Homozygosity for the common GAA gene splice site mutation c.-32-13T&gt;G in Pompe disease is associated with the classical adult phenotypical spectrum

Musumeci, Olimpia; Thieme, Andrea; Claeys, Kristl G.; Wenninger, Stephan; Kley, Rudolf A.; Kuhn, Marius; Lukács, Zoltán; Deschauer, Marcus; Gaeta, Michele; Toscano, Antonio; Gläser, Dieter; Schöser, Benedikt

doi:10.1016/j.nmd.2015.07.002

Cited by 35 publications

(42 citation statements)

References 31 publications

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“…Clearly this has not been reported [20 21 34–36], suggesting that most c.-32-13T>G homozygotes are unaffected or have only a very subtle phenotype with the few symptomatic homozygotes described in the literature representing an extreme end of the phenotypic spectrum. Symptomatic patients with c.-32-13T>G variant in homozygosity could also be explained by other factors including modifier genes, other variants in the GAA gene, exercise, diet or other environmental factors influencing the clinical presentation.…”

Section: Discussionmentioning

confidence: 97%

“…Musumeci et al describe only one patient, among six adult patients with c.-32-13T>G variant in homozygosity, with childhood motor disease onset at age 12 years who had a sole symptom of leg weakness at onset. The other 5 patients had a collective symptomatology of myalgia, hyperCKemia, and/or exercise induced fatigue at the age of onset (39–58 years) [21]. Another report by the same group describes two adult patients with c.-32-13T>G variant in homozygosity grouped with 27 adult patients with c.-32-13 T>G variant in compound heterozygosity with a phenotype of presymptomatic hyperCKemia (37 %), proximal/axial muscle weakness (53 %) and respiratory impairment [25].…”

Section: Discussionmentioning

confidence: 99%

“…Patients with the c.-32-13T>G variant in homozygosity have historically been thought to be asymptomatic or very mildly affected [16 19 20]. Contrary to that assumption, a recent report described six adult Pompe disease patients with c.-32-13T>G variant in homozygosity with myalgia, hyperCKaemia, and/or exercise induced fatigue, with symptom onset between 12–55 years [21]. The management and treatment of infants diagnosed with this “late-onset” GAA variant following NBS remains unclear, due to diagnostic delay and the paucity of published literature on this patient population [16 22–26].…”

Section: Introductionmentioning

confidence: 99%

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Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

Rairikar

Case

Bailey

et al. 2017

Molecular Genetics and Metabolism

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Objective Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68–90% cases with LOPD and has been presumed to result in “adult” disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation. Methods Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc4), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy. Results All seven patients demonstrated motor involvement by age 6 months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments. Conclusion This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the “late-onset” GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

Rairikar

Case

Bailey

et al. 2017

Molecular Genetics and Metabolism

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“…Currently, > 400 pathogenic variants have been reported in the GAA gene (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html?lang=en accessed May 22, 2017) [29,30]. The c.-32-13T > G variant, seen in 68–90% of Caucasian patients with LOPD in a heterozygous or homozygous state [31–36], results in alternatively spliced transcripts with deletion of exon 2 and leakage of some normal transcripts [32,37]. This variant has never been observed in classic IOPD, though it has been observed in atypical IOPD.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Mori

Haskell

Kazi

et al. 2017

Molecular Genetics and Metabolism

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Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32-13T > G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T > C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms.

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“…Are those with it asymptomatic? A recent report by Musumeci and coworkers concluded that the most possible explanation for a low frequency of a homozygous c.32-13T>G genotype in Caucasian Pompe patients was reduced or incomplete penetrance, based on the fact that these patients were phenotypically similar to those reported for patients who were compound heterozygous for their c.32-13T>G mutation and another mutation [39]. There are multiple hypotheses for reduced penetrance and efforts are underway to better understand these observations [40].…”

Section: Second-tier Molecular Testingmentioning

confidence: 99%

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

Orsini

Casini

2017

IJNS

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Newborn screening (NBS) for Krabbe disease (KD) began in New York (NY) in August 2006. In summary, after eight years of screening there were five infants identified with early-onset Krabbe disease. Four underwent transplant, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. An additional forty-six asymptomatic infants were found to be at moderate or high risk for disease. Screening for KD is both analytically and medically challenging; since screening for KD possesses both of these challenges, and many more, the lessons learned thus far could be used to predict the challenges that may be faced when screening for other lysosomal storage disorders (LSDs). This paper briefly reviews reports of NBS for LSDs from varied world programs. The challenges encountered in screening for KD in NY will be highlighted, and this experience, combined with hindsight, will inform what may be expected in the future as screening for LSDs expands.

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Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum

Cited by 35 publications

References 31 publications

Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

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