Objective: Pathogenic mutations of COL4A1 are associated with young-onset stroke and porencephaly. We present a case of a 32-year-old female patient with juvenile onset right hand and foot dystonia and mild mental retardation due to hemorrhagic stroke associated with COL4A1 mutation.

Background: COL4A1 is one of the components of type IV collagen. Specific alterations of vascular basement membrane due to COL4A1 mutations frequently manifest infantile porencephaly, cerebral small vessel diseases, dilated perivascular spaces, intracranial aneurysm, glomerular hematuria, and retinal arteriolar tortuosity[1, 2]. Although patients with COL4A1 mutations frequently manifest hemorrhagic stroke in the basal ganglia, movement disorders have not been reported.

Methods: Genomic DNA was captured using the SureSelect Human All Exon v5 Kit (Agilent Technologies, Santa Clara, CA), and sequenced with on HiSeq2500 (Illumina, San Diego, CA) with 101 bp paired-end reads. Exome data processing was performed as previously described. In this analysis, 96.2 % of coding sequences of RefSeq genes were covered by 10 reads or more in the patient. This study was approved by the Ethics Committee of the Yokohama City and the Juntendo University. All participants gave informed consent prior to participation in the study, according to the Declaration of Helsinki.

Results: The patient’s clinical history was as follows: At birth, she had a high fever of unknown origin. She could not walk by herself until 18 months of age and showed abnormal posture in her right leg. At age 3, she was diagnosed with foot dystonia. At age 6, she had a seizure and was diagnosed with epilepsy. At age 17, she suddenly developed transient right side leg weakness and sensory disturbance. Brain computed tomography showed an abnormal low-density area in the basal ganglia. At age 29, she experienced transient tinnitus and vertigo; at that time, cranial FLAIR-MRI depicted an abnormal low intensity area in the bilateral caudate head and dentate nucleus, dilated perivascular spaces, and white matter hyper intensities. Neurological examination indicated dyscalculia without any other higher cerebral dysfunction. She had dystonia of the right hand and foot without parkinsonism or cerebellar ataxia.Cranial SWI-MRI depicted abnormal low intensity areas in the bilateral caudate head and dentate nucleus. These findings are indicative of NBIA. However, fundoscopic analysis revealed retinal arteriolar tortuosity.Sequencing for COL4A1 revealed a previously undescribed c.2494G>A mutation in exon 32, resulting in an amino acid change from glycine to arginine at position 832. This mutation was not found in her parents, indicating it had occurred de novo.

Conclusions: Neurologist should be aware that dystonia with ferritin deposition in the basal ganglia and dentate nucleus might be associated with not only NBIA but also juvenile hereditary hemorrhagic stroke, such as COL4A1 related cerebrovascular disease.

References: 1. D.B. Gould, F.C. Phalan, S.E.van Mil, J.P. Sundberg, K. Vahedi, P. Massin, M.G. Bousser, P. Heutink, J.H. Miner, E. Tournier-Lasserve, S.W.M. John. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 2006;354:1489-1496. 2. K. Vahedi, M. Boukobza, P. Massin, D. B. Gould, E. Tournier-Lasserve, M. G. Bousser. Clinical and brain MRI follow-up study of a family with COL4A1 mutation. Neurology 2007;69:1564-1568.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dystonia-due-to-bilateral-caudate-hemorrhage-associated-with-a-col4a1-mutation/