The genotype–phenotype correlation in Pompe disease

Abstract

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that is caused by acid α-glucosidase (GAA) deficiency and is due to pathogenic sequence variations in the corresponding GAA gene. The correlation between genotypes and phenotypes is strict, in that patients with the most severe phenotype, classic infantile Pompe disease, have two pathogenic mutations, one in each GAA allele, that prevent the formation of GAA or totally obliterates its function. All patients with less progressive phenotypes have at least one sequence variation that allows normal or low level synthesis of GAA leading to the formation of analytically measurable, low level GAA activity in most cases. There is an overall trend of finding higher GAA enzyme levels in patients with onset of symptoms in adulthood when compared to patients who show clinical manifestations in early childhood, aged 0-5 years, with a rapidly progressive course, but who lack the severe characteristics of classic infantile Pompe disease. However, several cases have been reported of adult-onset disease with very low GAA activity, which in all those cases corresponds with the GAA genotype. The clinical diversity observed within a large group of patients with functionally the same GAA genotype and the same c.-32-13C > T haplotype demonstrates that modifying factors can have a substantial effect on the clinical course of Pompe disease, disturbing the GAA genotype-phenotype correlation. The present day challenge is to identify these factors and explore them as therapeutic targets.

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease

“…Early onset infantile PD results from a complete deficiency of the enzyme (activity < 1%), while late onset PD (juvenile or adult) results from partial deficiency of GAA (1-30%). Onset may occur as early in childhood or as late as at the sixth decade of life 6,7 (B). The cause of PD is the progressive accumulation of intralysosomal glycogen due to the inability of the cell to breakdown the lysosomal glycogen into glucose.…”

“…Mutations can be similar (homozygote); or, different (compound heterozygote); however, both within the GAA gene. The most common mutation observed in PDJ-A patients, including Brazilians, is the intronic alteration c.-32-13 T > G (IVS1-13T > G), which is observed in more than two-thirds of the patients worldwide 7,30 . The type and combination of these mutations will determine the amount of residual GAA activity in the cells 6,7 .…”

“…The most common mutation observed in PDJ-A patients, including Brazilians, is the intronic alteration c.-32-13 T > G (IVS1-13T > G), which is observed in more than two-thirds of the patients worldwide 7,30 . The type and combination of these mutations will determine the amount of residual GAA activity in the cells 6,7 . The combination of two severe mutations leads to a complete lack of GAA protein and, as a consequence, an extremely low residual GAA activity (< 1%); such genotype is associated with the severe early onset PD On the other hand, any other combination of mutations, being at least one of then considered a "milder" mutation, such as the classic c. -32-13 T > G, enzyme production will occur, even if abnormally, resulting in different levels of residual GAA activity of up to 30% of the normal value 6,7 .…”

“…The type and combination of these mutations will determine the amount of residual GAA activity in the cells 6,7 . The combination of two severe mutations leads to a complete lack of GAA protein and, as a consequence, an extremely low residual GAA activity (< 1%); such genotype is associated with the severe early onset PD On the other hand, any other combination of mutations, being at least one of then considered a "milder" mutation, such as the classic c. -32-13 T > G, enzyme production will occur, even if abnormally, resulting in different levels of residual GAA activity of up to 30% of the normal value 6,7 . Patients with at least one mild mutation constitute most cases of juvenile and late-onset PD and present a clinical phenotype with a slower progression 1,7 .…”

“…family history and genetic counseling PD is an autosomal recessive disease caused by pathogenic mutations in both alleles of the GAA gene 1,7 . Parents of individuals with PD are healthy obligatory heterozygotes with a risk of PD recurrence in their future offspring of approximately 25%.…”