GAA gene mutation detection following clinical evaluation and enzyme activity analysis in Azeri Turkish patients with Pompe disease

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.

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Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20180018 ◽

2018 ◽

Vol 76 (4) ◽

pp. 247-251 ◽

Cited By ~ 3

Author(s):

Paulo José Lorenzoni ◽

Cláudia Suemi Kamoi Kay ◽

Nádia Sugano Higashi ◽

Vânia D'Almeida ◽

Lineu Cesar Werneck ◽

...

Keyword(s):

Enzyme Activity ◽

Muscle Biopsy ◽

Pompe Disease ◽

Late Onset ◽

Dried Blood Spots ◽

Muscular Weakness ◽

Inherited Disease ◽

Blood Spots ◽

Vacuolar Myopathy ◽

Gaa Gene

ABSTRACT Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with “unexplained” limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an “unexplained” limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

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Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation

BMC Medical Genetics ◽

10.1186/s12881-014-0141-2 ◽

2014 ◽

Vol 15 (1) ◽

Cited By ~ 19

Author(s):

Xiao Liu ◽

Zhaoxia Wang ◽

Weina Jin ◽

He Lv ◽

Wei Zhang ◽

...

Keyword(s):

Gene Mutation ◽

Mutation Analysis ◽

Pompe Disease ◽

Late Onset ◽

Chinese Patients ◽

Common Mutation ◽

Mainland Chinese ◽

Gene Mutation Analysis ◽

Gaa Gene

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Clinical and GAA gene mutation analysis in 21 Chinese patients with classic infantile pompe disease

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2020.103997 ◽

2020 ◽

Vol 63 (12) ◽

pp. 103997

Author(s):

Xueying Su ◽

Huiying Sheng ◽

yonglan huang ◽

Xiuzhen Li ◽

Wen Zhang ◽

...

Keyword(s):

Gene Mutation ◽

Mutation Analysis ◽

Pompe Disease ◽

Chinese Patients ◽

Infantile Pompe Disease ◽

Gene Mutation Analysis ◽

Gaa Gene

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Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease

Life ◽

10.3390/life11060507 ◽

2021 ◽

Vol 11 (6) ◽

pp. 507

Author(s):

Aniko Gal ◽

Zoltán Grosz ◽

Beata Borsos ◽

Ildikó Szatmari ◽

Agnes Sebők ◽

...

Keyword(s):

Enzyme Activity ◽

Pompe Disease ◽

Late Onset ◽

Common Finding ◽

Compound Heterozygous ◽

Gene Variation ◽

Enzyme Replacement ◽

C 32 ◽

The Impact ◽

Gaa Gene

Pompe disease is caused by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid-α-glucosidase (GAA) enzyme. Depending on residual enzyme activity, the disease manifests two distinct phenotypes. In this study, we assess an enzymatic and genetic analysis of Hungarian patients with Pompe disease. Twenty-four patients diagnosed with Pompe disease were included. Enzyme activity of acid-α-glucosidase was measured by mass spectrometry. Sanger sequencing and an MLPA of the GAA gene were performed in all patients. Twenty (83.33%) patients were classified as having late-onset Pompe disease and four (16.66%) had infantile-onset Pompe disease. Fifteen different pathogenic GAA variants were detected. The most common finding was the c.-32-13 T > G splice site alteration. Comparing the α-glucosidase enzyme activity of homozygous cases to the compound heterozygous cases of the c.-32-13 T > G disease-causing variant, the mean GAA activity in homozygous cases was significantly higher. The lowest enzyme activity was found in cases where the c.-32-13 T > G variant was not present. The localization of the identified sequence variations in regions encoding the crucial protein domains of GAA correlates with severe effects on enzyme activity. A better understanding of the impact of pathogenic gene variations may help earlier initiation of enzyme replacement therapy (ERT) if subtle symptoms occur. Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans.

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The First Year Experience of Newborn Screening for Pompe Disease in California

International Journal of Neonatal Screening ◽

10.3390/ijns6010009 ◽

2020 ◽

Vol 6 (1) ◽

pp. 9 ◽

Cited By ~ 2

Author(s):

Hao Tang ◽

Lisa Feuchtbaum ◽

Stanley Sciortino ◽

Jamie Matteson ◽

Deepika Mathur ◽

...

