Autosomal recessive NOTCH3-related leukodystrophy in two siblings and review of the literature
Fatema Al Amrani, Khalid Al Thihli , Amna Al Futaisi
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
Fatema Al Amrani
Sultan Qaboos University Hospital
Khalid Al Thihli
Sultan Qaboos University Hospital
Amna Al Futaisi
Sultan Qaboos University Hospital
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
Fatema Al Amrani
Sultan Qaboos University Hospital
Khalid Al Thihli
Sultan Qaboos University Hospital
Amna Al Futaisi
Sultan Qaboos University Hospital
Fatema Al Amrani
Sultan Qaboos University Hospital
Sultan Qaboos University Hospital