Clinical/Scientific Notes
Silvia Bianchi, PhD Chiara Di Palma, BSc Gian Nicola Gallus, PhD Ilaria Taglia, BSc Antonella Poggiani, BSc Francesca Rosini, MD Alessandra Rufa, MD Dafin Fior Muresanu, MD Alfonso Cerase, MD Maria Teresa Dotti, MD Antonio Federico, MD
Supplemental data at Neurology.org
898
TWO NOVEL HTRA1 MUTATIONS IN A EUROPEAN CARASIL PATIENT
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary, nonhypertensive cause of recurrent lacunar stroke and cognitive decline associated with alopecia, spondylosis deformans, and lumbago.1 The disease has been linked to mutations in the HTRA1 gene, encoding for serine protease HTRA1, loss of which causes dysregulation of transforming growth factor-b signaling.2 Since the first description,3 most affected patients have been reported in Japanese and Chinese pedigrees with typical and atypical phenotypes. No strong genotype– phenotype correlation has yet been found, and homozygous patients with nonsense or missense mutations may be clinically indistinguishable.2 The recent unique report of a Caucasian case suggests that the disease is not limited to Asia.4 Here we report a new European patient with a peculiar phenotype carrying 2 novel mutations of the HTRA1 gene. The heterozygous proband’s parents showed variable leukoencephalopathy but no clinical signs of the disease. Case report. The proband was a 29-year-old Romanian female with unrelated parents. Family history was unremarkable. She complained of chronic lumbar and cervical pain since the age of 14 years. She had 2 ischemic strokes with left hemiparesis and dysarthria at ages 24 and 29, respectively. Neurologic examination showed ataxic gait, gazeevoked nystagmus, dysmetria, hypoactive deep tendon reflexes at legs, and no alopecia. Cognitive status was normal. Brain MRI showed severe diffuse leukoencephalopathy, including subcortical infarcts and evidence of microbleeds, while spine MRI showed degenerative disc disease (figure 1A). Several idiopathic and metabolic causes of ischemic strokes were excluded (MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], Fabry disease, rheumatologic diseases, and vasculitis). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was ruled out by automatic sequencing of exons 2–24 of the NOTCH3 gene and no evidence of granular osmiophilic material in skin and muscle biopsy. The parents were neurologically normal: the father, age 61 years, had negative history for Neurology 82
March 11, 2014
neurologic and cardiovascular diseases and hypertension; the mother, age 60 years, reported mild hypertension under treatment since the age of 54 years without other vascular risk factors. After genetic diagnosis of the daughter, the parents underwent brain MRI. The father showed mild supratentorial leukoencephalopathy (figure 1, B1, B3, B5, B7) and the mother diffuse infratentorial and supratentorial leukoencephalopathy (figure 1, B2, B4, B6). Methods and Results. With institutional review board approval and informed patient consent, we directly sequenced exons 1–9 of the HTRA1 gene in the proband. Two novel heterozygous mutations were identified: the c.961G.A in exon 4 (inherited from the father) and a G deletion (c.126delG) in exon 1 (inherited form the mother). The missense mutation in exon 4 results in substitution of a highly conserved alanine residue with threonine (p.Ala321Thr). This mutation is predicted to be pathogenic by PolyPhen2, SIFT, and Mutation Taster software. The deletion in exon 1 causes a frameshift, altering the amino acid sequence from position 42 (p.Glu42fs), and introduces a stop codon at position 214 (figure e-1 on the Neurology® Web site at Neurology.org). Neither mutation was found in public databases (http:// browser.1000genomes.org/index.html; http://www. ncbi.nlm.nih.gov/projects/SNP/, build 137) or 320 control chromosomes. Discussion. We here report a compound heterozygosity with 2 new mutations of the HTRA1 gene