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Eur J Med Genet. 2018 Dec;61(12):765-772. doi: 10.1016/j.ejmg.2018.10.004. Epub 2018 Oct 11.

Further refinement of COL4A1 and COL4A2 related cortical malformations.

Author information

1
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Imagine Institute, Paris, France.
2
AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Reference des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France; INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France.
3
Pediatric Radiology, Necker Enfants Malades University Hospital, APHP, Paris, France; Image - Institut Imagine, INSERM UMR 1163, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France.
4
Service de Neuropédiatrie CHU Rennes, France.
5
Sección de Genética Médica y Dismorfología, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
6
Service de Néonatologie, CHU Estaing, Clermont-ferrand, France.
7
Service de Génétique CHU Rennes, France.
8
Néonatologie et Pédiatrie, Hôpital Louis-Mourier, Colombes, France.
9
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; CNRS U7104, Illkirch, France; INSERM U964, Illkirch, France; Université de Strasbourg, Illkirch, France; Service de Diagnostic Génétique, Hôpital Civil de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
10
Department of Neuroscience, Evelina London Children's Hospital, St Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.
11
Pediatric Neurology, APHP- Necker Enfants Malades Hospital, Paris, France; French Centre for Paediatric Stroke, AP-HP, Necker Enfants Malades, 75015, Paris, France.
12
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Imagine Institute, Paris, France; Pediatric Neurology, APHP- Necker Enfants Malades Hospital, Paris, France; National Rare Disease Center- Centre de Référence "Déficiences Intellectuelles de Causes Rares", AP-HP, Necker Enfants Malades, 75015, Paris, France. Electronic address: nadia.bahi-buisson@aphp.fr.

Abstract

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia.

METHODS:

We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly.

RESULTS:

One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations.

CONCLUSIONS:

Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.

KEYWORDS:

COL4A1/A2; Cortical malformations; Polymicrogyria; Schizencephaly; Subcortical heterotopia

PMID:
30315939
DOI:
10.1016/j.ejmg.2018.10.004
[Indexed for MEDLINE]

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