Current
Glycogen Storage Diseases
(GSDs)
Executive Editors: Janice
Y. Chou and Nina Raben
Glycogen and its Metabolism Pp.101-120
Peter
J. Roach
Type I Glycogen Storage Diseases: Disorders
of the Glucose-6-Phosphatase Complex Pp.121-143
Janice
Yang Chou, Dietrich Matern, Brian C. Mansfield and Yuan-Tsong Chen
Acid a-Glucosidase
Deficiency (Glycogenosis Type II, Pompe Disease) Pp.145-166
Nina
Raben, Paul Plotz and Barry J. Byrne
Molecular Characterization of Glycogen
Storage Disease Type III
Pp.167-175
J.-J.
Shen and Y.-T. Chen
The Variable Presentations of Glycogen
Storage Disease Type IV: A Review of Clinical, Enzymatic and Molecular Studies Pp.177-188
Shimon
W. Moses and Ruti Parvari
Myophosphorylase Deficiency (Glycogenosis
Type V; McArdle Disease)
Pp.189-196
S.
DiMauro, A. L. Andreu, C. Bruno and G.M. Hadjigeorgiou
Phosphofructokinase Deficiency; Past, Present
and Future Pp.197-212
Hiromu
Nakajima, Nina Raben, Tomoya Hamaguchi and Tomoyuki Yamasaki
Fanconi-Bickel Syndrome - A Congenital Defect
of Facilitative Glucose Transport Pp.213-227
R.
Santer, B. Steinmann and J. Schaub
[Back to top] Glycogen and its Metabolism
Peter J. Roach
Glycogen is a branched
polymer of glucose which serves as a reservoir of glucose units.The two largest
deposits in mammals are in the liver and skeletal muscle but many cells are
capable synthesizing glycogen. Its accumulation and utilization are under
elaborate controls involving primarily covalent phosphorylation and allosteric
ligand binding. Both muscle and liver glycogen reserves are important for whole
body glucose metabolism and their replenishment is linked hormonally to
nutritional status. Control differs between muscle and liver in part due to the
existence of different tissue-specific isoforms at key steps. Control of
synthesis is shared between transport into the muscle and the step catalyzed by
glycogen synthase. Breakdown of liver glycogen, as part of blood glucose
homeostasis,is also in response to nutritional cues. Muscle glycogen serves
only to fuel muscular activity and its utilization is controlled by muscle
contraction and by catecholamines. Though the number of enzymes directly
involved in the metabolism of glycogen is quite small, many more proteins act
indirectly in a regulatory capacity. Defects in the basic metabolizing enzymes
lead to severe consequences whereas, with some exceptions, mutations in the
regulatory proteins appear to cause a more subtle phenotypic change.
[Back to top] Type I Glycogen Storage Diseases: Disorders
of the Glucose-6-Phosphatase Complex
Janice Yang Chou, Dietrich Matern, Brian C. Mansfield
and Yuan-Tsong Chen
Glycogen storage disease
type I (GSD-I) is a group of autosomal recessive disorders with an incidence of
1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a
deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by
a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and
G6PT are associated with the endoplasmic reticulum (ER) membrane. G6PT
translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the
ER, where G6Pase hydrolyses the G6P into glucose and phosphate.Together G6Pase
and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic
tissues, the liver, kidney, and intestine. However G6PT, which transports G6P
efficiently only in the presence of G6Pase, is expressed ubiquitously. This
suggests that G6PT may play other roles in tissues lacking G6Pase. Both GSD-Ia
and GSD-Ib patients manifest phenotypic G6Pase deficiency,characterized by
growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia,
hyperuricemia, and lactic academia and the current treatment is a dietary
therapy. GSD-Ib patients also suffer from chronic neutropenia and functional
deficiencies of neutrophils and monocytes, which is treated with granulocyte
colony stimulating factor to restore myeloid function. The GSD-Ia and GSDIb
genes have been cloned. To date, 76 G6Pase and 69 G6PT mutations have been
identified in GSDI patients. A database of the residual enzymatic activity
retained by the G6Pase missense mutants is facilitating the correlation of the
disease phenotype with the patients’ genotype. While the molecular basis for
the GSD-I disorders are now known and symptomatic therapies are available, many
aspects of the diseases are still poorly understood, and there are no cures.
