OBJECTIVEType III glycogen storage disease (GSD-III, McKusick 232400), is a rare autosomal recessive disorder, also known as Cori's or Forbe's disease. The affected enzyme is amylo-1,6-glucosidase, 4-alpha-glucanotransferase (glycogen debrancher enzyme, GDE or amylogluco-sidase, AGL), which is responsible for the debranching of the glycogen molecule during catabolism. The AGL gene is located on chromosome 1p21 and contains 35 exons translated in a monomeric protein product. The clinical manifestations of GSD-III are represented by hepatomegaly, recurrent hypoglycemia, seizures, growth failure, dysmorphism, hyperlipidemia, raised transaminases and creatine kinase concentrations and, in a number of subjects, myopathy and cardiomyopathy. The hepatocellular adenoma, hepatocellular carcinoma, diabetes mellitus and liver fibrosis remain rare events. The diagnosis of debrancher deficiency was established by laboratory tests, electromyography (EMG), and muscle and liver biopsy.

METHODSWe studied six GSD-III families after patients or parental consent and the clinical characteristics were documented. Analysis of 33 exons and part exon-intron boundaries of the AGL gene in patients and their parents were carried out by PCR and direct DNA sequencing.

RESULTSThe clinical features included hepatomegaly, splenomegaly, recurrent hypoglycemia, hyperlipidemia, growth failure, raised transaminases and acidosis. Administration of epinephrine 2 hours after a carbohydrate meal could provoke normal rise of blood glucose in the affected individuals, but could not evoke any response after overnight fasting. Administration of raw-corn-starch could maintain normoglycemia and improve the disease condition. Mutation analysis for patient 1 was normal. Patient 2 had a compound heterozygote: a C-to-T transition at nucleotide 1294 (come from father, 1294C > T, L 298 L) in exon 8 and a G-to-T transition at nucleotide 4747 (from mother, 4747G > T, E1450X) in exon 34. Patient 3 had a compound heterozygote: a C-to-T transition at nucleotide 1294 (from father, 1294C > T, L 298 L) in exon 8 and a G-to-A transition at nucleotide -10 (from mother, -10G > A) in exon 3. Patient 4 was a homozygote: an insertion of a nucleotide CT into position +65 in exon 35 (4664 ins CT). Patient 5 had a compound heterozygote: a 8 bp deletion at nucleotide 2341 (from father, 2341delGCCATAGA, frameshift mutation) in exon 16 and a G-to-A transition at nucleotide 1559 (from mother, 1559G > A, R 387 Q) in exon 10. Patient 6 had a compound heterozygote: a T-to-G transition at nucleotide 1686 (from mother, 1686T > G, Y429 X) in exon 12 and a G-to-A transition at nucleotide 3742 (from father, 3742G > A, G 1115 R) in exon 26.

CONCLUSIONGSD-III patients have variable phenotypic characteristics. Administration of raw-corn-starch can effectively improve the disease outcome. We identified 8 new mutations on AGL gene through nucleotide sequence analysis.