causing CARASIL in a patient with unrelated parents. The deletion (c.126delG) in exon 1, causing a frameshift of the protein with a truncated product, was inherited from the mother. The missense mutation in the protease domain of the HTRA1 gene (p.Ala321Thr) was inherited from the father. The patient did not have alopecia, usually considered a phenotypic marker of the disease. However, 3 women and 1 man without alopecia have been described among CARASIL subjects.2,5 If further confirmed, this observation could suggest a sex-linked difference in the presence of alopecia in the CARASIL population. The number of female patients would be underestimated, misrepresenting the male: female ratio of 3:1 in clinically defined CARASIL cases.1 Our patient had severe leukoencephalopathy with temporal lobe involvement, the latter an overlapping
Figure 1
Compound heterozygous cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): Summary of results
(A) MRI of the brain and cervical and thoracolumbosacral spine of the proband. T1-weighted sagittal (1), T2-weighted coronal (2), serial nonconsecutive fluidattenuated inversion recovery axial (3), and T2*-weighted axial (4) images of the brain show diffuse confluent high signal intensity areas and lacunar infarctions in the pons, where wallerian degeneration of the transverse pontine fibers is evident, and in both cerebral hemispheres, where superficial white matter (U-fibers) is relatively spared and alterations extend to the anterior temporal lobes, genu of the corpus callosum, internal capsules, and left external capsule. Signs of microbleeds are evident in the pons, right thalamus, and right temporal and bilateral cortico-subcortical frontal regions. Brain atrophy is also remarkable. T2-weighted sagittal images of the cervical and thoracolumbosacral spine (5) show degenerative disc disease, more evident in the lumbar spine, including displacements of intervertebral disc tissue into the vertebral bodies, i.e., so-called Schmorl nodes, in the thoracolumbar junction. (B) MRI of the brain of the proband’s father (upper row) and mother (lower row). T1-weighted sagittal (1, 2), serial nonconsecutive T2-weighted axial (3, 4), and fluid-attenuated inversion recovery coronal (5, 6) images show larger involvement in the proband’s mother’s brain tissue than in the proband’s father’s, including bilateral deep white matter, left external capsule, and subtle signal alterations in the pons bilaterally. In the proband’s mother, there was involvement of the temporal stem, mainly on the right side. There was no proper involvement of the anterior temporal lobes in either parent. Nonserial consecutive T2*-weighted axial images in the proband’s father (7) show small punctate corticomeningeal foci of hemosiderosis in the cerebellar vermis and frontal (not shown) and parietal regions. T2*-weighted images were negative in the proband’s mother (not shown). In the proband’s father, note also an empty sella. (C) Schematic representation showing domain organization and location of the mutations of the HTRA1 protein. Previously reported pathogenic mutations are represented below the protein, with the 2 novel mutations above the protein. IGFBP 5 insulin-like growth factor-binding protein; PDZ 5 postsynaptic density protein; SP 5 signal peptide domain. (D) Multiple protein alignment showing highly conserved serine protease domain across a broad range of different HTRA1 orthologous proteins. The missense substitution of threonine (T) for alanine (A) in codon 321 is shown (#). Consensus sequences were obtained from the UniProt database (http://www.uniprot.org/). Symbols below the sequence alignment indicate when residues across species encode for identical (*) or conserved (:) amino acids. (E) Family pedigree indicating mutation status for HTRA1 (N 5 normal genotype; arrow 5 index case); black symbol indicates CARASIL phenotype, white symbols indicate leukoencephalopathy.