Recently developed animal models of the disorders are now being exploited to
delineate the disease more precisely and develop new,more causative therapies.
[Back to top] Acid a-Glucosidase
Deficiency (Glycogenosis Type II, Pompe Disease)
Nina Raben, Paul Plotz and Barry J. Byrne
Glycogenosis type
II (GSDII, Pompe disease) is an autosomal recessive lysosomal storage disease
caused by a deficiency of acid a-glucosidase
(acid maltase, GAA). The enzyme degrades a-1,4
and a -1,6 linkages in glycogen, maltose, and
isomaltose. Deficiency of the enzyme results in accumulation of glycogen within
lysosomes and in cytoplasm eventually leading to tissue destruction.
The discovery of
the acid a-glucosidase gene has led to rapid progress
in understanding the molecular basis of glycogenosis type II and the biological
properties of the GAA protein. The last decade has seen several developments:
1) extensive mutational analysis in patients with different forms of the
disease, 2) characterization of the enzyme biosynthesis, processing, and
lysosomal targeting, 3) generation of knockout mouse models, 4) development of
viral vectors for gene replacement therapy, 5) the production of recombinant
human enzyme, and 6) a shift in the enzyme replacement therapy approach from
theory to practice. It is anticipated that the enzyme replacement therapy will
be widely available for human use in the near future.
Several recent
reviews (including the most comprehensive one by R. Hirschhorn and A. Reuser
[1]), address clinical, biochemical and genetic aspects of the disease, as well
as development of new therapies for GSDII [2, 3, 4]. In this article we will
review recent findings in the area including rapidly accumulating molecular
genetic data (more than 20 mutations need to be added to the list),
transcriptional control of gene expression, studies in mouse models, and new
approaches to gene therapy. We will also highlight some emerging questions
following the introduction of enzyme replacement therapy.
[Back to top] Molecular Characterization of Glycogen
Storage Disease Type III
J.-J. Shen and Y.-T. Chen
Deficiency of the
glycogen debranching enzyme (gene, AGL) causes glycogen storage disease type
III (GSD-III), an autosomal recessive disease affectingglycogen
metabolism. Most GSDIII patients have AGL deficiency in both the liver
and muscle (type IIIa), but some have it in the liver but not muscle (type
IIIb). Cloning of human AGL cDNAs and determination of the genomic structure
and mRNA isoforms of AGL have allowed for the study of GSD-III at the molecular
level. In turn, the resulting information has greatly facilitated our
understanding of the molecular basis of this storage disease with remarkable
clinical and enzymatic variability. In this review, we summarize all 31 GSD-III
mutations in the literature and discuss their clinical and laboratory
implications. Most of the mutations are nonsense mutations caused by a
nucleotide substitution or small insertion or deletion; only one is caused by a
missense amino acid change. Some important genotype-phenotype correlation have
emerged, in particular, that exon 3 mutations (17delAG and Q6X) are
specifically associated with GSDIIIb.Three other mutations have appeared to
have some phenotype correlation. Specifically, the splice mutation
IVS32-12A>G was found in GSD-III patients having mild clinical symptoms,
while the mutations 3965delT and 4529insA are associated with a severe
phenotype and early onset of clinical manifestations. A molecular diagnostic
scheme has been proposed to diagnose GSD-III noninvasively.The characterization
of AGL mutations in GSD-III patients has also helped the structure-function
analysis of this bifunctional enzyme important for glycogen metabolism.
[Back to top] The Variable Presentations of Glycogen
Storage Disease Type IV: A Review of Clinical, Enzymatic and Molecular Studies
Shimon W. Moses and Ruti Parvari
Glycogen storage disease
type IV (GSD-IV), also known as Andersen disease or amylopectinosis (MIM
23250), is a rare autosomal recessive disorder caused by a deficiency of
glycogen branching enzyme (GBE) leading to the accumulation of amylopectin-like
structures in affected tissues. The disease is extremely heterogeneous in terms
of tissue involvement, age of onset and clinical manifestations. The human GBE
cDNA is approximately 3-kb in length and encodes a 702- amino acid protein. The
GBE amino acid sequence shows a high degree of conservation throughout species.
