Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center

Abstract

Purpose

Pompe disease (PD) is an autosomal recessive disorder caused by a deficiency of acid alphaglucosidase resulting from pathogenic GAA variants. This study describes the clinical features, genotypes, changes before and after enzyme replacement therapy (ERT), and long-term outcomes in patients with infantile-onset PD (IOPD) and late-onset PD (LOPD) at a tertiary medical center.

Methods

The medical records of 5 Korean patients (2 male, 3 female patients) diagnosed with PD between 2002 and 2013 at Samsung Medical Center in Seoul, Republic of Korea were retrospectively reviewed for data, including clinical and genetic characteristics at diagnosis and clinical course after ERT.

Results

Common initial symptoms included hypotonia, cyanosis, and tachycardia in patients with IOPD and limb girdle weakness in patients with LOPD. Electrocardiography at diagnosis revealed hypertrophic cardiomyopathy in all patients with IOPD who showed a stable disease course during a median follow-up period of 10 years. Patients with LOPD showed improved hepatomegaly and liver transaminase level after ERT.

Conclusion

As ERT is effective for treatment of PD, early identification of this disease is very important. Thus, patients with IOPD should be considered candidates for clinical trials of new drugs in the future.

Three patients with IOPD showed HCMP without outflow tract obstruction (at the age of 2 months in P1 and 9 months in P2 and P3). P3 had moderate mitral regurgitation. These patients showed improvement of ejection fraction and left ventricular posterior wall thickening after ERT (Table 3, Fig. 1, 2). Two patients with LOPD have shown normal echocardiography to date.

6. Hepatomegaly

All patients showed elevated liver enzymes at diagnosis and a decrease in these levels with ERT. Four patients (P2, P3, P4, and P5) had hepatomegaly at diagnosis, but this was improved after ERT (Tables 1, 3).

7. Skeletal deformity

Four patients (P1, P3, P4, and P5) had scoliosis, and all patients with IOPD had valgus deformity mainly in the knee or ankle (Table 3, Fig. 5). P1 had knee contracture. Three patients (P1, P3, and P5) were wheelchair-dependent.

8. Swallowing test

P1 underwent gastrostomy and fundoplication at the age of 2 years due to gastroesophageal reflux and swallowing muscle weakness according to a modified barium swallow test. P3 had silent penetration before/during/after swallowing on the test at the age of 11 years and received frequent oral feedings in small amounts. No other patients had swallowing abnormalities (Table 1).

9. Speech-language testing

P2, P3, and P5 showed an articulation disorder in the pronunciation of consonants on speech-language evaluations. The accuracy of consonant pronunciation was expressed as a percentage (Table 1). P1 could not be evaluated due to tracheostomy and severe language developmental delay.

10. Alpha-glucosidase immunoglobulin G antibody measurement

Alpha-glucosidase IgG antibody levels of all patients were measured after 9 years (range, 5–11 years) of starting ERT. All 3 patients with IOPD had no alpha-glucosidase IgG antibody, while 2 patients with LOPD showed alpha-glucosidase IgG antibody level of 1,600 U/mL in P4 and 200 U/mL in P5.

11. Developmental delay

Motor, personal-social, and language development was evaluated using the Denver Developmental Screening Test at diagnosis. The motor, personal-social, and language developmental levels in P1 were 5 months, 6 months, and 8 months, respectively, at 13 months. The developmental levels of P3 were 2 months, 5 months, and 8 months at the age of 15 months. P5 had normal language and personal-social development, but motor development was delayed to 20 months at the age of 10 years and eight months. P2 and P4 showed normal development at the time of diagnosis. The recent overall total intelligence of the P2, P4, and P5 measured by K-WISC-IV was 89 score (22.2th percentile), 86 score (18th percentile), 80 score (10th percentile), respectively, with lower scores than the average.

12. Manual muscle testing

P1 and P2 underwent MMT after 9 years of ERT. P1 only showed slight toe movement. P2 was unable to dorsiflex the ankles due to Achilles shortening, but the strength in the other muscles was good. P3 underwent MMT after 4 years and 11 years of ERT. Elbow strength showed no difference, and all other muscles showed reduced strength. P4 underwent MMT after 1 year and 5 years of ERT. In this patient, bilateral upper motor strength was grade 4 and above, but knee flexion/extension remained at grade 3/4; additionally, ankle dorsiflexion/plantarflexion increased from 4/4 to 4/5. P5 underwent MMT after 6 years and 12 years of ERT. Upper/lower motor strength decreased from 3/4 to 2/3 (Table 4).

13. Sort Form 36 Health Survey

The SF-36v2 Health Survey uses 36 questions to measure functional status and was performed at the ages of 10 years 4 months in P1, 10 years 8 months in P2, 12 years 2 months in P3, 22 years 8 months in P4, and 18 years 3 months in P5 (Table 5). The physical component score (PCS) in P1, P3, and P5, who were wheelchairdependent, was less than 20 points, while the PCS in P2 and P4, who showed no progression of muscle weakness on MMT, was 70 points or more after ERT. In P2 with IOPD, ERT began at the age of 12 months, and this patient showed a higher total score for the survey, with a mental component score of 85.3125 and a PCS of 72.5 (Table 5).

14. Side effects of ERT in patients with PD

All patients continued to receive ERT without side effects, such as sweating, headaches, elevated temperature, or hypotension via infusions of recombinant human alglucosidase alfa [23].

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