Abstract
Background: Individuals with late-onset Pompe disease (LOPD) and the common c.-32–13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Previous reports of LOPD in children do not include description of the early-onset phenotype. This description of signs and symptoms, some of which are subtle and less known, is important to facilitate prompt identification and appropriate treatment in symptomatic children. Methods: Retrospective chart review of a cohort of 84 LOPD patients with the c.-32–13 T > G variant was conducted to identify patients diagnosed clinically (as opposed to through newborn screening) who had clinically documented symptom-onset within the first two years of life. Results: Four patients had early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea. Early and characteristic alterations in posture and movement were identified in all patients. Age at diagnosis ranged from 10 months to 26 months. Median age at enzyme replacement therapy (ERT) initiation was 23.5 months. Despite ERT, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lordosis, scapular winging, and trunk and lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, the Peabody Developmental Motor Scales-2, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the six-minute walk test. Conclusions: Onset of symptoms including delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea in the first two years of life is not uncommon in individuals with LOPD and the c.-32–13 T > G variant. Patients with early-onset disease appear to have a more, rapid and severe progression of disease with persistent residual muscle deficits which partially improve with higher doses of ERT. Careful evaluation for specific and characteristic patterns of posture and movement in patients with this variant is necessary to identify those who have early onset of disease. Increased awareness of the early-onset signs and symptoms may also enable early identification of disease onset in children who are diagnosed through newborn screening.
| Original language | English |
|---|---|
| Pages (from-to) | 106-116 |
| Number of pages | 11 |
| Journal | Molecular Genetics and Metabolism |
| Volume | 126 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2019 |
Bibliographical note
Publisher Copyright:© 2018
Funding
The authors, MH, MR and HC declare that they have no competing interests. LB, SLA, and LEC have received honoraria from Genzyme Corporation. PSK has received research/grant support from Sanofi Genzyme, Amicus, Valerion, and AskBio. PSK has recevied honoraria from Sanofi Genzyme, Amicus, and AskBio. LEC has participated in research funded by Genzyme Corporation, the Leal Foundation, Valerion, and Roivant Sciences. PSK serves as an Advisory Board member for Sanofi Genzyme, AMicus, Baebies, and AskBio. LEC is a member of the Pompe Registry North American Board of Advisors for Genzyme Corporation of Sanofi. PSK has equity in Actus Theraputics, which is developing gene therapy for Pompe disease. The authors are thankful to Sophia's Pompe Strong Team, The Emerson and Barbara Kampen Foundation, and Mr. and Mrs. Allen Boger for their generous support towards research in Pompe disease. The authors are thankful to the Lysosomal Storage Disease Network for their support allowing for continued research into Pompe disease. This research was supported in part by the Lysosomal Disease Network, a part of the National Institutes of Health Rare Diseases Clinical Research Network (RDCRN) - Grant number (5U54NS065768-05) (Subaward number N004689101). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The content is solely thae responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are thankful to Sophia's Pompe Strong Team, The Emerson and Barbara Kampen Foundation, and Mr. and Mrs. Allen Boger for their generous support towards research in Pompe disease. The authors are thankful to the Lysosomal Storage Disease Network for their support allowing for continued research into Pompe disease. This research was supported in part by the Lysosomal Disease Network, a part of the National Institutes of Health Rare Diseases Clinical Research Network (RDCRN) - Grant number ( 5U54NS065768-05 ) (Subaward number N004689101). The Lysosomal Disease Network is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK. The content is solely thae responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
| Funders | Funder number |
|---|---|
| Emerson and Barbara Kampen Foundation | |
| Leal Foundation | |
| Lysosomal Disease Network | |
| National Institutes of Health Rare Diseases Clinical Research Network | |
| ORDR | |
| NIH Office of Rare Diseases Research | |
| Rare Diseases Clinical Research Network | 5U54NS065768-05, N004689101 |
| National Institutes of Health (NIH) | |
| National Institute of Diabetes and Digestive and Kidney Diseases | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | U54NS065768 |
| Genzyme Corporation | |
| National Center for Advancing Translational Sciences (NCATS) | |
| Valerion Therapeutics |
Keywords
- C.-32–13 T > G
- Enzyme replacement therapy
- Glycogen storage disease type II
- IVS variant
- Late-onset Pompe disease
- Pompe disease
- Six minute walk test
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Molecular Biology
- Genetics
- Endocrinology
