De novo and inherited monoallelic variants in TUBA4A cause ataxia and spasticity.

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely pathogenic variants in patients from distinct ALS and FTD cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in-silico tools. In addition, gene burden analyses in the 100,000 genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls (OR: 57.0847 [10.2- 576.7]; p = 4.02 x10-07). Altogether, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense showed significant alterations in microtubule organisation and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.

Failure to screen for sickle cell disease at the University Hospital of the West Indies

OBJECTIVE: Universal neonatal screening for sickle cell disease using cord blood has taken place in the University Hospital of the West Indies (UHWI) since 1997. Comprehensive quality control of the screening programme has not been implemented. Our aim was to determine how many deliveries were left unscreened, and to ascertain factors contributing to failure to screen for sickle cell disease. METHODS: All live births in 1999 entered in the delivery book of the Labour Ward, UHWI, were scrutinized against the sample book of the Neonatal Screening Laboratory, Sickle Cell Unit. Identified unscreened infants were matched with a randomly chosen control, born on the same day. Time and mode of delivery, persons assisting the delivery, birth weight, level of urgency, location of delivery and Apgar scores at 1 and 5 minutes were collected for unscreened infants and screened controls. Secular variation within the year was assessed by comparing the frequency of unscreened births in each month to the previous month. Frequencies of potential determinants of failure to screen were tabulated. The independent predictive power of these potential determinants was assessed using conditional logistic regression, to account for correlations between predictors, and for the case-control design of the study. RESULTS: Of 2,763 live births in 1999, 139 (5 percent) infants were not screened for sickle cell disease. There was no statistically significant secular variation within the year (relative risk 1.02, 95 percent confidence interval 0.97, 1.07, x2 = 0.77, p = 0.38). Independently significant predictors of failure to screen were: emergency delivery (odds ratio 4.8, 95 percent confidence interval 2.3, 10.0), nigttime delivery (OR2.5, 0.9) CONCLUSIONS: This study identified that 5 percent of infants born in UHWI in 1999 were discharged from hospital without having been screened for sickle cell disease. Statistically significant associations with failure to screen were found to be emergency delivery, night-time delivery, and low 5 minute Apgar score. The risk of being left unscreened increased 5-fold for emergency deliveries. Increased awareness of these risk factors may reduce failure to screen. Of course, such effort does not obviate the need for regular quality control, including timely identification and tracing of unscreened infants. (AU)

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 (AU)

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

Is there an energy deficiency in homozygous sickle-cell disease? - abstract

Low weight, reduced height for age, delayed skeletal maturation and retarded puberty in children with homozygous sickle-cell (SS) disease are consistent with chronic malnutrition. Voluntary energy intake in SS patients remains similar to that of controls with a normal (AA) haemoglobin genotype, despite a higher resting metabolic rate (RMR) suggesting a suboptimal nutritional state. Patients may therefore conserve energy by reducing physical activity and this hypothesis has been tested by comparing total daily energy expenditure (TDEE) in 16 SS adolescent boys with 16 AA controls matched for age, sex and pubertal stage. The RMR of SS patients (mean, SD:7.0 MJ/d, 0.9) significantly exceeded that of AA controls (6.3, 0.5; p = 0.018) but TDEE was greater in AA controls (mean, SD: 13.8 MJ/d, 4.9) than in SS patients (10.5, 2.2; p = 0.034). The physical activity level (TDEE/RMR was 45 percent greater in AA controls ( mean, SD: 2.2, 0.8) than in SS patients (1.5, 0.3), this difference being highly significant (p = 0.006). Reducing physical activity is a compensatory mechanism in normal children on low energy intakes and a similar adaptive response may occur in SS disease (AU)

Delayed adolescent growth in homozygous sickle cell disease

Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95 percent confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth (AU)

Adolescent growth in homozygous sickle-cell disease is delayed but follows a normal pattern - abstract

Analysis of the growth abnormalities in homozygous sickle-cell (SS) disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. In the Jamaican cohort study, longitudinal observations of height and other anthropometric indicies have been made since birth. These data have been fitted to a mathematical model of growth allowing investigation of the timing and pattern of the adolescent growth spurt of children with homozygous sickle-cell (SS) disease and sickle-cell-haemoglobin C (SC) disease. The study included all live, post-pubertal children with SS disease aged over 16 years at the study date. There were 44 SS subjects (21 male, 23 female) matched by age and sex with 44 patients with SC disease and 44 children with a normal haemoglobin (AA) genotype, giving a study group of 132 subjects. Compared to normal AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (p<0.001) with no significant sex difference. The growth spurt occurred normally in SC disease. The age at peak height was normal and there was no difference in the predicted adult height. The normally co-ordinated but slightly delayed pattern of adolescent growth in SS patients argues against an endocrine abnormality. Most children with SS disease can therefore be reassured on the outcome of the retarded growth and delayed skeletal maturation (AU)

Sickle cell disease in primary health care in Dominica: a study in the Marigot Health District

Increased understanding of sickle cell disease (SCD) and improved management strategies of the disease in recent decades have been shown to reduce morbidity and mortality. For this, neonatal screening and specialized sickle cell clinics are prerequisites. In Dominica, there is one out-patient clinic for SCD patients at the Princess Margaret Hospital, but there is no neonatal screening for SCD. Based on available data, 10 of the approximately 2000 babies in Dominica are estimated to have homozygous SCD at birth each year. In the Marigot Health District where 200 births take place annually, the expected incidence is 1. The present study aimed to assess the known prevalence of SCD and its co-morbidity in the Marigot Health District, as well as the utilization of the available health care services by patients with SCD. In one year, 17 episodes of SCD were registered at the district clinics in patients aged 1 to 43 years. It appeared that not all SCD patients were known, especially in the youngest age group, where mortality is highest. Most encounters were prompted by acute complications of the disease. Registered co-morbidity was especially related to pregnancy and chronic leg ulcers. Follow-up at the sickle cell clinic appeared to be poor. For adequate care of SCD patients, implementation of a neonatal screening programme for SCD appears to be essential, together with a protocol for its follow-up and management. Such a protocol should optimize cooperation between primary and secondary levels of care in the management of SCD.(AU)

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 anxillary temperature o 39.0§c (102.4§F). MAIN OUTCOME MEASURES: Diagnosis, death. RESULTS: There were 165 event in 144 patients (66 (45.8 percent) boys) with a median age of 6.1 years. Bacteraemia was found in 10 (6.1 percent) events (three Streptococcus pneumoniae, two Haemophilus influenzae type b, two Salmonella sp, one Escherichia coli, one Enterobactor sp, and one Acinetobacter sp), and urinary tract infections in four (2.4 percent). All cultures of cerebrospinal fluid were sterile. Acute chest syndrome occured in 36 (21.8 percent) events. A painful crisis was associated with 45 (27.3 percent) events and was the only pathology identified in 20 events (12.1 percent). 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 percent of positive blood cultures. (AU)

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 (AU)

Nephrotic syndrome and human parvovirus infection in homozygous sickle-cell disease: a temporal association - abstract

Proteinuria of sufficient severity to manifest the nephrotic syndrome and renal impairment has been associated with human parvovirus (B19) infection in 7 patients with homozygous sickle-cell (SS) disease. In most patients, the proteinuria resolved but renal impairment remained. The glomerular histology showed evidence of segmental proliferative glomerulonephritis in 4 out of 5 biopsies. Most events occurred within 2 weeks of B19 associated aplastic crisis, and the mechanism is at present unknown. This association may add to the pathogenic significance of B19 infection in SS disease (AU)