of the disease entities. Two major classes of glucose transporters can be distinguished: sodium-dependent glucose trans- porters (SGLTs) couple the transport of the sugar to the transport of sodium, and the driving force for this type of transporters is the electrochemical gra- dient of the ion. Members of the glucose transporter (GLUT) family mediate so-called facilitative diffusion along an existing glucose gradient.
A common principle in disorders of glucose transport is the lack of glucose in one compartment of the body and/or the accumulation of glucose (with the consequence of osmotic effects) in another. Treatment, in general, is directed toward the dietetic substitution of alternative substrates that are able to use other transport pathways.
In intestinal glucose-galactose malabsorption (disorder 16.1), a condition characterized by severe osmotic diarrhea after the introduction of these two monosaccharides in the diet, symptoms can be circumvented by the use of fructose as the only carbohydrate (Wright 1998).
Renal glucosuria (disorder 16.2), a primary, isolated renal tubular transport defect for glucose, can clinically either present as a mild type (with a daily glucose excretion <10 g/1.73 m2body surface area) with dominant inheritance or as a severe type (with a daily glucose excretion >10 g/1.73 m2) with recessive inheritance. Apart from osmotic diuresis, both conditions show a benign course and do not need any treatment. Only very high glucose loss may be associated by a propensity to hypovolemia and a delay of growth and maturation (Brodehl 1992; Santer 2003).
GLUT1 deficiency syndrome (disorder 16.3) represents the first transport defect across the blood-brain barrier. Sporadic and autosomal-dominant het- erozygous mutations in the GLUT1 gene impair the facilitative glucose trans- porter GLUT1 and result in a low cerebrospinal fluid (CSF) glucose concen- tration (hypoglycorrhachia). The lack of glucose as an essential fuel for brain
182 Disorders of Glucose Transport
energy metabolism results in an early-onset epileptic encephalopathy with a variable clinical spectrum. An effective treatment is available by means of a ketogenic diet providing ketones as an alternative fuel for the brain (De Vivo et al. 2002; Klepper and Voit 2002).
Patients with the Fanconi-Bickel syndrome (FBS; disorder 16.4) present with clinical symptoms that result from diminished postprandial hepatic uptake of monosaccharides and an impaired release of glucose in the fasted state.
Furthermore, glucose transport is impaired at the basolateral membrane of renal proximal tubular cells, leading to glycogen and glucose overload and a general functional impairment of these cells (which results in the renal Fanconi syndrome). Treatment of disturbed hepatic glucose transport is directed toward a continuous oral supply of carbohydrates or by the use of carbohydrates from which glucose is slowly released. Only symptomatic treatment is available for renal tubular dysfunction (Santer et al. 1998, 2002).
16.1 Nomenclature
No. Disorder Definition/comment Symbol OMIM No.
16.1 Intestinal glucose-galactose malabsorption
SGLT1 defect GGM 182380
16.2 Renal glucosuria SGLT2 defect:
heterozygous: mild glucosuria (< 10 g/1.73 m2);
homozygous: severe glucosuria (> 10 g/1.73 m2)
RG 233100; 182381
16.3 GLUT1 deficiency syndrome GLUT1 defect GLUT1 DS 138140
16.4 Fanconi-Bickel syndrome GLUT2 defect FBS 227810; 138160
16.2 Treatment
I 16.1 Intestinal glucose-galactose malabsorption
Hypertonic dehydration frequently requires intravenous fluid therapy for which glucose-containing solutions can be used. Long-term enteral nutrition has to avoid both glucose and galactose as monomers, as well as disaccharides and polymers of these sugars. Specialized commercial infant formulas containing fat and protein but free of a carbohydrate component can be used. Fructose should be added according to the dietary allowances for carbohydrates to meet caloric needs (Abad-Sinden et al. 1997). High fluid intake is recommeded to prevent renal stone formation, which is repeatedly reported in this condition (Tasic et al. 2004).
I 16.2 Renal glucosuria
Allow free access to fluid. Caloric intake should compensate for renal losses in the severe cases. No specific treatment is necessary (Scholl-Bürgi et al. 2003).
