Tuesday, May 24, 2016

Intrauterine stroke and COL4A1 mutation

Inspired by a recent patient

Shaheen Durrani-Kolarik, Kandamurugu Manickam and Bernadette Chen.  COL4A1 Mutation in a Neonate with Intrauterine Stroke and Anterior Segment Dysgenesis. Pediatric Neurology in press.

COL4A1 , located on chromosome 13q34, encodes the alpha 1 chain of type IV collagen that is a component of basal membranes. It is expressed mainly in the brain, muscles, kidneys and eyes. COL4A1 mutations can vary in presentation, from asymptomatic carriers to severe devastating disease secondary to the effects on small vessels, including porencephaly, intracerebral hemorrhage, infantile hemiparesis in neonates and children, intracerebral hemorrhage, intracranial aneurysms and retinal arteriolar tortuosities in adults. Given its limited description in the medical literature, diagnosis of this mutation can be overlooked. This is important, as identification of this mutation in affected individuals has implications for perinatal management and genetic counseling with availability of prenatal testing to determine inheritance in additional family members. In addition, making this diagnosis may help tailor appropriate screening tests for organs typically involved with COL4A1 mutations. In this case report, we describe a term infant with an extensive intrauterine stroke and anterior segment dysgenesis with a de novo mutation in COL4A1 .

Non-contrast Brain MRI with coronal fast spin echo (FSE) T2-weighted (a) and sagittal T1-weighted (b) imaging demonstrating bilateral hemorrhagic MCA infarction with severe cystic encephalomalacia/absent parenchyma with mass effect on brainstem. Bilateral cerebellar hemisphere infarction with severe cystic encephalomalacia also demonstrated.

From the article:

At present, no diagnostic criteria have been established for COL4A1 -related disorders. There is a wide spectrum of clinical symptoms that variably include brain, ocular, renal, and muscle involvement, as well as reports of Raynaud phenomenon and supraventricular arrhythmia.  Brain involvement can include infantile hemiplegia, migraines with or without aura, seizures, dementia, intellectual disability, intracerebral hemorrhage presenting at various ages, including antenatal  and recurrent episodes, and ischemic stroke.    Neuroimaging demonstrates the features of brain small-vessel disease such as porencephaly characterized by a fluid-filled cavity in the brain; leukoencephalopathy, usually bilateral and symmetric, located mainly in the supratentorial posterior periventricular areas; cerebral microhemorrhages; lacunar infarcts; deep intracerebral hemorrhages; dilated perivascular spaces; and single or multiple intracranial aneurysms.   On ophthalmologic examination, a multitude of findings have variably been described including bilateral tortuosity of the second- and third-order arteries, hemorrhagic spots, and Axenfeld-Reiger anomaly with microcornea, congenital or juvenile cataract, increased intraocular pressure, iris hypoplasia, retinal detachment and optic nerve excavation.  Renal involvement includes hematuria and renal cysts.  Muscle cramps have been reported involving a variety of muscles with associated persistent elevation of serum creatine kinase concentrations.

The inheritance of COL4A1 mutation is autosomal dominant with near 100% penetrance with expression varying in age of onset and severity of clinical symptoms, even within the same family. Therefore, if a parent of the proband is affected, the risk to the siblings is 50%. There may also be de novo mutations or low-level parental mosaicism; however, the proportion of these cases in the population remains unknown.

In our patient and as others have shown, the clinical onset of small vessel disease in the brain as a result of COL4A1 mutations can occur as early as the antenatal period. In neonatology and pediatrics, patients diagnosed with stroke, both in utero and postnatal, often do not have an etiology identified. Therefore, a detailed family history as well as ophthalmologic exam may be warranted to determine other small-vessel organ involvement, as COL4A1 mutations may be grossly underestimated in this patient population.  Despite not having a family history of small-vessel disease with the associated clinical spectrum of COL4A1 mutations, this mutation needs to be recognized by practitioners and be considered on the list of differential diagnoses in patients with no known etiology for an in utero or postnatal stroke. In one case series, three of the four neonates with extensive prenatal porencephaly had no known family history and were found to have sporadic COL4A1 mutations.

