DOI: 10.5061/dryad.gj58t0v
title: Data from: Neurologic phenotypes associated with COL4A1/2 mutations: expanding the spectrum of disease

description: Objective: To characterize the neurological phenotypes associated with
 COL4A1/2 mutations and to seek genotype-phenotype correlation. Methods We
 analyzed clinical, EEG and neuroimaging data of 44 new, and 55 previously
 reported patients with COL4A1/COL4A2 mutations. Results Childhood-onset
 focal seizures, frequently complicated by status epilepticus and
 resistance to anti-epileptic drugs, was the most common phenotype. EEG
 typically showed focal epileptiform discharges in the context of other
 abnormalities, including generalized sharp waves or slowing. In 46.4% of
 new patients with focal seizures, porencephalic cysts on brain MRI
 co-localized with the area of the focal epileptiform discharges. In
 patients with porencephalic cysts, brain MRI frequently also showed
 extensive white matter abnormalities, consistent with the finding of
 diffuse cerebral disturbance on EEG. Notably, we also identified a
 subgroup of patients with epilepsy as their main clinical feature, in
 which brain MRI showed non-specific findings, in particular
 periventricular leukoencephalopathy and ventricular asymmetry. Analysis of
 fifteen pedigrees suggested a worsening of the severity of clinical
 phenotype in succeeding generations, particularly when maternally
 inherited. Mutations associated with epilepsy were spread across COL4A1
 and a clear genotype-phenotype correlation did not emerge. Conclusions
 COL4A1/COL4A2 mutations typically cause a severe neurological condition
 and a broader spectrum of milder phenotypes, in which epilepsy is the
 predominant feature. Early identification of patients carrying
 COL4A1/COL4A2 mutations may have important clinical consequences, whilst
 for research efforts, omission from large-scale epilepsy sequencing
 studies of individuals with abnormalities on brain MRI may generate
 misleading estimates of the genetic contribution to the epilepsies
 overall.
description: Additional
 materialTable 1 summarizes the
 methods of identification of COL4A1/2 mutations in the cohort of new
 patients. Table 2 reports the phenotypes of previously-published patients
 with COL4A1/2 mutations and epilepsy. Tables 3a/b describes the clinical,
 EEG and brain MRI data of the new cohort of patients with COL4A1/2
 mutations. Additional Method describes immunohistochemistry performed from
 consented surplus resected tissue from 1 case.Dryad material 22.05
 .docxFigure
 5Figure 5. Family
 pedigrees from published cases. Fig.5a. COL4A2 c. 2399 G&gt;A; p. G800E.
 Ref. Ha et al., 2016. Fig.5b. COL4A2 c. 3455 G&gt;A; p. G1152D. Ref.
 Yoneda et al., 2012. Fig.5c. COL4A1 c. 1249G&gt;C; p.G417R. Ref. Giorgio
 et al., 2015. Fig.5d. COL4A1 c.3796G&gt;C; p.G1266R. Ref. Shah et al.,
 2012. Fig.5e: COL4A1 c.2662G&gt;C; p.G888R. Ref. Giorgio et al., 2015.
 Fig.5f: COL4A1 p.G562E. Ref. Vahedi et al., 2003 and Vahedi et al., 2007.
 Fig.5g.: COL4A1 p. G749S. Ref. Gasparini et al., 2006. Fig.5h: COL4A1
 c.3389G&gt;A; p.G1130D. Ref. Breedved et al. 2006 Fig.5i: COL4A1
 c.2159G&gt;A. Ref. Tonduti et al., 2012. Fig.5j: COL4A1 c.3715G&gt;A;
 p.G1239R. Ref. Takenouchi et al., 2015. Fig.5k: COL4A1 c. 2645G&gt;A. Ref.
 Shah et al., 2012. Fig.5l: COL4A1 c.1973 G&gt;A. Ref. Livingston et al.,
 2011. Fig.5m: COL4A1 c.4031G&gt;C; p.G1344A. Ref. Leung et al., 2012.
 Fig.5n: COL4A2 c.3455G&gt;A; p.G1152D. Ref. Yoneda et al., 2012. Fig.5o:
 COL4A1 c.2085del; p. G696fs. Ref. Lemmens et al., 2013. wt/m:
 wild-type/mutated.Figure5.ppt