I 16.3 GLUT1 deficiency syndrome
The only effective treatment available is the introduction of a ketogenic diet, as ketones enter the brain via the facilitative MCT1 transporter and serve as an alternative fuel for the brain (Nordli and De Vivo 1997). The diet needs to be introduced in a clinical setting and requires a pediatrician and dietician experienced with the diet in order to be successful. A 3:1 (fat vs nonfat) ratio using long-chain triglycerides is usually sufficient. Fluids and calories are not restricted. Supplements (multivitamins, calcium, and often carnitine) are re- quired. Certain anticonvulsive drugs (phenobarbital, chloralhydrate, valproate, topiramate) interfere with the diet (Klepper et al. 1999, 2003) while others (methylxanthines, ethanol) impair GLUT1 function in vitro (Ho et al. 2001).
I Ketogenic Diet (3:1): Nutritional Requirements
Age Fat requirements
(g/kg BW per day)
Protein requirementsa (g/kg BW per day)
Carbohydrates (g/kg BW per day)
Energy demandb (kcal/kg BW per day)
0–4 months 9.0 2.2 0.8 93
4–12 months 9.0 1.6 1.4 91
1–3 years 8.7 1.2 1.7 90
4–6 years 7.8 1.1 1.5 80
7–9 years 7.0 1.0 1.3 72
10–12 years 5.8 1.0 0.9 60
13–15 years 5.0 1.0 0.7 52
Adults 5.0 1.0 0.7 52
aRecommendations from the German Society for Nutrition (DGE; 1991)
bGerman-Austrian-Swiss (DACH) recommendations (2000)
Dangers/Pitfalls
1. Dangers of contraindications to a ketogenic diet (β-oxidation defects, defects of ketolysis and ketoneogenesis, etc.).
2. Assess compliance by measuring ketones in blood and urine. If ketones are inappropriately low, intensify dietary instructions and be aware that many medications have a high carbohydrate content.
3. The ratio of the ketogenic diet is defined in grams, not in calories or percentages! A 3:1 ratio means that, for 3 g of ingested fat, only 1 g of protein and carbohydrates is allowed. Thus, on a 3:1 ketogenic diet, 87% of kilocalories per day are supplied by fat. Percentages of protein and carbohydrates vary due to age-dependent protein requirements.
184 Disorders of Glucose Transport
I 16.4 Fanconi-Bickel syndrome
Patients with FBS show signs of a hepatic glycogen storage disease (GSD) with impaired glycogenolysis and gluconeogenesis. Therefore, treatment should be similar to GSD 1 (see disorder 15.6), with frequent feeds and the use of slowly ab- sorbed carbohydrates (Lee et al. 1995). Due to the propensitiy to hypoglycemia of FBS patients, the use of insulin for impaired glucose tolerance has to be considered with extreme caution and only after dietary measures have failed.
Doses for nocturnal oligosaccharide or cornstarch treatment can be found in Chap. 15. In contrast to GSD 1, there is no evidence that a fructose-/saccharose- free diet is beneficial to FBS patients. Likewise, there are patients with FBS that have ingested high amounts of galactose/lactose without developing cataracts.
Therefore, galactose restriction is not generally recommended, but galactose and galactose-1-phosphate levels should be monitored.
There is no specific treatment for the Fanconi-type nephropathy. Symp- tomatic treatment is recommended to compensate for losses of water, sodium, potassium, calcium, phosphate, and bicarbonate. Vitamin D should be given for floride rickets; maintenance therapy should be monitored by urinary calcium excretion. Carnitine supplementation should only be performed at low plasma levels or when signs and symptoms of a secondary mitochondrial disorder are observed (Odièvre et al. 2002; see also Chap. 21, Cystinosis).
