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Three New Variants of Uncertain Significance Discovered Through Newborn Screening for Pompe Disease
February 18, 2017—San Diego, California—Three variants of uncertain significance uncovered in newborn screening may be benign or pseudodeficiency alleles. None have been associated with infantile-onset Pompe disease, though their pathogenicity is still largely unknown.
This description of findings of a state newborn screening program over a 2-year period was presented at the 13th Annual WORLDSymposium, from February 13–18.
Infantile-onset Pompe disease is usually diagnosed at 4–8 months. Muscles appear normal but are limp and weak, preventing infants from lifting their head or rolling over. As the disease progresses, heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness.
Infantile-onset Pompe disease usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%), and failure to thrive (50%).
The main clinical findings include floppy baby appearance, delayed motor milestones, and feeding difficulties. Moderate hepatomegaly may be present. Facial features include macroglossia, wide-open mouth, wide-open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone.
Cardiopulmonary involvement is manifested by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias, and evidence of heart failure.
Median age at death in untreated cases is 8.7 months and is usually due to cardiorespiratory failure.
The usual initial investigations include chest X-ray, electrocardiogram, and echocardiography. Typical findings are those of an enlarged heart with nonspecific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10-fold) with lesser elevations of serum aldolase, aspartate transaminase, alanine transaminase, and lactic dehydrogenase.
Amy C. Yang, MD, of the Icahn School of Medicine at Mount Sinai, New York, explained that in the first 2 years of the New York State Newborn Screening Program for Pompe disease (2014–2016), 29 patients were evaluated at the Mount Sinai Hospital.
“I think it important,” Dr. Yang said, “to highlight the occasional challenges and ambiguities of newborn screening programs. These programs are expanding to include more disease testing. To better serve our regional communities, we need systematic and collaborative studies on the large data coming from all state screening programs. We also need to establish registries to collect outcomes data from follow-up evaluations.”
A positive screen was described as below 15% daily mean activity for acid alpha-glucosidase with at least one mutation or variant of uncertain significance identified in the acid alpha-glucosidase gene.
Seventeen babies (59%) carried at least one variant of uncertain significance in conjunction with a pathogenic mutation, pseudodeficiency allele, or another variant of uncertain significance. Dr. Yang described the clinical findings of these families to date.
Three babies were discharged after repeat enzyme testing was in the normal range. For two of these cases, the variant of uncertain significance was in the cis gene along with the other gene change. Fourteen are being followed. All were found to be normal, without hepatomegaly, hypotonia, or motor delays on examination. Nine received an echocardiogram, of whom none exhibited left ventricular hypertrophic cardiomyopathy.
Creatine phosphokinase was elevated in four; aspartate and alanine transaminase levels were normal in all. Urine Hex4, a marker of Pompe disease, was examined in 11 patients and none were elevated.
Of note, two recurrent variants of uncertain significance were present in unrelated families. Variant p.P690L was seen in two families of Ecuadorian background. This gene exhibits an allele frequency of 3.444e-05 according to the Exome Aggregation Consortium browser. One child homozygous for p.P690L was discharged due to normal enzyme activity.
Variant p.V222M was seen in four families of South Asian, Trinidadian, and Guyanese background. In the Exome Aggregation Consortium browser, p.V222M was seen in 96 South Asians with two being homozygotes, with an allele frequency of 0.0058 in South Asians.
Dr. Yang concluded that some of these variants of uncertain significance uncovered in newborn screening for Pompe disease may eventually be reclassified as benign or pseudodeficiency alleles. None have been associated with infantile-onset Pompe disease, though the pathogenicity is still largely unknown. The variants represent a notable challenge in newborn screening follow-up for Pompe disease.