- Email: [email protected]
A novel Notch3 deletion mutation in a Chinese patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
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Case Reports / Journal of Clinical Neuroscience 20 (2013) 322–323
10. Tiwari D, Amar K. A case of corticobasal degeneration presenting with alien limb syndrome. Age Ageing 2008;37:600–1. 11. Lalive PH, Personeni O, Slosman DO, et al. Lower limb corticobasal degeneration. Eur Neurol 2000;44:248–9. 12. Denes G, Mantovan MC, Gallana A, et al. Limb-kinetic apraxia. Mov Disord 1998;13:468–76.
13. Black SE. Focal cortical atrophy syndromes. Brain Cogn 1996;31:188–229. 14. Rinne JO, Lee MS, Thompson PD, et al. Corticobasal degeneration. A clinical study of 36 cases. Brain 1994;117:1183–96. 15. Litvan I, Grimes DA, Lang AE. Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv Neurol 2000;82:183–96.
doi:http://dx.doi.org/10.1016/j.jocn.2012.02.026
A novel Notch3 deletion mutation in a Chinese patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) Fan Weiming a,⇑, Wang Yuliang a, Li Youjie b, Liu Xinsheng c, Xie Shuyang b, Liu Zhaoxia c a
The Affiliated Hospital of BinZhou Medical University, 661 HuangHe Second Road, BinZhou, Shandong 256600, China Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Shandong, China c The Affiliated MuPing Hospital of Binzhou Medical University, Shandong, China b
a r t i c l e
i n f o
Article history: Received 9 October 2011 Accepted 14 February 2012
Keywords: CADASIL Deletion mutation Notch3 gene
a b s t r a c t Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL. We describe a novel 100 base pair base fragment deletion mutation (ENST 00000263388, c.512-611del) in the Notch3 gene from a Chinese patient with CADASIL. The present patient has the characteristic clinical and family history for CADASIL, which suggests that C.512del611 may be a cause of CADASIL as well as most of the previously reported Notch3 mutations. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL.1 Most mutations in the Notch3 gene in individuals with CADASIL are located in exon 4, followed by exons 3, 5, 6, and 11.2–5 To date, more than 170 mutations have been reported in people of many ethnic origins.6 In the current paper, we report a novel 100 base pair (bp) base fragment deletion mutation (ENST 00000263388, c.512–611del) in the Notch3 gene from a Chinese patient with CADASIL.
2. Case report By the time the proband had reached 40 years of age, she had already suffered repeated strokes; she had been hospitalised three times in the previous six months. At 46 years of age, her personality changed. She began to suffer memory problems, and her cognitive impairment gradually evolved. She had no stroke risk factors, such as hypertension, diabetes, smoking, or coronary heart disease. The carotid ultrasound, electrocardiogram, echocardiography, and routine blood examination results were all normal. MRI brain scan showed extensive areas of hypointensity on T1-weighted images, and hyperintensy it on T2-weighted and fluid-attenuated inversion ⇑ Corresponding author. Tel.: +86 543 3258743. E-mail address: [email protected] (F. Weiming).
recovery images in the periventricular and subcortical white matter of both cerebral hemispheres (Fig. 1). The patient’s younger brother, four cousins, father, one uncle, and one aunt had had the same progressive condition and had died, except the younger brother. No personal history of headaches was provided. The family lineage is shown in Fig. 2. Based on the clinical manifestations and the strong family history of the proband, we suspected that she had CADASIL. Follow-up gene examinations on the Notch3 gene of the patient and her son were examined. Exons and exon/intron boundaries of the Notch3 gene were amplified by polymerase chain reaction and sequenced. DNA sequencing identified a novel fragment deletion mutation in exon 4 of the Notch3 gene. Base deletion of 100 bp (ENST 00000263388, c.512–611del) was found in the proband (Fig. 3); her son was normal. Further examination of 100 normal controls did not reveal this deletion. To our knowledge, no similar results have been reported previously. Unfortunately, the patient and her family refused to have further biopsies conducted.
3. Discussion Since the early 2000s, numerous patients with CADASIL have been reported, but the prevalence of CADASIL remains unclear. Some patients have been reported in China7, but the disease remains underdiagnosed. CADASIL should be considered when recurrent strokes with typical multiple imaging abnormalities occur or when vascular risk factors are absent or begin in the mid-adult years (30–60 years of age), especially when a family history of stroke is present. Further detection of the Notch3 gene is necessary. If migraine does not occur in the family, then it may be correlated with a novel mutation or different ethnic origins.
