Epilepsia Partialis Continua a Clinical Feature of a Missense Variant in the ADCK3 Gene and Poor Response to Therapy.

INTRODUCTION: Coenzyme Q10 deficiency can be due to mutations in Coenzyme Q10-biosynthesis genes (primary) or genes unrelated to biosynthesis (secondary). Primary Coenzyme Q10 deficiency-4 (COQ10D4), also known as autosomal recessive spinocerebellar ataxia-9 (SCAR9), is an autosomal recessive disorder caused by mutations in the ADCK3 gene. This disorder is characterized by several clinical manifestations such as severe infantile multisystemic illness, encephalomyopathy, isolated myopathy, cerebellar ataxia, or nephrotic syndrome. METHODS: In this study, whole-exome sequencing was performed in order to identify disease-causing variants in an affected girl with developmental regression and Epilepsia Partialis Continua (EPC). Next, Sanger sequencing method was used to confirm the identified variant in the patient and segregation analysis in her parents. CASE PRESENTATION: The proband is an affected 11-year-old girl with persistent seizures, EPC, and developmental regression including motor, cognition, and speech. Seizures were not controlled with various anticonvulsant drugs despite adequate dosing. Progressive cerebellar atrophy, stroke-like cortical involvement, multifocal hyperintense bright objects, and restriction in diffusion-weighted imaging (DWI) were seen in the brain magnetic resonance imaging (MRI). CONCLUSIONS: A novel homozygous missense variant [NM_020247.5: c.814G>T; (p.Gly272Cys)] was identified within the ADCK3 gene, which is the first mutation in this gene in the Iranian population. Bioinformatics analysis showed this variant is damaging. Based on our patient, clinicians should consider genetic testing earlier to instant diagnosis and satisfactory treatment based on exact etiology to prevent further neurologic sequelae.

Epilepsia partialis continua associated with the p.Arg403Cys variant of the DNM1L gene: an unusual clinical progression with two episodes of super-refractory status epilepticus with a 13-year remission interval.

Dynamin-1-like (DNM1L) is a gene located on chromosome 12p11.21 that encodes for dynamin-related protein (DRP1), a GTPase involved in mitochondrial and peroxisomal fusion, which plays a pivotal role in brain development. The missense variant, p.Arg403Cys, is clinically associated with childhood-onset super-refractory status epilepticus, with either subsequent poor neurological outcome or death (described in 13 patients). We present a 20-year-old girl carrying this mutation with a history of two episodes of super-refractory focal myoclonic status epilepticus which manifested as epilepsia partialis continua (EPC) with a 13-year interval, during which she displayed moderate intellectual disability, social and school reintegration, without complete control of myoclonic manifestations. The first status, which occurred at the age of six, was associated with transient left side thalamic involvement and the second episode with right side transient basal ganglia hyperintensity on MRI. After the second status, a persistent vegetative state with both drug-resistant epilepsia partialis continua and reticular myoclonus endured; the MRI showed progressive brain atrophy. In contrast to previous published cases, this new case of childhood-onset DNM1L encephalopathy demonstrated biphasic clinical progression. The main features of our patient were EPC, super-refractory status epilepticus, and transient and migrating subcortical thalamic hyperintensity on MRI at onset. The unusual clinical course is also noticeable, indicating possible epigenetic and/or protective factors, without underestimating the progressive and genetic basis of this encephalopathy. Precise characterization of seizures and whole-exome sequencing are crucial in order to establish early diagnosis.

Infantile epilepsy with multifocal myoclonus caused by TBC1D24 mutations.

PURPOSE: To summarize the clinical features and neuroimaging changes of epilepsy associated with TBC1D24 mutations. METHODS: Genetic testing was conducted in all epilepsy patients without acquired risk factors for epilepsy. Epilepsy patients identified with TBC1D24 compound heterozygous mutations by next-generation sequencing (NGS) epilepsy panel or whole exome sequencing (WES) were enrolled. The enrolled patients were followed up to summarize the clinical features. RESULTS: Nineteen patients were identified with TBC1D24 compound heterozygous mutations. Nine patients carried the same pathogenic variant c.241_252del. The seizure onset age ranged from 1 day to 8 months of age (median age 75 days). The most prominent features were multifocal myoclonus and epilepsia partialis continua (EPC). Myoclonus could be triggered by fever or infection in 15 patients, and could be terminated by sleep or sedation drugs. Psychomotor developmental delay was presented in 11 patients. Six patients exhibited hearing loss. Brain MRIs were abnormal in eight patients. Twelve patients were diagnosed with epilepsy syndromes including one patient who was diagnosed with Dravet syndrome. Two patients died due to status epilepticus at 4 months and 19 months of age, respectively. CONCLUSION: TBC1D24 mutation related epilepsy was drug-resistant. Multifocal myoclonus, EPC, and fever-induced seizures were common clinical features. Most patients presented psychomotor developmental delay. The neuroimaging abnormality and hearing loss could exacerbate during follow-up.

Alternating Hemiplegia and Epilepsia Partialis Continua: A new phenotype for a novel compound TBC1D24 mutation.

