Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficient acid α-glucosidase (GAA) activity, which results in progressive, debilitating, and often life-threatening symptoms, involving musculoskeletal, respiratory, and cardiac systems. In infantile-onset Pompe disease, enzyme replacement therapy can prolong survival and reverse cardiomegaly; however, some of patients cannot recover their motor and respiratory function. In late-onset Pompe disease, most of the symptoms cannot be reversed by treatment. In this study, we hypothesize that newborn screening for Pompe disease can offer an opportunity for early treatment of Pompe disease.
The primary manifestations of Pompe disease are muscle weakness and cardiomyopathy. Although accumulation of glycogen has also been seen in the nervous system in patients, the significance of brain involvement in infantile-onset Pompe disease is not clear. In the first part, we evaluated the brain development in five cases of infantile-onset Pompe disease, whose survivals have been prolonged by enzyme replacement therapy (ERT). Brain magnetic resonance imaging (MRI) and MR spectroscopy (MRS) studies revealed all patients having delay in myelination milestones at a median age of 6 months before the initiation of treatment. After ERT, four of the five cases showed good progression in myelination, left with only mild dilatation of the ventricles. In one case who had no response to ERT in the muscles, his brain myelination was slow and MRI and MRS studies both suggested neuron and myelination loss. Therefore, although myelination defects occur early in
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infantile-onset Pompe disease, it does not prevent an effective treatment.
In the second part of the study, we tested the feasibility of screening newborns for Pompe disease using a fluorometric assay measuring GAA activity in dried blood spots (DBS). We conducted a large-scale newborn screening pilot program involving approximately 45% of newborns in Taiwan.
The unscreened population was served as a control. Between October 2005 and March 2007, 132,538 newborns were screened; 1093 (0.82%) repeat DBS samples were requested; 121 babies (0.091%) were called for a confirmatory testing. Pompe disease was finally diagnosed in 4 babies. The prevalence of infantile-onset Pompe disease from the screening program was similar to data from the control group (three patients diagnosed). However, newborn screening resulted in an earlier diagnosis: less than 1 month of age in comparism to 3–6 months in the control group. At diagnosis, three of the four babies already had cardiomegaly and vaculomyopathy, though clinically they were asymptomatic.
This is the first large-scale study to prove the feasibility of newborn screening for Pompe disease.
Since diagnosis prior to the development of severe symptoms can be made by newborn screening, we then report the improvement in outcomes for the six patients screened from 206,088 newborns. ERT was immediately started for five of the six paitents who had the rapidly progressive form of Pompe disease characterizing by both cardiac and motor involvements; treatment for the other one patient started at 14 months of age because of slow progressive muscle weakness. Results of the the treatment were then compared to those patients diagnosed clinically or the untreated historical controls. At the time of
this report, patients have been treated for 14 to 32 months. The five infants who had early cardiac involvement demonstrated normalization of cardiac size and muscle pathology with normal physical growth and age-appropriate gains in motor development. The infant without cardiac involvement also achieved normal motor development with treatment. Survival in the screened patients was significantly improved as compared to the untreated reference cohort (P=0.001). Survival in the treated clinical comparators was reduced but was not statistically different from the newborn screening group (P=0.48). Results from this study indicate that early treatment can benefit infants with Pompe disease and highlight the advantages of early diagnosis, which can be achieved by newborn screening.
Besides the four patients, another 117 babies were asked for a confirmatory blood test due to persistent low GAA activity. We analyzed 107 of them for both GAA activity and gene mutations. Nine of them have GAA activity lower than 3% of the normal mean, a status of GAA deficiency, but only 7 bearing 2 mutatecd alleles. Four of them had infantile-onset Pompe disease, and have been treated for cardiomegaly (in 3) or hypotonia (in 1).
Another three of them were suspected to have late-onset pompe disease because they remained asymptomatic. Sixty-eight of the 103 newborns (66.0%) had a known deleterious mutation (44/103) or a sequence variant of unknown significance (31/103) and seven had both. One reported mutation, p.D645E, was the most common mutation Thirty-three (33/103 or 31.4%) of the 35 newborns without detectable mutation were homozygous for the [p.G576S + p.E689K] pseudodeficient allele. We also identified 16 novel variants and 6 distinct haplotypes, one of which has never been described in this population.
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These results increase our knowledge of Pompe disease and demonstrate the benefits of newborn screening programs.
We further expand the mutation detection in all clinical IOPD and LOPD patients, and babies suspecting an LOPD phenotype. The common mutation, p.D645E, is the most common mutation in all groups, although the prevelance is highes in clinical IOPD patients, but its prevalence is lower in clinical LOPD patients, and is lowest in babies suspecting an LOPD phenotype.
Babies suspecting an LOPD phenotype have a higher incidence of mutation alleles with unknown significance. Through the screening, we found many gene variations in our population, some of them cause “pseudodeficiency” of acid alpha glucosidase activity, and we cannot exclude that those variations can modify the clinical manifestations of the disease.
Results from this study highlight the benefits of early diagnosis, which can only be achieved by newborn screening. The intense gene variation in the population may confuse the diagnosis. The incidence of late-onset Pompe disease needs to be proved, but clinical underdiagnosis of Pompe disease is certainly possible.