Innovative therapy for Classic Galactosemia - tale of two HTS.

Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-phosphate uridylyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism. While the neonatal morbidity and mortality of the disease are now mostly prevented by newborn screening and galactose restriction, long-term outcome for older children and adults with this disorder remains unsatisfactory. The pathophysiology of Classic Galactosemia is complex, but there is convincing evidence that galactose-1-phosphate (gal-1P) accumulation is a major, if not the sole pathogenic factor. Galactokinase (GALK) inhibition will eliminate the accumulation of gal-1P from both dietary sources and endogenous production, and efforts toward identification of therapeutic small molecule GALK inhibitors are reviewed in detail. Experimental and computational high-throughput screenings of compound libraries to identify GALK inhibitors have been conducted, and subsequent studies aimed to characterize, prioritize, as well as to optimize the identified positives have been implemented to improve the potency of promising compounds. Although none of the identified GALK inhibitors inhibits glucokinase and hexokinase, some of them cross-inhibit other related enzymes in the GHMP small molecule kinase superfamily. While this finding may render the on-going hit-to-lead process more challenging, there is growing evidence that such cross-inhibition could also lead to advances in antimicrobial and anti-cancer therapies.

Identifying homozygous sickle cell disease when neonatal screening is not available: a clinic-based observational study.

OBJECTIVES: Life-threatening clinical complications can occur in the first years of life in people with homozygous sickle cell disease. There is consensus that a clinical care programme comanaged by a specialist clinic should follow early-life disease identification. In a setting without widespread neonatal screening for this disease, we predict the percentage of affected births that enrol in specialist clinics during childhood, and the percentage that enrol early enough to benefit from penicillin prophylaxis (which is offered until five years of age). SETTING: A retrospective study of enrolment between 1973 and 1999 at three clinics in Jamaica, the country's only referral centres for sickle cell disease. RESULTS: Among enrolees not screened at birth, observed enrolment by age five was 10.1% (95% confidence interval [CI] 5.7-16.7%) among 1974 births, which is predicted to rise to 35.7% (95% CI 35.0-36.4%) among 1999 births. Observed enrolment by 18 years of age was 45.9% (95% CI 35.7-58.2%) among 1974 births, which is predicted to peak at 61.9% (95% CI 60.5-63.2%) among 1984 births, and fall to 48.9% (95% CI 40.9-56.9%) among 1999 births. Median age at enrolment was 10.5 years (95% CI 10.0-11.3). CONCLUSIONS: Based on 1999 estimates, almost 65% of children affected by homozygous sickle cell disease not identified at birth will not benefit from important early-life clinical intervention, and half will not enrol for specialised care by their 18th birthday. Among patients that enrol, half do so in adolescence when management is less focused on preventive care.

Cerebrovascular complications and parvovirus infection in homozygous sickle cell disease.

Human parvovirus B19 infection causes most clinically defined aplastic crises in homozygous sickle cell (SS) disease. With transfusion support, the outcome is generally benign; however, cerebrovascular complications in close temporal association with B19-induced aplastic crises have been described. We carried out a retrospective review, between 1978 and 1999, of 346 aplastic crises in patients with SS disease attending the Sickle Cell Clinic of the University Hospital of the West Indies, Kingston, Jamaica. Six cerebrovascular episodes, 5 with hemiplegia, occurred within 2 days of aplastic crises; and 4, all with features of encephalitis, occurred within 2 to 5 weeks. Hemiplegia in 2 children resolved completely, one is improving, and one persists 20 years later; one patient died from recurrent strokes. Of the 4 children whose events occurred later, all had seizure disorders and 2 had transient cortical blindness. The crude risk of cerebrovascular episodes in the 5-week interval after B19 infection was calculated as 58 times greater than expected, which is suggestive of a causal association.

Survival estimates for patients with homozygous sickle-cell disease in Jamaica: a clinic-based population study.

BACKGROUND: Information about life expectancy of patients with homozygous sickle-cell disease is needed for research and patient counselling. Our aim was to study two Jamaican populations, one clinic-based and one birth cohort and, by careful consideration of data quality and statistical analysis, to identify ways to increase the chances of obtaining valid and generalisable results. METHODS: We investigated the survival experience of 3301 patients with homozygous sickle-cell disease attending the Jamaican sickle-cell clinic between Jan 1, 1987, and Dec 31, 1996. We applied and assessed a simulation technique for incorporating early life mortality using a birth cohort, and analysed the precision of this technique. Kaplan-Meier survival estimates are produced. FINDINGS: 290 of the 3301 patients died. Median survival calculated with the excess mortality rate simulation data was 53 years (95% CI 49.3-57.0) for men and 58.5 (55.1-67.5) for women. INTERPRETATION: Our simulation technique, with realistic assumptions based on empirical evidence, offers a new estimate of median survival for patients with homozygous sickle-cell disease. We present the precision of these survival estimates, which introduces an important level of uncertainty. The inherent biases of clinically ascertained populations of patients, and the assumptions underlying analysis techniques are crucial features of survival studies in sickle-cell disease, and can modify summary statistics substantially.

