CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients.

CACNA1A pathogenic mutations are involved in various neurological phenotypes including episodic ataxia (EA2), spinocerebellar ataxia (SCA6), and familial hemiplegic migraine (FHM1). Epilepsy is poorly documented. We studied 18 patients (10 males) carrying de novo or inherited CACNA1A mutations, with median age of 2,5 years at epilepsy onset. Eight mutations were novel. Two variants known leading to gain of function (GOF) were found in 5 patients. Five other patients had non-sense variants leading to loss of function (LOF). Seizures were most often revealed by either status epilepticus (SE) (n = 8), eventually triggered by fever (n = 5), or absences/behavioural arrests (n = 7). Non-epileptic paroxysmal events were frequent and consisted in recurrent hemiplegic accesses (n = 9), jitteriness in the neonatal period (n = 6), and ocular paroxysmal events (n = 9). Most of the patients had early permanent cerebellar dysfunction (n = 16) and early moderate to severe global developmental delay (GDD)/intellectual deficiency (ID) (n = 17). MRI was often abnormal, with cerebellar (n = 8) and/or cerebral (n = 6) atrophy. Stroke-like occurred in 2 cases. Some antiepileptic drugs including topiramate, levetiracetam, lamotrigine and valproate were effective on seizures. Acetazolamide and calcium channel blockers were often effective when used. More than half of the patients had refractory epilepsy. CACNA1A mutation should be evoked in front of 2 main electro-clinical phenotypes that are associated with permanent cerebellar dysfunction and moderate to severe GDD/ID. The first one, found in all 5 patients with GOF variants, is characterized by intractable seizures, early and recurrent SE and hemiplegic accesses. The second, less severe, found in 5 patients with LOF variants, is characterized by refractory early onset absence seizures.

The epileptology of GNB5 encephalopathy.

Pathogenic variants in GNB5 cause an autosomal recessive neurodevelopmental disorder with neonatal sinus bradycardia. Seizures or epilepsy occurred in 10 of 22 previously reported cases, including 6 children from one family. We delineate the epileptology of GNB5 encephalopathy. Our nine patients, including five new patients, were from seven families. Epileptic spasms were the most frequent seizure type, occurring in eight of nine patients, and began at a median age of 3 months (2 months to 3 years). Focal seizures preceded spasms in three children, with onset at 7 days, 11 days, and 4 months. One child presented with convulsive status epilepticus at 6 months. Three children had burst suppression on electroencephalography (EEG), three had hypsarrhythmia, and one evolved from burst suppression to hypsarrhythmia. Background slowing was present in all after age 3 years. Magnetic resonance imaging (MRI) showed cerebral atrophy in one child and cerebellar atrophy in another. All nine had abnormal development prior to seizure onset and ultimately had profound impairment without regression. Hypotonia was present in all, with contractures developing in two older patients. All individuals had biallelic pathogenic variants in GNB5, predicted by in silico tools to result in protein truncation and loss-of-function. GNB5 developmental and epileptic encephalopathy is characterized by epileptic spasms, focal seizures, and profound impairment.

Abnormal Interhemispheric Synchrony in Neonatal Hypoxic-Ischemic Encephalopathy: A Retrospective Pilot Study.

BACKGROUND: Abnormal interhemispheric synchrony has been described in many clinical compromises in brain function, but its prognostic value in neonatal hypoxic-ischemic encephalopathy (HIE) is unknown. OBJECTIVES: The study aimed at describing the frequency of abnormal interhemispheric synchrony in infants with HIE and to explore its prognostic value. The main outcome was survival without major disabilities. METHODS: We performed a single-center retrospective cohort study and enrolled 40 neonates with HIE who underwent hypothermia. RESULTS: Abnormal interhemispheric synchrony was observed in 23% of the patients with HIE. Sensitivity and specificity values for predicting survival without major disabilities were 90 and 67% for seizures, 50 and 97% for status epilepticus, 60 and 97% for highly abnormal EEG in the first 48 h, and 80 and 97% for EEG asynchrony, respectively. The prognostic value of asynchrony improved to 100% sensitivity, whereas specificity remained unchanged, when associated with highly abnormal EEG within the first 48 h of life. CONCLUSIONS: Abnormal interhemispheric synchrony was observed in a quarter of the patients with HIE. This pilot study suggests that the prognostic value of asynchrony is excellent, especially when combined with EEG background analysis.

The Indian Basket Trick: a case of delayed paraplegia with complete recovery, caused by misplaced thoracic pedicle screw.

