Early Detection of CRIM Negative Mutations in Pompe Disease With Newborn Screening

James Radke

Recent studies examining the benefits of newborn screening for Pompe disease have dramatically changed our perceptions of this rare disease.  In February, studies presented at WORLDSymposium showed that our definition of late-onset Pompe disease may need to change since some of those patients may begin to show symptoms when they are less than a year old.
And at the ACMG Annual Clinical Genetics Meeting in Phoenix, new data is showing that newborn screening of early-onset Pompe disease can also assist patients  get the most effective care possible.
Dempsey et al presented a case study involving baby identified through newborn screening with infantile-onset Pompe disease. At 3 weeks the baby looked healthy with no signs of hepatomegaly, hypotonia, or cardiac mumru. 
A diagnose of Pompe disease was confirmed with low GAA enzyme activity (1.00 pmol/punch/hr; reference >3.88) and elevated urine Glc4 (glucose tetrasaccharide; 28.6 mmol/mol creatinine; reference =<20.0). Mutation analysis revealed two pathogenic mutations in the GAA gene (C.525delT  [p.Glu176Argfs*45]  and C.2560C>T [p.Arg854X]). These 2 mutations are cross-reactive immunological material (CRIM)-negative mutations Previous studies have shown that Pompe patients with CRIM-negative mutations should begin enzyme replacement therapy (ERT) early along with prophylactic immune tolerance induction (ITI) therapy.
ITI therapy ( rituximab, methotrexate, and IVIG) plus ERT (with alglucosidase alfa) began at 5-weeks of age. Physical exam at that time was significant for interim development of hypotonia and hepatomegaly with liver edge palpated 3cm below the costal margin. A 2/6 systolic murmur was heard and echocardiogram showed severe biventricular hypertrophy (L>R) with mild left ventricular outflow tract obstruction. Following initial treatment, infusions occurred every two weeks and have been well tolerated.
At three months of age the patient is doing well.  His hepatomegaly has resolved and repeat echocardiograms show marked improvement (no right ventricular hypertrophy, mild left ventricular hypertrophy, and no outflow tract obstruction). Urinary Glc4, a biomarker for monitoring ERT efficacy, is within the normal range.
This case further illustrates the important benefit that newborn screening has to patients with Pompe disease as well as verifying the algorithm developed last year for identifying and managing various subpopulations of Pompe patients (see algorithm below).


Dempsey K, Schillaci L, Desai A, et al. Newborn Screen for Pompe Disease Requires Rapid Evaluation and Initiation of Immune Tolerance Induction for a CRIM-Negative Infant. Poster presented at the ACMG Annual Clinical Genetics Meeting; Phoenix AZ; March 21-24, 2017. Abstract 67.
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