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Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

INTRODUCTION: Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking. METHODS: This was a retrospective study describing our centers' experiences in treating SMA1 patients with combination therapy. RESULTS: Five children received nusinersen and onasemnogene abeparvovec-xioi (onasemnogene). Four were receiving nusinersen prior to onasemnogene. Nusinersen was continued in three. Marked liver enzyme elevations resulted in prolonged corticosteroid treatment in two patients with hospitalization and liver biopsy in one; milder liver enzyme elevations were noted in the other two. One patient received onasemnogene first, and then nusinersen. No adverse effects were noted. All patients improved. DISCUSSION: Combination molecular therapy is tolerated in SMA1 patients. Further studies are needed to determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy. Prolonged corticosteroid use and liver toxicity monitoring may be necessary with onasemnogene therapy. This article is protected by copyright. All rights reserved.

Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.

A 74-year-old man with no relevant medical history presented with 5 years of slowly progressive bilateral foot drop. He had used ankle foot orthoses for 3 years prior to presentation. There was no report of upper extremity weakness, numbness, paresthesia, myalgias, muscle cramps, or stiffness. He had attained age-appropriate developmental milestones as a child and was athletic, keeping up with his peers. His mother had bilateral foot drop, ankle contractures, and difficulty with ambulation. His brother, 2 daughters, and a son lacked similar symptoms. Neurologic examination showed bilateral distal lower extremity weakness (Medical Research Council grade 0/5 ankle dorsiflexion and eversion and grade 4/5 ankle plantar flexion and inversion), symmetric distal leg and intrinsic foot muscle wasting, absent patellar and Achilles tendon reflexes, and a steppage gait. Tone was reduced at bilateral ankles. Sensory examination including light touch, pinprick, vibration, and proprioception was intact. Mild bilateral pes cavus and hammertoes were noted. The remainder of the neurologic and physical examination was normal.

Introduction Clinical trials data concerning use of nusinersen in older spinal muscular atrophy (SMA) patients is lacking. We describe our center's experience in using intrathecal nusinersen for older patients in the clinical setting. Methods Retrospective study. Results Twelve patients (12-52 years old) were treated with nusinersen. Mean follow-up duration was 17.4 months (range, 4-26 months). All patients had scoliosis; 10 had spinal fusion/instrumentation. All procedures (30 cervical and 57 lumbar punctures) were technically successful. The only side effects were postprocedural headache (9%) and site pain (5.7%). Functional assessments showed stability in 6/9 patients and improvement in 3/9 patients. Subjective improvements in endurance, hand strength, and bulbar functioning critical for activities of daily living were reported in 8/12 patients. None of the patients has discontinued treatment so far. Discussion Intrathecal nusinersen can be safely delivered in older SMA patients. Available functional outcome measures are not adequate to capture meaningful subjective improvements.

Dystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

Foot drop is common in chronic inflammatory demyelinating polyneuropathy (CIDP), but its prognosis is uncertain.CIDP patients with less than anti-gravity strength (3/5 power) of ankle dorsiflexion (ADF) on Medical Research Council manual muscle testing on presentation at our center were identified by retrospective review. After initiation of standard treatment, ADF power was serially tabulated, and predictors of recovery were determined.Of the 27 identified patients, ADF power at presentation was3/5 in 48/54 legs. At 1 y after treatment, ADF power improved to/= 3/5 in 17/27 patients in one (N = 6) or both (N = 11) legs. On multi-variate analysis, predictors of recovery of ADF power were tibialis anterior compound muscle action potential amplitude at presentation, shorter disease duration, and female gender.Foot drop improves to anti-gravity power in most treated CIDP patients depending in part on the severity of fibular motor axon loss at onset of treatment.

Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children’s Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing.

