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 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.

The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: A multicenter study

2016 ◽  
Vol 26 (11) ◽  
pp. 796-800 ◽  
Author(s):  
Olcay Ünver ◽  
Nilüfer Eldeş Hacıfazlıoğlu ◽  
Elif Karatoprak ◽  
Ayfer Sakarya Güneş ◽  
Güneş Sağer ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Multicenter Study ◽  
Pompe Disease ◽  
Pediatric Patients ◽  
Late Onset ◽  
Girdle Muscle

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 Distal muscle weakness is a common and early feature in long-term enzyme-treated classic infantile Pompe patients

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
J. J. A. van den Dorpel ◽  
E. Poelman ◽  
L. Harlaar ◽  
H. A. van Kooten ◽  
L. J. van der Giessen ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Pompe Disease ◽  
Muscle Function ◽  
Late Onset ◽  
Walking Ability ◽  
Proximal Muscle ◽  
Muscle Involvement ◽  
Enzyme Replacement ◽  
Distal Muscle ◽  
Over Time

Abstract Background Enzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT. Methods In this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head). Results Median age at start of ERT was 3.2 months (0.1–5.8 months), median age at study end was 5.6 years (2.9–18.2 years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit. Conclusions We found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.

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 Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

2018 ◽  
Vol 13 ◽  
Author(s):  
Francesco Menzella ◽  
Luca Codeluppi ◽  
Mirco Lusuardi ◽  
Carla Galeone ◽  
Franco Valzania ◽  
...  
Keyword(s):  
Case Report ◽  
Respiratory Failure ◽  
Acute Respiratory Failure ◽  
Pompe Disease ◽  
Late Onset ◽  
Correct Diagnosis ◽  
Ventilatory Support ◽  
Diagnostic Process ◽  
Caucasian Woman ◽  
Enzyme Replacement

Background: Acute respiratory failure can be triggered by several causes, either of pulmonary or extra-pulmonary origin. Pompe disease, or type II glycogen storage disease, is a serious and often fatal disorder, due to a pathological accumulation of glycogen caused by a defective activiy of acid α-glucosidase (acid maltase), a lysosomal enzyme involved in glycogen degradation. The prevalence of the disease is estimated between 1 in 40,000 to 1 in 300,000 subjects. Case presentation: This case report describes a difficult diagnosis of late-onset Pompe disease (LOPD) in a 52 year old Caucasian woman with acute respiratory failure requiring orotracheal intubation and subsequent tracheostomy for long-term mechanical ventilation 24 h/day. Despite a complex diagnostic process including several blood tests, bronchoscopy with BAL, chest CT, brain NMR, electromyographies, only a muscle biopsy allowed to reach the correct diagnosis. Discussion: The most frequent presentation of myopathies, including LOPD, is proximal limb muscle weakness. Respiratory related symptoms (dyspnea on effort, reduced physical capacity, recurrent infections, etc.) and respiratory failure are often evident in the later stages of the diseases, but they have been rarely described as the onset symptoms in LOPD. In our case, a third stage LOPD, the cooperation between pulmonologists and neurologists was crucial in reaching a correct diagnosis despite a very complex clinical scenario due to different confounding co-morbidities as potential causes of respiratory failure and an atypical presentation. In this patient, enzyme replacement therapy with infusion of alglucosidase alfa was associated with progressive reduction of ventilatory support to night hours, and recovery of autonomous walking.

scholarly journals Practical Recommendations for Diagnosis and Management of Respiratory Muscle Weakness in Late-Onset Pompe Disease

2016 ◽  
Vol 17 (10) ◽  
pp. 1735 ◽  
Author(s):  
Matthias Boentert ◽  
Hélène Prigent ◽  
Katalin Várdi ◽  
Harrison Jones ◽  
Uwe Mellies ◽  
...  
Keyword(s):  
Muscle Weakness ◽  
Pompe Disease ◽  
Respiratory Muscle ◽  
Late Onset ◽  
Respiratory Muscle Weakness ◽  
Diagnosis And Management ◽  
Practical Recommendations

scholarly journals Tetraparesis and sensorimotor axonal polyneuropathy due to co-occurrence of Pompe disease and hereditary ATTR amyloidosis

2020 ◽  
Author(s):  
Milan Zimmermann ◽  
Natalie Deininger ◽  
Sophia Willikens ◽  
Tobias B. Haack ◽  
Kathrin Grundmann-Hauser ◽  
...  
Keyword(s):  
Clinical Features ◽  
Muscle Weakness ◽  
Pompe Disease ◽  
Late Onset ◽  
Single Gene ◽  
Lower Limbs ◽  
Sensory Loss ◽  
Motor Neuropathy ◽  
Transthyretin Amyloidosis ◽  
Attr Amyloidosis

Abstract Introduction/aims Hereditary transthyretin amyloidosis with polyneuropathy (hATTRPN) is an autosomal dominant multi-organ disorder manifesting in the third to fifth decade with the key clinical features of distal and painful sensory loss of the lower limbs and autonomic dysregulation. Motor neuropathy and cardiomyopathy evolve in the course of the disease. Pompe disease is an autosomal recessive disease leading to decreased levels of lysosomal enzyme acid α-glucosidase and proximal muscle weakness. We report the clinical features and diagnostic workup in the rare case of a patient with ATTR amyloidosis and late-onset Pompe disease, both genetically confirmed. Methods We performed a detailed clinical assessment, exome sequencing, and biochemical measurements. Results The patient presented with a distal, painful hypaesthesia of both legs, a cardiomyopathy, and a muscle weakness in the form of a girdle-type pattern of the arms and legs at the beginning and a spreading to distal muscle groups in the course of disease. Discussion This study highlights the importance of searching for co-occurrence of rare monogenetic neuromuscular diseases, especially in cases in which all clinical features can be readily explained by a single gene defect.

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