feature with CADASIL. In fact, these 2 conditions may present with similar characteristics, despite the fact that the molecular pathways involved are apparently unrelated. This is the second CARASIL case in a Caucasian subject. The previously reported Spanish patient with a typical CARASIL phenotype featured a new homozygous HTRA1 missense mutation.4 The observation
of leukoencephalopathy in the heterozygous mother increases the complexity of the clinical spectrum4 and suggests that carrier condition may be paucisymptomatic, as supported by a recent report by Chen et al.6 Indeed, mild cerebral involvement was evident in the heterozygous parents in our family as well. In conclusion, our data suggest that CARASIL may not be as rare as initially supposed outside of Asia. Neurology 82
March 11, 2014
899
Moreover, the paucity of extracerebral features and absence of consanguinity in our patient imply that CARASIL should be considered in the screening for earlyonset leukoaraiosis and stroke-like episodes, as well as in sporadic cases and in subjects without alopecia, mainly females. From the Department of Medical, Surgical and Neurological Sciences (S.B., C.D.P., G.N.G., I.T., A.P, F.R., A.R., M.T.D., A.F.), University of Siena, Siena, Italy; Department of Neurology (D.F.M.), University of Medicine and Pharmacy “Iuliu Hatieganu,” ClujNapoca, Romania; and Neuroimaging and Neurointervention Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Policlinico “Santa Maria alle Scotte,” Siena, Italy. Author contributions: S. Bianchi, PhD: study concept, acquisition and interpretation of data, drafting and revising the manuscript. C. Di Palma, Bsc: acquisition and interpretation of data. G.N. Gallus, PhD: acquisition and interpretation of data, critical revision of the manuscript. I. Taglia, BSc: acquisition and interpretation of data. A. Poggiani, BSc: acquisition and interpretation of data. F. Rosini, MD: acquisition and interpretation of data, drafting the manuscript. A. Rufa, MD: study concept, acquisition and interpretation of data, drafting and revising the manuscript, including medical writing for content. D.F. Muresanu, MD: acquisition and interpretation of data. A. Cerase, MD: acquisition and interpretation of data, critical revision of the manuscript. M.T. Dotti, MD: study concept, drafting and revising the manuscript, including medical writing for content. A. Federico, MD: study concept, drafting and revising the manuscript, including medical writing for content. Study funding: Supported by MIUR (prot. 20095JPSNA_005) (M.T.D.) and by Ministry of Health and Regione Toscana (Regional Health Research Program 2009) (A.F.).
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received June 14, 2013. Accepted in final form November 26, 2013.
Correspondence to Dr. Federico: [email protected] © 2014 American Academy of Neurology
REFERENCES 1. Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke Cerebrovasc Dis 2011; 20:85–93. 2. Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729–1739. 3. Maeda S, Nakayama H, Isaka K, Aihara Y, Nemoto S. Familial unusual encephalopathy of Binswanger’s type without hypertension. Folia Psychiatr Neurol Jpn 1976;30:165–177. 4. Mendioroz M, Fernández-Cadenas I, Del Río-Espinola A, et al. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 2010;75:2033–2035. 5. Nishimoto Y, Shibata M, Nihonmatsu M, et al. A novel mutation in the HTRA1 gene causes CARASIL without alopecia. Neurology 2011;76:1353–1355. 6. Chen Y, He Z, Meng S, et al. A novel mutation of the hightemperature requirement A serine peptidase I (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). J Int Med Res 2013;41:1445–1455.
Pre-order 2014 Annual Meeting On Demand and Save Take the meeting home with you. AAN Annual Meeting On Demand is the comprehensive digital library of presentations from the 2014 Annual Meeting providing more than 500 hours* of educational content. Special discounted pricing is available when you pre-order before the Annual Meeting. Learn more at AANonDemand.com/ad *Total hours of presentations available subject to speaker permissions.
It’s Time to Plan for ICD-10, and the AAN Can Help All health care providers are required to transition to ICD-10 on October 1, 2014. Claims for services performed on or after this date with an ICD-9 code will not be processed and payments will be delayed. The AAN provides information and resources to help you make this a smooth transition, and has partnered with Complete Practice Resources to provide you with an affordable online project management tool to help walk you through each phase of the necessary preparation to ensure you’re ready. Learn more at AAN.com/view/ICD10 and start your transition today!
