Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome.

Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier. Here, we report the characterizations of Mfsd7c-KO mice and compare these characterizations to phenotypic findings in humans with biallelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late-gestation lethality, likely due to CNS phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c-KO embryos was inhibited in cortical ventricular zones and ganglionic eminences. Vascular tips were dilated and fused, resulting in glomeruloid vessels. Nonetheless, CNS blood vessels were intact, without hemorrhage. Both embryos and humans with biallelic FLVCR2 mutations exhibited reduced cerebral cortical layers, enlargement of the cerebral ventricles, and microcephaly. Transcriptomic analysis of Mfsd7cK-KO embryonic brains revealed upregulation of genes involved in glycolysis and angiogenesis. The Mfsd7c-KO brain exhibited hypoxia and neuronal cell death. Our results indicate that MFSD7c is required for the normal growth of CNS blood vessels and that ablation of this gene results in microcephaly-associated vasculopathy in mice and humans.

Acute ataxia in children: Common causes and yield of diagnostic work-up in the era of varicella vaccination.

We aimed to identify the most common causes of acute ataxia in children in the era of widespread varicella vaccination and the yield of commonly used diagnostic work-up. This retrospective study reviewed the medical records of children who presented with ataxia of less than 72 h duration, over the last 12 years. Associated signs and symptoms, laboratory, EEG and neuroimaging studies, final diagnosis and clinical findings at discharge and during follow-up were studied. A total of 58 patients (35 boys, 23 girls), mean age 4.9 ±â€¯3.8 years, were enrolled. The most common etiology of acute ataxia in our study was post-infectious acute cerebellar ataxia (50%). Children diagnosed with post-infectious acute cerebellar ataxia were significantly younger (3.48 ±â€¯2.23 vs. 6.5 ±â€¯3.1 years, p = 0.01), as compared with children diagnosed with infection and acute disseminated encephalomyelitis. 86% of children with post-infectious cerebellar ataxia were younger than 5 years of age. The abnormality yield of work-up studies performed in our cohort was 39% for lumbar puncture, 36% for EEG, 7% for CT scan. MRI was done in children who showed extra cerebellar signs, when vascular or demyelinating diseases were suspected and in children with prolonged symptoms and was abnormal in 8 (14%) children. We conclude that post-infectious acute cerebellar ataxia remains the most common cause of acute ataxia in children. Although lumbar puncture and neuroimaging should be considered in all children with acute cerebellar ataxia, younger children with a history of previous viral illness and no extra cerebellar signs and symptoms may benefit from watchful waiting.

Whole-exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.

Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. We describe a 13-year-old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement. Whole-exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy. Our report highlights the importance of next-generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment.

Visual Outcome and Recurrence Rate in Children With Idiopathic Intracranial Hypertension.

The purpose of this retrospective study was to evaluate the visual outcome and recurrence rate of idiopathic intracranial hypertension in children. The study included 68 patients who were diagnosed with idiopathic intracranial hypertension according to the modified Dandy criteria. Permanent visual impairment was rare. Three percent remained with mild visual impairment, 4% with minimal visual field defects, and only 1 patient had severe visual impairment. However, 26% had either a prolonged course of disease or a recurring condition. Higher cerebrospinal fluid opening pressure was the only clinical predictor at presentation (P = .04). Recurrence rate was 18%, and in most cases, the second episode occurred during the first year after remission. There was no significant difference between the group of patients with only 1 episode and the group of patients with more than 1 episode. We suggest long-term follow-up after remission, for at least a year, for all children with idiopathic intracranial hypertension.

[Acute hemiplegia and hemianesthesia together with decreased tendon reflexes mimicking acute stroke representing a conversion disorder].

Acute hemiplegia and hemianesthesia is commonly caused by obstruction of major cortical arteries. Such a presentation secondary to a conversion reaction is very rare, especially in the pediatric age group. The authors report an adolescent presenting with acute complete left-sided hemiplegia and sensory loss together with decreased tendon reflexes mimicking an acute arterial stroke. Examination revealed Hoover's sign was present and the patient was oblivious to his stern neurological state. Movement of his paralytic limbs was observed during sleep. Cortical and spinal CT, cortical MRI, motor and somatosensory evoked potentials and a PET study were all normal. As such, the diagnosis of psychogenic hemiplegia was established, apparently within a period that the patient had experienced severe emotional stress while questioning his gender identity. After three days, the adolescent began to move the paralytic limbs along gradual resolution of sensory deficit, leading to complete clinical recovering within two months. Although extremely rare, a conversion reaction should be taken into account in children presenting with acute hemiplegia and anaesthesia, even accompanied with decreased tendon reflexes, when the patient is oblivious to his alleged grave state, and when clinical observations such as Hoover's sign remain intact, substantiated by normal extensive radiological and neurophysiological investigation. Intact motor evoked potentials serve as a key for the diagnosis of psychogenic hemiplegia and, should therefore be performed in suspected cases.