A 6-year-old biracial (Black and White) boy presented with worsening muscle twitching and stiffness. He had normal birth and development. His family noticed muscle twitching involving his thighs when he was 3 years old. Over the next 3 years, twitching spread to involve shoulders, chest, lower back, arms, and lower legs. The patient would feel muscle twitching underneath his skin and at times, these could be visible. His symptoms were worse with cold exposure. Recently, he started experiencing difficulties with fine motor activities such as writing, holding pencils, tying shoelaces, and buttoning. The patient denied myalgia, weakness, rhabdomyolysis, and paresthesias. Medical history includes well-controlled asthma, allergic rhinitis, right hydrocelectomy, and a small bowel intussusception. Family history was unremarkable. Neurologic examination revealed increased appendicular muscle tone, fasciculations involving upper and lower extremities, anterior chest, and paraspinal muscles, mild difficulty releasing hand grip, nasal dysarthria, and bilateral tight heel cords. Sensory examination, reflexes, and gait including heel and toe walking were normal.

The prevalence of coronavirus disease 2019 (COVID‐19) is lower in children compared to adults. Children contribute to 1‐5% of all COVID‐19 cases (1) . A recent study from China reported that 171(12.3%) of 1391 children with suspected disease had confirmed COVID‐19 infection (2) . As of May 15, 2020, there are 33,241 children with COVID‐19 in the United States (3) . The most common symptoms in children with confirmed and suspected COVID‐19 include fever and cough followed by diarrhea, and abdominal pain.

The coronavirus disease 2019 (COVID‐19) pandemic has resulted in the reorganization of health‐care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID‐19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon‐skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health‐care provider, considering any geographic or institution‐specific policies and precautions for COVID‐19. We advocate for continuing multidisciplinary care for these patients using telehealth.

The coronavirus disease 2019 (COVID‐19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID‐19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID‐19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic‐ or institution‐specific policies and precautions for COVID‐19.

We describe a 10-month-old boy with early-onset epileptic encephalopathy who was found to have a hemizygous deletion in 9q33.3-q34.11 involving STXBP1 and SPTAN1 genes. He presented at the age of 2.5 months with frequent upper extremity myoclonus, hypotonia, and facial dysmorphisms. Interictal EEG showed multifocal polyspike and wave during wakefulness and sleep. Ictal EEG revealed low-amplitude generalized sharp slow activity, followed by diffuse attenuation. Metabolic testing was unrevealing. Brain MRI showed thinning of the corpus callosum with an absence of rostrum. This patient is the second reported case with 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes associated with epileptic encephalopathy and myoclonic seizures. Larger case series are needed to better delineate this association.

Most cases of COVID-19 in children and adolescents are mild or asymptomatic, but a small number of individuals may develop severe disease, requiring PICU admission and/or mechanical ventilation. We assessed the factors associated with negative short-term outcomes of COVID-19 in 82 pediatric patients at three hospitals within the United States during the spring and summer of 2020 using medical records, laboratory data, and imaging studies of all patients admitted with a positive RT-PCR test for SARS-CoV-2. We found that older patients were more likely to have an extended hospital stay, and those with high BMIs (over 25) were more likely to be admitted to the PICU during the early pandemic. In addition, older patients, those with high BMIs, and those with underlying medical conditions, were more likely to receive respiratory support. Given the association of age, BMI, and underlying medical conditions with more severe COVID-19, clinicians should keep these factors in mind when treating patients.

Background Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder involving brainstem, pons in particular, characterized by a predominant T-cell pathology and responsiveness to glucocorticosteroids. We describe a difficult 6 year course of this rare syndrome in a 10-year-old girl. Case report Our patient presented with diplopia, spastic paraparesis, and unsteady gait. MRI showed characteristic punctate hyper-intensities with enhancement in the brain stem, cerebellar peduncles, and optic chiasm and diffuse nodular enhancement throughout the cervical and thoracic spinal cord. Brain biopsy revealed perivascular inflammatory lesions compatible with CLIPPERS. Pulse intravenous methylprednisolone followed by oral prednisolone resulted in significant clinical improvement. She had multiple clinical relapses associated with new brain and/or spinal cord lesions despite sequential maintenance methotrexate and rituximab with low dose steroids. Each relapse responded to pulse steroids. Conclusion Her overall clinical course was progressive but responsive to pulse steroids. Long-term treatment remains challenging.

