Substrate reduction therapy for lysosomal storage diseases

The treatment of disordered lipoprotein metabolism with the statin class of drugs is one of the most striking successes in the field of applied medical science: here the use of selective inhibitors of the first committed step of cholesterol biosynthesis, in a complex and highly regulated pathway, leads to improved outcome from a common lipid storage disease that is a blight on whole populations--atherosclerosis. By the same token, substrate reduction is an emerging therapeutic strategy for the arcane field of the lysosomal storage diseases (LSDs). Reduced biosynthesis of glucosylceramide is postulated to allow correction of the imbalance between formation and breakdown of glycosphingolipids; the therapeutic effect of substrate reduction depends upon the presence of residual hydrolytic activity towards those accumulated glycosphingolipid substrates derived from glucosylceramide. First pioneered in the laboratory by Norman Radin, this approach has now been introduced into the clinic: based on the ability to inhibit uridine diphosphate glucosylceramide transferase, the semi-selective iminosugar, N-butyldeoxynojirimycin, is licensed for the treatment of type 1 Gaucher disease. Conclusion: Inhibition of substrate formation has wide application in the treatment of LSDs. Decreased glucosylceramide biosynthesis has therapeutic potential in glycosphingolipidoses other than Gaucher disease, and offers promise in several neurodegenerative storage disorders that are currently beyond the reach of other procedures. The results of ongoing clinical trials of miglustat in type 3 Gaucher disease, Niemann-Pick disease type C and GM2 gangliosidosis are eagerly awaited.     

Substrate reduction therapy for lysosomal storage diseases

The treatment of disordered lipoprotein metabolism with the statin class of drugs is one of the most striking successes in the field of applied medical science: here the use of selective inhibitors of the first committed step of cholesterol biosynthesis, in a complex and highly regulated pathway, leads to improved outcome from a common lipid storage disease that is a blight on whole populations – atherosclerosis. By the same token, substrate reduction is an emerging therapeutic strategy for the arcane field of the lysosomal storage diseases (LSDs). Reduced biosynthesis of glucosylceramide is postulated to allow correction of the imbalance between formation and breakdown of glycosphingolipids; the therapeutic effect of substrate reduction depends upon the presence of residual hydrolytic activity towards those accumulated glycosphingolipid substrates derived from glucosylceramide. First pioneered in the laboratory by Norman Radin, this approach has now been introduced into the clinic: based on the ability to inhibit uridine diphosphate glucosylceramide transferase, the semi-selective iminosugar, N -butyldeoxynojirimycin, is licensed for the treatment of type 1 Gaucher disease.
Conclusion: Inhibition of substrate formation has wide application in the treatment of LSDs. Decreased glucosylceramide biosynthesis has therapeutic potential in glycosphingolipidoses other than Gaucher disease, and offers promise in several neurodegenerative storage disorders that are currently beyond the reach of other procedures. The results of ongoing clinical trials of miglustat in type 3 Gaucher disease, Niemann–Pick disease type C and GM2 gangliosidosis are eagerly awaited.     

Afterload reduction therapy in patients following intraatrial baffle operation for transposition of the great arteries

Patients with intraatrial baffle procedure for transposition of the great arteries (TGA) have diastolic dysfunction, decreased exercise capacity, stroke volume response and elevated systemic vascular resistance (SVR) during exercise. Angiotensin-converting enzyme (ACE) inhibitors improve exercise capacity in adults with congestive heart failure by improving diastolic function and decreasing SVR. We tested the hypothesis that ACE inhibitors decrease SVR and improve exercise capacity in patients after intraatrial baffle procedure for TGA. We studied the effects of enalapril in nine patients with TGA s/p intraatrial switch (mean age, 13.8 ± 3 years) 7 to 21 years (mean, 12 ± 4 years) after intraatrial baffle procedure. Enalapril (0.5 mg/kg/day, maximum dosage 20 mg bid) was administered for 12 months. Patients exercised using a cycle ergometer ramp protocol (0.25 W/kg/min) before enalapril (baseline), 1 month, 6 months, and 12 months after treatment initiation. Heart rate, blood pressure, cardiac output, respiratory rate, minute ventilation, oxygen consumption (VO2), total exercise time, work, and power were measured. SVR, cardiac index, and stroke volume index (SVI) were calculated. Two-tailed paired Student's t-test was used to compare data to those of normal control patients and the patients' baseline data. Patients had lower resting heart rate, cardiac index, maximum heart rate, cardiac index (CI), SVI, VO2, exercise time, work, and power and higher maximal SVR at baseline compared to normal control patients. There was no significant difference in total exercise time, work, power, VO2 (rest/peak), SVR, SVI, and CI after 12 months of therapy compared to patients' baseline values. We conclude that short-term (<1 year) use of enalapril does not improve exercise performance in patients with TGA in whom the intraatrial baffle procedure has been performed.     

