Dataset Information

Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

ABSTRACT:

Objective

To characterize the neurologic 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 antiepileptic 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 colocalized 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 nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 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.

Conclusion

COL4A1/COL4A2 mutations typically cause a severe neurologic 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, while 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.

SUBMITTER: Zagaglia S

PROVIDER: S-EPMC6282239 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

Neurologic phenotypes associated with <i>COL4A1</i>/<i>2</i> mutations: Expanding the spectrum of disease.

Zagaglia Sara S Selch Christina C Nisevic Jelena Radic JR Mei Davide D Michalak Zuzanna Z Hernandez-Hernandez Laura L Krithika S S Vezyroglou Katharina K Varadkar Sophia M SM Pepler Alexander A Biskup Saskia S Leão Miguel M Gärtner Jutta J Merkenschlager Andreas A Jaksch Michaela M Møller Rikke S RS Gardella Elena E Kristiansen Britta Schlott BS Hansen Lars Kjærsgaard LK Vari Maria Stella MS Helbig Katherine L KL Desai Sonal S Smith-Hicks Constance L CL Hino-Fukuyo Naomi N Talvik Tiina T Laugesaar Rael R Ilves Pilvi P Õunap Katrin K Körber Ingrid I Hartlieb Till T Kudernatsch Manfred M Winkler Peter P Schimmel Mareike M Hasse Anette A Knuf Markus M Heinemeyer Jan J Makowski Christine C Ghedia Sondhya S Subramanian Gopinath M GM Striano Pasquale P Thomas Rhys H RH Micallef Caroline C Thom Maria M Werring David J DJ Kluger Gerhard Josef GJ Cross J Helen JH Guerrini Renzo R Balestrini Simona S Sisodiya Sanjay M SM

Neurology 20181109 22

<h4>Objective</h4>To characterize the neurologic phenotypes associated with <i>COL4A1/2</i> mutations and to seek genotype-phenotype correlation.<h4>Methods</h4>We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with <i>COL4A1/COL4A2</i> mutations.<h4>Results</h4>Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform disch ...[more]

PMID: 30413629

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