Neurologic complications of thiamine (B1) deficiency following bariatric surgery in adolescents.

BACKGROUND: The prevalence of obesity among children and adolescents is rising and poses a major health concern. Bariatric surgery is well established in adults and has become an option for adolescents. Thiamine (B1) deficiency is common following bariatric surgery in adults. It may present as Beri-Beri, Wernicke encephalopathy, or Korsakoff psychosis. OBJECTIVE: Our aim was to describe the clinical features, diagnosis, and treatment of adolescents who presented with B1 deficiency after bariatric surgery at one center, and to summarize the data from the literature. PATIENTS: Three adolescents with morbid obesity (two boys and one girl, aged 15.5 to- 17-years-old), presented at Schneider Children's Medical Center of Israel with progressive lower limb pain and weakness 2-3 month following a bariatric procedure (sleeve gastrectomy or narrowing of a bariatric band). The girl also had upper limb involvement and cerebellar signs. All three were non-compliant with micronutrient supplementation. After admission, they received intravenous B1 and oral multivitamin supplementation, and their symptoms improved considerably. CONCLUSIONS: Micronutrient supplementation following bariatric surgery is crucial to prevent deficiencies. In adolescents, compliance with micronutrient supplementation should be assessed before and after such surgery. Thiamine deficiency may cause polyneuropathy, among other symptoms. Treatment reduces the severity of neurological complications.

A New Mechanism in THRA Resistance: The First Disease-Associated Variant Leading to an Increased Inhibitory Function of THRA2.

The nuclear thyroid hormone receptors (THRs) are key mediators of thyroid hormone function on the cellular level via modulation of gene expression. Two different genes encode THRs (THRA and THRB), and are pleiotropically involved in development, metabolism, and growth. The THRA1 and THRA2 isoforms, which result from alternative splicing of THRA, differ in their C-terminal ligand-binding domain (LBD). Most published disease-associated THRA variants are located in the LBD of THRA1 and impede triiodothyronine (T3) binding. This keeps the nuclear receptor in an inactive state and inhibits target gene expression. Here, we investigated a new dominant THRA variant (chr17:g.38,241,010A > G, GRCh37.13 | c.518A > G, NM_199334 | p.(E173G), NP_955366), which is located between the DNA- and ligand-binding domains and affects both splicing isoforms. Patients presented partially with hypothyroid (intellectual disability, motor developmental delay, brain atrophy, and constipation) and partially with hyperthyroid symptoms (tachycardia and behavioral abnormalities) to varying degrees. Functional characterization of THRA1p.(E173G) by reporter gene assays revealed increased transcriptional activity in contrast to THRA1(WT), unexpectedly revealing the first gain-of-function mutation found in THRA1. The THRA2 isoform does not bind T3 and antagonizes THRA1 action. Introduction of p.(E173G) into THRA2 increased its inhibitory effect on THRA1, which helps to explain the hypothyroid symptoms seen in our patients. We used protein structure models to investigate possible underlying pathomechanisms of this variant with a gain-of-antagonistic function and suggest that the p.(E173G) variant may have an influence on the dimerization domain of the nuclear receptor.

Association of pediatric idiopathic intracranial hypertension with olfactory performance.

OBJECTIVE: To assess the association between pediatric Idiopathic intracranial hypertension (IIH) and olfactory performance. METHODS: A cross-sectional comparative study was conducted including 17 patients under 18 years diagnosed with IIH at a tertiary hospital and 17 healthy age- and sex-matched subjects. All participants underwent the semi-objective chemosensory Sniffin' Sticks test for evaluation of odor threshold (OT), indicative of peripheral olfactory function, and odor identification (OI), reflecting higher cognitive olfactory processing. Scores were compared and referred to the updated normative values. Demographic, clinical, and neuroimaging data were collected from the medical files. The patients with IIH were reassessed for olfactory function and clinical state at the subsequent follow-up, under treatment. RESULTS: Compared to controls, the IIH group had a significantly lower mean OT score (6.41 ± 3.43 vs 10.21 ± 2.79, p = 0.001) and higher rate of OT score below the 10th percentile for age and sex according to the normative values (47.1% vs 0%, p = 0.001). There was no significant between-group difference in mean OI scores (9.82 ± 1.63, vs 10.59 ± 1.84, p = 0.290). OT scores were not associated with sex, age, body mass index, neuroimaging abnormalities, or lumbar puncture opening pressure. At the follow-up assessment, the OT scores were improved (9.36 ± 4.17 vs 6.7 ± 3.32, p = 0.027) whereas the OI scores were unchanged (9.88 ± 2.5 vs 9.69 ± 1.58, p = 0.432). CONCLUSIONS: As reported in adults, children and adolescents with IIH appear to have a selective reversible deficit in olfactory detection threshold, which may imply a reduction in peripheral olfactory perceptual ability. Future studies should examine the predictive value of olfactory function for IIH.

