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

Kexin Jiao; Jihong Dong; Sushan Luo; Liqiang Yu; Qing Ke; Zhiqiang Wang; Xinghua Luan; Xiaojie Zhang; Junhong Guo; Yan Chen; Xihua Li; Song Tan; Fangyuan Qian; Jianming Jiang; Xuen Yu; Dongyue Yue; Changxia Liu; Lijun Luo; Jianping Li; Yanzhou Qu; Lan Chen; Jianglong Tu; Chong Sun; Chong Yan; Jie Song; Jianying Xi; Jie Lin; Jiahong Lu; Chongbo Zhao; Wenhua Zhu; Qi Fang

doi:10.3389/fneur.2022.965207

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

Front Neurol. 2022 Sep 27:13:965207. doi: 10.3389/fneur.2022.965207. eCollection 2022.

Authors

Kexin Jiao^{1

2

3}, Jihong Dong⁴, Sushan Luo^{1

2

3}, Liqiang Yu⁵, Qing Ke⁶, Zhiqiang Wang⁷, Xinghua Luan⁸, Xiaojie Zhang⁸, Junhong Guo⁹, Yan Chen¹⁰, Xihua Li¹¹, Song Tan¹², Fangyuan Qian¹³, Jianming Jiang¹⁴, Xuen Yu¹⁵, Dongyue Yue¹⁶, Changxia Liu¹⁷, Lijun Luo¹⁸, Jianping Li¹⁹, Yanzhou Qu²⁰, Lan Chen²¹, Jianglong Tu²², Chong Sun^{1

2

3}, Chong Yan^{1

2

3}, Jie Song^{1

2

3}, Jianying Xi^{1

2

3}, Jie Lin^{1

2

3}, Jiahong Lu^{1

2

3}, Chongbo Zhao^{1

2

3}, Wenhua Zhu^{1

2

3}, Qi Fang⁵

Affiliations

¹ Department of Neurology, Huashan Hospital Fudan University, Shanghai, China.
² National Center for Neurological Disorders (NCND), Shanghai, China.
³ Huashan Rare Disease Center, Shanghai Medical College, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Department of Neurology, The First Affiliated Hospital of Soochow University, Shanghai, China.
⁶ Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, Zhejiang, China.
⁷ Department of Neurology, Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁸ Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁹ Department of Neurology, First Hospital, Shanxi Medical University, Taiyuan, China.
¹⁰ Department of Neurology, Tongji Hospital, Tongji University, Shanghai, China.
¹¹ Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.
¹² Department of Neurology, School of Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
¹³ Department of Neurology, School of Medicine, Affiliated ZhongDa Hospital, Research Institution of Neuropsychiatry, Southeast University, Nanjing, China.
¹⁴ Department of Neurology, First Affiliated Hospital to Naval Medical University, Shanghai, China.
¹⁵ Affiliated Hospital of the Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China.
¹⁶ Department of Neurology, Jing'an District Center Hospital of Shanghai, Fudan University, Shanghai, China.
¹⁷ Department of Neurology, The Fourth Affiliated Hospital of Nantong University, Yancheng, China.
¹⁸ Department of Neurology, Wuhan No.1 Hospital, Wuhan, China.
¹⁹ Department of Geriatrics, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
²⁰ Department of Neurology, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
²¹ Department of Neurology, Nantong first people's Hospital, Nantong, Jiangsu, China.
²² Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.

Abstract

Introduction: The 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.

Methods: Between 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.

Results: Among 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.

Conclusion: Less 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.

Keywords: dried blood spot; high-risk screening; late-onset Pompe disease; respiratory failure; tandem mass spectrometry.