900
Neurology 82
March 11, 2014
Two novel HTRA1 mutations in a European CARASIL patient Silvia Bianchi, Chiara Di Palma, Gian Nicola Gallus, et al. Neurology 2014;82;898-900 Published Online before print February 5, 2014 DOI 10.1212/WNL.0000000000000202 This information is current as of February 5, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/10/898.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/02/05/WNL.0000000000 000202.DC1.html
References
This article cites 6 articles, 3 of which you can access for free at: http://www.neurology.org/content/82/10/898.full.html##ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Silvia Bianchi, PhD Chiara Di Palma, BSc Gian Nicola Gallus, PhD Ilaria Taglia, BSc Antonella Poggiani, BSc Francesca Rosini, MD Alessandra Rufa, MD Dafin Fior Muresanu, MD Alfonso Cerase, MD Maria Teresa Dotti, MD Antonio Federico, MD
Supplemental data at Neurology.org
898
TWO NOVEL HTRA1 MUTATIONS IN A EUROPEAN CARASIL PATIENT
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary, nonhypertensive cause of recurrent lacunar stroke and cognitive decline associated with alopecia, spondylosis deformans, and lumbago.1 The disease has been linked to mutations in the HTRA1 gene, encoding for serine protease HTRA1, loss of which causes dysregulation of transforming growth factor-b signaling.2 Since the first description,3 most affected patients have been reported in Japanese and Chinese pedigrees with typical and atypical phenotypes. No strong genotype– phenotype correlation has yet been found, and homozygous patients with nonsense or missense mutations may be clinically indistinguishable.2 The recent unique report of a Caucasian case suggests that the disease is not limited to Asia.4 Here we report a new European patient with a peculiar phenotype carrying 2 novel mutations of the HTRA1 gene. The heterozygous proband’s parents showed variable leukoencephalopathy but no clinical signs of the disease. Case report. The proband was a 29-year-old Romanian female with unrelated parents. Family history was unremarkable. She complained of chronic lumbar and cervical pain since the age of 14 years. She had 2 ischemic strokes with left hemiparesis and dysarthria at ages 24 and 29, respectively. Neurologic examination showed ataxic gait, gazeevoked nystagmus, dysmetria, hypoactive deep tendon reflexes at legs, and no alopecia. Cognitive status was normal. Brain MRI showed severe diffuse leukoencephalopathy, including subcortical infarcts and evidence of microbleeds, while spine MRI showed degenerative disc disease (figure 1A). Several idiopathic and metabolic causes of ischemic strokes were excluded (MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], Fabry disease, rheumatologic diseases, and vasculitis). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was ruled out by automatic sequencing of exons 2–24 of the NOTCH3 gene and no evidence of granular osmiophilic material in skin and muscle biopsy. The parents were neurologically normal: the father, age 61 years, had negative history for Neurology 82
March 11, 2014
neurologic and cardiovascular diseases and hypertension; the mother, age 60 years, reported mild hypertension under treatment since the age of 54 years without other vascular risk factors. After genetic diagnosis of the daughter, the parents underwent brain MRI. The father showed mild supratentorial leukoencephalopathy (figure 1, B1, B3, B5, B7) and the mother diffuse infratentorial and supratentorial leukoencephalopathy (figure 1, B2, B4, B6). Methods and Results. With institutional review board approval and informed patient consent, we directly sequenced exons 1–9 of the HTRA1 gene in the proband. Two novel heterozygous mutations were identified: the c.961G.A in exon 4 (inherited from the father) and a G deletion (c.126delG) in exon 1 (inherited form the mother). The missense mutation in exon 4 results in substitution of a highly conserved alanine residue with threonine (p.Ala321Thr). This mutation is predicted to be pathogenic by PolyPhen2, SIFT, and Mutation Taster software. The deletion in exon 1 causes a frameshift, altering the amino acid sequence from position 42 (p.Glu42fs), and introduces a stop codon at position 214 (figure e-1 on the