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

Cytokine Production by Mononuclear Cells from Patients with Familial Infantile Bilateral Striatal Necrosis.

Prompted by findings suggesting immune instability in infantile bilateral striatal necrosis (IBSN), we evaluated levels of proinflammatory (tumor necrosis factor α, interleukin [IL]-1ß, IL-6, interferon [IFN]γ) and anti-inflammatory (IL-10 and IL-1ra) cytokines produced by peripheral blood mononuclear cells (PBMC) from 6 children with IBSN and 11 age-matched controls. Compared to controls, non-stimulated PBMC from the IBSN group produced a significantly lower level of IL-1ra (by 38%; p < 0.001) and significantly lower levels of TNFα, IL-1ß, and IFNγ (by 36% [p < 0.001], 25% [p = 0.06], and 32% [p < 0.02]) under PBMC stimulation. The severe cachexia manifesting shortly after IBSN onset may impair the immunological state, placing patients at risk of death from hyperpyrexia and sepsis.

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

The Adhesion G Protein-Coupled Receptor GPR56/ADGRG1 Is an Inhibitory Receptor on Human NK Cells.

Natural killer (NK) cells possess potent cytotoxic mechanisms that need to be tightly controlled. Here, we explored the regulation and function of GPR56/ADGRG1, an adhesion G protein-coupled receptor implicated in developmental processes and expressed distinctively in mature NK cells. Expression of GPR56 was triggered by Hobit (a homolog of Blimp-1 in T cells) and declined upon cell activation. Through studying NK cells from polymicrogyria patients with disease-causing mutations in ADGRG1, encoding GPR56, and NK-92 cells ectopically expressing the receptor, we found that GPR56 negatively regulates immediate effector functions, including production of inflammatory cytokines and cytolytic proteins, degranulation, and target cell killing. GPR56 pursues this activity by associating with the tetraspanin CD81. We conclude that GPR56 inhibits natural cytotoxicity of human NK cells.

Early onset epileptic encephalopathy caused by de novo SCN8A mutations.

OBJECTIVE: De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs). METHODS: A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples). RESULTS: We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability. SIGNIFICANCE: Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.

Variable myopathic presentation in a single family with novel skeletal RYR1 mutation.

We describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at θ = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C) within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C) in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+) stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRα1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies.

Schilder's disease: non-invasive diagnosis and successful treatment with human immunoglobulins.

Schilder's disease (SD) is a rare variant of multiple sclerosis with a predilection to children. It is characterized by focal neurological abnormalities, which are atypical for MS, in conjunction with tumor-like white matter lesions on MRI. We report the case of an 11-year-old girl that demonstrates two important features of the disease: a) the clinical presentation and subsequent course in conjunction with the serial neuroradiological findings stress the feasibility of a non-invasive diagnosis of SD; and b) we report a significant clinical response to treatment with intravenous human Immunoglobulins.

A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Vertebral artery dissection and posterior stroke in a child.

Vertebral artery dissection is a relatively rare disease. Its symptoms and signs can be misleading, making the diagnosis, even with imaging assistance, difficult. We describe an 8-year-old boy in whom a brain tumor was suspected because of neurological signs and findings on computerized tomography of the brain. The differential diagnosis was broadened with further imaging evaluation. Magnetic resonance angiography demonstrated vertebral artery dissection, which was attributed to a trivial trauma the child had experienced 1 week before presentation. During the follow-up period, the child recovered, except for residual right hemianopsia.

Benign hereditary chorea: clinical, neuroimaging, and genetic findings.