INTRODUCTION: Pedicle screw fixation allows purchase of all three spinal columns without encroaching into the spinal canal improving fracture fixation, as well as deformity correction. Fortunately, neurologic injury associated with pedicle screw malposition is rare. CASE PRESENTATION: A 19-year-old boy was surgically treated for severe right thoracic scoliosis associated with a Chiari Type 1 malformation and a C6 to T7 syringomyelia. Six months after the initial surgery, the patient was referred to our institution after three weeks of gait disturbances and repeated falls. Imaging showed the gross misplacement of the left T5 pedicle screw, which crossed the center of the vertebral canal. The initial surgery used a freehand technique of pedicle screw insertion, with anteroposterior and lateral postoperative X-ray control. During the surgery, no SEP modifications were noted during pedicle screw placement. However, after insertion of the second rod and scoliosis correction by posterior translation technique, SEP responses decreased considerably. Revision surgery was performed to remove the misplaced screw. During the first three months after screw removal, repeated clinical examinations showed progressive recovery of the neurological deficits. Gait and bladder functions were normal six months after screw removal, and clinical signs of spasticity disappeared. SEP explorations performed at final follow-up showed similar responses to those performed before the initial surgery for scoliosis correction. DISCUSSION AND EVALUATION: Neurologic injury associated with pedicle screw malposition is rare. In early or delayed neurological status worsening, intraoperative or postoperative imaging must be done to detect pedicle screw misplacement. In the current case, thanks to cobalt-chromium and titanium use, MRI and CT scan allowed good visualization of the spinal canal and spinal cord. Experimental studies have shown that neurophysiological monitoring of the spinal cord does not detect moderate compression. In that way, neurophysiological monitoring is an all-or-nothing technique which can misdiagnose early stage of spinal cord injuries. Major penetration of the spinal canal by pedicle screw may conduct to hardware removal. CONCLUSIONS: In early or delayed neurological status worsening, intraoperative or postoperative imaging must be done to detect pedicle screw misplacement. In the current case, thanks to cobalt-chromium and titanium use, MRI and CT scan allowed good visualization of the spinal canal and spinal cord. Major penetration of the spinal canal by pedicle screw may conduct to hardware removal.

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation.

BACKGROUND: Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling. METHODS: By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX. RESULTS: We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate. CONCLUSIONS: Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.

Usher syndrome type 1: early detection of electroretinographic changes.

BACKGROUND: Usher syndrome type 1 needs to be diagnosed at early age in order to timely manage speech therapy, cochlear implantation, and genetic counseling. Few data are available regarding electroretinographic testing before the age of six years. AIM: To describe electroretinographic changes in young children with Usher syndrome type 1. METHODS: Retrospective study of fourteen patients. Age at first neurophysiologic testing was between 17 months and 5 years 4 months. Electroretinogram was performed using flash stimulation in mesopic conditions in the conscious child. Analysis was focused on the amplitudes and latencies of a- and b-waves. RESULTS: Whatever the age, an abnormal fundus was always confirmed with an absent electroretinogram. The youngest patient with absent electroretinogram was 17 month-old. When recorded on and after the 29th month of age, electroretinogram was absent in all cases, including 6 patients with normal fundus. In three patients a low-amplitude electroretinogram was present at first recording within the 26th and 27th months. CONCLUSION: Electroretinogram showed retinopathy in young children with Usher syndrome type 1, even in the absence of fundoscopic signs of retinal degeneration.

Early neurological phenotype in 4 children with biallelic PRODH mutations.

Hyperprolinemia type I (HPI) results from a deficiency of proline oxidase (POX), involved in the first step in the conversion of proline to glutamate. Diverse phenotypes were described in patients with HPI, prior to the identification of the POX gene (PRODH): whereas various patients were asymptomatic, others had neurological and extraneurological defects. The PRODH gene is located in the region deleted in velocardiofacial syndrome (VCFS). Heterozygous and homozygous mutations have been identified in patients with variable hyperprolinemia and various features (patients with schizophrenia, chromosome 22q11 microdeletions and/or neurological defects). A functional study has divided the PRODH missense mutations into three groups: those leading to mild, moderate, or severe reduction of POX activity. In this study, we report four unrelated children with HPI and a homogeneous severe neurological phenotype. We identified biallelic abnormalities in PRODH in these patients that led to severe reduction of POX activity. These included missense and non-sense mutations, deletions of PRODH and a 22q11 microdeletion. Four other children have been reported with severe biallelic PRODH mutations. The phenotype of these eight patients associates early psychomotor development delay with predominant cognitive defects, autistic features and epilepsy. Their values of hyperprolinemia ranged from 400 to 2200 micromol/L. Patients with biallelic PRODH alterations resulting in severely impaired POX activity had an early onset and severe neurological features. Thus, children with this phenotype and those with a microdeletion in chromosome 22q11, especially those with mental retardation and autistic features, should be tested for hyperprolinemia. Hyperprolinemic patients should be screened for PRODH mutations.