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Combination Assay for Newborns Proves Effective for Assessing Risk of Later-Onset Pompe Disease

Chien - Speaker World Symposium 2017

February 18, 2017—San Diego, California—A combination risk assessment correlated well with genotypes, and probably can serve as a useful reference for infants suspected of harbouring late-onset Pompe disease identified through newborn screening.

This outcome of a retrospective assessment of three markers from newborns over a 10-year period was reported at the 13th Annual WORLDSymposium, from February 13–18.

Yin-Hsiu Chien, MD, PhD, of the National Taiwan University Hospital, Taipei, explained that newborn screening for Pompe disease detects infants with both infantile-onset and later-onset Pompe disease.

A two-tier strategy combining acid alpha-glucosidase activity measurement and a cardiac evaluation can diagnose infants with cardiac involvement easily to enable immediate initiation of treatment. In infants without cardiac involvement, however, if later-onset Pompe disease is suspected, it is crucial to predict their risk of developing symptoms during childhood.

Late- or later-onset Pompe disease occurs later than 1 to 2 years and progresses more slowly than the infantile-onset form, which is usually diagnosed at 4–8 months of age.

One of the first symptoms is a progressive decrease in muscle strength, starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm and other muscles required for breathing.

Respiratory failure is the most common cause of death. Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur in some cases.

Later-onset Pompe disease differs from the infantile form principally in the relative lack of cardiac involvement. Onset is more insidious and progresses more slowly.

Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent, with a predilection for the lower limbs.

Late-onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing, and reduced vital capacity.

Prognosis depends on the age of onset of symptoms. Later-onset disease carries a better prognosis than the infantile-onset form.

In late-onset Pompe disease, creatinine kinases may be normal in some cases. Diagnosis is by estimation of enzyme activity in a suitable sample.

Respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counselling can provide families with information regarding risk in future pregnancies.

Dr. Chien and colleagues set out to determine concentrations of urinary glucose tetrasaccharide (a marker of glycogen storage and tissue damage; acid alpha-glucosidase in lymphocytes; and serum creatine kinase levels; and contrast their genotypes in 29 infants suspected of harbouring late-onset Pompe disease. The infants were identified through newborn screening from 2005 to 2015.

Comparison groups included:

  • Classic infantile-onset Pompe disease (n=12), defined as patients with evidence of hypertrophic cardiomyopathy by EKG, X-ray, and echocardiogram
  • False–positive infants (n=33)

Urinary glucose tetrasaccharide concentrations were determined using tandem mass spectrometry.

Baseline glucose tetrasaccharide concentrations were at or above the 90th percentile of the age-matched reference range in all patients with late-onset Pompe disease. All also showed marked elevation of creatine kinase levels at baseline.

Fourteen of the total 29 infants with late-onset Pompe disease exhibited elevated baseline glucose tetrasaccharide concentrations. Six, however, harboured normal serum creatine kinase at baseline. The high-risk group, defined as demonstrating elevated creatine kinase and glucose tetrasaccharide, contained 12 patients with late-onset Pompe disease and eight infants with late-onset Pompe disease.

Five of the eight patients at high risk of late-onset Pompe disease were already receiving enzyme replacement therapy. Thirteen infants with normal creatine kinase and glucose tetrasaccharide were classified as being at low risk, and most of their genotypes were novel pathologic mutations.

Dr. Chien concluded that this combination risk assessment correlated well with genotypes, and probably can serve as a useful reference for infants suspected of harbouring late-onset Pompe disease identified through newborn screening.

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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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