Benign hereditary chorea is an autosomal dominant disease with an early onset of symptoms. In some families, symptoms tend to decrease in adulthood, suggesting that the disorder results from a developmental disturbance in the brain. Individuals with benign hereditary chorea, a nonprogressive disease, have normal or slightly below normal intelligence. The locus for benign hereditary chorea is on chromosome 14. Benign hereditary chorea is a result of mutations in the thyroid transcription factor 1 gene. Previous neuroimaging and pathological investigations of the brain showed no notable abnormalities in patients with this condition. In this study, 5 patients from 1 family with typical clinical features of benign hereditary chorea are presented. Clinical severity varied considerably in the family. Brain magnetic resonance imaging results were normal. Brain single photon emission computed tomography in 3 children, performed 1 hour after intravenous injection of 0.35 mCi/kg of body weight of technetium 99m ethyl cysteinate dimer, showed markedly decreased uptake in the right striatum and the right thalamus in 1 child. The oldest child had mildly reduced uptake in the right putamen and the left thalamus. Brain single photon emission computed tomographic findings in the youngest child were normal. Contrary to other reports of radionuclide brain imaging, notable brain single photon emission computed tomography changes were detected in 2 of 5 patients. Brain single photon emission computed tomography findings did not seem to correlate with the clinical status of the children.

Phagocytic capacity and apoptosis of peripheral blood cells from patients with iron deficiency anemia.

Following clinical observations that patients with iron deficiency anemia (IDA) are more susceptible to infections than non-anemic individuals, the phagocytic capacity and number of apoptotic peripheral white blood cells (PWBC) from patients with IDA were examined. PWBC from 15 patients with IDA and from 18 healthy donors were incubated with various doses of iron. Phagocytosis was examined using latex particles and apoptosis was evaluated by a flow cytometric assay using propidium iodide staining. The percentage of phagocyting polymorphonuclear cells was lower in IDA patients compared to that of the controls. However, there was no difference in the percentage of phagocyting monocytes from individuals of both groups. The number of latex beads engulfed by each polymorphonuclear or monocyte was lower in IDA patients. Incubation with 100 microg% of iron did not affect the phagocytic ability of both cell types in IDA patients, but increased that of control cells. Incubation with 300 microg% of iron caused an increase in the phagocytic capacity of patients' cells and a decrease in that function in cells from controls. Higher dose (500 microg%) induced suppression of phagocytosis in cells from both groups. There was no difference in the number of apoptotic cells from individuals of both groups. Apoptosis of polymorphonuclears, but not mononuclear cells from both controls and IDA patients showed a linear dependency on the iron concentration in the medium. It is possible that the impaired phagocytic capacity of the PBWC found in patients with IDA contribute to the increased susceptibility to infections observed in these individuals.

In vitro cytokine production in patients with iron deficiency anemia.

The in vitro production of interleukin (IL)-1beta, IL-2, IL-6, IL-10, and tumor necrosis factor alpha (TNFalpha) by peripheral blood mononuclear cells (PBMC) from 20 patients with iron deficiency anemia (IDA) was examined before and after iron supplementation and compared to values obtained for PBMC from healthy controls. A significant decrease in IL-2 production was observed in IDA patients, whereas the secretion of the other cytokines did not differ from that of controls. Addition of iron to the culture medium did not affect the secretion of IL-2 and IL-1beta, but caused an increase in IL-6, IL-10, and TNF-alpha production. Since a deficiency in IL-2 production plays a role in the pathogenesis of certain infectious and malignant diseases, the results of the present study may explain in part the increased susceptibility to infections observed in patients with IDA.

Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.

Pseudotumor cerebri manifesting as stiff neck and torticollis.

Stiff neck and torticollis are significant signs of neurologic disease. Nuchal rigidity is often associated with meningitis, subarachnoid hemorrhage, and posterior fossa tumor. Torticollis may be encountered in inflammatory disorders, such as cervical lymphadenitis, or it can be a sign of spinal cord syrinx or of central nervous system neoplasm. We report on three prepubertal children in whom stiff neck and torticollis were the presenting signs of pseudotumor cerebri. In all, the removal of 6-7 mL of cerebrospinal fluid led to prompt relief of symptoms and signs. We suggest that in the presence of unexplained stiff neck or torticollis in children, the optic discs should be examined to exclude pseudotumor cerebri.