Significance of fever in Jamaican patients with homozygous sickle cell disease.

OBJECTIVE: To investigate the cause and outcome of high fever in Jamaican children with homozygous sickle cell disease. DESIGN: Retrospective review of febrile episodes in a three year period (1 September 1993 to 31 August 1996). SETTING: Sickle cell clinic, an outpatient clinic in Kingston run by the Medical Research Council Laboratories (Jamaica). PATIENTS: Patients with homozygous sickle cell disease under 17 years of age presenting with an axillary temperature >/= 39.0 degrees C (102.4 degrees F). MAIN OUTCOME MEASURES: Diagnosis, death. RESULTS: There were 165 events in 144 patients (66 (45.8%) boys) with a median age of 6.1 years. Bacteraemia was found in 10 (6.1%) events (three Streptococcus pneumoniae, two Haemophilus influenzae type b, two Salmonella sp, one Escherichia coli, one Enterobacter sp, and one Acinetobacter sp), and urinary tract infections in four (2.4%). All cultures of cerebrospinal fluid were sterile. Acute chest syndrome occurred in 36 (21.8%) events. A painful crisis was associated with 45 (27.3%) events and was the only pathology identified in 20 events (12.1%). Hospital admission was necessary in 66 cases including all those with bacteraemia and 31 with acute chest syndrome. There were two deaths: a 5 year old boy with septic shock associated with H influenzae septicaemia, and a 3 year old boy with the acute chest syndrome. CONCLUSIONS: Painful crisis and acute chest syndrome were the most common complications associated with high fever, but other important associated features included bacteraemia and urinary tract infection. Enteric Gram negative organisms accounted for 50% of positive blood cultures.

Is there an energy deficiency in homozygous sickle cell disease?

The low weight, low height-for-age, delayed skeletal maturation, and retarded puberty in children with homozygous sickle cell disease are consistent with chronic malnutrition. Voluntary energy intake in sickle cell patients (SS) appears to be similar to that of control subjects with a normal hemoglobin genotype (AA) despite a higher resting metabolic rate (RMR), which suggests a suboptimal nutritional state. Patients may therefore conserve energy by reducing physical activity; this hypothesis was tested by comparing RMR, total daily energy expenditure (TDEE), and physical activity level (TDEE:RMR) in 16 postpubertal boys with sickle cell disease with those in 16 normal control subjects matched for age, sex, and pubertal stage. The RMR of sickle cell patients measured by indirect calorimetry (mean +/- SD: 7.0 +/- 0.9 MJ/d) significantly exceeded that of the normal control subjects (6.3 +/- 0.5 MJ/d; P = 0.018) but TDEE measured by the heart rate method was greater in the control subjects (13.8 +/- 4.9 MJ/d) than in the sickle cell patients (10.5 +/- 2.2 MJ/d; P = 0.034). Physical activity level was 46% greater in control subjects (2.2 +/- 0.8) than in sickle cell patients (1.5 +/- 0.3; P = 0.006). Adjustment for genotype differences in body weight reduced the genotype difference in physical activity level from 0.70 (95% CI: 0.3, 1.1) to 0.6 (95% CI: -0.06, 1.2). Reducing physical activity is a compensatory mechanism in children with an energy deficiency and a similar adaptive response may occur in sickle cell disease.

[Neonatal screening for sickle-cell disease]. / Neonatale screening op sikkelcelziekte.

Through migration and birth sickle cell disease has become an important health problem in the Netherlands: it is estimated that each year between 25 and 40 children are born with a form of sickle cell disease. A programme designed towards parental education, prevention and early intervention for complications of sickle cell disease (notably penicillin prophylaxis to prevent pneumococcal septicaemia and meningitis) may lead to reduction in morbidity. Early diagnosis is indicated since children with sickle cell disease will benefit most from such a programme in the first few years of life.

Penicillin-resistant Streptococcus pneumoniae in a Jamaican patient with homozygous sickle-cell disease.

Penicillin prophylaxis against infection by Streptococcus pneumoniae is now routine in young children with homozygous sickle-cell (SS) disease and the emergence of penicillin-resistant strains is a serious clinical concern. The first death associated with such resistance in a Jamaican child with SS disease is reported.

Glomerulonephritis after human parvovirus infection in homozygous sickle-cell disease.

Glomerulonephritis with proteinuria of sufficient degree to manifest the nephrotic syndrome followed aplastic crises induced by human parvovirus (B19) in seven patients with homozygous sickle-cell disease, within 7 days in five patients and 6-7 weeks in two. Segmental proliferative glomerulonephritis was found in all four patients who underwent acute renal biopsies and focal segmental glomerulosclerosis was found in the fifth patient who had a biopsy 4 months later. One patient recovered completely, one died in chronic renal failure after 3 months, and the others had impaired creatinine clearance, four with continuing proteinuria.