The remarkably variable expressivity of CADASIL: report of a minimally symptomatic man at an advanced age

Abstract

Sir, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset, dominantly inherited disorder caused by NOTCH3 mutations. It is characterized by recurrent subcortical infarctions, dementia, and less frequently, migraine and psychiatric symptoms. NOTCH3 has 33 exons, and most CADASIL-associated NOTCH3 mutations result in a gain or loss of one cysteine residue within a given extracellular epidermal growth factor (EGF)-like repeat domain and, in Caucasians, with a strong cluster in exon 3–6 encoding the first five EGF-like repeats [1]. The typical MRI features in CADASIL include multi-focal lacunar infarcts and diffuse T2-weighted hyperintensity of cerebral white matter with involvement of the anterior temporal lobes [1]. The presence of granular osmiophilic material (GOM), which is seen in close vicinity to the basement membrane of the smooth muscle cells of the arterioles on electron microscopy (EM), is pathognomonic for CADASIL [1]. Although the penetrance of MRI changes has been reported to be complete by 40 years of age [2], the spectrum of clinical phenotypes has remained elusive. Herein, we report the case of an 86-year-old minimally symptomatic male with CADASIL mutation, representing one extreme of the remarkably variable expressivity of CADASIL. The 86-year-old man had been doing very well before. His past history is only remarkable for heavy cigarette smoking without migraine or psychiatric symptoms. He came to our attention because of a mild numbness in the left hand following two falls 2 months earlier. The neurological examinations revealed only subtly increased deep tendon reflexes in the right biceps and brachioradialis. The brain MRI with gadolinium-enhanced magnetic resonance angiography (MRA) revealed a diffuse leukoencephalopathy without anterior temporal lobe involvement, one single and small lacunar infarct in the left putamen (Fig. 1a), and patent cerebral vessels. Subsequent mutational analysis of NOTCH3 uncovered a missense mutation, c. 1708C [ T, in exon 11, which putatively may result in a substitution of cysteine for arginine at amino acid 544 (R544C). The EM exam of a skin biopsy demonstrated the presence of characteristic GOM (Fig. 1b, c). His family history was unclear because of his early separation, at teenage, from the family and he has no children. He had received 7 years of education. His score of Mini-Mental State Examination (MMSE) was 27 out of 30 and the Cognitive Abilities Screening Instruments (CASI) was 81 out of 100. The cutoff scores of CASI in our population for the diagnosis of dementia in those who received 6 or more years of education is 79/80 [3]. NOTCH3 R544C has previously been reported manifesting typical CADASIL features [4, 5]. In the literature, the clinical manifestations of NOTCH3 mutations are enormously variable [6], with another report of a 14-yearold boy presenting with recurrent hemiplegia [7]. The observation in this patient highlights that, because the clinical manifestations may be extremely subtle, NOTCH3 Y.-C. Lee B.-W. Soong (&) Department of Neurology, National Yang-Ming University School of Medicine and Taipei Veterans General Hospital, #155, Sec.2, Li-Nung Street, Peitou District, Taipei 11217, Taiwan, ROC e-mail: bwsoong@vghtpe.gov.tw