A 39-year-old man of Ecuadorian descent presented with a history of seizures, visual impairment, and ataxia. He had a normal birth and early developmental history. His first seizure was a generalized tonic-clonic seizure (GTCS) at 16 years old. Around the same time, he also started experiencing 1–2 myoclonic jerks per day. The myoclonic jerks progressively worsened over a period of 20 years to 15–20 episodes per day. GTCS continued to occur 1–2 times a year until the age of 24 years. EEG revealed multiple brief myoclonic seizures and generalized slow spike/polyspike wave complexes consistent with primary generalized epilepsy. Despite valproic acid, zonisamide, and clonazepam, his seizure control remained poor. When he was 30 years old, he began to have blurring of his vision; ophthalmologic evaluation at that time revealed bilateral cherry-red spots. Optical coherence tomography showed hyperreflectivity in the superficial layers of the retina at the posterior pole consistent with abnormal storage in the ganglion cells. An electroretinogram showed normal rod and cone responses. Flash visual evoked responses demonstrated a delay in the P100 response consistent with dysfunction of the visual pathways. His medical and family history was otherwise noncontributory. Gross physical examination was within normal limits. Neurologic examination demonstrated severe myoclonus of the face interrupting his speech, frequent myoclonus of the arms, truncal and appendicular ataxia, and broad-based ataxic gait. MRI of the brain with and without gadolinium was normal. Chromosome single nucleotide polymorphism microarray revealed long contiguous regions of allele homozygosity (>10 MB) in multiple chromosomes. A query of the regions of homozygosity that was subsequently narrowed down using his clinical presentation identified NEU1 as a candidate gene. Sequencing of NEU1 revealed a homozygous missense mutation c.629C>T (p.Pro210Leu). Enzymatic testing in fibroblasts showed sialidase activity to be deficient (0 nmol/h/mg; ref: 23–74). β-Galactosidase activity was within normal limits.

Spinal muscular atrophy is a neurodegenerative disease resulting from irreversible loss of anterior horn cells owing to biallelic deletions/mutations in the survival motor neuron (SMN) 1 gene. Gene replacement therapy using an adeno-associated virus vector containing the SMN gene was approved by the US Food and Drug Administration in May 2019. We report 2 cases of transient, drug-induced liver failure after this therapy.

Andersen-Tawil syndrome is an autosomal dominant potassium channelopathy characterized by episodic flaccid muscle weakness (periodic paralysis), cardiac abnormalities (ventricular arrhythmias, prolonged QT interval, and prominent U waves), and characteristic skeletal features (low set ears, ocular hypertelorism, small mandible, fifth digit clinodactyly, syndactyly, short stature, scoliosis, and broad forehead).1 Mutations in the KCNJ2 gene on chromosome 17q23 are found in about 60% of the patients with Andersen-Tawil syndrome.2 In the absence of a genetic change in KCNJ2 , diagnosis of Andersen-Tawil syndrome is established by the presence of well-defined clinical findings. The distinctive clinical triad of Andersen-Tawil syndrome is present in 60%–80% of patients with KCNJ2 mutations.1,2 KCNJ2 encodes the pore-forming subunit of an inward-rectifying potassium channel protein, Kir2.1, helping in skeletal and cardiac muscle resting membrane potential stabilization. Mutations in this gene cause loss of function and dominant-negative suppression effects on the Kir2.1 protein, leading to disruption of the cardiac and skeletal muscle excitability.2,3 KCNJ2 mutations in Andersen-Tawil syndrome affect multiple tissues and results in a wide phenotypic variability causing diagnostic difficulties and delay.2 We describe the varied clinical characteristics of Andersen-Tawil syndrome in a Caucasian family (mother and her 2 daughters) with a rare missense mutation in KCNJ2 .

