Lubov Blumkin

Pediatric Refractory Partial Status Epilepticus Responsive to Topiramate

Topiramate was safely administered to two young children with refractory partial status epilepticus via nasogastric tube in rapid titration up to a very high total daily dose. An excellent clinical response occurred in both cases. Reaching high daily doses of topiramate within days allowed for safe discontinuation of other antiepileptic drugs in both patients. Given the high efficacy of rapidly titrated topiramate in our patients, this medication may be useful in some cases of pediatric refractory partial status epilepticus. However, more clinical studies on this therapeutic approach are needed to establish the precise role of topiramate in status epilepticus in children.( J Child Neurol 2005;20:239—241).

Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .

We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis, intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.

GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.

Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations.

Neurologic involvement in a child with systemic capillary leak syndrome.

Idiopathic systemic capillary leak syndrome (SCLS) is a rare and life-threatening disorder of unknown pathology. It is characterized by recurrent episodes of shock resulting from leakage of plasma, which is reflected by accompanying hemoconcentration, hypoalbuminemia, and edema. Since its first description (Clarkson B, Thompson D, Horwith M, Luckey A. Am J Med. 1960;29:193–216), there have been only 3 descriptions of children with the disorder. Familial cases have not been reported. Brain involvement has only been described for adults and with minimal radiologic findings. We report here an unusual case of an 8-year-old boy with multiple episodes of SCLS since the age of 5 months and an exceptional presentation characterized by substantial neurologic involvement with cerebellar edema and autonomic dysfunction. The patients family history was remarkable for 8 more relatives with the disorder, including his sister who died during a similar episode in infancy and a first-degree cousin of his father who was diagnosed as suffering from recurrent episodes of SCLS. Our patient is, to our knowledge, the first patient with SCLS with a family history of the disorder. Additional genetic studies in the extended family might shed light on the pathogenesis of this rare disorder.

A new locus (SPG47) maps to 1p13.2–1p12 in an Arabic family with complicated autosomal recessive hereditary spastic paraplegia and thin corpus callosum

The hereditary spastic paraplegias (HSP) are a heterogeneous group of genetic neurodegenerative disorders in which the main feature is progressive spasticity of the lower limbs due to pyramidal tract dysfunction. Clinically HSP are divided into two forms: a pure form that presents with progressive lower limb spasticity and weakness, sensory signs and bladder dysfunction, and a complicated form, associated with more extensive neurological and extra neurological signs as well as pathological findings on brain imaging. The clinical variability observed in HSP is supported by the large underlying genetic heterogeneity. Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterized by a slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the most frequent gene associated with HSP-TCC, encodes spatacsin, a protein of unknown function. We describe two siblings from an Arabic consanguineous family with slowly progressive spastic paraparesis, mental retardation, seizures, thin corpus callosum and periventricular white matter abnormalities. Homozygosity mapping identified a novel single candidate region of 7.3 Mb on chromosome 1p13.2-1p12. The finding of a new locus for AR-HSP-TCC further demonstrates the extensive genetic heterogeneity of this condition.

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene

Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.

Clinical Correlates of Occipital Intermittent Rhythmic Delta Activity (OIRDA) in Children

Summary:  Purpose: The clinical significance of occipital intermittent rhythmic delta activity (OIRDA) on the electroencephalogram has not been fully established. Recent studies suggest that this pattern occurs almost exclusively in children and is probably of epileptic origin in most cases. We sought to characterize the electrographic features and clinical correlates of occipital intermittent rhythmic delta activity.

Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A

OBJECTIVE Paroxysmal tonic upward gaze was initially described as a benign phenomenon with negative investigations and eventual complete resolution of symptoms. Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the CACNA1A gene has only been reported once. METHODS We describe three patients with multiple episodes of paroxysmal tonic upward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. RESULTS Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. CONCLUSION CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event.

Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability.

UNLABELLED We describe a highly variable clinical presentation of cerebellar ataxia in two sisters. The younger sister demonstrates early onset rapidly progressive cerebellar ataxia accompanied by motor and nonmotor cerebellar features, as well as cognitive decline and psychiatric problems. Mitochondrial respiratory chain enzyme analysis in muscle showed a decrease in complex I + III. Progressive cerebellar atrophy was demonstrated on serial brain MR imaging. Coenzyme Q10 (CoQ10) supplementation, started at the age of 5 years, led to a significant improvement in motor and cognitive abilities with partial amelioration of the cerebellar signs. Discontinuation of this treatment resulted in worsening of the ataxia, cognitive decline, and severe depression.The older sister, who is 32 years old, has nonprogressive dysarthria and clumsiness from the age of 10 years and MRI reveals cerebellar atrophy.Exome sequencing identified compound heterozygosity for a known (p. Thr584delACC (c.1750_1752delACC)) and a novel (p.P502R) mutation in the ACDK3 gene. CONCLUSIONS Patients with primary CoQ10 deficiency due to ADCK3 mutations can demonstrate a wide spectrum of clinical presentations even in the same family. It is difficult to diagnose CoQ10 deficiency based solely on the clinical presentation.Exome sequencing can provide the molecular diagnosis but since it is expensive and not readily available, we recommend a trial of CoQ10 treatment in patients with ataxia and cerebellar atrophy even before confirmation of the molecular diagnosis.

Congenital Ataxia, Mental Retardation, and Dyskinesia Associated With a Novel CACNA1A Mutation

The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type Ca 2+ channels. Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events, or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation, interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations, especially when associated with recurrent unexplained coma.