PracticeUpdate Conference Series_WORLDSymposium 2019

Early-Onset Pompe Disease Linked to c.-32-13TNG Variant Careful evaluation of symptoms is needed in patients with the variant.

T he onset of symptoms, including gross motor delay, swallow/feeding difficulties and sleep apnea, in the first 2 years of life is not uncom- mon in individuals with late-onset Pompe disease, conclude results of a retrospective chart review. Stephanie Austin, MD, of Duke University in Durham, North Carolina, and colleagues set out to identify patients diagnosed clinically (as opposed to through newborn screening). The charts of a cohort of 84 patients with late-onset Pompe disease with the c.-32-13TNG variant were reviewed. Their symptom onset was documented clinically within the first 2 years of life. Four patients experi- enced early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included gross motor delay, swallow/feeding difficul- ties and sleep apnea. Early deviations in skeletal muscle posture and move- ment were identified in all subjects. Age at diagnosis ranged from 10 to 26 months. Median age at the initiation of enzyme replacement therapy was 23.5 months. Despite enzyme replacement therapy, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lor- dosis, scapular winging, and trunk/lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, Peabody Developmental Motor Scales-2, Bruininks-Oseretsky Test of Motor Proficiency (second edition), and 6-minute walk test. Dr. Austin explained that individuals with late-onset Pompe disease and the common c.-32-13TNG variant are widely thought to suffer from milder, adult-onset disease. Reports of late-onset Pompe disease in children have not included a description

of the early-onset phenotype. This description of subtle signs and symptoms is important to facilitate prompt identification and appropriate treatment in symptomatic children. The leaky c.-32-13TNG variant is the most frequent mutation in late-onset Pompe disease. The variant gives rise to alternatively spliced transcripts, including a deletion of the frst coding exon, but still allows the production of a low amount of normally processed mRNA. The c.-32-13TNG mutation has been found in over 40% of patients of Caucasian origin. A 2012 study of a large cohort of patients with a similar genotype – c.-32-13TNG in combination with a second null mutation – unexpectedly showed a signifcant variability in the age of disease onset, suggesting the role of secondary modifying factors on the clinical course. A possible factor responsible for the wide clinical variability is the deletion/deletion polymorphism in the gene coding for the angiotensin-converting enzyme, which is known to increase the number of type II fbers and influence muscle properties, is associated with earlier onset, higher creatine kinase levels, muscle pain, and more severe progression of the disease in patients with adult form. Dr. Austin concluded that the onset of symptoms, including gross motor delay, swallow/feeding difficul- ties and sleep apnea, in the first 2 years of life is not uncommon in individuals with late-onset Pompe disease and the c.-32-13TNG variant. Careful evaluation for specific gross motor posture and movement in patients with this variant is nec- essary to identify early-onset disease. Increased awareness of the early-onset signs and symptoms will enable early identification of disease onset in children diagnosed through newborn screening.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 3