Sintia Kolbjer1, Daniel A Martin2, Maria Pettersson3, Maria Dahlin4, Britt-Marie Anderlid3. 1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Neuropaediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. Electronic address: sintia.kolbjer@sll.se. 2. Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden; Department of Paediatric Radiology, Karolinska University Hospital, Stockholm, Sweden. 3. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Neuropaediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Abstract
INTRODUCTION: Lissencephaly is a rare malformation of cortical development due to abnormal transmantle migration resulting in absent or reduced gyration. The lissencephaly spectrum consists of agyria, pachygyria and subcortical band heterotopia. In this study we compared genetic aetiology, neuroradiology, clinical phenotype and response to antiepileptic drugs in patients with epilepsy and lissencephaly spectrum malformations. METHODS: The study group consisted of 20 patients - 13 males and 7 females, aged 18 months to 21 years at the time of data collection. Genetic testing was performed by oligonucleotide array comparative genomic hybridization (microarray), multiplex ligation-dependent probe amplification (MLPA), targeted gene panels and whole exome/genome sequencing. All neuroradiological investigations were re-evaluated and the malformations were classified by the same neuroradiologist. Clinical features and response to anti-epileptic drugs (AEDs) were evaluated by retrospective review of medical records. RESULTS: In eleven patients (55%) mutations in PAFAH1B1 (LIS1) or variable microdeletions of 17p13.3 including the PAFAH1B1 gene were detected. Four patients (20%) had tubulin encoding gene mutations (TUBA1A, TUBG1 and TUBGCP6). Mutations in DCX, DYNC1H1, ADGRG1 and WDR62 were identified in single patients. In one patient, a possibly pathogenic intragenic deletion in TRIO was detected. A clear radiologic distinction could be made between tubulinopathies and PAFAH1B1 related lissencephaly. The majority of the patients had therapy resistant epilepsy and epileptic spasms was the most prominent seizure type. The best therapeutic response to seizure control in our cohort was obtained by the ketogenic diet, vigabatrin, clobazam, phenobarbital and valproate. CONCLUSION: The most common genetic aetiologies in our cohort of 20 individuals with epilepsy and lissencephaly spectrum were intragenic deletions or single nucleotide mutations in PAFAH1B1 or larger deletions in 17p13.3, encompassing PAFAH1B1, followed by mutations in tubulin encoding genes. Radiological findings could reliably predict molecular results only in agyria with a posterior to anterior gradient. Radiological and molecular findings did not correlate consistently with severity of clinical outcome or therapeutic response.
INTRODUCTION: Lissencephaly is a rare malformation of cortical development due to abnormal transmantle migration resulting in absent or reduced gyration. The lissencephaly spectrum consists of agyria, pachygyria and subcortical band heterotopia. In this study we compared genetic aetiology, neuroradiology, clinical phenotype and response to antiepileptic drugs in patients with epilepsy and lissencephaly spectrum malformations. METHODS: The study group consisted of 20 patients - 13 males and 7 females, aged 18 months to 21 years at the time of data collection. Genetic testing was performed by oligonucleotide array comparative genomic hybridization (microarray), multiplex ligation-dependent probe amplification (MLPA), targeted gene panels and whole exome/genome sequencing. All neuroradiological investigations were re-evaluated and the malformations were classified by the same neuroradiologist. Clinical features and response to anti-epileptic drugs (AEDs) were evaluated by retrospective review of medical records. RESULTS: In eleven patients (55%) mutations in PAFAH1B1 (LIS1) or variable microdeletions of 17p13.3 including the PAFAH1B1 gene were detected. Four patients (20%) had tubulin encoding gene mutations (TUBA1A, TUBG1 and TUBGCP6). Mutations in DCX, DYNC1H1, ADGRG1 and WDR62 were identified in single patients. In one patient, a possibly pathogenic intragenic deletion in TRIO was detected. A clear radiologic distinction could be made between tubulinopathies and PAFAH1B1 related lissencephaly. The majority of the patients had therapy resistant epilepsy and epileptic spasms was the most prominent seizure type. The best therapeutic response to seizure control in our cohort was obtained by the ketogenic diet, vigabatrin, clobazam, phenobarbital and valproate. CONCLUSION: The most common genetic aetiologies in our cohort of 20 individuals with epilepsy and lissencephaly spectrum were intragenic deletions or single nucleotide mutations in PAFAH1B1 or larger deletions in 17p13.3, encompassing PAFAH1B1, followed by mutations in tubulin encoding genes. Radiological findings could reliably predict molecular results only in agyria with a posterior to anterior gradient. Radiological and molecular findings did not correlate consistently with severity of clinical outcome or therapeutic response.
Authors: Inga Harting; Steffen Syrbe; Julian Schröter; Bernt Popp; Heiko Brennenstuhl; Jan H Döring; Stephany H Donze; Emilia K Bijlsma; Arie van Haeringen; Dagmar Huhle; Leonie Jestaedt; Andreas Merkenschlager; Maria Arelin; Daniel Gräfe; Sonja Neuser; Stephanie Oates; Deb K Pal; Michael J Parker; Johannes R Lemke; Georg F Hoffmann; Stefan Kölker Journal: Eur J Hum Genet Date: 2022-01-11 Impact factor: 4.246