James B. Sidbury

Cornstarch Therapy in Type I Glycogen-Storage Disease

TYPE I glycogen-storage disease, an inherited absence or deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestines, is associated with the accumulation of glycogen in those ...

Renal Disease in Type I Glycogen Storage Disease

Although kidney enlargement occurs in Type I glycogen storage disease, renal disease has not been considered a major problem. Death from renal failure in three patients known to us prompted a study of renal function in this disorder. Of the 38 patients with Type I glycogen storage disease under our care, the 18 children under 10 years old had normal renal function. Fourteen of the 20 older patients (13 to 47 years) had disturbed renal function, manifested by persistent proteinuria; many also had hypertension, hematuria, or altered creatinine clearance. Progressive renal insufficiency developed in 6 of these 14 patients, leading to three deaths from renal failure. At the onset of proteinuria, creatinine clearance was increased in seven patients (3.05 +/- 0.68 ml per second per 1.73 m2 of body-surface area; range, 2.47 to 4.13 [normal range, 1.33 to 2.33 ml per second per 1.73 m2]). Renal biopsies were performed in three patients after an average of 10 years of proteinuria. All three biopsies demonstrated focal segmental glomerulosclerosis in various stages of progression. Our data suggest that chronic renal disease is a frequent and potentially serious complication of Type I glycogen storage disease. In addition to treating hypoglycemia vigorously, physicians should monitor renal function carefully in patients with this disorder.

Thiamine-responsive megaloblastic anemia

An 11-year-old Caucasian girl is presented who had a megaloblastic anemia responsive only to thiamine. Other abnormalities included diabetes mellitus, aminoaciduria, and sensorineural deafness. Initially the anemia, refractory to vitamin B 12 and folic acid therapy, responded to administration of a multiple vitamin preparation. Vitamin supplementation was withdrawn followed by a recurrence of anemia 3½ months later. The implicated vitamins were then administered sequentially. A reticulocytosis followed administration of thiamine. Anemia again recurred 4 months after cessation of vitamin supplementation. On this occasion the anemia was corrected by the oral administration of 20 mg. thiamine daily. Thiamine blood levels and activities of 3 thiamine-dependent enzymes of the patients blood cells were normal, excluding a generalized defect of thiamine metabolism. The patient therefore appeared to have a thiamine-dependent megaloblastic anemia. This represents the first demonstration of a role for this vitamin in DNA metabolism.

Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.

Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an autosomal recessive disease with heterogenous symptoms. Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. Conversely, the conformation-substrate-transport model suggests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities. We have recently demonstrated that mutations in the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients. Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Arg at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type 1aSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type 1a patients, indicating that type 1aSP is a misclassification of GSD type 1a. We have also analyzed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.

Type I glycogen storage disease: nine years of management with cornstarch.

Long-term effects of cornstarch (CS) therapy on biochemical values and physical growth in children with type I glycogen storage disease (GSD I) were compared to those of children receiving continuous nocturnal nasogastric glucose feedings (CNG). Only patients who had received more than 5 years of dietary therapy (either CS or CNG) were evaluated. Six patients (five female, age 13.5 years±1.3, range 11.7–16.5 years) received CS (1.75–2.5 g/kg, four times daily) and seven patients (five female, age 9.6±2.5 years, range 7.3–14.8 years) received CNG. Blood glucose, lactate, cholesterol and triglyceride levels were not significantly different between the two methods of treatment. All patients maintained linear growth rates normal for their age. The standard deviation score of height after 6.7±1.6 years (range 5–9 years) of CS treatment was −1.29±0.59 and after 8.8±2.4 years (range 7–14 years) of CNG was −1.24±0.63. These values did not differ significantly from each other or from the target height, an estimate of genetic potential for height as determined from parental heights. With the exceptions of diarrhea, increased flatulence and excess weight gain, there were no adverse effects of CS after 9 years of treatment. Our data suggests that cornstarch is a simple, effective and safe therapy for GSD I.

An inborn error of short-chain fatty acid metabolism: The odor-of-sweaty-feet syndrome†

Two families are described, in each of which infants have developed an unusual odorsimilar to that of sweaty feet a few days after birth. In each case this was followed by lethargy, seizures, acidosis, dehydration, and death within the first month of life. Butyric and hexanoic acids have been identified in body fluids.

Computed Tomography of the Liver and Kidneys in Glycogen Storage Disease

Glycogen, in concentrations encountered in von Gierkes disease, has computed tomography (CT) attenuation coefficients in the 50 to 70 Hounsfield unit (HU: 1,000 scale) range and accounts for the increased density of the liver. However, in eight patients with Type I glycogen storage disease, simultaneous hepatic infiltration with fat and glycogen led to a range of liver CT densities from 13 to 80 HU. Fatty infiltration may facilitate the demonstration of hepatic tumors in older patients with this disease. Half the patients showed increased attenuation coefficients of the renal cortex, indicating glycogen deposition in the kidneys.

Generalized glycogenosis and associated endocardial fibroelastosis. Report of 3 cases with biochemical studies.

Absence of lysosomal alpha-glucosidase was shown in 2 patients with type II glycogenosis. Preliminary observation revealed that measurement of alpha-glucosidase in the cord and the placenta of newborn infants at risk for this disease is a useful method for determining the presence of the disease before it is clinically manifest. Two siblings had concomitant endocardial fibroelastosis. A review of the literature, together with our observation, has led us to the conclusion that the endocardial fibroelastosis in generalized glycogenosis is a secondary phenomenon and probably occurs more frequently than was previously suspected.

Cystic Disease of Liver and Kidney with Portal Hypertension A Cause of Sudden Unexpected Hematemesis

Cystic disease of the liver and kidney has a genetic basis, and is more frequent in females. When portal hypertension accom panies this malformation the patient often presents with sudden, unexpected hemateme sis. Severe or unusual infections, difficult to treat, represent other problems for the clini cian. One of the two patients here described was found at autopsy to have superimposed signs of cytomegalic inclusion disease in lungs and liver.

843 AMNIOTIC MEMBRANE IMPLANTATION IN MUCOPOLYSACCHARIDOSIS

Amniotic membrane implantation has been performed as an approach to enzyme replacement in mucopolysaccharidosis (MPS). The rationale for this study is based on the findings that cultured amniocytes secrete lysosomal enzymes and that amnion membranes are non-immunogenic. 19 patients (MPS I,II,III), ages 3 to 16 yr., have had implantation of human amniotic membranes obtained from elective repeat C-sections. The subcutaneous implants in the abdominal wall have been well tolerated with follow-up between 4 to 12 mo. The effects of amniotic membrane implantation on the clinical status of the patients was evaluated by comparing the following studies pre- and 6 mo. post-implantation: EKG, echocardiography, head and liver CT, liver/spleen scan, skeletal survey, fundus exam, electroretinography, audiological assessment, auditory brain stem response and joint range of motion. Objective clinical improvement was noted as an increased range of motion in 3 of 18 patients. Biochemical analysis demonstrated no change in serum or WBC enzyme activity. Urinary GAG transiently decreased in 2 of 10 patients with levels returning to pre-treatment range at 6 mo. post implantation. Biopsy of the implantation site at 6 mo. post implantation demonstrated a foreign body reaction with no evidence of amnion tissue. Amniotic membrane implantation appears to have limited success as a means of enzyme replacement.