Acute transient deafness representing a negative epileptic phenomenon.

We report herein 2 children who presented with acute deafness heralding an epileptic event manifesting thereafter by loss of consciousness and tonic generalized posturing, possibly reflecting a negative epileptic phenomenon. The first previously healthy male had 2 paroxysmal episodes 7 months apart, starting with acute deafness lasting for a few minutes followed by loss of consciousness and generalized tonic posturing for 10 minutes. Electroencephalography (EEG) during the second episodes demonstrated generalized epileptiform discharges. The second with previously controlled partial complex seizures presented with episodes of complete deafness lasting for a few minutes followed by loss of consciousness and focal tonic posturing lasting 10 minutes. Such acute deafness represented an aura of a focal seizure substantiated by right focal temporal epileptic discharges within the region of the primary auditory cortex. Therefore, EEG should be performed in any case of acute transient deafness, even in the absence of accompanying overt clinical seizures.

The complementary value of sleep-deprived EEG in childhood onset epilepsy.

BACKGROUND: Although EEG is an important diagnostic tool in suspected childhood onset epilepsy, as many as 50% of wakefulness records remain normal. Sleep-deprived EEG has been reported in adults to serve as an activator of epileptic discharges but such effect is still not agreed upon in children reporting small series. PURPOSE: Assess the complementary diagnostic value of sleep deprivation on the induction of epileptic discharges in childhood onset epilepsy having a normal awake record within a period of 5 years. EEG recording was performed during the awake, drowsiness and sleep states following sleep deprivation of 6h. BACKGROUND RESULTS: Fifty five children of whom the initial record failed to detect epileptiform discharges, were assessed at age 5-17 years (mean: 10+/-3.7), 27 boys and 28 girls. Sleep occurred in 51 (92.7%) after sleep deprivation and in only 1 (1.8%) during an awake record. Epileptic discharges were detected in 15 of 55 (27.2%) previous non-epileptic awake records during the sleep-deprived EEG either during wakefulness and more frequent during sleep. Eight abnormal records were detected in 18 (44%) children presenting with a focal seizure and 7 of 35 (20%) associated with generalized seizures. Epileptic discharges were recorded mainly and more frequent during sleep. CONCLUSIONS: Our data suggests that sleep deprivation imposes an apparent activating impact uncovering epileptic discharges children corroborating with overt clinical seizures even beyond the sampling effect of repeat records.

Effect of high-dose methyl-prednisolone on brainstem encephalopathy and basal ganglia impairment complicating cat scratch disease.

Cat scratch disease (CSD) is a zoonotic illness caused by the Gram negative bacillus Bartonella henselae characterized by a small skin lesion at the site of a bite, lick or scratch by a cat, commonly followed by regional lymphadenopathy 1 or 2 weeks later. We report herein on severe neurological complications of CSD combining brainstem encephalopathy and basal ganglia impairment. This 12-year-old female acutely presented to a local hospital with profound coma and a prolonged tonic posturing of extremities. On the neurological examination she was deeply comatose with pin-point pupils and lack of vestibulo-ocular responses, suggestive of brainstem encephalopathy, along with marked rigid hypertonicity suggestive also of basal ganglia impairment. Initially suspecting Herpes simplex encephalitis or acute disseminated encephalomyelitis she was promptly started with high-dose methyl-prednisolone and acyclovir. Her parents apparently reported that she was scratched by a kitten some 4 weeks prior to her present admission and as such, suspecting CSD, she was begun with doxycycline and rifampicin. Her serology had proven positive for IgM antibodies to Bartonella henselae establishing the diagnosis. She regained consciousness after 4 days and the signs of brainstem and extra-pyramidal impairment also gradually abated and disappeared after 10 days. A follow-up exam after a month disclosed mild extra-pyramidal abnormalities which disappeared after 3 months. Although extremely rare, CSD should be also considered in a patient presenting with a severe encephalopathy and associated basal ganglia impairment. The prompt administration of high-dose methyl-prednisolone upon admission may have contributed to the favorable outcome in our patient and therefore should be advocated in any patient presenting with profound encephalopathy regardless the underlying etiology recovered later.