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COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage
ARTICLE IN PRESS
Case Report
COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage € edad, MD,* David Campo-Caballero, MD,* Jon Rodriguez-Antigu Jon Ekiza-Bazan, MD,* Pablo Iruzubieta-Agudo, MD,* ~ oz-Lopetegui, MD,* Gorka Fernandez-Eulate, MD,*,† Amaia Mun Maite Martínez-Zabaleta, MD,* Patricia de la Riva, MD,* pez de Munain, PhD,*,† and Miguel Urtasun-Ocariz, PhD,* Adolfo Lo Ana de Arce, MD*
The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation. Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations. Key Words: COL4—intracerebral hemorrhage—microhemorrhages—leukoaraiosis © 2020 Elsevier Inc. All rights reserved.
Introduction Recent years have seen great developments in the epidemiology of intracerebral hemorrhage (ICH). Estimates based on genetic studies show that up to 30% of ICH risk may be explained by genetic variation.1 In most cases, multiple genes contribute to that risk. The COL4A1 mutation is a very rare monogenic cause of small vessel disease, reported in less than 100 families, that may be the From the *Neurology Department, Donostia University Hospital, San Sebasti an, Gipuzkoa, Spain; and †Neuroscience Department, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain. Received September 26, 2019; revision received December 5, 2019; accepted January 8, 2020. Address correspondence to David Campo-Caballero, MD, Neurology Department, Donostia University Hospital, Paseo Dr. Begiristain 20014, San Sebasti an, Gipuzkoa, Spain. E-mail: [email protected]. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104652
cause of recurrent ICH.2 We report a family with a COL4A1 mutation.
Clinical Cases The index case is a 48-year-old man that had 2 ICHs at the ages of 26 and 47 years. Both involved the left basal ganglia. The notable finding in magnetic resonance imaging after the second episode was large confluent areas of periventricular leukoaraiosis (Fig 1A). He had no vascular risk factors and neuroimaging studies, including computed tomography angiography and catheter angiography, ruled out underlying lesions of tumoral or vascular origin. Extensive laboratory analyses also ruled out thrombophilia and hypercoagulability as causes and he tested negative for the CADASIL mutation. The ophthalmological study revealed a white cataract in the right eye as well as vascular tortuosity on fundoscopy. Finally, single-gene molecular testing of the COL4A1 gene revealed a
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2020: 104652
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ARTICLE IN PRESS D. CAMPO-CABALLERO ET AL.
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Figure 1. (A) MRI (T2) shows a left lenticular hemorrhage (arrow) with hemosiderin deposition dorsally with respect to the previous hemorrhage (arrowhead) and large confluent areas of hyperintensity in the periventricular white matter. (B) MRI (FFE) shows microbleeds in the corona radiata and centrum semiovale with supratentorial leukoaraiosis. (C) MRI (FLAIR) shows a large left porencephalic cavity and diffuse involvement of the white matter in the right hemisphere.
heterozygous change in the long arm of chromosome 13, consisting in a change of a guanine to an adenine (c.2086G>A) that leads a replacement of a glycine by a serine (p.Gly696Ser). On discharge, strict control of vascular risk factors and avoidance of antiplatelet and anticoagulant drugs were recommended. His twin brother had a blind right eye due to a congenital cataract as well as vascular tortuosity in the retina of the left eye. Magnetic resonance imaging showed severe leukoaraiosis and multiple microhemorrhages bilaterally in the subcortical area (Fig 1B). Single-gene molecular testing also showed the same mutation in the COL4A1 gene. The older sister, aged 52 years, had inborn cerebral palsy with a porencephalic cyst and involvement of the white matter of the right hemisphere (Fig 1C). At the age of 46, she had a frontal hemorrhagic stroke. She also tested positive for the same mutation. The father was known to have had an ICH at the age of 30 years, but it was not possible to obtain a more detailed history. The mother is healthy and there are no more siblings.
Discussion We report 4 familial cases of ICH related to the COL4A1 mutation, 3 of them confirmed by genetic testing. The COL4A1 mutation is inherited in an autosomal dominant pattern in the majority of cases. It inhibits type 4 collagen deposits in the basement membrane of capillaries, leading
to their disruption and resulting in multisystem small vessel disease.2 As we have reported in our familial cases, severe leukoaraiosis and subcortical hemorrhages are the hallmark, but carriers may also develop ischemic strokes, porencephalic cysts, intracerebral calcifications, and migraine. Although less frequent, congenital cataracts, myopathy, and cardiac or renal involvement have also been reported.2 4 The presence of intracerebral hemorrhages or microhemorrhages, mainly located in subcortical areas, together with severe subcortical leukoaraiosis sparing arcuate fibers and temporal lobes should prompt us to search for COL4 mutations, especially in young patients and if a familial involvement is suspected.
References 1. Falcone GJ, Woo D. Genetics of spontaneous intracerebral hemorrhage. Stroke 2017;48:3420-3424. 2. Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol 2015;262:2601-2616. 3. Meuwissen ME, Halley DJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015;17:843-853. 4. Plaisier E, Ronco P. COL4A1-related disorders. 2009 [Updated July 7, 2016]. In: Adam MP, Ardinger HH, Pagon RA, eds. GeneReviewsÒ [Internet], Seattle WA: University of Washington; 1993-2019.
