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KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate tRNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction and immuno-hematological problems are emerging phenotypes in KARS1-related disorders. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients. This article is protected by copyright. All rights reserved.

OBJECTIVE: The goal was to investigate the prevalence of renal and urinary tract anomalies (RUTAs) in a Down syndrome (DS) population. METHODS: Data were obtained from the New York State Congenital Malformation Registry (NYS-CMR) in this retrospective cohort study. The occurrence of RUTAs was assessed for children with and without DS who were born in NYS between 1992 and 2004. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each malformation. RESULTS: Between 1992 and 2004, 3832 children with DS and 3411833 without DS were born in NYS. The prevalence of RUTAs in the DS population was 3.2%, compared with 0.7% in the NYS population (OR: 4.5 [95% CI: 3.8–5.4]). Children with DS had significantly increased risks of anterior urethral obstruction (OR: 29.7 [95% CI: 4.0–217.7]), cystic dysplastic kidney (OR: 4.5 [95% CI: 1.5–14.1]), hydronephrosis (OR: 8.7 [95% CI: 6.8–11.0]), hydroureter (OR: 8.5 [95% CI: 3.5–20.4]), hypospadias (OR: 2.0 [95% CI: 1.4–2.9]), posterior urethral valves (OR: 7.1 [95% CI: 1.8–28.8]), prune belly syndrome (OR: 11.9 [95% CI: 1.6–85.4]), and renal agenesis (OR: 5.4 [95% CI: 2.8–10.4]). There was no significantly increased risk of ectopic kidney (OR: 1.6 [95% CI: 0.2–11.2]) or ureteropelvic junction obstruction (OR: 1.4 [95% CI: 0.2–9.9]) in the DS population. CONCLUSION: Children with DS have significantly increased risks of RUTAs.

Antisperm antibodies are formed as a result of vasal and epididymal obstruction. Fourteen males of different ages (pre-, peri- and post-pubertal) with bilateral congenital vasal agenesis and epididymal obstruction secondary to cystic fibrosis (CF), and seven men with congenital bilateral aplasia of the vas deferens (CBAVD) were evaluated with regard to both the presence and levels of serum antisperm antibodies, and the CF-genotype. While IgA and IgG were not detected among pre- and peri-pubertal CF patients, 4 out of 10 (40%) exhibited IgM binding to sperm tail-tip. Post-pubertal CF patients showed high antisperm antibody (ASA) levels in 3 of the 4 males (75%) evaluated for the three isotypes assayed. ASA were found in 5 of 7 CBAVD patients (71%); IgG (n = 3) and IgM (n = 4) were found to be the predominant isotypes bound to sperm tail-tip. CF-genotype analysis revealed two pre-pubertal patients with the DeltaF508/DeltaF508 CF-genotype and a positive ASA response, thus suggesting an earlier or more severe blockage. In addition, the two CBAVD patients found to have a ?/? CF-genotype on the initial screening did not have ASA. The altered antigenicity of sperm associated with initiation of spermatogenesis appears to modify the antisperm antibody isotypes. Further studies on a larger number of patients may allow for a better understanding of the ASA response, as well as a better understanding of a possible phenotype/genotype association between the CF-genotype and the immunologic response.

We describe a mother and daughter with a distinct phenotype that is different from previous reports. This is likely to constitute a new syndrome for which we propose the mnemonic GMS for G goniodysgenesis, M mental deficiency, and S short stature. The pattern of occurrence is compatible with either autosomal dominant or X-linked inheritance.