Slow, natural reduction in blood lead level after chelation therapy for lead poisoning in childhood

Lead poisoning is treated with chelating agents. We report the natural decline of blood lead (Pb-B) concentration after treatment(s) (1967 to 1972) in 74 patients whose maximal Pb-B level ranged from 100 to 471 micrograms/dL (4.83 to 22.73 mumol/L). These longitudinal data (range, nine to 17 years) disclose a predictable decrease in Pb-B levels after treatment that is independent of the maximal Pb-B level before therapy. The correlation between age in months and the logarithm of the Pb-B level was significant, and the equation defined by the regression line allows one to predict Pb-B levels at specific ages after chelation therapy. It is important to recognize the slow, natural decline of Pb-B levels after chelation therapy once the level is stable and below 70 micrograms/dL (3.38 mumol/L). Multiple repeated courses of calcium disodium edetate are unlikely to influence the natural decline of the Pb-B level in asymptomatic children.     

Successful anti-D immunoglobulin therapy in refractory chronic idiopathic thrombocytopenic purpura showing reduction in thrombocytes even after splenectomy

An 8 year old female child was treated with steroid hormones, anabolic steroid hormones and high dose γ-globulin therapy for 2 years since being diagnosed with idiopathic thrombocytopenic purpura at the age of 6 years. Treatment produced only transient efficacy, and thrombocytopenia persisted. A scintigram taken 2 years after the onset of the disease using [^l25 I]-labelled heated auto red cells revealed accumulation of radioactivities in the spleen, and therefore splenectomy was performed. However, thrombocytopenia (10 times 10⁹/L) developed again 3 weeks after the operation, for which she was treated again with high dose γ-globulin with only transient recovery. Then, anti-D immunoglobulin was injected intramuscularly at 250 μg per dose for a total of four doses and the platelet count was restored to the normal range. Since then her platelet count has been maintained higher than 200 times 10⁹/L for these 11 months. The scintigram taken after splenectomy showed an accumulation of radioactivities in the liver. After administration of anti-D immunoglobulin, transient subclinical hemolysis appeared. The mechanism whereby anti-D immunoglobulin exerts the efficacy described here may be considered to be by blockage of Fc receptors of macrophages, as is the case for high dose γ-globulin therapy. However, since the recovery in the platelet count persisted, it appears that changes in the immune system other than the above described mechanism have contributed to the recovery.     

Increase of serum lipids and serum lipoproteins in girls under therapy with estrogen and norethisteron for height reduction

The effect of a combined treatment with ethinyl estradiol and norethisteron for height reduction on serum lipids and lipoproteins was investigated in 23 excessively tall girls (greater than 97th percentile). Serum cholesterol, triglycerides, HDL-C and LDL-C were determined before and 3, 6, 9 and 12 months after the onset and 3 to 12 months after cessation of therapy. Treatment with ethinyl estradiol and norethisteron resulted in significant (p less than 0.01) mean increases in serum cholesterol, triglycerides, HDL-C, and LDL-C of 20.6%, 95.5%, 23.6%, and 22.2% above pretreatment values, respectively. This increase occurred during the first 3 months of therapy and thereafter no further significant change was observed. After cessation of therapy elevated levels returned to pretreatment levels within 3 to 12 months in all but two patients. The results obtained suggest an influence of ethinyl estradiol and norethisteron on serum lipids and lipoproteins. Whether these reversible changes of serum lipids and lipoproteins are associated with an increased risk for developing atherosclerosis has to be evaluated in long term investigations.     

Substrate utilization during the first weeks of life

It is assumed that substrate utilization changes markedly around birth, from mainly glucose utilization before, to glucose/fat utilization after birth. We studied substrate oxidation and turnover in preterm infants on the first day and during the first weeks of life. We found that only part of the glucose that is infused on the first day of life is oxidized, while glucose is also converted into fat at the same time. Almost half of the energy expenditure is provided by fat oxidation on day 7 and 28 of life. Fat oxidation is dependent on the type of fat oxidized; the rate of oxidation of medium chain triglycerides (MCT) is higher than that of long chain fatty acids. MCT can replace glucose as an energy source. Proteins contribute only to a small extent (approximately 7%) to the energy expenditure at all ages.     

The fallacy of reduction

The "accelerator hypothesis" has made a significant impact on research into the etiology of type 1 diabetes. Some, but not all prospective studies have confirmed a weak association between insulin resistance and faster progression to diabetes among persons with advanced islet autoimmunity. However, there is hardly any evidence that insulin resistance can cause development of islet autoimmunity, thus be responsible for the ongoing pandemic of type 1 diabetes in children.     