Neurology® Web site at Neurology.org). Neither mutation was found in public databases (http:// browser.1000genomes.org/index.html; http://www. ncbi.nlm.nih.gov/projects/SNP/, build 137) or 320 control chromosomes. Discussion. We here report a compound heterozygosity with 2 new mutations of the HTRA1 gene causing CARASIL in a patient with unrelated parents. The deletion (c.126delG) in exon 1, causing a frameshift of the protein with a truncated product, was inherited from the mother. The missense mutation in the protease domain of the HTRA1 gene (p.Ala321Thr) was inherited from the father. The patient did not have alopecia, usually considered a phenotypic marker of the disease. However, 3 women and 1 man without alopecia have been described among CARASIL subjects.2,5 If further confirmed, this observation could suggest a sex-linked difference in the presence of alopecia in the CARASIL population. The number of female patients would be underestimated, misrepresenting the male: female ratio of 3:1 in clinically defined CARASIL cases.1 Our patient had severe leukoencephalopathy with temporal lobe involvement, the latter an overlapping
Figure 1
Compound heterozygous cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): Summary of results
(A) MRI of the brain and cervical and thoracolumbosacral spine of the proband. T1-weighted sagittal (1), T2-weighted coronal (2), serial nonconsecutive fluidattenuated inversion recovery axial (3), and T2*-weighted axial (4) images of the brain show diffuse confluent high signal intensity areas and lacunar infarctions in the pons, where wallerian degeneration of the transverse pontine fibers is evident, and in both cerebral hemispheres, where superficial white matter (U-fibers) is relatively spared and alterations extend to the anterior temporal lobes, genu of the corpus callosum, internal capsules, and left external capsule. Signs of microbleeds are evident in the pons, right thalamus, and right temporal and bilateral cortico-subcortical frontal regions. Brain atrophy is also remarkable. T2-weighted sagittal images of the cervical and thoracolumbosacral spine (5) show degenerative disc disease, more evident in the lumbar spine, including displacements of intervertebral disc tissue into the vertebral bodies, i.e., so-called Schmorl nodes, in the thoracolumbar junction. (B) MRI of the brain of the proband’s father (upper row) and mother (lower row). T1-weighted sagittal (1, 2), serial nonconsecutive T2-weighted axial (3, 4), and fluid-attenuated inversion recovery coronal (5, 6) images show larger involvement in the proband’s mother’s brain tissue than in the proband’s father’s, including bilateral deep white matter, left external capsule, and subtle signal alterations in the pons bilaterally. In the proband’s mother, there was involvement of the temporal stem, mainly on the right side. There was no proper involvement of the anterior temporal lobes in either parent. Nonserial consecutive T2*-weighted axial images in the proband’s father (7) show small punctate corticomeningeal foci of hemosiderosis in the cerebellar vermis and frontal (not shown) and parietal regions. T2*-weighted images were negative in the proband’s mother (not shown). In the proband’s father, note also an empty sella. (C) Schematic representation showing domain organization and location of the mutations of the HTRA1 protein. Previously reported pathogenic mutations are represented below the protein, with the 2 novel mutations above the protein. IGFBP 5 insulin-like growth factor-binding protein; PDZ 5 postsynaptic density protein; SP 5 signal peptide domain. (D) Multiple protein alignment showing highly conserved serine protease domain across a broad range of different HTRA1 orthologous proteins. The missense substitution of threonine (T) for alanine (A) in codon 321 is shown (#). Consensus sequences were obtained from the UniProt database (http://www.uniprot.org/). Symbols below the sequence alignment indicate when residues across species encode for identical (*) or conserved (:) amino acids. (E) Family pedigree indicating mutation status for HTRA1 (N 5 normal genotype; arrow 5 index case); black symbol indicates CARASIL phenotype, white symbols indicate leukoencephalopathy.
