Sophia Varadkar

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances

Rasmussens encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussens encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussens encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussens encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussens encephalitis, without changing the eventual outcome.

Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children

To gain insight into the long‐term impact of vagus nerve stimulation (with VNS Therapy) in children with drug‐resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow‐up period of up to 24 months.

Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

Mutations in PNPO are a known cause of neonatal onset seizures that are resistant to pyridoxine but responsive to pyridoxal phosphate (PLP). Mills et al. show that PNPO mutations can also cause neonatal onset seizures that respond to pyridoxine but worsen with PLP, as well as PLP-responsive infantile spasms.

Inborn errors of metabolism causing epilepsy

Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), for example in a neonate with pyridoxine‐dependent epilepsy. In other IEMs, seizures may be preceded by other major symptoms: by a reduced level of consciousness in a child with an organic acidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.

Evolution of the EEG in children with Rasmussen's syndrome

Purpose:  The early diagnosis of Rasmussen’s syndrome (RS) is often difficult, with differentiation between RS and focal cortical dysplasia (FCD) at epilepsy onset problematic. This study reviewed electroencephalography (EEG) in the two conditions for early indicators of either pathology.

Acetazolamide and autosomal dominant nocturnal frontal lobe epilepsy

To the Editor: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an inherited seizure syndrome characterized by childhood or adolescence onset of stereotyped clusters of motor seizures from sleep. Intelligence, neurologic examination, and structural neuroimaging are normal (1,2). Interictal EEG is usually normal. Ictal EEG may show bilateral frontal spike and wave or no abnormality (3). Seizures usually respond to carbamazepine (CBZ) (1–3). Mutations in genes encoding the neuronal nicotinic acetylcholine receptor ion channel have been described in some families, suggesting the condition to be a channelopathy (4–6). We report a female patient with ADNFLE, who, with other family members, responded to acetazolamide (ACZ). The family were included in the original article describing ADNFLE as a distinctive clinical disorder (2). Although linkage studies in this family localize to chromosome 15, mutational analysis for the known cholinergic receptor genes is negative. Seizures began at age 7 years and were characterized by arousal from sleep, clearing of her throat, aphasia, arm movements, and retained awareness. CBZ was initiated with response. Seizure frequency increased from age 12 years, with clusters of >20 seizures per night. Nocturnal waking resulted in daytime somnolence and inability to attend school. Neurologic examination, interictal EEG, and brain magnetic resonance imaging (MRI) were normal. Video-telemetry showed brief stereotyped attacks of frontal lobe semiology, after abrupt electrographic arousal from non–rapid eye movement (REM) sleep. Ictal EEG was unremarkable. ACZ, 500 mg at night, was added to CBZ. She became seizure free and was able to return to school full-time. When last reviewed at age 17 years, she

Delineation of the movement disorders associated with FOXG1 mutations

Objective: The primary objective of this research was to characterize the movement disorders associated with FOXG1 mutations. Methods: We identified patients with FOXG1 mutations who were referred to either a tertiary movement disorder clinic or tertiary epilepsy service and retrospectively reviewed medical records, clinical investigations, neuroimaging, and available video footage. We administered a telephone-based questionnaire regarding the functional impact of the movement disorders and perceived efficacy of treatment to the caregivers of one cohort of participants. Results: We identified 28 patients with FOXG1 mutations, of whom 6 had previously unreported mutations. A wide variety of movement disorders were identified, with dystonia, choreoathetosis, and orolingual/facial dyskinesias most commonly present. Ninety-three percent of patients had a mixed movement disorder phenotype. In contrast to the phenotype classically described with FOXG1 mutations, 4 patients with missense mutations had a milder phenotype, with independent ambulation, spoken language, and normocephaly. Hyperkinetic involuntary movements were a major clinical feature in these patients. Of the symptomatic treatments targeted to control abnormal involuntary movements, most did not emerge as clearly beneficial, although 4 patients had a caregiver-reported response to levodopa. Conclusions: Abnormal involuntary movements are a major feature of FOXG1 mutations. Our study delineates the spectrum of movement disorders and confirms an expanding clinical phenotype. Symptomatic treatment may be considered for severe or disabling cases, although further research regarding potential treatment strategies is necessary.

Rasmussen Syndrome and Other Inflammatory Epilepsies

An underlying immune basis is emerging in an increasing number of epileptic and encephalopathic syndromes. The immunopathological mechanisms may be categorized into antibody-mediated, T-cell cytotoxicity, and microglia-induced degeneration. The immune basis in Rasmussen syndrome is thought to be T-cell mediated. Antibodies to extracellular and intracellular epitopes are implicated in limbic and other encephalitides, characterized by seizures, movement disorder, sleep disorder, obtundation, psychosis, mutism, and other psychiatric symptoms. Extracellular antibodies are directed at cell-surface-expressed neuronal or glial proteins: glutamate receptors (N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid), voltage-gated potassium channel complex (contactin-associated-protein 2 [CASPR2], contactin-2 and leucin-rich, glioma-inactivated 1 [LGI1]), and γ-aminobutyric acid (GABA) receptors (GABABR and GABAAR). Antibodies to intracellular antigens are less commonly seen (for example, glutamic acid decarboxylase). Diseases caused by antibodies to cell-surface-expressed antigens are better expected to respond to immune treatments than to those where the presumed mechanism is T-cell driven. Antibodies to the folate receptor FR1 are a cause of primary cerebral folate deficiency. Febrile infection-related epilepsy syndrome (FIRES) may also have an immune basis, although this is yet to be proven. For all these epilepsies, the best treatment and the long-term outcomes are not yet clear.

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes

Targeted gene panels can be used to establish molecular diagnoses in paediatric cohorts. Reid et al. report that this approach is accurate, efficient and can be preferred to whole-exome or genome sequencing for patients with neurological symptomatology and clues suggestive of an inherited metabolic disorder.