Case Reports / Journal of Clinical Neuroscience 20 (2013) 322–323
Fig. 1. MRI brain scans showing: (a) extensive hypointensities on axial T1-weighted images; and (b) hyperintensities on axial T2-weighted images.
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Fig. 2. Family lineage of a Chinese patient with a novel Notch3 deletion mutation with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).
Fig. 3. Sequencing of Notch3. Arrows indicate the deletion mutation, which was present in the proband but not in her son.
The Notch3 gene codes the transmembrane receptor Notch3. The exact pathogenesis of the mutation in the Notch3 gene, which leads to the characteristic vascular pathology and clinical features of CADASIL, remains unclear. To our knowledge, more than 170 mutations in the Notch3 gene have been determined, most of which occur in exons 3 and 4. Among these mutations, five small deletion mutations that cause CADASIL have been reported. In this test, we initially screened these two exons. We discovered a new 100 bp base deletion mutation (ENST 00000263388, c.512– 611del) in exon 4. Thus, a novel 100 bp base fragment deletion mutation, a large deletion mutation in the Notch3 gene, which could affect the function of the Notch3 protein, was found. The patient in the current study showed the classic clinical features and family history characteristic of CADASIL, suggesting that the 100 bp base deletion mutation could be a cause of CADASIL, similar to most of the mutations previously reported. Genotype–phenotype correlations are indefinite.8 The relationship between the clinical manifestations and the novel mutation is unknown because of the lack of more related cases. doi:http://dx.doi.org/10.1016/j.jocn.2012.02.026
Reference 1. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–10. 2. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997;350:1511–5. 3. Oberstein SA, Ferrari MD, Bakker E, et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology 1999;52:1913–5. 4. Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology 2002;59:1134–8. 5. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 2005;62:1091–4. 6. Tikka S, Mykkänen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009;132:933–9. 7. Wang Z, Yuan Y, Zhang W, et al. Wu S. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psych 2011;82:534–9. 8. Singhal S, Bevan S, Barrick T, et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 2004;127:2031–8.
Case Reports / Journal of Clinical Neuroscience 20 (2013) 322–323
10. Tiwari D, Amar K. A case of corticobasal degeneration presenting with alien limb syndrome. Age Ageing 2008;37:600–1. 11. Lalive PH, Personeni O, Slosman DO, et al. Lower limb corticobasal degeneration. Eur Neurol 2000;44:248–9. 12. Denes G, Mantovan MC, Gallana A, et al. Limb-kinetic apraxia. Mov Disord 1998;13:468–76.
13. Black SE. Focal cortical atrophy syndromes. Brain Cogn 1996;31:188–229. 14. Rinne JO, Lee MS, Thompson PD, et al. Corticobasal degeneration. A clinical study of 36 cases. Brain 1994;117:1183–96. 15. Litvan I, Grimes DA, Lang AE. Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv Neurol 2000;82:183–96.
doi:http://dx.doi.org/10.1016/j.jocn.2012.02.026
A novel Notch3 deletion mutation in a Chinese patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) Fan Weiming a,⇑, Wang Yuliang a, Li Youjie b, Liu Xinsheng c, Xie Shuyang b, Liu Zhaoxia c a
The Affiliated Hospital of BinZhou Medical University, 661 HuangHe Second Road, BinZhou, Shandong 256600, China Key Laboratory of Tumour Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, Shandong, China c The Affiliated MuPing Hospital of Binzhou Medical University, Shandong, China b
a r t i c l e
i n f o
Article history: Received 9 October 2011 Accepted 14 February 2012
Keywords: CADASIL Deletion mutation Notch3 gene
a b s t r a c t Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL. We describe a novel 100 base pair base fragment deletion mutation (ENST 00000263388, c.512-611del) in the Notch3 gene from a Chinese patient with CADASIL. The present patient has the characteristic clinical and family history for CADASIL, which suggests that C.512del611 may be a cause of CADASIL as well as most of the previously reported Notch3 mutations. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL.1 Most mutations in the Notch3 gene in individuals with CADASIL are located in exon 4, followed by exons 3, 5, 6, and 11.2–5 To date, more than 170 mutations have been reported in people of many ethnic origins.6 In the current paper, we report a novel 100 base pair (bp) base fragment deletion mutation (ENST 00000263388, c.512–611del) in the Notch3 gene from a Chinese patient with CADASIL.