feature with CADASIL. In fact, these 2 conditions may present with similar characteristics, despite the fact that the molecular pathways involved are apparently unrelated. This is the second CARASIL case in a Caucasian subject. The previously reported Spanish patient with a typical CARASIL phenotype featured a new homozygous HTRA1 missense mutation.4 The observation
of leukoencephalopathy in the heterozygous mother increases the complexity of the clinical spectrum4 and suggests that carrier condition may be paucisymptomatic, as supported by a recent report by Chen et al.6 Indeed, mild cerebral involvement was evident in the heterozygous parents in our family as well. In conclusion, our data suggest that CARASIL may not be as rare as initially supposed outside of Asia. Neurology 82
March 11, 2014
899
Moreover, the paucity of extracerebral features and absence of consanguinity in our patient imply that CARASIL should be considered in the screening for earlyonset leukoaraiosis and stroke-like episodes, as well as in sporadic cases and in subjects without alopecia, mainly females. From the Department of Medical, Surgical and Neurological Sciences (S.B., C.D.P., G.N.G., I.T., A.P, F.R., A.R., M.T.D., A.F.), University of Siena, Siena, Italy; Department of Neurology (D.F.M.), University of Medicine and Pharmacy “Iuliu Hatieganu,” ClujNapoca, Romania; and Neuroimaging and Neurointervention Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Policlinico “Santa Maria alle Scotte,” Siena, Italy. Author contributions: S. Bianchi, PhD: study concept, acquisition and interpretation of data, drafting and revising the manuscript. C. Di Palma, Bsc: acquisition and interpretation of data. G.N. Gallus, PhD: acquisition and interpretation of data, critical revision of the manuscript. I. Taglia, BSc: acquisition and interpretation of data. A. Poggiani, BSc: acquisition and interpretation of data. F. Rosini, MD: acquisition and interpretation of data, drafting the manuscript. A. Rufa, MD: study concept, acquisition and interpretation of data, drafting and revising the manuscript, including medical writing for content. D.F. Muresanu, MD: acquisition and interpretation of data. A. Cerase, MD: acquisition and interpretation of data, critical revision of the manuscript. M.T. Dotti, MD: study concept, drafting and revising the manuscript, including medical writing for content. A. Federico, MD: study concept, drafting and revising the manuscript, including medical writing for content. Study funding: Supported by MIUR (prot. 20095JPSNA_005) (M.T.D.) and by Ministry of Health and Regione Toscana (Regional Health Research Program 2009) (A.F.).
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures. Received June 14, 2013. Accepted in final form November 26, 2013.
Correspondence to Dr. Federico: [email protected] © 2014 American Academy of Neurology
REFERENCES 1. Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke Cerebrovasc Dis 2011; 20:85–93. 2. Hara K, Shiga A, Fukutake T, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729–1739. 3. Maeda S, Nakayama H, Isaka K, Aihara Y, Nemoto S. Familial unusual encephalopathy of Binswanger’s type without hypertension. Folia Psychiatr Neurol Jpn 1976;30:165–177. 4. Mendioroz M, Fernández-Cadenas I, Del Río-Espinola A, et al. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 2010;75:2033–2035. 5. Nishimoto Y, Shibata M, Nihonmatsu M, et al. A novel mutation in the HTRA1 gene causes CARASIL without alopecia. Neurology 2011;76:1353–1355. 6. Chen Y, He Z, Meng S, et al. A novel mutation of the hightemperature requirement A serine peptidase I (HTRA1) gene in a Chinese family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). J Int Med Res 2013;41:1445–1455.
Pre-order 2014 Annual Meeting On Demand and Save Take the meeting home with you. AAN Annual Meeting On Demand is the comprehensive digital library of presentations from the 2014 Annual Meeting providing more than 500 hours* of educational content. Special discounted pricing is available when you pre-order before the Annual Meeting. Learn more at AANonDemand.com/ad *Total hours of presentations available subject to speaker permissions.
It’s Time to Plan for ICD-10, and the AAN Can Help All health care providers are required to transition to ICD-10 on October 1, 2014. Claims for services performed on or after this date with an ICD-9 code will not be processed and payments will be delayed. The AAN provides information and resources to help you make this a smooth transition, and has partnered with Complete Practice Resources to provide you with an affordable online project management tool to help walk you through each phase of the necessary preparation to ensure you’re ready. Learn more at AAN.com/view/ICD10 and start your transition today!
900
Neurology 82
March 11, 2014
Two novel HTRA1 mutations in a European CARASIL patient Silvia Bianchi, Chiara Di Palma, Gian Nicola Gallus, et al. Neurology 2014;82;898-900 Published Online before print February 5, 2014 DOI 10.1212/WNL.0000000000000202 This information is current as of February 5, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/10/898.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/02/05/WNL.0000000000 000202.DC1.html
References
This article cites 6 articles, 3 of which you can access for free at: http://www.neurology.org/content/82/10/898.full.html##ref-list-1
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
