J Neurol DOI 10.1007/s00415-013-7224-4

ORIGINAL COMMUNICATION

COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy Bence Gunda • Manuele Mine • Tibor Kova´cs • Csilla Hornya´k Da´niel Bereczki • Gyo¨rgy Va´rallyay • Ga´bor Rudas • Marie-Pierre Audrezet • Elisabeth Tournier-Lasserve



Received: 17 October 2013 / Revised: 13 December 2013 / Accepted: 17 December 2013 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Type IV collagen a1 and a2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the a1 chain, cause a multisystem disease with prominent cerebrovascular manifestations, including porencephaly, bleeding-prone cerebral small vessel disease, and intracranial aneurysms. Mutations in COL4A2 have only been reported in a few porencephaly families so far. Herein, we report on a young adult patient with recurrent intracerebral hemorrhage, leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy associated with a novel COL4A2 mutation. We extensively investigated a 29-yearold male patient with recurrent deep intracerebral hemorrhages causing mild motor and sensory hemisyndromes. Brain MRI showed deep intracerebral hemorrhages of

different age, diffuse leukoencephalopathy, multiple cerebral microbleeds and small aneurysms of the carotid siphon bilaterally. Laboratory work-up revealed significant microscopic hematuria and elevation of creatine-kinase. Genetic testing found a de novo glycine mutation within the COL4A2 triple helical domain. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1 mutations. Therefore, we emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent intracerebral hemorrhage of unknown etiology, particularly if associated with leukoencephalopathy. Keywords COL4A2  Intracerebral hemorrhage  Leukoencephalopathy  MRI  Neurogenetics

B. Gunda and M. Mine have contributed equally to the manuscript.

Electronic supplementary material The online version of this article (doi:10.1007/s00415-013-7224-4) contains supplementary material, which is available to authorized users. B. Gunda (&)  T. Kova´cs  C. Hornya´k  D. Bereczki Department of Neurology, Semmelweis University, Balassa u. 6, Budapest 1083, Hungary e-mail: [email protected] M. Mine  E. Tournier-Lasserve Service de Ge´ne´tique Neuro-vasculaire, Hoˆpital Lariboisie`re, UMR-S 740, Universite´ Paris Diderot, Sorbonne Paris Cite´, Paris, France G. Va´rallyay  G. Rudas MRI Research Center, Semmelweis University, Budapest, Hungary M.-P. Audrezet Institut National de la Sante´ et de la Recherche Me´dicale, U1078 Brest, France

Introduction Type IV collagen a1 and a2 chains form a1 a1 a2 heterotrimers that constitute an essential component of basement membranes including those of the cerebral vasculature [1]. Mutations in COL4A1, encoding the a1 chain, cause a large spectrum of autosomal dominant disorders affecting the cerebral vasculature, eyes, kidneys, and muscles to varying degrees [2]. Cerebrovascular manifestations include often recurrent deep intracerebral hemorrhages (ICH) associated with microbleeds, lacunar infarcts, and diffuse leukoencephalopathy, suggestive of a cerebral small vessel disease [2–5]. Various ocular abnormalities have also been reported in some families [6]. HANAC syndrome (hereditary angiopathy with nephropathy, aneurysm and cramps)––a distinct phenotype––is characterized

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by hematuria, renal cysts, muscle cramps with elevated creatine-kinase (CK), and frequently bilateral, small aneurysms of the intracranial segment of the internal carotid artery (ICA) [7]. Most pathogenic mutations affect glycine residues within the COL4A1 triple helical domain, interfering with the triple helix formation or its stability [4]. Mutations in COL4A2 have also been reported very recently in five families with early onset porencephaly [8– 10]. Scattered white matter lesions and bilateral intracranial ICA aneurysms were found in two asymptomatic members of these families [8]. Herein we report on a young adult patient with recurrent deep ICH associated with diffuse leukoencephalopathy, intracranial aneurysms, nephropathy, and myopathy caused by a de novo mutation affecting a glycine residue of the COL4A2 triple helical domain.

