Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13 T > G variant

Mol Genet Metab. 2019 Feb;126(2):106-116. doi: 10.1016/j.ymgme.2018.08.009. Epub 2018 Aug 23.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Replacement Therapy
  • Female
  • Genetic Variation*
  • Glycogen Storage Disease Type II / diagnosis*
  • Glycogen Storage Disease Type II / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Phenotype
  • Retrospective Studies
  • Time Factors
  • alpha-Glucosidases / genetics*


  • GAA protein, human
  • alpha-Glucosidases