Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study.

BACKGROUND: Though enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome. METHODS: Eight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated. RESULTS: All eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3-5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation. CONCLUSIONS: Our data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions.

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy.

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months -12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended.

Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapy.

OBJECTIVE: Classic infantile Pompe disease affects many tissues, including the brain. Untreated infants die within their first year. Although enzyme-replacement therapy (ERT) significantly increases survival, its potential limitation is that the drug cannot cross the blood-brain barrier. We therefore investigated long-term cognitive development in patients treated with ERT. METHODS: We prospectively assessed cognitive functioning in 10 children with classic infantile Pompe disease who had been treated with ERT since 1999. Brain imaging was performed in 6 children. RESULTS: During the first 4 years of life, developmental scores in 10 children ranged from above-average development to severe developmental delay; they were influenced by the type of intelligence test used, severity of motor problems, speech/language difficulties, and age at start of therapy. Five of the children were also tested from 5 years onward. Among them were 2 tetraplegic children whose earlier scores had indicated severe developmental delay. These scores now ranged between normal and mild developmental delay and indicated that at young age poor motor functioning may interfere with proper assessment of cognition. We found delayed processing speed in 2 children. Brain imaging revealed periventricular white matter abnormalities in 4 children. CONCLUSIONS: Cognitive development at school age ranged between normal and mildly delayed in our long-term survivors with classic infantile Pompe disease treated with ERT. The oldest was 12 years. We found that cognition is easily underestimated in children younger than 5 years with poor motor functioning.

Effects of alpha-thrombin on superoxide dismutase levels in human cerebral microvascular endothelial cells.

BACKGROUND: Sequelae of traumatic brain injury include generation of oxygen-free radicals and fibrin deposition, which worsen the initial injury. Superoxide dismutases (SODs) scavenge and bind to the free-radical superoxide anion (O2-), potentially defending against oxidative stress. In the present study, we investigated the production of SOD within human cerebral microvascular endothelial (HCME) cells after exposure to alpha-thrombin, hypothesizing that manganese SOD (MnSOD) expression is increased. Our aims were to determine whether alterations in SOD are observed at the mRNA level, to examine whether a particular species is preferentially expressed, and to determine the requirement of the active site of alpha-thrombin. METHODS: HCME cells were characterized and grown to confluence. Control cells and cells exposed to 10 nmol/L alpha-thrombin were harvested for mRNA isolation using reverse transcriptase-polymerase chain reaction. Quantitation of mRNA production determined the levels of copper-zinc SOD and MnSOD. Active site blocked alpha-thrombin was used as a negative control and determined the specificity of the response. RESULTS: The cells in culture were identified as endothelial after fulfilling criteria, such as positive immunocytochemical staining for factor VIII/von Willebrand factor antigen and binding of Ulex europaeus agglutinin-1 lectin. Levels of MnSOD mRNA were elevated at all time points in response to alpha-thrombin, whereas the cytosolic form was undetectable. HCME cells that were exposed to active site-blocked alpha-thrombin produced mRNA levels of MnSOD that were increased above those of controls, but this increase was half that of mRNA levels of MnSOD produced by HCME cells that were exposed to alpha-thrombin. CONCLUSION: Our study showed for the first time that alpha-thrombin partially modulates SOD in HCME cells, causing a preferential increase in MnSOD. Further investigation into secondary brain injury will provide insights into the role of alpha-thrombin in the mechanism of free radical-induced alterations, potentially improving the outcome of patients with head injury.