The human GBE gene is located on chromosome 3p14 and consists of 16 exons
spanning at least 118 kb of chromosomal DNA. Clinically the classic Andersen
disease is a rapidly progressive disorder leading to terminal liver failure
unless liver transplantation is performed. Several mutations have been reported
in the GBE gene in patients with classic phenotype. Mutations in the GBE gene
have also been identified in patients with the milder non-progressive hepatic
form of the disease. Several other variants of GSD-IV have been reported: a
variant with multi-system involvement including skeletal and cardiac muscle,
nerve and liver; a juvenile polysaccharidosis with multi-system involvement but
normal GBE activity; and the fatal neonatal neuromuscular form associated with
a splice site mutation in the GBE gene. Other presentations include
cardiomyopathy, arthrogryposis and even hydrops fetalis. Polyglucosan body
disease, characterized by widespread upper and lower motor neuron lesions, can
present with or without GBE deficiency indicating that different biochemical
defects could result in an identical phenotype. It is evident that this disease
exists in multiple forms with enzymatic and molecular heterogeneity
unparalleled in the other types of glycogen storage diseases.
[Back to top] Myophosphorylase Deficiency (Glycogenosis
Type V; McArdle Disease)
S. DiMauro, A. L. Andreu, C. Bruno and G.M.
Hadjigeorgiou
McArdle disease,
one of the most common metabolic causes of exercise intolerance and recurrent
myoglobinuria, is due to biochemical defects of the muscle isoform of glycogen
phosphorylase. The gene for myophosphorylase (PGYM) is on chromosome 11, and 33
distinct mutations have been identified in patients from all over the world. In
Caucasians, a nonsense mutation in exon 1 (R49X) is common enough to warrant
screening of genomic DNA from blood before considering muscle biopsy. Other
mutations are prevalent in different ethnic groups or are "private".
Mutations are spread throughout the gene and there is no clear
genotype:phenotype correlation. Highprotein diet and aerobic exercise are
beneficial, and gene therapy appears promising.
[Back to top] Phosphofructokinase Deficiency; Past, Present
and Future
Hiromu Nakajima, Nina Raben, Tomoya Hamaguchi and
Tomoyuki Yamasaki
Phosphofructokinase
deficiency (Tarui disease, glycogen storage disease VII, GSD VII) stands out
among all the GSDs. PFK deficiency was the first recognized disorder that
directly affects glycolysis. Ever since the discovery of the disease in 1965, a
wide range of biochemical, physiological and molecular studies of the disorder
have greatly expanded our understanding of the function of normal muscle,
general control of glycolysis and glycogen metabolism. The studies of PFK
deficiency vastly enriched the field of glycogen storage diseases, as well as
the field of metabolic and neuromuscular disorders. This article cites a
historical overview of this clinical entity and the progress that has been made
in molecular genetic area. We will also present the results of a search
in-silico, which allowed us to identify a previously unknown sequence of the
human platelet PFK gene (PFK-P).In addition, we will describe phylogenetic
analysis of evolution of PFK genes.
[Back to top] Fanconi-Bickel Syndrome - A Congenital Defect
of Facilitative Glucose Transport
R. Santer, B. Steinmann and J. Schaub
Fanconi-Bickel syndrome
(FBS, OMIM 227810) is a rare type of glycogen storage disease (GSD). It is
caused by homozygous or compound heterozygous mutations within GLUT2, the gene
encoding the most important facilitative glucose transporter in hepatocytes,
pancreatic b-cells, enterocytes, and renal tubular cells.
To date, 112 patients have been reported in the literature. Most patients have
the typical combination of clinical symptoms: hepatomegaly secondary to
glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia,
a characteristic tubular nephropathy, and severely stunted growth. In 63
patients, mutation analysis has revealed a total of 34 different GLUT2
mutations with none of them being particularly frequent. No specific therapy is
available for FBS patients. Symptomatic treatment is directed towards a
stabilization of glucose homeostasis and compensation for renal losses of
various solutes. In addition to the clinical and molecular genetic aspects of
FBS, this review discusses the pathophysiology of the disease and compares it
to recent findings in GLUT2 deficient transgenic animals. An overview is also
provided on recently discovered members of the rapidly growing family of
facilitative glucose transporters, which are novel candidates for congenital disorders
of carbohydrate metabolism.