Objective: Cranial computed tomography (CT) is not recommended in the routine evaluation of children with first afebrile seizure due to its low yield. The objective was to assess the current practice in our pediatric emergency department regarding the use of head CT in children with first afebrile seizure and to identify the factors that lead to ordering a head CT. Methods: Medical records of patients between 1 month and 18 years old evaluated at our emergency department for presentation of first afebrile seizure between 2010 and 2014 were retrospectively reviewed. Data extracted include age, gender, seizure type, single or multiple seizures at presentation, seizure duration, predisposing conditions to seizures (ie, history of developmental delay), and whether a head CT was performed. Contingency tables with chi-square analyses were used to determine which variables were associated with increased use of head CT. Results: Of 155 patients (88M/67F) included in the study, 72 (46.5%) underwent head CT and only 3 had clinically significant findings that did not require acute management. There were no differences in CT use by age, sex, seizure type, seizure number, seizure risk factors, or findings on physical examination. Head CT was performed more frequently in cases with seizures ≥5 minutes and unknown seizure duration ( P = .04). Conclusion: Despite existing evidence, the emergent head CT rate was high in our cohort. Children with seizure duration of ≥5 minutes or of unknown duration were more likely to undergo head CT in our emergency department.

Nonketotic Hyperglycinemia is an autosomal recessive disorder characterized by defects in the mitochondrial glycine cleavage system. Most patients present soon after birth with seizures and hypotonia, and infants that survive the newborn period often have profound intellectual disability and intractable seizures. Here we present a case report of a 4-year-old girl with NKH as well as hyperammonemia, an uncommon finding in NKH. Genetic analysis found a previously unreported homozygous mutation (c.878–1 G > A) in the AMT gene. Maximum Entropy Principle modeling predicted that this mutation most likely breaks the splice site at the border of intron 7 and exon 8 of the AMT gene. Treatment with L-Arginine significantly reduced both the proband’s glycine and ammonia levels, in turn aiding in control of seizures and mental status. This is the first time the use of L-Arginine is reported to successfully treat elevated glycine levels.

BackgroundPrior studies have reported that patients with epilepsy have a higher prevalence of obstructive sleep apnea (OSA) that contributes to poor seizure control. Detection and treatment of OSA can improve seizure control in some patients with epilepsy. In this study, we sought to develop, implement, and evaluate the effectiveness of an electronic health record (EHR) alert to screen for OSA in patients with epilepsy.MethodsA 3-month retrospective chart review was conducted of all patients with epilepsy >18 years of age who were evaluated in our epilepsy clinics prior to the intervention. An assessment for obstructive sleep apnea (AOSA) consisting of 12 recognized risk factors for OSA was subsequently developed and embedded in the EHR. The AOSA was utilized for a 3-month period. Patients identified with 2 or more risk factors were referred for polysomnography. A comparison was made to determine if there was a difference in the number of patients at risk for OSA detected and referred for polysomnography with and without an EHR alert to screen for OSA.ResultsThere was a significant increase in OSA patient recognition. Prior to the EHR alert, 25/346 (7.23%) patients with epilepsy were referred for a polysomnography. Postintervention, 405/414 patients were screened using an EHR alert for AOSA and 134/405 (33.1%) were referred for polysomnography (p < 0.001).ConclusionAn intervention with AOSA cued in the EHR demonstrated markedly improved identification of epilepsy patients at risk for OSA and referral for polysomnography.

ObjectiveTo report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access.BackgroundSMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration–approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen.MethodRetrospective chart review.ResultsIntrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.ConclusionCervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure.

Epilepsy is found to be frequently associated with many chromosomal disorders. We describe a 5-year-old boy with recurrent absence seizures, developmental delay, hypomelanosis of Ito, facial asymmetry and mild dysmorphic features that has tissue specific trisomy 7 mosaicism. We compare our patient w ith the long term surviving patients of mosaic trisomy 7 reported to date in the literature to highlight that epilepsy is a comm on feature in this chromosomal condition. The wide phenotypic variability of mosaic trisomy 7 is described. We conclude that a combination of epilepsy and hypomelanosis of Ito in a patient should prompt a clinician to think of chromosomal mosaicism, such as mosaic trisomy 7.