Gas reduction of intussusception

Efforts to improve the non-surgical management of childhood intussusception centre around (a) reassessment of selection criteria used to ensure as many children as possible have the advantage of hydrostatic reduction, and (b) improvements and modifications of enema technique to ensure successful and safe reductions without increased morbidity. Reports that pneumatic reduction was highly successful in treating childhood intussusception prompted the authors to evaluate this technique over an 18 month period using our previously reported technique of oxygen at 2 litres/minute and a pressure of 80 mm Hg. Pneumatic reduction was attempted in 114 of 129 consecutive cases of intussusception, and was successful in 85 (75%). Fifteen patients (8.6%) were considered unacceptable risks for gas reduction using our current selection criteria and had primary surgery. The overall success rate considering all cases of intussusception managed at our institution over this period was 66% (85/129). As with any form of hydrostatic reduction, pneumatic reduction of intussusception requires careful selection of patients, meticulous technique, and awareness of complications and their appropriate management. Because of its simplicity and improved success rate, pneumatic reduction has replaced traditional barium reduction at our institution. It may be that with further evaluation of selection criteria, higher pressures, and prolonged attempts that results will improve further.     

Temporal disparity between reduction of cot death and reduction of prone sleeping prevalence

According to several reports sudden infant death rates have decreased significantly after public campaigns aimed at reducing the incidence of sleeping in a prone position. The Styrian population (1.2 million inhabitants), who have been studied from 1984, also showed a significant drop in the incidence of cot death during 1989 (from 2%o to 1%o). The year before, a campaign for the prevention of cot death had been launched. This included the recommendation to prevent infants from lying in a prone position during sleep. Part of the prevention programme consisted of a detailed questionnaire filled in and returned by the parents. These data, on 29 970 infants from 1989 to 1994, provided information on the frequency of prone sleeping in 37% of our total population and as a consequence on parental response to the campaign. Calculating the data per year led to the surprising result that the reduction by half (from 50% to 25%) in the prevalence of sleeping in a prone position did not occur in 1989, when the drop in the incidence of cot death occurred, but 3 years later, in 1992. The following years saw a further decrease of prone position to 7% but no appreciable change in the incidence of cot death. However, during those 11 years of study about 80% of the victims were consistently found dead lying in a prone position. Our results show a temporal disparity between the reduction of sudden infant death and the decrease of prone sleeping in a population. Although we do not deny sleeping in a prone position as a risk factor for cot death, there cannot be a simple relationship between sleeping habits in the population and incidence of cot death.     

Corticosteroid-dependent reduction of leukocyte count in blood as a prognostic factor in acute lymphoblastic leukemia in childhood (therapy study ALL-BFM 83)

In therapy study ALL-BFM 83 a total of 630 patients with acute lymphoblastic leukemia (ALL) have prospectively been evaluated for initial response on therapy with corticosteroids. It was the aim to qualify the in vivo cytoreduction as a new predictor for therapy failure. All patients were exposed for 7 days to prednisone before combination chemotherapy at day 8 has been started. At day 0 one additional dose of Methotrexate was given intrathecally. Therapy for all patients with non-B-ALL has been stratified according to initial tumor burden (risk factor) providing four therapy branches: standard risk low (SR-L), standard risk high (SR-H), medium risk (MR), high risk (HR). After a median duration of study of 21 months, event-free survival (EFS) is for all 630 patients 73%, 81% for SR-L, 76% for SR-H, 69% for MR, and 35% for HR patients (date of evaluation Jan. 1, 1987). In this prospective study, a small subgroup of patients (n = 48; 7.6% of total group) is characterized by greater than 1000 leukemic blasts/mm3 peripheral blood at day 8 after exposure to prednisone. In this subgroup the EFS is only 43% in contrast to 76% in the complementary group of 582 patients with less than 1000 leukemic blasts/mm3 peripheral blood at day 8. Patients of that risk group are derived from therapy branches SR-H, M and HR, the latter contributing relatively most patients. In this negatively selected group all patients with an initial high white blood count, CNS disease at diagnosis, immune subtypes as prae-T-ALL (n = 6), T-ALL (n = 18), null-ALL (n = 5), and males clearly dominate. Of 48 patients with greater than 1000 blasts/mm3 at day 8 4 subsequently failed to enter remission and 8 were qualified as lateresponders. 18 patients relapsed, most of them earlier compared to those of the complementary group. The initial in vivo response on corticosteroid therapy is considered a supplementary prognostic predictor for early failure. It will be utilized in trial ALL/NHL-BFM 86 to qualify patients at the highest risk for relapse. This group of patients is supplemented in addition by non- and lateresponders and children with acute undifferentiated leukemia (AUL). The in vivo corticosteroid test is simple, generates early and reliable results and can be obtained almost always. Thus it may be recommended for use in a multicenter trial.