Molecular analysis and protein processing in late‐onset pompe disease patients with low levels of acid α‐glucosidase activity

Bali, Deeksha; Tolun, Adviye A.; Goldstein, Jennifer; Dai, Jinghong; Kishnani, Priya S.

doi:10.1002/mus.21933

Cited by 25 publications

(28 citation statements)

References 48 publications

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“…We screened our database and found that 4 of the 106 adults in our patient cohort have a Molecular Genetics and Metabolism 107 (2012) 485-489 low GAA activity in fibroblasts within the range of classic-infantile patients. None of these four patients have the common c.-32-13 T > G mutation but other pathogenic mutations, as described previously [12][13][14][15]. We described one of the patients earlier [16].…”

Section: Introductionsupporting

confidence: 54%

“…It is notable that none of the adult patients with unexpected low activity in fibroblasts, including the thirteen cases recently reported by Bali et al [12], carry the most common mutation c.-32-13 T > G which is frequently associated with a later onset and slowly progressive phenotype [13][14][15][16]. It is also remarkable that in all these exceptional cases, close to normal synthesis of the 110 kDa precursor form can be demonstrated in the fibroblasts by immunoblotting, but that processed forms of 95 kDa and 76 kDa are virtually lacking.…”

Section: Discussionmentioning

confidence: 90%

“…The three adult patients that we described fit into the category of exceptional cases of adult Pompe disease with very low GAA activity in fibroblasts [12][13][14][15][16]. Whereas the activity in fibroblasts, either measured with 4-MU or glycogen as substrates, usually discriminates very well between classic-infantile and more slowly progressive forms of Pompe disease, it seems that in these particular cases the activity in fibroblasts does not reflect the activity in muscle.…”

Section: Discussionmentioning

confidence: 94%

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Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease

Wens

Kroos

Vries

et al. 2012

Molecular Genetics and Metabolism

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Section: Introductionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 94%

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Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease

Wens

Kroos

Vries

et al. 2012

Molecular Genetics and Metabolism

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“…Kroos et al [38] reported that the presence of at least one mutation allows the production of a protein with some residual activity that leads to the late-onset forms. However, another study showed that no common mutation is associated with b1%GAA activity in LOPD patients [39]. The documented clinical variability in patients with similar genotypes [36] still makes genotype-phenotype correlation an unresolved issue.…”

Section: Discussionmentioning

confidence: 99%

Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years

Stępień

Hendriksz

Roberts

et al. 2016

Molecular Genetics and Metabolism

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Pompe disease is an autosomal recessive disease resulting from deficiency of the acid alpha-glucosidase (GAA). The late-onset Pompe Disease (LOPD) patients develop muscular and respiratory complications later in life. We describe a retrospective observational cohort study including 22 patients with LOPD. The cohort was assessed at baseline before Enzyme Replacement Therapy (ERT) with alglucosidase alpha (20 mg/kg biweekly) was com-menced and subsequently relevant information was collected at 2, 4 and 5 years later. The median age of the patients at study entry was 44 years (16-64 years), with median disease duration of 11.5 years (4-31 years). At baseline, 10 patients (45%) could walk without support, 12 (55%) could walk with unilateral or bilateral sup-port including 3/12 were wheelchair bound. Mean predicted FVC % was 55.7 (95% CI 45-66) of predicted normal at baseline and showed no significant change after 5 years (54.6 (95% CI 43-66)), (all p = 0.9815). Mean FVC %supine was 41.8 (95% CI 33.8-49) of predicted normal at baseline and remained significantly unchanged at 5 years (48.4 (95% CI 37-59.6)), (all p = 0.8680). The overnight non-invasive ventilator dependence increased by 18.2% as compared with baseline and requirement of mobility aids increased during this period by 5.2% as compared with the baseline. Mean walking distance at 6 min walk test was 411.5 (95% CI 338-485) at baseline, 266.5 (95% CI 187-346) m at 2 years, 238.6 (95% CI 162-315) m at 4 years and 286.8 (95% CI 203-370) m at 5 years (p = 0.1981; ANOVA was completed only for 14 patients). A gradual decline in FVC% predicted was noted only in four cases and a decline in FVC% supine in two other. Only one patient showed a decline in both pulmonary function tests. In all remaining cases (17/22) respiratory function remains stable. In conclusion overall pulmonary function tests and mobility remained stable for 5 years in majority of patients on ERT. However, in some patients they continued to decline in spite of ERT resulting in increased number of patients requiring ventilation and increase wheel chair dependence at the end of 5 years.

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“…All of them had the most common leaky splice variant c.-32-13T>G as second mutation [23]. W746* has also been reported in heteroallelic combination with the less severe P285S variant and was in that case associated with late-onset disease [24]. The fact that W746* was rather frequently seen in humans and is now also found in dogs suggests that the chromosomal region around c.2237G is a mutation hotspot.…”

Section: Discussionmentioning

confidence: 98%

A Nonsense Mutation in the Acid α-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds

2013

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Pompe disease is a recessively inherited and often fatal disorder caused by the deficiency of acid α-glucosidase, an enzyme encoded by the GAA gene and needed to break down glycogen in lysosomes. This glycogen storage disease type II has been reported also in Swedish Lapphund dogs. Here we describe the genetic defect in canine Pompe disease and show that three related breeds from Scandinavia carry the same mutation. The affected dogs are homozygous for the GAA c.2237G>A mutation leading to a premature stop codon at amino acid position 746. The corresponding mutation has previously been reported in humans and causes infantile Pompe disease in combination with a second fully deleterious mutation. The affected dogs from both the Finnish as well as the Swedish breed mimic infantile-onset Pompe disease genetically, but also clinico-pathologically. Therefore this canine model provides a valuable tool for preclinical studies aimed at the development of gene therapy in Pompe disease.

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Molecular analysis and protein processing in late‐onset pompe disease patients with low levels of acid α‐glucosidase activity

Abstract: There is no common mutation associated with <1% GAA activity in late-onset Pompe disease patients. Most patients produce unprocessed forms of GAA protein compared with patients with higher GAA activity.

Cited by 25 publications

References 48 publications

Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease

Remarkably low fibroblast acid α-glucosidase activity in three adults with Pompe disease

Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years

A Nonsense Mutation in the Acid α-Glucosidase Gene Causes Pompe Disease in Finnish and Swedish Lapphunds

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