To date, 14 infants with the congenital form have been characterized genetically (Table ).
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
). 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
). They harboured a splice-site mutation leading to exon skipping in the first case, and a homozygous single-nucleotide deletion in the second (17
). 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
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
). 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 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