High-risk screening of late-onset Pompe disease: A different early portrait in China

Abstract

IntroductionThe lack of knowledge regarding the differences between Chinese and other ethnicities in the early manifestation of late-onset Pompe disease (LOPD) prohibits the development of an effective screening strategy. We conducted a multicenter screening study to determine LOPD prevalence in high-risk populations and define the early manifestation of LOPD in China.MethodsBetween August 2020 and April 2021, the participants were prospectively identified through medical examination at 20 centers from inpatient departments and outpatient neuromuscular clinics in China. The inclusion criteria were as follows: (1) age ≥ 1 year and (2) either one of the following conditions: (a) persistent hyperCKemia, (b) muscle weakness of the axial and/or limb-girdle muscles, or (c) unexplained restrictive respiratory insufficiency (RI). Enzymatic activity of acid α-glucosidase (GAA) was measured in a dried blood spot (DBS) using a tandem mass spectrometry (MS/MS) assay. Next-generation sequencing (NGS) was used to evaluate all samples with decreased GAA activity, searching for GAA mutations and pseudodeficiency alleles.ResultsAmong the 492 cases, 26 positive samples (5.3%) were detected in the DBS test. Molecular studies confirmed a diagnosis of LOPD in eight cases (1.6%). Using MS/MS assay, GAA activities in individuals with pseudodeficiency could be distinguished from those in patients with LOPD. The median interval from the onset of symptoms to diagnosis was 5 years. All patients also showed RI, with a mean forced vital capacity (FVC) of 48%, in addition to axial/proximal muscle weakness. The creatine kinase (CK) level ranged from normal to no more than 5-fold the upper normal limit (UNL). LOPD with isolated hyperCKemia was not identified.ConclusionLess frequent hyperCKemia and predominant RI depict a different early portrait of adult Chinese patients with LOPD. A modified high-risk screening strategy should be proposed for the early diagnosis of Chinese patients with LOPD.

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

“…The c.2238G>C (p.W746C) variant was the most prevalent, found in 32.4% (22/68) of alleles. Besides the previously reported c.568C>G (p.R190G) and c.1928G>C (p. G643A), 17 two novel variants, c.1444C>T (p.P482S) and c.521A>G (p.E174G), were identified in two independent patients, respectively. They were categorized as “Likely pathogenic” and “uncertain significance” according to established criteria, respectively (Table S2 ).…”

“…This indicates that China is still an underrepresented region, in which the full genetic landscape of LOPD remains uncharted. Nevertheless, the finding that hyperCKemia was rarely solely presented as an initial symptom illustrated a different early portrait of Chinese LOPD 17–21 …”

“…Unlike in south China where most of the childhood‐onset LOPD are carriers of the c.1935C>A variant, 15 in our study carriers of c.2238G>C variant with the manifestation in adolescence presented with LGMW with/without hyperCKemia instead of early respiratory failure. On the other hand, compared to populations that carriers of the leaky splicing mutation IVS1 comprising the majority of adult LOPD patients, adult‐onset patients with c.2238G>C tended to develop respiratory insufficiency earlier 17,26 . Whether there are other phenotypic modifiers at play besides the hotspots remains to be elucidated.…”

“…Nevertheless, the finding that hyperCKemia was rarely solely presented as an initial symptom illustrated a different early portrait of Chinese LOPD. [17][18][19][20][21] The prompt diagnosis in patients presenting LGMW symptoms is challenging due to its non-specificity in a variety of neuromuscular disorders and other systemic conditions. The red flag of Pompe disease would not be raised until histological studies revealed vacuolar myopathy with excessive glycogen, resulting in diagnostic delay in general approach of differentiation.…”

“…Nevertheless, the finding that hyperCKemia was rarely solely presented as an initial symptom illustrated a different early portrait of Chinese LOPD. 17 , 18 , 19 , 20 , 21 …”