The implications for making a diagnosis of COL4A1 mutation in a patient such as the one presented herein are considerable. Prenatal testing can be performed by chorionic villus sampling or by amniocentesis if one of the parents is known to carry the mutation. Preimplantation genetic diagnosis may also be an option for these families. In animal studies of mice with the COL4A1 mutation, it was demonstrated that none of the surgically delivered mutant pups had severe cerebral hemorrhage as was observed in the heterozygous mutant pups that were born naturally.  Therefore, preventive measures could be taken in cases of known familial COL4A1 mutation, specifically cesarean delivery.

Courtesy of:  http://www.mdlinx.com/neurology/medical-news-article/2016/05/16/fetal-porencephaly-hemorrhagic-stroke-cataract-axenfeld/6645193/?category=sub-specialty&page_id=3&subspec_id=317

My patient (see comment):


  1. My patient: A 2 1/2 yo boy with a history of microcephaly and plagiocephaly began having seizures at 9 months of age. Levetiracetam and then topiramate were tried. He was treated with ACTH and then given a trial of ketogenic diet. Valproate was given, followed by vigatrin and clonazepam. Phenobarbital was next in line. Medical cannabis was given. Clobazam was started. Most recently, felbamate was begun and phenobarbital was tapered. A neurologist noted, "He has never had a response to medications, not even a honeymoon period. He has tolerated medications well." On assessment for surgery, it was felt that he could undergo palliative left frontocortical resection, but the risks and benefits would need to be weighed very carefully. He has multiple daily seizures. His seizures, although numerous, are brief in duration.

    He has a pathogenic COL4A1 mutation. An MRI showed a large wedge-shaped defect in the left frontal lobe extending down to the subependymal white matter of the left lateral ventricle. The defect was lined by white matter and a thin layer of calcification was present. A smaller porencephalic defect was also present in the right frontal bone in the region of the middle frontal gyrus. There was focal encephalomalacia along the periventricular white matter of the left posterior temporal lobe. The posterior horns of the lateral ventricles were colpocephalic with loss of the periventricular white matter. The corpus callosum was diffusely thinned. The optic chiasm and optic nerves were notably thin. The left cerebral hemisphere was small and a focal wedge-shaped defect was present posteriorly. The brainstem and, in particular, the pons was small in size. An EEG showed showed multifocal maximal right parietotemporal and frontal spikes and sharp waves. Multiple spasms were recorded with electroencephalographic correlate. The electroencephalographic correlate included diffuse sharp wave activity that was maximal over the bilateral frontal and frontopolar head regions. On another occasion, there was a burst over the right temporal and biparietal regions followed by generalized fast activity. An earlier EEG had shown high amplitude 1 to 4 Hz waveforms, higher in amplitude on the right, associated with periods of generalized electrodecrementation. No normal background rhythm was present. Multifocal bihemispheric spikes and sharp waves were maximal over the right hemisphere and often occurred in trains. Three infantile spasms were recorded characterized by bilateral arm abduction, head flexion, and head turning to the right.

    1. Hi, I am the mother of a 7 year old girl, diagnosed with 3 months with COL4A1, born 38 weeks old, with the opaque cornea in both eyes, with kidney in the horseshoe but functional, cornea transplanted and one rejected, and glaucoma. we did MRI at Head at 1 year of age and the result was diffuse cerebral atrophy, and optic nerve atrophy. He never made crises, he had a delayed development but I thought it was due to vision. The first tooth appeared at 1 year and 2 months, then the next one had problems with the teeth enamel, and most of them were caries, now I'm in change.
      I mention we have no family problems, and we are healthy parents. now we have sent blood tests for us to see if we have this change.
      We're going to do the second MRI to our head.
      Please help us with more information about this disease and how we can help our little girl.
      I'm from Romania, My Name, Daniela, email address danielatruica@yahoo.com