Mutations in the TBC1D24 gene (MIM 613577) cause familial infantile myoclonic epilepsy (FIME; 605021) and early infantile epileptic encephalopathy-16 (EIEE16; 615338), both inherited with an autosomal recessive trait. The TBC1D24 gene encodes a member of the TBC family domain proteins, involved in cell signaling and oxidative stress resistance. We studied, by a Next Generation Sequencing (NGS) target re-sequencing gene approach, the DNA of a 5 year-old girl, affected by recurrent attacks of Alternating Hemiplegia (AH) and by recurrent episodes of Epilepsia Partialis Continua (EPC). The NGS study showed the presence of two different heterozygous, probably pathogenic variants in the TBC1D24 gene, inherited in trans from her parents: the c.116C>T (p.Ala39Val) and the c.457G>A (p.Glu153Lys). This study describes for the first time the association between TBC1D24 variants and AH expanding the phenotypic spectrum of TBC1D24-related diseases and suggesting that TBC1D24 molecular analysis should be considered in the diagnostic work up of AH patients. An additional peculiar feature is the association of AH and EPC.

Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy.

TBC1D24 is a newly recognized gene in which variations lead to variable clinical phenotypes including drug-resistant epilepsy. We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration. All patients had seizure semiologies consisting of prolonged, unilateral, focal clonic activity of the arm, leg or face, in addition to generalized clonic or myoclonic seizures. Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal-ictal transitions. Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy. Our series suggests that TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures prone to electroclinical dissociation.

Alexander Disease: A Novel Mutation in GFAP Leading to Epilepsia Partialis Continua.

Alexander disease is a genetically induced leukodystrophy, due to dominant mutations in the glial fibrillary acidic protein (GFAP ) gene, causing dysfunction of astrocytes. We have identified a novel GFAP mutation, associated with a novel phenotype for Alexander disease. A boy with global developmental delay and hypertonia was found to have a leukodystrophy. Genetic analysis revealed a heterozygous point mutation in exon 6 of the GFAP gene. The guanine-to-adenine change causes substitution of the normal glutamic acid codon (GAG) with a mutant lysine codon (AAG) at position 312 (E312 K mutation). At the age of 4 years, the child developed epilepsia partialis continua, consisting of unabating motor seizures involving the unilateral perioral muscles. Epilepsia partialis continua has not previously been reported in association with Alexander disease. Whether and how the E312 K mutation produces pathologic changes and clinical signs that are unique from other Alexander disease-inducing mutations in GFAP remain to be determined.

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort.

Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes.

Alpers-Huttenlocher syndrome.

Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA replicase, polymerase-γ. Alterations in enzyme activity result in reduced levels or deletions in mitochondrial DNA. Phenotypic manifestations occur when the functional content of mitochondrial DNA reaches a critical nadir. The tempo of disease progression and onset varies among patients, even in identical genotypes. The classic clinical triad of seizures, liver degeneration, and progressive developmental regression helps define the disorder, but a wide range of clinical expression occurs. The majority of patients are healthy before disease onset, and seizures herald the disorder in most patients. Seizures can rapidly progress to medical intractability, with frequent episodes of epilepsia partialis continua or status epilepticus. Liver involvement may precede or occur after seizure onset. Regardless, eventual liver failure is common. Both the tempo of disease progression and range of organ involvement vary from patient to patient, and are only partly explained by pathogenic effects of genetic mutations. Diagnosis involves the constellation of organ involvement, not the sequence of signs. This disorder is relentlessly progressive and ultimately fatal.

Adult-onset Rasmussen's encephalitis: anatomical-electrographic-clinical features of 7 Italian cases.

PURPOSE: A limited number of cases of adult-onset Rasmussen's encephalitis (A-RE) have been reported, but the features of the syndrome are still unclear. The aim of this study was to verify the clinical features of A-RE, and outline a noninvasive approach that may allow its early diagnosis and treatment. METHODS: Retrospective evaluation of extensive noninvasive work-up of seven patients with A-RE, including repeat clinical, neurophysiological, and neuroimaging investigations. RESULTS: The study identified two distinct patterns of disease presentation, one characterized by focal motor epilepsy (the "epileptic" phenotype), and the other by focal cortical myoclonus (the "myoclonic" phenotype). Unilateral neurological deficits and brain atrophy were progressive in both phenotypes, but they were more prominent and were detected earlier in the "epileptic" phenotype. CONCLUSIONS: The anatomo-electroclinical features of these patients allowed a noninvasive diagnosis of A-RE and identification of two distinct disease phenotypes. Early noninvasive diagnosis can allow faster initiation of treatment.

Familial alternating epilepsia partialis continua with chronic encephalitis: another variant of Rasmussen syndrome?

Two brothers had infantile epilepsia partialis continua alternately involving both sides of the body. The children rapidly developed severe psychomotor regression and cerebral atrophy. A brain biopsy specimen showed evidence of chronic inflammatory changes. Extensive investigation did not provide evidence of a specific viral pathogenesis, mitochondrial disorder, or any identifiable neurodegenerative genetically determined disorder. This illness has the features of Rasmussen chronic encephalitis, in which bilateral involvement is quite unusual. Although few patients with bilateral hemispheral involvement have been described, to our knowledge there have been no reported cases involving affected siblings. The familial disorder described herein may represent yet another variant of the classically sporadic and unilateral childhood form. This group of disorders is probably immunologically determined.