Aviva Fattal Valevski

Background/Objectives: Pathogenic variants in collagen type 4 α5 chain (COL4A5), responsible for X-linked Alport syndrome, are classically associated with progressive kidney disease, sensorineural hearing impairment, and ocular abnormalities. Cerebrovascular involvement is not considered part of the COL4A5-related phenotype, although rare recent reports suggest it may occur. We describe a family with cerebrovascular events across three generations, segregating in a clear X-linked pattern, and evaluate whether these events could be linked to a pathogenic COL4A5 variant identified in the proband. Methods: We report the clinical, radiological, and genetic findings in a 16-year-old heterozygous female proband, interpreted in the context of her family’s cerebrovascular history. Exome sequencing, chromosomal microarray, and familial segregation analysis were performed. Results: The proband presented with severe migraine, cerebellar microhemorrhage, and poor visualization of the left distal posterior cerebral artery (PCA) branches. Exome sequencing detected the heterozygous COL4A5 pathogenic variant c.1871G>A; p.(Gly624Asp), inherited from her hemizygous father, who has Alport syndrome. The proband’s sister, an obligate carrier of the same variant with a history of migraine, was found to have a small brain aneurysm. In the paternal line, the great-grandmother died of a cerebrovascular event in her early 40 s, the great-aunt had a stroke at around 40, and her son died of a cerebrovascular event at 35; the obligate-carrier grandmother had chronic kidney disease and migraine. Conclusions: This COL4A5 variant is usually associated with late-onset Alport syndrome and variable renal involvement, even in obligate carriers, and has not previously been linked to cerebrovascular disease. In the present family, the X-linked clustering of cerebrovascular events raises the possibility that COL4A5 may contribute to cerebrovascular fragility, with an effect that may extend beyond the kidney. These findings suggest that COL4A5 may be relevant in selected families with unexplained cerebrovascular disease, even when renal manifestations are mild or absent.

HIKESHI-related hypomyelinating leukodystrophy (HHL) is a life-threatening disorder caused by homozygous pathogenic variants in HIKESHI. Symptoms include infantile onset progressive spastic dystonic quadriplegia, nystagmus, failure to thrive, diffused hypomyelination, and severe morbidity or death following febrile illness. V54L variants in HIKESHI are particularly prevalent within the Ashkenazi Jewish population. Here, we identified a novel P78S disease-causing variant in HIKESHI in a patient of Christian Arab origin, presenting with clinical and radiologic features characteristic of HHL. In silico analysis suggests that the mutated residue may affect the HIKESHI protein’s dimerization domain. We generated a comprehensive set of induced pluripotent stem cells (iPSCs) from the index case and two additional HHL patients. To investigate mechanisms potentially linked to febrile illness in HHL, we used these cells to study the heat shock (HS) response. HHL-iPSCs showed dramatically decreased levels of HIKESHI compared with healthy controls following HS. In addition, they exhibited increased HSP70 mRNA levels in response to HS, suggesting an increased sensitivity. HHL-iPSCs had impaired HSP70 translocation to the nucleus. Our results provide a human-relevant model for HHL.