eP026: Newborn screening for Pompe disease: The Indiana experience


      Pompe disease (OMIM# 232300) was added to the newborn screen in 2020. During our initial 18 months of screening, 2 newborns with infantile-onset Pompe disease (IOPD) and 6 newborns at risk for late-onset Pompe disease (LOPD) were identified. One of the newborns with IOPD was CRIM-positive, the other was CRIM-negative; both were started on treatment with alglucosidase alfa (Lumizyme) before 4 weeks of age. One newborn with variants consistent with LOPD presented with borderline left ventricular hypertrophy (LVH), prompting us to start treatment. Of the 5 other infants at risk for LOPD, 2 have persistent elevations of CK levels with normal muscle strength and echocardiograms; they are being closely monitored. Two have normal development and CK levels and 1 moved out of state. A literature review of surveillance recommendations for infants at risk of LOPD revealed a lack of consensus on optimal timing for treatment initiation in infants showing early signs of disease, such as elevated CK levels without overt weakness. We feel it is important to share our data in order to assist other states who are also new to newborn screening for Pompe disease.


      The pilot program for newborn screening of lysosomal storage diseases began 6/1/2020 with an official start date of 7/1/2020. Pompe disease, Krabbe disease, and Hurler syndrome were added. To screen for Pompe disease, Indiana chose a three-tiered approach to testing. Initial screen consists of qualitative acid alpha-glucosidase (GAA) enzyme activity on dried blood spot. If abnormal, the dried blood spot card is sent to Mayo Clinic for quantitative GAA activity and (Cr/Crn)/GAA ratio. Second-tier test results are reported to the newborn screen lab, who notifies our coordinator if positive. These patients are scheduled in clinic for initial evaluation and counseling by a physician and genetic counselor. Following positive second-tier testing, reflex GAA sequencing through Mayo Clinic is ordered. Sequencing results are typically received at roughly two weeks of age. The purpose of this three-tiered approach is to definitively diagnose all patients with IOPD and clarify CRIM status in time to start treatment before 4 weeks of age.


      Since screening began, 2 infants with infantile-onset Pompe disease (IOPD) and 6 infants with late-onset Pompe disease (LOPD), as determined by their variants on GAA sequencing, have been identified. One infant identified with IOPD was CRIM-positive started on Lumizyme 40 mg/kg weekly at 3.5 weeks of age. His echocardiograms, urine Hex4, and CK levels have remained within the normal range, and he is meeting gross motor milestones ahead of schedule. The second infant diagnosed with IOPD is CRIM-negative based on the two GAA variants identified. Initial CK level was 685 U/L and echocardiogram noted borderline left ventricular and mild right ventricular hypertrophy. He underwent immune tolerance induction (ITI) with rituximab, oral methotrexate, and IVIG with dosing per published guidelines, and he was started on Lumizyme 40 mg/kg weekly at 3 weeks of age. After 2 months on treatment, his CK level normalized to 119 U/L; he continues to have borderline LVH on repeat echocardiograms, though LVM/height (2.7) has decreased from 114.79 to 83.91. Weight gain slowed during ITI which we attributed to increased vomiting while taking methotrexate; this has since resolved.
      Six infants were diagnosed with LOPD. We arranged for regular surveillance including evaluation by a neuromuscular specialist and a physical therapist every 3 months, baseline echocardiogram, regular measurement of CK levels, and referral to speech therapy for swallow evaluation in infants with clinical concern. One infant was transferred to a local genetics department after relocating out of state. Interestingly, we found that the (Cr/Crn)/GAA ratio on the dried blood spot correlated with the severity of features in most LOPD infants. Those with a higher ratio, closer to that of our IOPD infants, tended to present with earlier symptoms. One infant has been started on Lumizyme following the development of borderline left ventricular hypertrophy, with LVM/height (2.7) increasing from 51.38 to 76.48 between initial and second echocardiograms. This has resolved since starting treatment. She has three variants in the GAA gene, and we continue to investigate whether this may play a role in her accelerated presentation. Two infants have persistent mild elevations of CK but have not started treatment yet: one is age 1 year with CK level persistently 500 U/L, and one is <1 year old with CK levels persistently 200-300 U/L. Both infants have normal strength/development and echocardiograms, so we have elected to monitor closely. The other two infants have been completely asymptomatic with normal CK levels and echocardiograms.


      There is a consensus on the importance of starting Lumizyme +/- ITI in newborns with IOPD as quickly as possible, ideally no later than 4 weeks old due to strong data supporting increased survival and decreased motor impairment. We achieved this goal by communicating early with our outpatient infusion center for planning and utilizing the charitable access program to provide drug while working on insurance prior authorization and appeals. We noticed a lack of strong data regarding the appropriate time to start Lumizyme in infants with LOPD showing early symptoms. This is important for future study; given that we know infants with IOPD can suffer from irreversible muscle damage, we want to ensure that the window of optimal treatment in infants with LOPD, which is much less well defined, is not missed.