scholarly journals Newborn Screening for Pompe Disease: Pennsylvania Experience

2020 ◽  
Vol 6 (4) ◽  
pp. 89
Author(s):  
Can Ficicioglu ◽  
Rebecca C. Ahrens-Nicklas ◽  
Joshua Barch ◽  
Sanmati R. Cuddapah ◽  
Brenda S. DiBoscio ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Compound Heterozygous ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Second Tier ◽  
Alpha Glucosidase ◽  
Gaa Gene

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.

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

Life ◽  
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.

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

2020 ◽  
Vol 6 (1) ◽  
pp. 9 ◽  
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.

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

2018 ◽  
Vol 76 (4) ◽  
pp. 247-251 ◽  
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.

scholarly journals Delivery and postpartum management of a patient with Pompe disease: Case report and review of the literature

2017 ◽  
Vol 10 (3) ◽  
pp. 150-151 ◽  
Author(s):  
Kazibe Koyuncu ◽  
Batuhan Turgay ◽  
Rusen Aytac ◽  
Feride Soylemez
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Autosomal Recessive Disorder ◽  
Enzyme Replacement ◽  
Disease Case ◽  
Alpha Glucosidase ◽  
Gaa Gene

Pompe disease is an autosomal-recessive disorder caused by acid alpha-glucosidase deficiency due to mutations in the GAA gene. There are two forms of the disease: infantile-onset Pompe disease and late-onset Pompe disease. The worldwide incidence of both forms of the disease is commonly reported to be 1 in 40,000. Adult patients are affected by limb-girdle muscular weakness and respiratory insufficiency. Enzyme replacement therapy with alglucosidase-alpha is available since 2006. There is little knowledge about pregnant woman with Pompe disease. These women should be considered as high-risk pregnant women. Here, we aim to present Cesarean delivery and postpartum management of a case with an interrupted enzyme replacement therapy during pregnancy.

scholarly journals At-Risk Testing for Pompe Disease Using Dried Blood Spots: Lessons Learned for Newborn Screening

2020 ◽  
Vol 6 (4) ◽  
pp. 96
Author(s):  
Zoltan Lukacs ◽  
Petra Oliva ◽  
Paulina Nieves Cobos ◽  
Jacob Scott ◽  
Thomas P. Mechtler ◽  
...  
Keyword(s):  
At Risk ◽  
Enzyme Activity ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Age Of Onset ◽  
Late Onset ◽  
Dried Blood Spots ◽  
Lessons Learned ◽  
Unknown Etiology ◽  
Activity Measurement

Pompe disease (GSD II) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid-α-glucosidase (GAA, EC 3.2.1.20), leading to generalized accumulation of lysosomal glycogen especially in the heart, skeletal, and smooth muscle, and the nervous system. It is generally classified based on the age of onset as infantile (IOPD) presenting during the first year of life, and late onset (LOPD) when it presents afterwards. In our study, a cohort of 13,627 samples were tested between January 2017 and December 2018 for acid-α-glucosidase (GAA, EC 3.2.1.20) deficiency either by fluorometry or tandem mass spectrometry (MS). Testing was performed for patients who displayed conditions of unknown etiology, e.g., CK elevations or cardiomyopathy, in the case of infantile patients. On average 8% of samples showed activity below the reference range and were further assessed by another enzyme activity measurement or molecular genetic analysis. Pre-analytical conditions, like proper drying, greatly affect enzyme activity, and should be assessed with measurement of reference enzyme(s). In conclusion, at-risk testing can provide a good first step for the future introduction of newborn screening for Pompe disease. It yields immediate benefits for the patients regarding the availability and timeliness of the diagnosis. In addition, the laboratory can introduce the required methodology and gain insights in the evaluation of results in a lower throughput environment. Finally, awareness of such a rare condition is increased tremendously among local physicians which can aid in the introduction newborn screening.

scholarly journals Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants

2020 ◽  
Vol 6 (1) ◽  
pp. 4 ◽  
Author(s):  
Barbara K. Burton ◽  
Joel Charrow ◽  
George E. Hoganson ◽  
Julie Fleischer ◽  
Dorothy K. Grange ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Definitive Diagnosis ◽  
Glucosidase Activity ◽  
Alpha Glucosidase

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes

2021 ◽  
pp. 1-13
Author(s):  
Tanushree Chawla ◽  
Veeramani Preethish-Kumar ◽  
Kiran Polavarapu ◽  
Seena Vengalil ◽  
Mainak Bardhan ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Muscle Weakness ◽  
Pompe Disease ◽  
Late Onset ◽  
Compound Heterozygous ◽  
Muscle Involvement ◽  
Genetic Characteristics ◽  
First Case ◽  
Girdle Muscle ◽  
Gaa Gene

Background: Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. Materials and methods: We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. Results: The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). Conclusion: We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

scholarly journals Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease

2017 ◽  
Vol 63 (7) ◽  
pp. 1271-1277 ◽  
Author(s):  
Hsuan-Chieh Liao ◽  
Min-Ju Chan ◽  
Chia-Feng Yang ◽  
Chuan-Chi Chiang ◽  
Dau-Ming Niu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Asian Population ◽  
Dried Blood Spots ◽  
Fluorimetric Assay ◽  
Analytical Range ◽  
Patient Referrals

Abstract BACKGROUND Deficiency of the lysosomal enzyme acid α-glucosidase (GAA) causes Pompe disease. Newborn screening for Pompe disease is ongoing, and improved methods for distinguishing affected patients from those with pseudodeficiency, especially in the Asian population, would substantially reduce the number of patient referrals for clinical follow-up. METHODS We measured the enzymatic activity of GAA in dried blood spots on newborn screening cards (DBS) using a tandem mass spectrometry (MS/MS) assay. The assay displayed a relatively large analytical range compared to the fluorimetric assay with 4-methylumbelliferyl-α-glucoside. DBS from newborns confirmed to have infantile-onset Pompe disease (IOPD, n = 11) or late-onset Pompe disease (LOPD) (n = 12) and those from patients bearing pseudodeficiency alleles with or without Pompe mutations, or Pompe disease carriers (n = 230) were studied. RESULTS With use of the MS/MS GAA assay in DBS, 96% of the pseudodeficiency newborns and all of the Pompe disease carriers were well separated from the IOPD and LOPD newborns. The fluorimetric assay separated &lt;10% of the pseudodeficiencies from the IOPD/LOPD group. CONCLUSIONS The relatively large analytical range MS/MS GAA assay but not the fluorimetric assay in DBS provides a robust approach to reduce the number of referrals and should dramatically facilitate newborn screening of Pompe disease.

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