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Ptosis in Pompe Disease: Common Genetic Background in Infantile and Adult Series

Ravaglia, Sabrina MD, PhD; Moglia, Arrigo MD; Garaghani, Kolsoum Saeidi MD; Danesino, Cesare MD, PhD

Journal of Neuro-Ophthalmology: December 2010 - Volume 30 - Issue 4 - p 389
doi: 10.1097/WNO.0b013e3181f9a923
Letters to the Editor

Department of Neurological Sciences (SR, AM), University of Pavia, Pavia,; Institute of Medical (KSG, CD), Genetics University of Pavia, Pavia, Italy

Yanovitch et al (1) reported a patient with nonclassic infantile Pompe disease, who developed “slowly progressive, variable, bilateral ptosis” at the onset of myopathic signs at an age of 9 months. Ptosis slowly progressed through the adolescence along with the progression of skeletal and respiratory muscle weakness. At the age of 13 years, the patient started enzyme replacement therapy (ERT), which failed to produce any change either of the degree of ptosis or of the skeletal muscle function. When ERT dosage was doubled, both ptosis and skeletal muscle weakness improved.

In infantile Pompe disease, the development of ptosis has not been described previously. Literature data are limited to 4 reports concerning adults, recently reviewed by Yanovitch et al (2): a total of 7 patients (6 women), 6 of 7 with unilateral ptosis, are described. Mutation analysis was available for 5 of 7 cases. All had the IVS13T-G mutation in 1 allele, and the second mutation led to complete loss of alpha-glucosidase activity, which is typically found in infantile-onset disease: the 525delT in 2 patients; delExon18 in 2 patients; and Trp516Stop in 1 patient (see Pompe mutation database: In the same publication (2), the authors reported the development of bilateral ptosis in 4 of 30 ERT-treated infant patients, who survived beyond the first years of life. This figure is remarkably high (13%) compared to the seemingly rare occurrence of ptosis in late-onset Pompe disease.

The effectiveness of ERT on ptosis is unknown. In our cohort of 28 patients with late-onset disease, only 1 patient, carrying the 525delT mutation, had bilateral severe ptosis. After 3 years of ERT, despite improvement in walking and respiratory function, the patient still shows severe bilateral ptosis. We do not know about the treatment outcome of the 4 patients with Pompe disease described by Groen et al (3), but we suspect that a positive response would have been considered worth reporting.

Based on our own experience and that reported by Yanovitch et al (1), we can draw the following conclusions:

1. Ptosis has a higher prevalence and is more severe in children than in adults with Pompe disease. All the reported infantile cases showed bilateral ptosis, while bilateral ptosis has been reported in only 1 adult (the remainder showing unilateral involvement).

2. The above clinical finding is consistent with the observation that the mutations detected in adult patients with ptosis (in addition to the IVS13T-G) are those typically found in the infantile disease. Ptosis was previously unrecognized in the infantile form because of the shortened lifespan of these patients. This suggests that ERT has altered the natural history of the infantile form, leading to the development of additional disease complications such as hearing loss, cognitive dysfunction, and ptosis. When observed in adults, ptosis is a sentinel sign of a more severe genotype, thus possibly reflecting a more severe disease course.

3. Regardless of the age of the patient, and unlike other disease manifestations (eg, impairment of skeletal muscle strength and respiratory involvement), ptosis seems not to respond to ERT at standard dosages. The lack of response characterized the patient described by Yanovich et al (1) (in whom other disease manifestations also were resistant to treatment) as well as our patient (otherwise a responder). We do not know whether this lack of improvement of ptosis may be due to a different fiber type composition of the levator muscles compared to skeletal muscles, including the contribution of smooth muscle fibers, or with additional CNS dysfunction (affecting, for instance, the third cranial nerve nuclei in the midbrain).

Sabrina Ravaglia, MD, PhD

Arrigo Moglia, MD

Department of Neurological Sciences, University of Pavia, Pavia, Italy

Kolsoum Saeidi Garaghani, MD

Cesare Danesino, MD, PhD

Institute of Medical Genetics, University of Pavia, Pavia, Italy

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1. Yanovitch TL, Casey R, Banugaria SG, Kishnani PS. Improvement of bilateral ptosis on higher dose enzyme replacement therapy in Pompe disease. J Neuroophthalmol. 2010;30:165-166.
2. Yanovitch TL, Banugaria SG, Proia AD, Kishnani PS. Clinical and histologic ocular findings in Pompe disease. J Pediatr Ophthalmol Strabismus. 2010;47:34-40. doi: 10.3928/01913913-20100106-08.
3. Groen WB, Leen WG, Vos AM, Cruysberg JR, van Doorn PA, van Engelen BG. Ptosis as a feature of late-onset glycogenosis type II. Neurology. 2006;67:2261-2262.
© 2010 by North American Neuro-Ophthalmology Society