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive disorder that causes psychomotor regression. Clinicopathological features include truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, cerebellar ataxia, bulbar dysfunction, and cerebellar atrophy. INAD is associated with a variety of mutations in the PLA2G6 gene that encodes the group VI calcium-independent phospholipase A2 protein which is important in cell membrane homeostasis. Defects in this protein cause axonal dystrophy. We report a 2-year-old boy with INAD who was found to have a novel deletion c.1019_1025del7 leading to a frame shift in the PLA2G6 gene. We suggest that this change may be an addition to the array of mutations causing INAD.

We describe the electroencephalographic and clinical seizure manifestations of pyridoxal 5'-phosphate-dependent epilepsy (PLP-DE) in two patients [diagnosis confirmed by low cerebrospinal fluid (CSF) PLP, complete resolution of previously intractable seizures with PLP supplementation, negative pyridoxine-dependent epilepsy CSF biomarkers, and/or positive disease causing pyridox(am)ine 5'-phosphate oxidase gene mutation] along with a comprehensive review of the literature. One patient presented with neonatal tonic status epilepticus with subsequent generalized tonic-clonic seizures, and the second, with refractory complex partial seizures starting at 2 years of age. The pretreatment EEG revealed, interictally, burst suppression, multifocal independent sharp waves, and electrical status epilepticus in sleep. Ictally and interictally, it revealed runs of unilateral spike/slow waves. Previously reported features include burst suppression, myoclonus, tonic seizures, clonic seizures, and spasms. In the appropriate clinical scenario, the aforementioned features should raise the possibility of PLP-DE and appropriate treatment should be initiated. The first late-onset case (at 2 years) of PLP-DE is reported.

Objective: To report our experience with cephalometry in evaluating velopharyngeal dysfunction (VPD) in velocardiofacial syndrome (VCFS) and its utility in assessing the role of cervical spine abnormalities in VPD, prior to surgical correction of VPD. Design: Clinical charts and cephalometric radiographs done prior to surgery for VPD were retrospectively analyzed to ascertain velopharyngeal measurements and cervical spine abnormalities. Patients: Twenty-six patients (age: 6–23 years) with molecularly confirmed VCFS. Setting: Wake Forest University Health Sciences (1997–2005). Measurements: Cranial base angle, nasopharyngeal depth, velum length, and Need ratio at rest, velar dimple location, and velopharyngeal length during phonation; information on presence/absence of submucous cleft palate and cervical spine abnormalities were also obtained. The relationship between C1 anterior arch abnormalities and Need ratio was examined. Results: Seventy-three percent of the VCFS patients had excessive nasopharyngeal depth, 80% had an abnormal Need ratio, 50% had a short velum, 81% had a submucous or occult submucous cleft palate, 90.5% had a cervical spine abnormality (C1 anterior arch abnormalities in 38%) and 11.5% had platybasia. There was a significant difference in the Need ratio between patients with and without C1 anterior arch abnormalities. Conclusion: Cephalometry can be used to delineate factors such as C1 vertebral abnormalities, excessive pharyngeal depth, and short velum that contribute to VPD in VCFS. This would help otolaryngologists better understand the anatomy prior to surgical treatment of VPD. This is the first study to highlight the frequent occurrence of C1 anterior arch abnormalities in VCFS. Laryngoscope, 2011

