Mahida, Sonal

Abstract The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.

AbstractBiallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl‐tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult‐onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51‐year‐old man with adult‐onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34‐year‐old man with childhood‐onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57‐year‐old woman with childhood‐onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2‐related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult‐onset AARS2‐related neurological decline without leukodystrophy, and the third is biallelic AARS2‐related disorder involving a partial gene deletion.