TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes

Scientific articles have hardly changed in 50 years: ... and “scientific rigour” may be to blame for current dullness...

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Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

Background: The POLG1 gene encodes the catalyticsubunit of DNA polymerase gamma, essential formitochondrial DNA replication and repair. Mutations inPOLG1 have been linked to a spectrum of clinicalphenotypes, and may account for up to 25% of all adultpresentations of mitochondrial disease.Methods and results: We present 14 patients, withcharacteristic features of mitochondrial disease includingprogressive external ophthalmoplegia (PEO) and Alpers–Huttenlocher syndrome and laboratory findings indicativeof mitochondrial dysfunction, including cytochrome coxidase (COX) deficiency and multiple deletions ordepletion of the mitochondrial DNA. Four novel POLG1missense substitutions (p.R597W, p.L605R, p.G746S,p.A862T), are described, together with the first adultpatient with a recently described polymerase domainmutation (p.R1047W). All novel changes were rare in acontrol population and affected highly conserved aminoacids.Conclusion: The addition of these substitutions—including the first report of a dinucleotide mutation(c.1814_1815TT.GC)—to the growing list of defectsfurther confirms the importance of POLG1 mutations asthe underlying abnormality in a range of neurologicalpresentations

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease

Objectives To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients withandnbsp;POLGandnbsp;disease. Methods We identified children with genetically confirmedandnbsp;POLGandnbsp;disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age‐related reference ranges and to non‐POLGandnbsp;patients presenting with status epilepticus. Results Forty‐one patients withandnbsp;POLGandnbsp;disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non‐epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5‐hydroxyindoleacetic acid levels. Conclusions Children withandnbsp;POLGandnbsp;mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.</p

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease

Objectives To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. Methods We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age‐related reference ranges and to non‐POLG patients presenting with status epilepticus. Results Forty‐one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non‐epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5‐hydroxyindoleacetic acid levels. Conclusions Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.</p