Case Report
COL4A1 Mutation as a Cause of Familial Recurrent Intracerebral Hemorrhage € edad, MD,* David Campo-Caballero, MD,* Jon Rodriguez-Antigu Jon Ekiza-Bazan, MD,* Pablo Iruzubieta-Agudo, MD,* ~ oz-Lopetegui, MD,* Gorka Fernandez-Eulate, MD,*,† Amaia Mun Maite Martínez-Zabaleta, MD,* Patricia de la Riva, MD,* pez de Munain, PhD,*,† and Miguel Urtasun-Ocariz, PhD,* Adolfo Lo Ana de Arce, MD*
The COL4A1 mutation is a very rare monogenic cause of small vessel disease related to recurrent intracerebral hemorrhage. We report a family in which the index case presented with two intracerebral hemorrhages in the basal ganglia with severe periventricular leukoaraiosis and a cataract and vascular tortuosity in the ophthalmological study. His twin brother also had severe leukoaraiosis and multiple subcortical microhemorrhages as well as a congenital cataract and vascular tortuosity in the retina. The older sister had a porencephalic cyst and involvement of the periventricular white matter and intracerebral hemorrhage. In single-gene testing, all three were found to have the same COL4A1 mutation. Intracerebral subcortical hemorrhages or microhemorrhages and severe subcortical leukoaraiosis in familial cases may be related to COL4 mutations. Key Words: COL4—intracerebral hemorrhage—microhemorrhages—leukoaraiosis © 2020 Elsevier Inc. All rights reserved.
Introduction Recent years have seen great developments in the epidemiology of intracerebral hemorrhage (ICH). Estimates based on genetic studies show that up to 30% of ICH risk may be explained by genetic variation.1 In most cases, multiple genes contribute to that risk. The COL4A1 mutation is a very rare monogenic cause of small vessel disease, reported in less than 100 families, that may be the From the *Neurology Department, Donostia University Hospital, San Sebasti an, Gipuzkoa, Spain; and †Neuroscience Department, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain. Received September 26, 2019; revision received December 5, 2019; accepted January 8, 2020. Address correspondence to David Campo-Caballero, MD, Neurology Department, Donostia University Hospital, Paseo Dr. Begiristain 20014, San Sebasti an, Gipuzkoa, Spain. E-mail: [email protected]. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104652
cause of recurrent ICH.2 We report a family with a COL4A1 mutation.
Clinical Cases The index case is a 48-year-old man that had 2 ICHs at the ages of 26 and 47 years. Both involved the left basal ganglia. The notable finding in magnetic resonance imaging after the second episode was large confluent areas of periventricular leukoaraiosis (Fig 1A). He had no vascular risk factors and neuroimaging studies, including computed tomography angiography and catheter angiography, ruled out underlying lesions of tumoral or vascular origin. Extensive laboratory analyses also ruled out thrombophilia and hypercoagulability as causes and he tested negative for the CADASIL mutation. The ophthalmological study revealed a white cataract in the right eye as well as vascular tortuosity on fundoscopy. Finally, single-gene molecular testing of the COL4A1 gene revealed a
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2020: 104652
1
ARTICLE IN PRESS D. CAMPO-CABALLERO ET AL.
2
Figure 1. (A) MRI (T2) shows a left lenticular hemorrhage (arrow) with hemosiderin deposition dorsally with respect to the previous hemorrhage (arrowhead) and large confluent areas of hyperintensity in the periventricular white matter. (B) MRI (FFE) shows microbleeds in the corona radiata and centrum semiovale with supratentorial leukoaraiosis. (C) MRI (FLAIR) shows a large left porencephalic cavity and diffuse involvement of the white matter in the right hemisphere.
heterozygous change in the long arm of chromosome 13, consisting in a change of a guanine to an adenine (c.2086G>A) that leads a replacement of a glycine by a serine (p.Gly696Ser). On discharge, strict control of vascular risk factors and avoidance of antiplatelet and anticoagulant drugs were recommended. His twin brother had a blind right eye due to a congenital cataract as well as vascular tortuosity in the retina of the left eye. Magnetic resonance imaging showed severe leukoaraiosis and multiple microhemorrhages bilaterally in the subcortical area (Fig 1B). Single-gene molecular testing also showed the same mutation in the COL4A1 gene. The older sister, aged 52 years, had inborn cerebral palsy with a porencephalic cyst and involvement of the white matter of the right hemisphere (Fig 1C). At the age of 46, she had a frontal hemorrhagic stroke. She also tested positive for the same mutation. The father was known to have had an ICH at the age of 30 years, but it was not possible to obtain a more detailed history. The mother is healthy and there are no more siblings.
Discussion We report 4 familial cases of ICH related to the COL4A1 mutation, 3 of them confirmed by genetic testing. The COL4A1 mutation is inherited in an autosomal dominant pattern in the majority of cases. It inhibits type 4 collagen deposits in the basement membrane of capillaries, leading
to their disruption and resulting in multisystem small vessel disease.2 As we have reported in our familial cases, severe leukoaraiosis and subcortical hemorrhages are the hallmark, but carriers may also develop ischemic strokes, porencephalic cysts, intracerebral calcifications, and migraine. Although less frequent, congenital cataracts, myopathy, and cardiac or renal involvement have also been reported.2 4 The presence of intracerebral hemorrhages or microhemorrhages, mainly located in subcortical areas, together with severe subcortical leukoaraiosis sparing arcuate fibers and temporal lobes should prompt us to search for COL4 mutations, especially in young patients and if a familial involvement is suspected.
References 1. Falcone GJ, Woo D. Genetics of spontaneous intracerebral hemorrhage. Stroke 2017;48:3420-3424. 2. Tan RY, Markus HS. Monogenic causes of stroke: now and the future. J Neurol 2015;262:2601-2616. 3. Meuwissen ME, Halley DJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015;17:843-853. 4. Plaisier E, Ronco P. COL4A1-related disorders. 2009 [Updated July 7, 2016]. In: Adam MP, Ardinger HH, Pagon RA, eds. GeneReviewsÒ [Internet], Seattle WA: University of Washington; 1993-2019.