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Acta Myol. Jul 2007; 26(1): 75–78.
PMCID: PMC2949312
Neuromuscular forms of glycogen branching enzyme deficiency
C Bruno,1 D Cassandrini,1 S Assereto,1 H Orhan Akman,2 C Minetti,1 and S Di Mauro2
1Muscular and Neurodegenerative Disease Unit, University of Genova, Istituto Giannina Gaslini, Genova, Italy
2Department of Neurology, Columbia University, New York, NY, USA
Address for correspondence: Claudio Bruno Muscular and Neurodegenerative Disease Unit, University of Genova Istituto Giannina Gaslini, largo G. Gaslini 5, 16147 Genova, Italy, Phone: +34 93489 4057, Fax: +34 93274 6763, ; claudiobruno/at/
Deficiency of glycogen branching enzyme is causative of Glycogen Storage Disease type IV (GSD-IV), a rare autosomal recessive disorder of the glycogen synthesis, characterized by the accumulation of amylopectin-like polysaccharide, also known as polyglucosan, in almost all tissues. Its clinical presentation is variable and involves the liver or the neuromuscular system and different mutations in the GBE1 gene, located on chromosome 3, have been identified in both phenotypes. This review will addresses the neuromuscular clinical variants, focusing on the molecular genetics aspects of this disorder.
Keywords: Glycogen storage disease, branching enzyme, GBE1 gene, metabolic myopathy
Glycogen branching enzyme
The Glycogen branching enzyme (GBE catalyzes the last step in glycogen biosynthesis by transferring short glucosyl chains (about six α-1,4-linked glucosyl units in length) in α,1-6 glucosidic links to naked peripheral chains of nascent glycogen. Its deficiency causes accumulation of an abnormal glycogen – similar to amylopectin – with less branching points, more 1,4 linked glucose units and longer outer chains than normal glycogen (1).
This abnormal glycogen, made of long chains of glucose units infrequently branched, known as polyglucosans, is intensely positive to periodic acid-Schiff stain and partially resistant to diastase digestion. Ultrastructurally, it consists of filamentous and finely granular material. Polyglucosan accumulates in skin, liver, muscle, heart and central nervous system, but to different degrees (1).
Polyglucosan deposition is not peculiar of GSD-IV, but can be found in other disorders, such as phosphofructokinase (PFK) deficiency and Lafora disease. As previously discussed, the polyglucosan deposition in PFK deficiency is caused by the alteration of the normal ratio of glycogen synthase and branching enzyme (2).
The typical presentation of GSD-IV, originally described by Andersen in 1956 (3), is characterized by failure to thrive, hepatosplenomegaly, and liver cirrhosis leading to death in early childhood. Non-progressive hepatic form is rarely reported (4). However, the neuromuscular system can be primarily involved, and three clinical variants based on age at onset can be identified: i) congenital, ii) juvenile, and iii) adult. The congenital phenotype can, in turn, be subdivided into two clinical subgroups. The first is characterized by severe perinatal disorder presenting as fetal akinesia deformation sequence (FADS) with by multiple congenital contractures (arthrogryposis multiplex congenita), hydrops fetalis, and perinatal death. The second is characterized by severe congenital myopathy, inconsistently associated with cardiopathy, often simulating Werding-Hoffman disease (58).
The juvenile phenotype is dominated by myopathy (7, 9) or by cardiopathy (10).
The adult form can present as isolated myopathy (11) or as a multisystem disorder with central and peripheral nervous system dysfunction (adult polyglucosan body disease, APBD) (12, 13).
However, it may be wiser to consider GSD-IV as a clinical continuum, with different degrees of involvement of each organ system, rather than splitting the disease in separate clinical variants (14).
Biochemical analysis
The diagnosis is confirmed by the determination of the branching enzyme activity in affected tissues. However, the commonly use assays are indirect and not sensitive enough for precise assessment of low levels of branching activity (15).
Human GBE is a monomeric protein, which consists of 702 amino acids, and contains two highly conserved domains that have sequence similarities to the isoamylase N-terminus and to -amylase (15). It is encoded by a single gene, GBE1, which has been cloned, sequenced, and localized on chromosome 3p12 (16).
The GBE amino acid sequence shows a high degree of conservation throughout species (15).
Since the first description of a molecular defect in 1996 by Bao and colleagues (17), different mutations have been identified throughout the GBE1 gene in all different phenotypes.
In patients with the neuromuscular variant of GSD-IV, up to December 2006, 21 mutations in the GBE1 gene have been identified by sequencing genomic DNA and/or mRNA: 4 nonsense mutations, 9 missense mutations, 3 small deletion, 2 large deletions, 1 insertion, and 2 splicing mutations, spanning the entire coding region (Table (Table1).1). It is interesting to note that 24% of all mutations are in exon 12, which appears to be a “hot-spot” for GBE1 gene mutations.
