Autosomal recessive NOTCH3-related leukodystrophy in two siblings and review of the literature

Background: Cerebral autosomal dominant areteriopathey with subcortical infarcts and leukoencephalopathy (CADASIL) is autosomal dominant disease caused by pathogenic heterozygous variants in the NOTCH-3 gene. A lot is unknown about biallelic loss-of-function variants in this gene. Objective: To described two patients with homozygous loss of function variants in NOTCH3 along with the clinical manifestations and neuroimaging findings. Case description: Older sister was ten-year-old female with antenatal history of oligohydroamnios and was diagnosed with ventricular septal defect (VSD) and patent ductus arteriosus (PDA) at 3 weeks after birth. She presented at the age of 11 months with global developmental delay (GDD). Subsequently she developed seizures and required antiepileptic medications. Neuroimaging showed symmetric and confluent T2/FLAIR hyperintensities in the deep and periventricular white matter with relative sparing of the subcortical white matter. Younger sister was twenty-two months when she presented to the neurology clinic with history of GDD, seizures and congenital strabismus. Brain-MRI showed bilateral periventricular asymmetric focal areas of T2/FLAIR hyperintensities. There was an increased signal intensity of T2/FLAIR are seen in the left basal ganglia and in the dentate nuclei. Both patients were homozygous likely pathogenic variant in the NOTCH-3 (NM_000435.3:c.686_687delAG:p.[Glu229GlyfsTer5]) confirming the diagnosis of autosomal recessive NOTCH-3 related leukodystrophy. Parents were found to be heterozygous for the same variants. Conclusion: Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3 gene. The phenotype of biallelic null variants is associated with more severe phenotype.
Keywords: NOTCH-3, Homozygous null mutation, Leukoencephalopathy, Cerebral arteriopathy