Neonatal Med.  2020 Feb;27(1):16-20. 10.5385/nm.2020.27.1.16.

A Novel COL4A1 Mutation in a Neonate with Intrauterine Intraventricular Hemorrhage and Porencephaly

• Noh J
• Jung E
• Jung AY
• Lee BH
• Lee BS
• Kim EAR
• Kim KS

• KMID: 2502088
• DOI: http://doi.org/10.5385/nm.2020.27.1.16

Abstract

Collagen type IV alpha 1 (COL4A1) plays an important role in construction of the basement membranes of all human tissues, especially vessels. Mutations in COL4A1 lead to various multisystemic dysfunctions, including hereditary porencephaly, hemorrhagic stroke, hemiplegia, cerebral small vessel disease, and nephropathy. In this study, we describe a neonatal case featuring a novel de novo COL4A1 mutation, manifesting as fetal intraventricular hemorrhage and porencephaly. This patient is one of the youngest to have been diagnosed with the most severe phenotype. Our experience may assist clinicians in the diagnosis and management of this extremely rare genetic condition.

Keyword

Cerebrovascular disorders; Collagen; Genetics; Hemorrhage; Stroke

Figure

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  Figure 1. Bilateral frontal porencephaly on fetal sonography at 21 weeks of gestation (white arrows).

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  Figure 2. Right cataract of the patient.

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  Figure 3. Images of a microcephalic newborn boy with collagen type IV alpha 1 (COL4A1) mutation. (A) Cranial ultrasonography revealed dysmorphic enlarged lateral ventricles. (B) Axial T2-weighted imaging of the brain revealed bilateral dilated lateral ventricles communicating with extensive frontal porencephaly. Marked thinning of the cortical mantle was noted in the bilateral frontal region. T2 dark signal intensity suggesting hemosiderin deposition was observed along the linings of the lateral ventricles. (C) Axial susceptibility weighted imaging revealed multiple foci of susceptibility in the cerebellum suggesting microhemorrhages.

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  Figure 4. Sequence chromatograms revealed that a single heterozygous nucleotide change, c.2645G>T (p.Gly882Val), was present (A) in the patient, but not in his (B) father or (C) mother.

Reference

1. Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, et al. Mutations in COL4A1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005; 308:1167–71.

2. Decio A, Tonduti D, Pichiecchio A, Vetro A, Ciccone R, Limongelli I, et al. A novel mutation in COL4A1 gene: a possible cause of early postnatal cerebrovascular events. Am J Med Genet A. 2015; 167A:810–5.

3. Durrani-Kolarik S, Manickam K, Chen B. COL4A1 mutation in a neonate with intrauterine stroke and anterior segment dysgenesis. Pediatr Neurol. 2017; 66:100–3.

4. Meuwissen ME, Halley DJ, Smit LS, Lequin MH, Cobben JM, de Coo R, 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; 17:843–53.

5. Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, et al. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol. 2013; 73:48–57.

6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17:405–24.

7. Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel genetic multisystem disease. Curr Opin Neurol. 2011; 24:63–8.

8. Adam MP, Ardinger HH, Pagon RA, Wallace SE. GeneReviews [Internet]. Seattle: University of Washington;2016. Chapter, COL4A1-related disorders [cited 2020 Jan 22]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7046.

9. Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med. 2007; 357:2687–95.

10. Takenouchi T, Ohyagi M, Torii C, Kosaki R, Takahashi T, Kosaki K. Porencephaly in a fetus and HANAC in her father: variable expression of COL4A1 mutation. Am J Med Genet A. 2015; 167A:156–8.

11. Van Agtmael T, Schlotzer-Schrehardt U, McKie L, Brownstein DG, Lee AW, Cross SH, et al. Dominant mutations of COL4A1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy. Hum Mol Genet. 2005; 14:3161–8.

12. Sibon I, Coupry I, Menegon P, Bouchet JP, Gorry P, Burgelin I, et al. COL4A1 mutation in Axenfeld-Rieger anomaly with leukoencephalopathy and stroke. Ann Neurol. 2007; 62:177–84.

13. Kelley PB, Sado Y, Duncan MK. Collagen IV in the developing lens capsule. Matrix Biol. 2002; 21:415–23.

14. Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M, Goizet C. Ophthalmological features associated with COL4A1 mutations. Arch Ophthalmol. 2010; 128:483–9.

15. Cavallin M, Mine M, Philbert M, Boddaert N, Lepage JM, Coste T, et al. Further refinement of COL4A1 and COL4A2 related cortical malformations. Eur J Med Genet. 2018; 61:765–72.

16. Zagaglia S, Selch C, Nisevic JR, Mei D, Michalak Z, HernandezHernandez L, et al. Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease. Neurology. 2018; 91:e2078–88.

17. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006; 354:1489–96.