High Morbidity, Mortality Rates Seen in Long-Term Study of Infantile-Onset Pompe Disease


Patients with the rare disease typically present with hypertrophic cardiomyopathy and muscular hypotonia before the age of 1.

A new observational study detailed the long-term outcomes of one of the largest cohorts of patients with classical infantile-onset Pompe disease (IOPD), the most severe form of Pompe disease. 

Findings, published in the European Journal of Neurology, revealed patients demonstrated high mortality and morbidity rates over the long-term, with a secondary decline in muscular and respiratory functions.

“This decreased efficacy seems to be multifactorial, highlighting the importance to develop new therapeutic approaches targeting various aspects of pathogenesis,” authors wrote.

Pompe disease is a rare progressive metabolic myopathy that has different clinical phenotypes depending on age of onset and rate of progression.

Patients with classical IOPD often present with hypertrophic cardiomyopathy and muscular hypotonia before age 1, while “natural history studies suggest median ages of death at 6-9 months due to cardiorespiratory failure,” researchers explained. It’s estimated around 1 in 100,000 individuals will present with IOPD.

Since 2004, enzyme replacement therapy (ERT) with recombinant human (rh) lysosomal acid α-glucosidase (GAA) has been available in France to treat Pompe disease. In IOPD, the treatment has been shown to “substantially prolong survival by reducing muscular and cardiac damage.”

To better understand the long-term efficacy of ERT in patients with classical IOPD, researchers analyzed data from 64 individuals diagnosed with the condition between 2004 and 2020 in France.

At the time of diagnosis (median age 4 months), all patients had cardiomyopathy and 92% had severe hypotonia.

Analyses revealed:

  • ERT was initiated in 50 (78%) patients, and stopped later as ineffective in 10 (21%)
  • 37 (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients
  • Mortality was higher during the first 3 years of life and after the age of 12
  • Persistence of cardiomyopathy during follow-up, and/or the presence of heart failure, were highly associated with an increased risk of death
  • Cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT
  • Beside survival, a decrease of ERT-efficacy appeared after the age of 6 with a progressive decline in motor and pulmonary functions for most survivors

Patient information was gleaned from French expert centers for rare diseases. Eight individuals had a previous case of classical IOPD in their families. For those with a familial history of the condition, median age at diagnosis was earlier and median age of treatment initiation was advanced, compared with those without a family history.

The high mortality rate reported underscores the fact classical IOPD remains a severe disease despite substantial therapeutic progress made in the last couple decades, authors said.

Furthermore, “the evolution of mortality seems to be in three phases, with a high mortality rate during the three first years of life (half of the patients died during this period in our study), followed by a relatively stable period from three to twelve years of age (mortality rate about 50%), and with finally a new increase of mortality rate after twelve,” they explained.

Nearly 30% of patients with classical IOPD treated with ERT and tested for audition were deaf, suggesting hearing impairment persists despite ERT. The sensorineural type is the most common type of hearing impairment in classical IOPD.

“The main results of ourstudy were the high mortality and morbidity rates at long term, with after an initial improvement with ERT, [and] a secondary decline in muscular and respiratory functions,” authors said.

“This decrease of efficacy with time seems to be multifactorial, including a restricted diffusion of ERT in muscle and central nervous system cells, a massive autophagy buildup, an immunological response to ERT and other still unknown factors. This highlights the importance to develop new therapeutic approaches to target variousaspects of pathogenesis and to improve long-term outcomes,” they concluded.


Tardieu M, Cudejko C, Cano A, et al. Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: a French real-life observational study. Eur J Neurol. Published online May 26, 2023. doi:10.1111/ene.15894

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