Headache in a middle-aged man due to a rare mutation in the NOTCH 3 gene

Sir, A 46-year old man presented with a history of frequent headache since the age of 14 years. The headache was generalized and throbbing in nature. It was associated with nausea and intolerance to light. He tried propranolol and amitriptyline for 6 weeks each with no major relief. He was also diagnosed with borderline personality disorder (BPD) since his teen-age years. His mother and younger brother suffered from headache since early adulthood. The clinical examination revealed mild truncal ataxia but no other cranial nerve, motor or sensory deficit; and, the psychometric analysis revealed no obvious cognitive impairment. Magnetic resonance imaging (MRI) of the brain revealed increased T2 signal in the anterior poles of both temporal lobes, external capsules, basal ganglia, pons and the subcortical white matter [Figures 123] He was tested to rule out cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in view of the headache and temporal lobe lesions. The NOTCH 3 gene (gene responsible for CADASIL) study initially revealed no mutation in exon 3 and 4, the two most common exons implicated in CADASIL. However, given the strong clinical suspicion, further genetic study was conducted of exon 2 and exon 5-24 of the NOTCH 3 gene. This extended coverage revealed a missense mutation in exon 6 (DNA: c931T>A and protein pCys311Ser), confirming the diagnosis of CADASIL.[1]Figure 1: Magnetic resonance imaging (axial view) revealed high T2 signals in both temporal lobes (large arrows) and pons (small arrow)Figure 2: Magnetic resonance imaging (axial T2 weighted image) revealed high signals in both external capsules (white arrows)Figure 3: Magnetic resonance imaging (sagittal view of fluid attenuated inversion recovery or FLAIR sequences) revealed high signals in frontal lobes adjacent to the interhemispheric fissureCADASIL is a rare autosomal dominant monogenic vasculopathy resulting in recurrent transient ischemic attacks/strokes, migrainous headache and cognitive impairment.[1,2,3] The causative gene NOTCH 3 is situated on chromosome 19. The gene contains 33 exons.[4] NOTCH 3 gene codes for a receptor expressed in vascular smooth muscles.[3] NOTCH 3 is a protein with extracellular, transmembrane and intracellular portions. When a ligand binds to the extracellular component of the NOTCH 3 gene, the intracellular domain of the gene dissociates itself from rest of the gene to regulate the activities of the other genes inside the nucleus. More than 200 mutations in the NOTCH 3 gene have been described in the literature. The commonest sites for NOTCH 3 mutation are exon 3 and 4.[1,3,5] The prevalence of the mutation in exon 6 of NOTCH 3 gene is rare and occurs in 6%-7.5% of all genetically proven CADASIL patients.[2,4] MRI of the brain in CADASIL reveals white matter changes in the anterior temporal poles, external capsules, basal ganglia, thalamus, brainstem and the superior frontal gyrus, with cortical sparing.[1,2,3] Recently, intra-cerebral microhemorrhage have also been described in CADASIL.[6] CADASIL should be remembered as a differential diagnosis in young people with stroke, migrainous headache with or without an aura and a positive family history. However, a family history can be absent in some patients. The other rarer clinical symptoms are seizures, coma, pseudobulbar palsy and spinal cord infarct. The absence of a mutation in exon 3 and 4 of the NOTCH 3 gene should not preclude the study of rest of the 31 exons in the right clinical and radiological context. However, if the resources are limited for the extensive study of NOTCH3 gene, then at least exon 2, 5 and 6 must be studied additionally as 90% of all NOTCH 3 genetic mutations are detected within exon 2-6.[1,3] The mainstay of treatment of CADASIL is anti-migraine medication (for headache), anti-platelet therapy (for stroke prevention) and anti-depressants. Modification of other risk factors like hypertension, dyslipidaemia, and hyperglycaemia are also essential. Genetic counselling is also important as an affected individual can transfer this disease to 50% of his or her children. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.