Keyword(s):

Enzyme Activity ◽

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

First Year ◽

Sequencing Analysis ◽

Enzyme Activity Assay ◽

California Department ◽

Birth Prevalence ◽

Gaa Gene

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year of screening in a large and diverse screening population. With 453,152 screened newborns, the birth prevalence and GAA enzyme activity associated with various types of Pompe disease classifications are described. The frequency of GAA gene mutations and allele variants are reported. Of 88 screen positives, 18 newborns were resolved as Pompe disease, including 2 classic infantile-onset and 16 suspected late-onset form. The c.-32-13T>G variant was the most common pathogenic mutation reported. African American and Asian/Pacific Islander newborns had higher allele frequencies for both pathogenic and pseudodeficiency variants. After the first year of Pompe disease screening in California, the disease distribution in the population is now better understood. With the ongoing long-term follow-up system currently in place, our understanding of the complex genotype-phenotype relationships will become more evident in the future, and this should help us better understand the clinical significance of identified cases.

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Rupture of the middle cerebral artery aneurysm as a presenting symptom of late-onset Pompe disease in an adult with a novel GAA gene mutation

Acta Neurologica Belgica ◽

10.1007/s13760-013-0265-8 ◽

2013 ◽

Vol 114 (2) ◽

pp. 165-166 ◽

Cited By ~ 5

Author(s):

S. Peric ◽

K. Fumic ◽

K. Bilic ◽

A. Reuser ◽

V. Rakocevic Stojanovic

Keyword(s):

Middle Cerebral Artery ◽

Gene Mutation ◽

Cerebral Artery ◽

Pompe Disease ◽

Late Onset ◽

Artery Aneurysm ◽

Middle Cerebral Artery Aneurysm ◽

Cerebral Artery Aneurysm ◽

Gaa Gene

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Blood-based diagnostic testing for Pompe disease: Consistency between GAA enzyme activity in dried blood spots and GAA gene sequencing results

Muscle & Nerve ◽

10.1002/mus.24149 ◽

2014 ◽

Vol 49 (5) ◽

pp. 775-776 ◽

Cited By ~ 2

Author(s):

Jennifer L. Goldstein ◽

Gwen Dickerson ◽

Priya S. Kishnani ◽

Catherine Rehder ◽

Deeksha S. Bali

Keyword(s):

Enzyme Activity ◽

Pompe Disease ◽

Diagnostic Testing ◽

Gene Sequencing ◽

Dried Blood Spots ◽

Blood Spots ◽

Gaa Gene

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Purification and subunit structure of argininosuccinate lyase from Chlamydomonas reinhardi

Biochemical Journal ◽

10.1042/bj1670071 ◽

1977 ◽

Vol 167 (1) ◽

pp. 71-75 ◽

Cited By ~ 13

Author(s):

R F Matagne ◽

J P Schlösser

Keyword(s):

Enzyme Activity ◽

Crude Extract ◽

Enzyme Preparation ◽

Sodium Dodecyl ◽

Gel Filtration ◽

Deae Cellulose ◽

Activity Analysis ◽

Disc Electrophoresis ◽

Subunit Structure ◽

Argininosuccinate Lyase

Argininosuccinate lyase (EC 4.3.2.1) was purified by (NH4)2SO4 fractionation, chromatography on DEAE-cellulose and gel filtration on Sephadex G-200. The final enzyme preparation was purified 46-fold compared with the crude extract. Electrophoresis of this preparation revealed three bands, the major one having the enzyme activity. Analysis of the enzyme by gel filtration and by disc electrophoresis (in two different concentrations of acrylamide) gave mol.wts. of 200000 (+/- 15000) and 190000 (+/- 20000) respectively. Treatment with sodium dodecyl sulphate and mercaptoethanol dissociated the enzyme into subunits of mol.wt. 39000 (+/-2000). The results are indicative of the multimeric structure of the enzyme, which is composed of five (perhaps four or six) identical subunits.

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