16.3 Alternative Therapies/Experimental Trials
No. Symbol Age Medication/diet Dosage (mg/kg
per day)
Dosages per day
Reference
16.1 GGM n.a. n.a. n.a. n.a. n.a.
16.2 RG n.a. n.a. n.a. n.a. n.a.
16.3 GLUT1 DS All ages α-Lipoic acida 600–1800 3 De Vivo et al. 1996
16.4 FBS n.a. n.a. n.a. n.a. n.a.
aAntioxidant, increases glucose transport in cultured muscle cells
16.4 Follow-up/Monitoring
I 16.1 Intestinal glucose-galactose malabsorption
Age Clinical monitoringa Biochemical and paraclinical monitoringb
Preschool Every (1–)3(–6) monthsc Every (1–)3(–6) monthsc School Every (3–)6(–12) monthsc Every (3–)6(–12) monthsc Adult Every (6–)12 monthsc Every (6–)12 monthsc
aNutrient intake, growth, nutritional status, general health
bHemoglobin, total protein, general parameters of liver and kidney function, plasma osmolarity and electrolytes, urinary glucose and RBCs, renal ultrasound
cDepending on severity of initial decompensation and/or compliance
I 16.2 Renal glucosuria
Age Clinical monitoringa Biochemical and paraclinical monitoringb
Preschool Every (6–)12 monthsc Every (6–)12 monthsc School Every (6–)12 monthsc Every (6–)12 monthsc Adult Every (12–)36 monthsc Every (12–)36 monthsc
aNutrient intake, growth, nutritional status, general health
bHemoglobin, total protein, kidney function parameters, plasma osmolarity and elec- trolytes, urinary status
cOnly in the severe recessive type; patients with mild glucosuria do not need any follow-up
186 Disorders of Glucose Transport
I 16.3 GLUT1 deficiency syndrome
G Investigations on Introduction and Follow-up of a Ketogenic Diet
On admission Initiation of diet On discharge Follow-up
every 2–3(–6) months
Clinicala Clinicala Clinicala Clinicala
Paraclinicalb Paraclinicalb Paraclinicalb Paraclinicalb
Glc, OHB, BGA Glc, OHB, BGA Glc, OHB, BGA Glc, OHB, BGA
Electrolytes every 4–6 h Electrolytes Electrolytes
Liver/kidney parameters (bedside) Liver/kidney parameters Liver/kidney parameters
FBC, CRP Ketones in urine EEG FBC, CRP
Carnitine Abdominal sonography Carnitine
Blood lipids Blood lipids
Essential fatty acids Essential fatty acids
Drug monitoring Drug monitoring
EEG, EKG EEG (seizure control?)
Abdominal sonography EKG (long QT?)
Abdominal sonography (nephrolithiasis?)
aNutrient intake, growth, nutritional status, general health
bGlc, Blood glucose; OHB, hydroxybutyrate; BGA, blood gas analysis; FBC, full blood count
G Monitoring of Ketosis
Sample Ketone body Test Target value
Urine Acetoacetate Test strips 80(++)–160(+++) mg/dl
Blood Hydroxybutyrate Test strips >2 mmol/l
Blood Total ketone bodies Enzymatic 3–5 mmol/l
I 16.4 Fanconi-Bickel syndrome
Age Clinical monitoringa Biochemical and paraclinical monitoringb
Preschool Every (1–)2(–3) months Every (1–)2(–3) months School Every (2–)6(–12) months Every (2–)6(–12) months Adult Every (6–)12(–24) months Every (6–)12(–24) months
aNutrient intake, growth, nutritional status, general health
bBlood glucose should be checked by patient or parent at least once per day in the morning.
The following examinations should be performed at regular intervals: blood glucose profile, blood galactose, galactose-1-phosphate (erythrocytes), blood and urine lactate, hemoglobin, total protein, electrolytes, calcium, phosphate, alkaline phosphatase, vitamine D, parathormone, cholesterol, triglycerides, uric acid, parameters of liver and kidney function (including GFR determination), blood carnitine,α-fetoprotein. Check urine for glucose, protein, microalbinuria, calcium/creatinine ratio. Ophthalmologic examination (cataract?). Ultrasound of liver and kidney. X-ray of left hand (rickets? bone age?)
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