Patients and methods We examined a 29-year-old male patient with unexplained recurrent ICHs. The patient underwent detailed general physical, neurological, and ophthalmological examination; we perfomred an abdomino–pelvic ultrasound and did extensive laboratory work-up including biochemical, hematological, clotting, autoimmune, and inflammatory studies, urine analysis, brain MRI, and molecular genetic analysis of COL4A1 and COL4A2. Several family members have also been investigated and received brain imaging and genetic testing. In the proband’s father––in addition to COL4A1 and COL4A2–– polycystic kidney disease genes (PKD1 and PKD2) were also extensively tested (See Online Supplement for further details). All subjects gave a written informed consent to the genetic studies and their publication.

Results Our patient was born healthy after vaginal delivery and showed normal physical and cognitive development. Asymptomatic microscopic hematuria was detected at 5 years of age. The patient has complained about frequent cramps in the calves since his adolescence. He has no vascular risk factors (such as hypertension, diabetes or hyperlipidemia), and reported no smoking, alcohol, or drug consumption. At 23 years of age he was hospitalized for mild, right-sided, facio-brachial hemiparesis with abrupt onset during sexual intercourse. MRI revealed a minor subcortical hemorrhage affecting the left internal capsule. A year later he presented with a mild, left-sided hemiparesis and hemihypesthesia caused by a minor deep ICH.

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Five years later he was hospitalized again for mild, rightsided, brachiocrural numbness and hemihypesthesia occurring during body building. His blood pressure was normal (115/80 mmHg). MRI (Fig. 1) showed a new minor hemorrhage in the left parietal centrum semiovale together with previous subcortical hemorrhages and multiple microbleeds on T2* images. Diffuse white matter hyperintensity in the deep cerebellar and cerebral hemispheres was seen on FLAIR images. MR angiography revealed small (2.0 and 2.5 mm) aneurysms of both carotid siphons. Ophthalmological examination found no abnormality. Abdominal ultrasound showed a solitary 5 mm parenchymal cyst in the left kidney. Both kidneys were of normal size and appearance. Laboratory studies revealed significant microscopic hematuria (20/HPF) without proteinuria or compromised renal function; and elevation of creatine-kinase (CK 337 U/l). The rest of the work-up was unremarkable. The mother, two younger maternal half-brothers, and maternal grandparents of our patient were all in good health. His father had a ruptured 5 mm ACoA aneurysm, microscopic hematuria (20/HPF) and polycystic kidneys (multiple 7–30 mm cortical cysts in both kidneys). Other paternal family members are also known to have hematuria (grand aunt) and renal cysts (grandmother––multiple 10–40 mm cortical cysts in both kidneys, grand aunt–– single 40 mm cortical cyst in left kidney). The paternal grand aunt has four 4–10 mm unruptured intracranial aneurysms on the anterior communicating-, middle cerebral- and basilar-arteries. None of the family members had focal neurological signs or evidence of ICH on brain imaging. The hypertensive 74-year-old grand aunt had mild leukoencephalopathy. Sequencing of COL4A1 in the patient did not show any mutation within the entire coding sequence, nor deletion/ duplication in this gene. Sequencing of COL4A2 detected a heterozygous mutation in exon 32: c.2821G [ A (p.G941R) in the proband but not in his seven family members (Fig. 2). PKD1 and PKD2 were negative in his father (patient II.2), and the PKD1 locus could be excluded by haplotype reconstruction using the polymorphisms found in the family. See Online Supplement for further clinical and genetic details including family tree (eFigure).

Discussion Herein we report on a young adult patient with recurrent ICH in the absence of any vascular risk factors and show that this patient is affected by a multisystem disorder including cerebral small vessel disease, intracranial carotid aneurysms, hematuria, and muscle cramps with elevated CK; all features strongly suggestive of a COL4A1 mutation [2]. However, the proband’s screening for COL4A1

J Neurol

Fig. 1 Brain MRI. a, b, c: Axial T2* images showing multiple subcortical ICHs in the cerebral hemispheres and microbleeds (arrows) in the cerebellar hemispheres. The arrowhead points to the acute ICH. d, e: Axial FLAIR images showing diffuse, symmetric,

Fig. 2 DNA chromatogram. Control and mutated chromatogram showing the COL4A2 glycin mutation detected in the proband

mutation was negative. Further screening revealed a COL4A2 mutation that is most likely pathogenic since: (1) it occurred de novo; (2) it affects a highly conserved glycine residue located in the triple helical domain; (3) it is absent from all available polymorphism databases and is described as probably damaging by in silico prediction tools (see Online Supplement). Indeed, the de novo nature of this mutation and the fact that it changes a glycine residue of the triple helix are major arguments for its causality.

