Johanna Mp Van Den Hout

Enzyme replacement therapy in late-onset Pompe's disease : A three-year follow-up

Pompes disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid α‐glucosidase deficiency. Patients with late‐onset Pompes disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human α‐glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair‐bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of α‐glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human α‐glucosidase from rabbit milk has a therapeutic effect in late‐onset Pompes disease. There is good reason to continue the development of enzyme replacement therapy for Pompes disease and to explore further the production of human therapeutic proteins in the milk of mammals. Ann Neurol 2004;55:000–000

Low bone mass in Pompe disease Muscular strength as a predictor of bone mineral density

UNLABELLED Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase. The introduction of enzyme replacement therapy as treatment for the disease may change prospects for patients and may require that more attention be paid to co-morbidities such as osteoporosis. METHODS Bone mineral status was assessed in children and adults with Pompe disease and compared with reference values by means of dual energy X-ray absorptiometry (DXA) technology (GE Lunar DPX, GE Health Care). Bone mineral density (BMD) of the total body and the lumbar spine (L2-L4) was measured in adults and children; BMD of the femoral neck was measured in adults only. Exclusion criteria were: age<4 years, severe contractures, and inability to transfer the patient. RESULTS 46 patients were enrolled in the study; 36 adults and 10 children. The BMD was significantly lower in Pompe patients than in healthy individuals. Sixty-seven percent of patients had a BMD Z-score below -1, 26% were classified as osteoporosis/low bone mass for chronological age (T-score<-2.5 in adults or Z-score<-2 in children), 66% had a BMD Z-score below -1 of the femoral neck, and 34% had a BMD Z-score below -1 for the lumbar spine. Osteoporosis/low bone mass for chronological age was more frequent in patients who were wheelchair-bound, but was also observed in ambulant patients. We found a significant correlation between proximal muscle strength and total body BMD. Of the 10 children, 8 (all four patients with the classic infantile form) had a low BMD. CONCLUSION Low BMD is a frequent finding in patients with Pompe disease and may be causally related to decreased proximal muscle strength. BMD should be monitored at regular intervals. Children deserve specific attention.

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

To examine the long‐term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy.

High Sustained Antibody Titers in Patients with Classic Infantile Pompe Disease Following Immunomodulation at Start of Enzyme Replacement Therapy

Objective To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha‐glucosidase (rhGAA) in patients with classic infantile Pompe disease. Study design Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme‐linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator‐free) survival, reduction in left ventricular mass index, and improvement of motor function. Results Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. Conclusions Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.

Health Related Quality of Life, Disability, and Pain in Alpha Mannosidosis: Long-Term Data of Enzyme Replacement Therapy With Velmanase Alfa (Human Recombinant Alpha Mannosidase)

Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequel...

Cardiac outcome in classic infantile Pompe disease after 13 years of treatment with recombinant human acid alpha-glucosidase

BACKGROUND Cardiac failure is the main cause of death in untreated classic infantile Pompe disease, an inheritable metabolic myopathy characterized by progressive hypertrophic cardiomyopathy. Since the introduction of enzyme replacement therapy (ERT), survival has increased significantly due to reduced cardiac hypertrophy and improved cardiac function. However, little is known about ERTs long-term effects on the heart. METHODS Fourteen patients were included in this prospective study. Cardiac dimensions, function, conduction and rhythm disturbances were evaluated at baseline and at regular intervals thereafter. RESULTS Treatment duration ranged from 1.1 to 13.9 years (median 4.8 years). At baseline, all patients had increased left ventricular mass index (LVMI) (median LVMI 226 g/m2, range 98 to 599 g/m2, Z-score median 7, range 2.4-12.4). During the first four weeks, LVMI continued to increase in six patients. Normalization of LVMI was observed in 13 patients (median 30 weeks; range 3 to 660 weeks). After clinical deterioration, LVMI increased again slightly in one patient. At baseline, PR interval was shortened in all patients; it normalized in only three. A delta-wave pattern on ECG was seen in six patients and resulted in documented periods of supraventricular tachycardias (SVTs) in three patients, two of whom required medication and/or ablation. One patient had severe bradycardia (35 beats/min). CONCLUSION This study shows that ERT significantly reduced LVMI, and sustained this effect over a period of 13.9 years. The risk for rhythm disturbances remains. Regular cardiac evaluations should be continued, also after initially good response to ERT.