Childhood presentation of COL4A1 mutations

Abstract

AIM To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation.METHOD We retrospectively reviewed the clinical presentation. Investigations included radiological findings and COL4A1 mutation analysis of the four cases. Affected family members were identified. COL4A1 mutation analysis was performed in all index cases and, where possible, in affected family members. RESULTSThe three male and one female index cases presented with recurrent childhood-onset stroke, infantile hemiplegia ⁄ spastic quadriplegia, and infantile spasms. Additional features such as congenital cataracts and anterior segment dysgenesis were present. Microcephaly and developmental delay ⁄ learning difficulties were present in three cases. Three cases had one or more family member affected in multiple generations, with a total of 11 such individuals identified. The clinical features showed a wide intrafamilial variation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member. Unilateral or bilateral porencephaly was present in cases with infantile hemiplegia, and a diagnosis of clinical stroke was supported by the presence of intracerebral haemorrhage. The age at diagnosis was between 1 year and 6 years for the children with presentation in infancy and 12 months after stroke in a 14-year-old male. Three new pathogenic mutations were identified in the COL4A1 gene.INTERPRETATION COL4A1 mutations can present in children with infantile hemiplegia ⁄ quadriplegia, stroke or epilepsy, and a motor disorder. The presence of eye features and white matter change on MRI in childhood can help point towards the diagnosis. Once the diagnosis is made, a careful search can identify affected family members.

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature

“…17,20,31,34 Stroke in later childhood and young adulthood was not reported in our cohort. In the literature, cerebral hemorrhages in childhood or in young adulthood have been documented in patients with COL4A1 mutations.…”

“…For this, a PubMed search was performed, identifying 27 articles with clinical and mutation data on COL4A1 7,8,[10][11][12][13][14][15][16][17][18][19][20][21][22][29][30][31][32][33][34][35][36][37][38][39][40] and 3 articles with data on COL4A2 mutations. [26][27][28] A total of 137 individuals with a COL4A1 mutation from 60 families and 15 individuals with a COL4A2 mutation from 7 families have been reported.…”

“…Hemorrhagic strokes Review typically affect the deep white matter, in combination with diffuse leukoencephalopathy and microbleeds. 17,20,31,34 Recurrence of strokes has been reported. 20,31 Two of the documented cases were sporadic, 20,34 the others were familial.…”

“…Porencephaly is one of the most frequently reported findings, described in 53 patients with COL4A1 mutations 7,8,12,14,15,17,18,21,[37][38][39] and 6 patients with COL4A2 mutation 27,28 ( Table 2). Because porencephaly was the first reported associated phenotype, however, there may be a bias in the inclusion of patients for COL4A1 and COL4A2 testing.…”

“…The disorder related to COL4A1 mutations is now known as a systemic disease, including a broad spectrum of cerebrovascular lesions: porencephaly and transmantle lesions, causing hydranencephaly or schizencephaly; lesions of the kidneys, leading to nephrosis and hematuria; lesions of the eyes, causing cataract, microphthalmia, and blindness; lesions of the heart, causing arrhythmia; and lesions of the skeletal muscles, causing dystrophic changes, weakness, and myoglobinuria. [10][11][12][13][14][15][16][17][18][19][20][21][22] COL4A1 and COL4A2 encode proα1(IV) and proα2(IV) chains, respectively, which assemble to form a heterotrimeric helix with a constant 2:1 ratio (proα1(IV)) 2 (proα2 (IV)). This type IV collagen is a component of nonfibrillary collagen, a main constituent of the basement membranes of many tissues, among them vascular endothelia.…”