2. Case report By the time the proband had reached 40 years of age, she had already suffered repeated strokes; she had been hospitalised three times in the previous six months. At 46 years of age, her personality changed. She began to suffer memory problems, and her cognitive impairment gradually evolved. She had no stroke risk factors, such as hypertension, diabetes, smoking, or coronary heart disease. The carotid ultrasound, electrocardiogram, echocardiography, and routine blood examination results were all normal. MRI brain scan showed extensive areas of hypointensity on T1-weighted images, and hyperintensy it on T2-weighted and fluid-attenuated inversion ⇑ Corresponding author. Tel.: +86 543 3258743. E-mail address: [email protected] (F. Weiming).
recovery images in the periventricular and subcortical white matter of both cerebral hemispheres (Fig. 1). The patient’s younger brother, four cousins, father, one uncle, and one aunt had had the same progressive condition and had died, except the younger brother. No personal history of headaches was provided. The family lineage is shown in Fig. 2. Based on the clinical manifestations and the strong family history of the proband, we suspected that she had CADASIL. Follow-up gene examinations on the Notch3 gene of the patient and her son were examined. Exons and exon/intron boundaries of the Notch3 gene were amplified by polymerase chain reaction and sequenced. DNA sequencing identified a novel fragment deletion mutation in exon 4 of the Notch3 gene. Base deletion of 100 bp (ENST 00000263388, c.512–611del) was found in the proband (Fig. 3); her son was normal. Further examination of 100 normal controls did not reveal this deletion. To our knowledge, no similar results have been reported previously. Unfortunately, the patient and her family refused to have further biopsies conducted.
3. Discussion Since the early 2000s, numerous patients with CADASIL have been reported, but the prevalence of CADASIL remains unclear. Some patients have been reported in China7, but the disease remains underdiagnosed. CADASIL should be considered when recurrent strokes with typical multiple imaging abnormalities occur or when vascular risk factors are absent or begin in the mid-adult years (30–60 years of age), especially when a family history of stroke is present. Further detection of the Notch3 gene is necessary. If migraine does not occur in the family, then it may be correlated with a novel mutation or different ethnic origins.
Case Reports / Journal of Clinical Neuroscience 20 (2013) 322–323
Fig. 1. MRI brain scans showing: (a) extensive hypointensities on axial T1-weighted images; and (b) hyperintensities on axial T2-weighted images.
323
Fig. 2. Family lineage of a Chinese patient with a novel Notch3 deletion mutation with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).
Fig. 3. Sequencing of Notch3. Arrows indicate the deletion mutation, which was present in the proband but not in her son.
The Notch3 gene codes the transmembrane receptor Notch3. The exact pathogenesis of the mutation in the Notch3 gene, which leads to the characteristic vascular pathology and clinical features of CADASIL, remains unclear. To our knowledge, more than 170 mutations in the Notch3 gene have been determined, most of which occur in exons 3 and 4. Among these mutations, five small deletion mutations that cause CADASIL have been reported. In this test, we initially screened these two exons. We discovered a new 100 bp base deletion mutation (ENST 00000263388, c.512– 611del) in exon 4. Thus, a novel 100 bp base fragment deletion mutation, a large deletion mutation in the Notch3 gene, which could affect the function of the Notch3 protein, was found. The patient in the current study showed the classic clinical features and family history characteristic of CADASIL, suggesting that the 100 bp base deletion mutation could be a cause of CADASIL, similar to most of the mutations previously reported. Genotype–phenotype correlations are indefinite.8 The relationship between the clinical manifestations and the novel mutation is unknown because of the lack of more related cases. doi:http://dx.doi.org/10.1016/j.jocn.2012.02.026
Reference 1. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707–10. 2. Joutel A, Vahedi K, Corpechot C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997;350:1511–5. 3. Oberstein SA, Ferrari MD, Bakker E, et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology 1999;52:1913–5. 4. Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology 2002;59:1134–8. 5. Peters N, Opherk C, Bergmann T, et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 2005;62:1091–4. 6. Tikka S, Mykkänen K, Ruchoux MM, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009;132:933–9. 7. Wang Z, Yuan Y, Zhang W, et al. Wu S. NOTCH3 mutations and clinical features in 33 mainland Chinese families with CADASIL. J Neurol Neurosurg Psych 2011;82:534–9. 8. Singhal S, Bevan S, Barrick T, et al. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain 2004;127:2031–8.