Brown-Vialetto-Van Laere syndrome is a rare disorder characterized by motor, sensory, and cranial neuronopathies, associated with mutations in SLC52A2 and SLC52A3 genes that code for human riboflavin transporters RFVT2 and RFVT3, respectively. The authors describe the clinical course of a 6-year-old girl with Brown-Vialetto-Van Laere syndrome and a novel homozygous mutation c.1156T>C in the SLC52A3 gene, who presented at the age of 2.5 years with progressive brain stem dysfunction including ptosis, facial weakness, hearing loss, dysphagia, anarthria with bilateral vocal cord paralysis, and ataxic gait. She subsequently developed respiratory failure requiring tracheostomy and worsening dysphagia necessitating a gastrostomy. Following riboflavin supplementation, resolution of facial diplegia and ataxia, improvements in ptosis, and bulbar function including vocalization and respiration were noted. However, her sensorineural hearing loss remained unchanged. Similar to other cases of Brown-Vialetto-Van Laere syndrome, our patient responded favorably to early riboflavin supplementation with significant but not complete neurologic recovery.

Leigh syndrome is clinically and genetically heterogeneous, associated with mutations in mitochondrial and nuclear genes.(1) Diagnostic criteria include progressive disorder with motor and intellectual delay/regression; signs and symptoms of brainstem and/or basal ganglia disease; raised lactate concentration in blood and/or CSF; and one or more of the following: (1) characteristic features on neuroimaging (bilateral symmetrical hyperintensities in brainstem, basal ganglia, dentate nuclei, and optic nerves on T2-weighted MRI); (2) typical neuropathologic changes; and (3) typical neuropathology in a similarly affected sibling.(2) We describe 2 African American siblings who have a mutation in the mitochondrial MT-TL2 gene and a clinical diagnosis of Leigh syndrome. The same mutation is also identified in their neurologically asymptomatic mother.

Seizure semiology and electroencephalographic (EEG) manifestations of autoimmune-mediated cerebral folate deficiency (CFD) before and after therapy have yet to be fully characterized. Here, we report these findings in two such patients. Our first patient presented with the novel manifestation of infantile spasms at the age of 3months, while the second developed the previously reported initial onset of tonic seizures with static developmental delay, but subsequently manifested the novel finding of electrical status epilepticus in sleep at the age of 15years. Awareness of these new manifestations, together with the previously reported manifestations of developmental delay, seizure onset during the first 2years of life, occurrence of tonic, myoclonic-astatic, absence, and generalized tonic-clonic seizures, with an EEG of generalized spike-slow waves and multifocal spikes, is important to increase the index of suspicion of this treatable disorder.

Oxcarbazepine has been reported to precipitate myoclonic, generalised tonic-clonic, absence, and complex partial seizures, and carbamazepine to precipitate absences, myoclonic seizures and spasms. Here, we report a one-year, six-month-old girl with complex partial seizures who developed infantile spasms, developmental regression, and hypsarrhythmia during the two weeks directly following initiation of oxcarbazepine (14 mg/kg/day). All of these resolved within a few days after discontinuation of this medication. Although we cannot rule out that the above association may have been coincidental, or that the improvement may have been due to concurrent therapy, this case raises the possibility that oxcarbazepine, like carbamazepine, may precipitate infantile spasms and West syndrome.

We describe two boys whose distinct and remarkable clinical pictures suggested the possibility of anti-N-methyl-d-aspartate receptor antibody encephalitis. Both patients responded to immunotherapy, but neither manifested that antibody. Patient 1 exhibited florid encephalopathy with psychotic manifestations including inappropriate affect, intermittent delirium, visual hallucinations, severe anorexia, agitation, paranoid ideation, and abnormal electroencephalogram results. He responded to intravenous immunoglobulin, with steady improvement over 3 months to almost complete remission for 1 year, followed by a relapse that again responded, more quickly, to intravenous immunoglobulin. A second relapse occurred 1 month later, and again responded to intravenous immunoglobulin. Patient 2 exhibited progressive, severely debilitating limb dystonia that worsened over 1.5 years, with milder psychiatric symptoms including mood instability, aggressiveness, impulsivity, and depression. When he developed thymic hyperplasia 1.5 years into his illness, he underwent a thymectomy, and improved significantly on a regimen of plasmapheresis and intravenous immunoglobulin. Patients presenting with symptoms suggestive of autoimmune encephalitis, but without antibodies, may still respond to immunotherapy.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals.