Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy

Abstract

BackgroundEnzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients’ cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants.MethodsA retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002–January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months).ResultsMedian age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients.ConclusionsThese data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.

Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?

“…Current management is an increased dosage of ERT, and it is too soon to assess the effects of this. These results are similar to several reports of patients treated early-some clear advantages but evidence of progression of disease (e.g., [13]). Ongoing progressive disease is not the only problem in assessing how much benefit there is in early diagnosis, but it is a major concern.…”

Clinical and Technological Dependence Characteristics on a Series of Brazilian Cases with Infantile Onset Pompe Disease in Enzyme Replacement Therapy

“…The median duration of treatment before death was shown to be slightly higher than other studies (8 months vs. 5.52 months and 6.7 months) [27] [28]. The Kaplan Meier survival rate at the age of 3 years was between 64.2% to 72%; and at 6 years of age from 49% to 58.8% [29] [31].…”

“…Joint deformities are observed in many genetic disorders, especially with impaired tone and muscle strength [29] [58] [59]. Ankle deformity in equine is common complication related to anterior leg muscular weakness frequently identified in IOPD [12].…”

A Newborn with Infantile-Onset Pompe Disease Improving after Administration of Enzyme Replacement Therapy: Case Report

“…20 Although this mutation is classified as potentially of low severity in a paper written in 2015 21 , it constitutes the severe form of classical infantile-onset PD in a paper written in 2018. 22 The likely cause of this condition is considered to be the modifying effect of in-gene or out-gene variants. 23,24 Besides the severity of the mutation, the course of PD is variable due to CRIM status and residual GAA enzymatic activity in muscles.…”