subcortical white matter hyperintensities. The arrows point to scars of previous subcortical ICHs; the arrowhead shows the acute ICH. f: TOF MRA showing 2 and 2.5 mm aneurysms of both carotid siphons (arrows)

To our knowledge, this is the first reported case of COL4A2 glycine mutation leading to a cerebral small vessel disease causing recurrent ICH in an adult patient. Four other mutations changing a glycine residue in the COL4A2 triple helix have been reported so far [8–10]. Probands of these families all showed congenital hemiplegia and porencephaly. In one 8-year-old asymptomatic subject, patchy white matter lesions were found, and another asymptomatic adult subject of the same family had bilateral intracavernous ICA aneurysms. None of the adult members of these families suffered from ICH. It had been suggested previously––based on the stochiometry of COL4A1/A2 heterotrimers, the absence of extravascular defects, and the reduced penetrance of porencephaly in COL4A2 mutated families––that COL4A2 mutations would possibly be less severe than COL4A1 mutations [10]. Our case does not seem to confirm this notion since our patient shows features that closely resemble those encountered in COL4A1-mutated patients. Interestingly, three COL4A2 missense variants which do not affect glycine residues, Col4A2E1123G, Col4A2Q1150K, and Col4A2A1690T have been associated with sporadic intracerebral hemorrhage [11]. The putative pathogenicity of these variants was suggested based on their effect on secretion of COL4A1 and COL4A2 in a cell-based assay.

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Three paternal relatives of the proband presented with multiple renal cysts; in addition, two of them had intracranial aneurysms, none of which were located on the carotid siphon (typical for collagen mutations). These clinical features, as well as the absence of ICH and leukoencephalopathy in those patients (except for a mild leukoencephalopathy in a 74-year-old hypertensive relative), strongly suggest that they are affected by a distinct disorder. Indeed, none of them carries the COL4A2 mutation of the proband. The presented case completes the spectrum of cerebral and systemic manifestations of COL4A2 mutations that appears to be very similar to that in COL4A1-mutated patients. We therefore emphasize the importance of screening both COL4A1 and COL4A2 in patients showing recurrent ICH of unknown etiology, particularly when associated with diffuse leukoencephalopathy. Acknowledgments We thank A. Delaforge for her excellent technical help. Drs. Gunda, Kova´cs, Hornya´k and Bereczki were sup´ MOP Grant No: TA ´ MOP-4.2.1.B-09/1/KMR. ported by TA Conflicts of interest

None.

References 1. Kuo DS, Labelle-Dumais C, Gould DB (2012) COL4A1 and COL4A2 mutations and disease: insights into pathogenic

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2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

mechanisms and potential therapeutic targets. Hum Mol Genet 21:R97–R110 Vahedi K, Alamowitch S (2011) Clinical spectrum of type IV collagen (COL4A1) mutations: a novel genetic multisystem disease. Curr Opin Neurol 24:63–68 Gould DB, Phalan FC, van Mil SE et al (2006) Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 354:1489–1496 Lanfranconi S, Markus HS (2010) COL4A1 mutations as a monogenic cause of cerebral small vessel disease: a systematic review. Stroke 41:e513–e518 Vahedi K, Kubis N, Boukobza M et al (2007) COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage. Stroke 38:1461–1464 Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M, Goizet C (2010) Ophthalmological features associated with COL4A1 mutations. Arch Ophthalmol 128:483–489 Plaisier E, Gribouval O, Alamowitch S et al (2007) COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Eng J Med 357:2687–2695 Verbeek E, Meuwissen ME, Verheijen FW et al (2012) COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet 20:844–851 Yoneda Y, Haginoya K, Arai H et al (2012) De novo and inherited mutations in COL4A2, encoding the type IV collagen alpha2 chain cause porencephaly. Am J Hum Genet 90:86–90 Murray LS, Lu Y, Taggart A et al (2013) Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke. Hum Mol Genet. doi:10.1093/ hmg/ddt418 [Epub ahead of print] Jeanne M, Labelle-Dumais C, Jorgensen J et al (2012) COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am J Hum Genet 90:91–101

COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy.

Type IV collagen α1 and α2 chains form heterotrimers that constitute an essential component of basement membranes. Mutations in COL4A1, encoding the α...
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