LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population

Musumeci, Olimpia; Marca, Giancarlo la; Spada, Marco; Mondello, Stefania; Danesino, Cesare; Comi, Giacomo P.; Pegoraro, Elena; Antonini, Giovanni; Marrosu, Gianni; Liguori, Rocco; Morandi, Lucia; Moggio, Maurizio; Massa, Roberto; Ravaglia, Sabrina; Muzio, Antonio Di; Filosto, Massimiliano; Tonin, Paola; Iorio, Giuseppe Di; Servidei, Serenella; Siciliano, Gabriele; Angelini, C.; Mongini, Tiziana; Toscano, Antonio

doi:10.1136/jnnp-2014-310164

Cited by 45 publications

(78 citation statements)

References 24 publications

(16 reference statements)

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“…Most patients presented with a phenotype of LGMW 5 with or without hyperCKemia and only 18% as isolated hyperCKemia. Symptoms or signs of respiratory involvement were present in 21.4% and paraspinal muscle weakness was reported in 27.7%.…”

Section: Resultsmentioning

confidence: 99%

“…One patient had positive family history for neuromuscular disorder. All patients presented with LGMW 5 , corresponding to 4% of our cohort and 4.9% of patients presenting with LGMW. PD 1 patients were Caucasian, 75% male, with age of onset of symptoms ranging from 2.5 to 48 years (mean 22.6 y).…”

Section: Resultsmentioning

confidence: 99%

“…Estimated worldwide incidence of all forms of PD 1 is 1 in 40,000 live births [1,5], but several studies showed that incidence rate may vary among different ethnic populations, ranging from 1:14,000 in an African American population to 1:600,000 in a Portuguese population [7]. There are some data that permit estimate the prevalence of PD 1 in Caucasian to 1-2:100,000 [7].…”

Section: Pdmentioning

confidence: 99%

“…The clinical manifestations of LOPED 2 overlap with other neuromuscular disorders, mainly muscle dystrophies, but also include atypical clinical features as isolated respiratory failure or non-muscular symptoms such as scoliosis, hearing impairment and arrhythmia [5]. Some red flags for the diagnosis of PD 1 have been proposed as the disproportionate axial and respiratory muscle involvement, in comparison with limb muscle weakness, the presence of mild non-dystrophic myopathic features on muscle biopsy and mild CK elevation (usually below 1000) [6].…”

Section: Pdmentioning

confidence: 99%

“…Although an accurate and early diagnosis of LOPD 2 is difficult to achieve, early treatment was reported to be associated to a better efficacy of the therapy [4]. DBS 3 has been successfully used to screen for PD 1 and is suggested to be the optimal initial diagnostic test, followed by biochemical assays on a different tissue and/or genetic analysis to confirm positive cases [5]. Two DBS 3 techniques are currently available, fluorometry and tandem mass spectrometry, both with consistent results [5].…”

Section: Pdmentioning

confidence: 99%

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Screening for Pompe disease in a Portuguese high risk population

D’Almeida

Conceição

Fineza

et al. 2017

Neuromuscular Disorders

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Pompe disease is a rare metabolic disorder with available enzymatic replacement therapy. Contrasting with the classic infantile form, the others subtypes have a heterogeneous presentation that makes an early and accurate diagnosis difficult. We conducted a prospective, multicenter, observational study to identify undiagnosed patients. During a one-year period, patients followed in Portuguese neuromuscular outpatient clinics with proximal muscle weakness affecting upper and/or lower limbs, hyperCKemia in two or more determinations or hypotonia and hyperCKemia, were screened for acid α-glucosidase deficiency by dried blood spots. Lysosomal acid-alpha-1,4-glucosidase activity was determined by tandem mass spectrometry and positive results were confirmed by molecular study. From the 99 patients screened, Pompe disease was confirmed in 4, with age of onset ranging from 2.5 to 48 years, all with limb girdle muscle weakness, corresponding to a frequency of 4% in our cohort and 4.9% of limb girdle muscle weakness. Screening for Pompe disease in high risk populations, using dried blood spots, was already performed in some European populations. Apart from two negative Scandinavian studies, positive cases were confirmed in 2.8-7.9% of patients presenting with limb girdle muscle weakness and in 0-2.5% with isolated hyperCKemia.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Pdmentioning

confidence: 99%

Section: Pdmentioning

confidence: 99%

Section: Pdmentioning

confidence: 99%

See 3 more Smart Citations

Screening for Pompe disease in a Portuguese high risk population

D’Almeida

Conceição

Fineza

et al. 2017

Neuromuscular Disorders

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Vacuolated PAS‐positive lymphocytes as an hallmark of Pompe disease and other myopathies related to impaired autophagy

Pascarella¹,

Terracciano

Farina

et al. 2018

Journal Cellular Physiology

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Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-α-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive, and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the 13 LOPD offspring. These latter resulted to have all a single GAA mutation but low GAA levels. Immunostaining with the autophagy markers LC3 and p62 confirmed the autophagic nature of lymphocytes vacuoles. ROC curve assessment of PAS-positive lymphocytes disclosed 100% of sensitivity and 94% of specificity in recognizing both compound heterozygous and heterozygous GAA carriers. The other myopathies with more than 4 PAS-positive lymphocytes appeared to be all related to impaired autophagy, which seems to be responsible of PAS-positive vacuolated lymphocytes formation. Quantification of PAS-positive lymphocytes in blood films is useful to identify autophagic vacuolar myopathies and should be routinely used as first level test for Pompe disease.

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Diagnostic delay in late‐onset Pompe disease among Chinese patients: A retrospective study

Yue,

Jiao,

Xia

et al. 2023

JIMD Reports

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Surveys and retrospective studies have revealed considerable delays in diagnosing late‐onset Pompe disease (LOPD) in China, where the contributing factors remain poorly represented. Our study analyzed the diagnostic journey of 34 LOPD patients seen at our neuromuscular clinic from 2005 to 2022. We defined diagnostic delay as the time from the onset of the first relevant symptoms and laboratory findings suggestive of LOPD to the eventual diagnosis, and we constructed a correlation matrix to assess relationships among these variables. The cohort consisted of 34 patients with an equal male‐to‐female ratio, and the mean age at diagnosis was 27.68 ± 10.03 years. We found the median diagnostic delay to be 5 years, with a range of 0.3 to 20 years, with 97.1% having been misdiagnosed previously, most commonly with “Type II Respiratory insufficiency” (36.7%). Notably, patients at earlier onset (mean age, 18.19 years vs. 31 years; p < 0.005) tended to have higher creatine kinase (CK) levels. Furthermore, 92.6% reported difficulty in sitting up from a supine position since childhood. Our research emphasizes the role of early indicators like dyspnea and difficulty performing sit‐ups in adolescents for timely LOPD diagnosis and treatment initiation. The importance of early high‐risk screening using dried blood spot testing cannot be overstated.

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LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population

Cited by 45 publications

References 24 publications

Screening for Pompe disease in a Portuguese high risk population

Screening for Pompe disease in a Portuguese high risk population

Vacuolated PAS‐positive lymphocytes as an hallmark of Pompe disease and other myopathies related to impaired autophagy

Diagnostic delay in late‐onset Pompe disease among Chinese patients: A retrospective study

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