KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

Bindu Madhavi Parchuri, Vivek Jain, Ramshekhar N Menon, Sumita Danda, Akbar Mohamed Chettali, Daad AlSowat, Hesham Aldhalaan, Uddhava V Kinhal, Arun Y Bylappa, Jessie Cunningham, Juan P Appendino, Morris H Scantlebury, Aristides Hadjinicolaou, Christelle Moufawad El Achkar, Mahesh Kamate, Lakshminarayanan Kannan, Ranjith Kumar Manokaran, Musaad Abukhaled, Puneet Jain, Berge A Minassian, Elizabeth J Donner, Gregory Costain, Manna Jose, Asuri N Prasad, Sali M K Farhan, Lokesh Lingappa, Gillian Riordan, Vann Chau, Robyn Whitney, Vykuntaraju K Gowda, Sangeetha Yoganathan, Maya Thomas, Ramesh Konanki

Journal: Epilepsia 2024;65(3):709-724

PMID: 38231304

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Abstract

OBJECTIVE

KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort.

METHODS

Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized.

RESULTS

Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years).

SIGNIFICANCE

This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Address: Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India.; Comprehensive Pediatric Epilepsy Program, Division of Neurology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.; Department of Medical Genetics, Christian Medical College, Vellore, Tamil Nadu, India.; Department of Child Health, Royal Hospital, Muscat, Sultanate of Oman.; Division of Pediatric Neurology and Clinical Neurosciences, Department of Pediatrics, Children's Hospital, London Health Sciences Centre, London, Ontario, Canada.; Department of Neurology and Neurosurgery, and Department of Human Genetics, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.; Division of Pediatric Neurology, Neurosciences Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India.; Department of Pediatric Neurology, Rainbow Children's Hospital, Hyderabad, Telangana, India.; Bindu Child Neuro Center, Vijayawada, Andhra Pradesh, India.; Pediatric Neurology Service, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta Children's Hospital, Calgary, Alberta, Canada.; Departments of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.; Hospital Library and Archives, Learning Institute, Hospital for Sick Children, Toronto, Ontario, Canada.; Division of Neurology, Department of Pediatrics, CHU (Centre Hospitalier Universitaire) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Pediatric Neurology, Jawaharlal Nehru Medical College, KLE (Karnataka Lingayat Education) Academy of Higher Education and Research, KLE's Dr Prabhakar Kore (PK) Hospital, Belagavi, Karnataka, India.; Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India.; Department of Paediatric Neurology, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.; Advanced Center for Epilepsy, Gleneagles Global Health City, Chennai, Tamil Nadu, India.; Department of Pediatric Neurology, Neoclinic Children's Hospital, Jaipur, Rajasthan, India.; Division of Pediatric neurology, Department of Neurology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.; Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.; Epilepsy Program, Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.; Division of Clinical and Metabolic Genetics, Hospital for Sick Children, and Program in Genetics & Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada.; Division of Neurology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

DOI: 10.1111/epi.17880

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MeSH Terms: Adolescent, Child, Child, Preschool, Humans, Infant, Young Adult, Electroencephalography, Epilepsies, Myoclonic, Myoclonic Epilepsies, Progressive, Potassium Channels, Seizures, Unverricht-Lundborg Syndrome