Table 1
Table 1
Congenital forms: phenotype-genotype correlation.
To date, 14 infants with the congenital form have been characterized genetically (Table (Table22).
Table 2
Table 2
The GBE1 mutations in GSD-IV patients with neuromuscular presentation.
We have described the first case of FADS with genetically confirmed GBE deficiency in a baby girl carrying a homozygous missense mutation at the donor site of intron 1 of the GBE1 gene (7). In the parents of two deceased infants with FADS and GSD-IV, we identified an apparently mild missense homozygous mutation: using a human branching enzyme model based on the known three-dimensional E. coli structure, we have shown that this mutation seriously alters the enzyme protein (7).
In one family, three consecutive foeti were affected by GSD-IV and in all of them the 12-week-US examination revealed cervical cystic hygromas. In the first pregnancy, hydrops fetalis was present since the second trimester, while fetal akinesia developed in the second pregnancy (18).
Bao and Nambu independently reported two infants with neonatal hypotonia and dilated cardiomyopathy, who died in the first months of life (17, 19). They harboured a splice-site mutation leading to exon skipping in the first case, and a homozygous single-nucleotide deletion in the second (17, 19). Two other cases presented with severe neonatal hypotonia and died within 40 days of life: the first had two single-base pair deletions and the second had a large homozygous deletion encompassing exons 8 to 12 (6).
We reported three additional patients (two of them siblings) with decreased fetal movements and polyhydramnios, severe hypotonia at birth requiring mechanical ventilation, who died at ages ranging from 4 weeks to 4 months. The two siblings showed a nonsense mutation and a large deletion, while the third patient was a compound heterozygote for a nonsense mutation and a missense mutation in a highly conserved amino acid (7). Decreased fetal movements, polyhydramnios, severe hypotonia with respiratory insufficiency requiring ventilatory support, also characterized the clinical presentation of a baby-girl, who died at 2 months of age (20).
Recently, Burrow and collegues reported a child with non-lethal congenital hypotonia without hepatic or cardiac involvement, due to GSD-IV. Genetic analysis revealed the presence of two missense utations in the GBE1 gene (14).
Adult polyglucosan body disease
Adult polyglucosan body disease (APBD, MIM 263570) is a clinical variant of GBE deficiency. It is a late-onset neurological disease clinically characterized by progressive upper and lower motor neuron involvement, sensory loss, early urinary incontinence, and dementia in about half of the patients (12, 13). Polyglucosan bodies accumulate in the axons and hillocks of neurons in both gray and white matter, at difference from the polyglucosan bodies of Lafora disease, which are never seen in neuronal perikarya.
To date, genetic analysis of the GBE1 gene identified an homozygous missense mutation – c.986A > C (p.Y329S) – in several Ashkenazi Jewish patients (21). Ubogu and collegues reported a manifesting heterozygous patient with 48% of GBE activity and a single common Ashkenazi-Jewish Y329S mutation (22).
Ziemssen and collegues identified two heterozigous mutations in a non-Jewish patients with reduced GBE activity (c.1544G > A p.R515H.1571G > A p.R524Q) (23).
Prenatal diagnosis
Prenatal diagnosis can be performed by the measurement of the GBE activity in cultured chorionic villi cells and in cultured amniotic fluid cells (24), or by DNA analysis in genetically confirmed cases (25).
Animal models
Two naturally occurring animal models with GSD-IV are known, the Norwegian Forest cat and the American Quarter horse. In Norwegian Forest cats, the disease is fatal and affects primarily the striated muscles and the nervous system. A 6.1-kb deletion that causes exon 12 skipping has been identified in the feline gbe1 gene (26).
A fatal neonatal equine GSD IV, occurring in newborn foals of American Quarter Horses (27), is due to a 102C > A transversion in exon 1 of the equine gbe1 gene (28).
Although GBE deficiency is usually reported in textbooks as a liver disorder, in the last few years the involvement of the neuromuscular system has become apparent and several cases have been reported in close succession, suggesting that this disease has been underestimated.
GBE deficiency should be included in the differential diagnosis of pregnancies complicated by hydrops fetalis, polyhydramnios, and decreased fetal movements, and in infants with mild to severe hypotonia.
All cases characterized by perinatal death or by fatal infantile hypotonia have been associated with almost complete absence of GBE activity and with severe mutations in the GBE1 gene.
Reduced enzyme activity and mild or heterozygous GBE1 mutations result in APBD.
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