Transcranial Doppler ultrasonography in siblings with sickle cell disease

Summary. The risk of stroke in sickle cell disease (SCD) may be influenced by either genetic or environmental factors. Elevated blood flow velocity in the large cerebral arteries, detected by transcranial Doppler (TCD) ultrasonography, predicts an increased stroke risk in children with SCD. We undertook this study to investigate the possibility of a familial predisposition to elevated cerebral blood flow velocity, a surrogate marker for stroke risk. We analysed the results of TCD studies performed on 63 children from 29 families that had more than one child with SCD. We assessed the association of elevated cerebral blood flow velocity with sibling TCD results as well as age and haemoglobin level, which are factors known to affect cerebral blood flow velocity. Positive or negative TCD results were highly correlated between family members ( r =  0·61). The presence of a sibling with a positive TCD result was significantly associated with an elevated cerebral blood flow velocity in other siblings with SCD (odds ratio = 41·9, 95% confidence interval 8·2–214·7, P  < 0·001). Furthermore, children who had a sibling with a positive TCD result had a significantly higher TCD velocity than children with SCD but without a sibling who were matched for age, sex, genotype and haemoglobin level. Our results are consistent with a familial predisposition to cerebral vasculopathy in SCD.     

Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation

Foveal hypoplasia, always accompanied by nystagmus, is found as part of the clinical spectrum of various eye disorders such as aniridia, albinism and achromatopsia. However, the molecular basis of isolated autosomal recessive foveal hypoplasia is yet unknown. Individuals of apparently unrelated non consanguineous Israeli families of Jewish Indian (Mumbai) ancestry presented with isolated foveal hypoplasia associated with congenital nystagmus and reduced visual acuity. Genome-wide homozygosity mapping followed by fine mapping defined a 830 Kb disease-associated locus (LOD score 3.5). Whole-exome sequencing identified a single missense mutation in the homozygosity region: c.95T>G, p.(Ile32Ser), in a conserved amino acid within the first predicted transmembrane domain of SLC38A8. The mutation fully segregated with the disease-associated phenotype, demonstrating an ∼10% carrier rate in Mumbai Jews. SLC38A8 encodes a putative sodium-dependent amino-acid/proton antiporter, which we showed to be expressed solely in the eye. Thus, a homozygous SLC38A8 mutation likely underlies isolated foveal hypoplasia.