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All Children Diagnosed With “Adult” IVS Mutations at Birth Need Comprehensive Clinical Evaluation for Pompe Disease

Lauren Bailey - Speaker World Symposium 2017Lauren A. Bailey, MS

February 18, 2017—San Diego, California—The presence of clinical symptoms in early infancy and possibility of detecting the IVS mutation by newborn screening stresses the need for comprehensive clinical evaluation and a management guideline of all children diagnosed with “adult” mutations at birth.

This conclusion, based on results of a case series of five infants diagnosed with Pompe disease via newborn screening, was presented at the 13th Annual WORLDSymposium, from February 13–18.

Lauren A. Bailey, MS, of Duke University Medical Center, Durham, North Carolina, presented a series of five infants diagnosed with Pompe disease via newborn screening who carried the commonly associated “adult” mutation c.-32-13T ≤G in the heterozygous or homozygous state.

On vigilant clinical evaluation, these children exhibited subtle symptoms consistent with disease onset in the first months of life. Symptoms noted on physical therapy evaluation included feeding difficulties, failure to thrive, motor developmental delay, milestone regression, and motor dysfunction.

None of the cases had significant cardiac involvement. Urinary Glcα1-6Glcα1-4Glcα1-4Glc (Glc4) was within normal limits in these individuals, so this measurement may not be an appropriate screening tool in this situation.

Detailed physical therapy assessment, especially looking for limb-girdle muscle involvement and iliotibial band tightness, was often the mode of symptom ascertainment and was an essential part of the clinical workup determining the need for enzyme replacement therapy.

Prior to the implementation of newborn screening for Pompe disease, individuals with this mutation were not expected to exhibit any clinical symptoms until adulthood and, therefore, were not treated with enzyme replacement therapy until overtly symptomatic. Additionally, a long diagnostic odyssey from initial symptom onset to proper diagnosis further delayed intervention with enzyme replacement therapy.

At least three such cases diagnosed clinically prior to the implementation of newborn screening were used to contrast the severity of clinical symptoms, diagnostic delay, and resultant disease burden when enzyme replacement therapy was deferred.

In addition to glycogen accumulation, autophagy and lipofuscin accumulation in skeletal muscles occur in Pompe disease, leading to irreversible damage while also interfering with both lysosomal function and treatment efficacy. This deterioration further emphasises the need for early treatment initiation.

Ms. Bailey concluded that the presence of clinical symptoms in early infancy and possibility of detecting the IVS mutation by newborn screening stresses the need for comprehensive clinical evaluation and a management guideline of all children diagnosed with “adult” mutations at birth.

Specific physical therapy guidelines are also needed to standardise the evaluation that children receive after being diagnosed via newborn screening. The recommendation for treatment should be based on the presence of the often-overlooked subtle clinical symptoms, rather than on previously assumed genotype-phenotype correlations prior to the development of extensive and often irreversible skeletal muscle damage.

“As a genetic counsellor,” Ms. Bailey said, “what stood out was the impression that ‘late onset’ or ‘adult onset’ exerted on families. In the genetic community, ‘late onset’ could simply mean any presentation other than the classic infantile form with severe cardiac involvement. But to families, this was interpreted as truly adult onset. The idea that their children could show symptoms at age 2, 5, or 10 years was not a possibility in their minds. It is okay for clinicians to say ‘we don’t know.’ We don’t have a crystal ball and we cannot predict the exact age of symptom onset and the age at which enzyme replacement therapy is needed based on a patient’s mutations. While the uncertainty is challenging for a family, they cope better with this narrative rather than believing this scenario is decades away and having to readjust.”

She continued, “As newborn screening for Pompe and other genetic conditions continues to spread to more states, it is important for clinicians to monitor these children with clinical evaluation, laboratory values, and medical judgement, in addition to input from the family, on when to recommend the initiation of enzyme replacement therapy. We are not recommending that every child identified on newborn screening be started on enzyme replacement therapy, but rather, that they should be monitored closely so that the emergence of symptoms is not missed. In this way, the delay between symptom onset and early treatment intervention will be lessened.”

She added, “We are learning. Until these children who are diagnosed via newborn screening grow and their data can be analysed, we won’t know the overall lessons learned from this endeavour. But the physicians, advanced practice providers, and genetic counsellors involved are dedicated and passionate about this patient population and are learning along the way.”

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.


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