Involuntary Movements in Cobalamin Deficiency.

OBJECTIVE: Neurologic problems are frequently described in infants with nutritional vitamin B12 (cobalamin) deficiency.Major neurologic consequences of infantile cobalamin deficiency include delays or regression in neurodevelopment and the occurrence of involuntary movements METHODS: We reviewed the medical records of infants with cobalamin deficiency and divided infants with involuntary movements into two groups as those, who developed involuntary movements during vitamin B12 supplementation (Group I) and those, who developed involuntary movements prior to supplementation therapy (Group II). RESULTS: We evaluated a total of 32 infants with the diagnosis of cobalamin deficiency. Involuntary movements were observed in 12 out of 32 infants. Group I and Group II consisted of 6 infants each. Of the infants with involuntary movements, five were exclusively breastfed until the time of diagnosis. The majority of infants in Group II had choreoathetoid movements; twitching and myoclonus in the face, tongue, and lips, and tremor in the upper extremities. These involuntary movements disappeared in one to three weeks after clonazepam therapy. In Group I; shaking movements, myoclonus, tremor, and twitching or protrusion were observed in patients' hands, feet, tongue, and lips on the 3rd-5th day of cobalamin supplementation. These involuntary movements disappeared within 5-12 days of clonazepam therapy. CONCLUSION: Recognition of nutritional cobalamin deficiency is important to perform a differential diagnosis of the condition from seizures or other causes of involuntary movements and avoid aggressive therapy and over treatment.

VISUAL SNOW SYNDROME IN A PEDIATRIC CASE.

INTRODUCTION Visual snow (VS) is a rare condition that is characterized by continuous dynamically flickering dots in the entire visual field that imitate the 'static' or 'snow' of an analogue television set that is not connected to the antenna (1). VS was first described in 3 of 10 migraineurs patients who presented with a spectrum of positive visual symptoms (2). The symptoms of VS can persist for many years. Although VS might be expressed in patients with migraine as visual aura, persistent VS has been accepted as a distinct clinical entity and termed as visual snow syndrome (VSS) independently from migraine. Schankin et al. proposed that the criteria for diagnosis of VSS consisted of visual snow as the main criterion, with some additional criteria (3). A few cases with childhood VSS have been described in literature (4-6). Herein, the case of a teenager was presented to emphasize the importance of differential diagnosis in persistent positive visual phenomena.

Effect of Chronic Valproic Acid Use on Anterior Cerebral Blood Flow of Children with Idiopathic Generalized Epilepsy.

OBJECTIVE: Cerebral blood flow has been blamed as a factor in the negative effect of antiepileptic drugs on neurocognition. This study aimed to investigate whether valproic acid (VPA), used for the treatment of idiopathic generalized epilepsy (IGE), causes a change in cerebral blood flow in children. METHODS: Included in this study were 33 children who were receiving VPA for IGE and 34 age-matched controls. Doppler and spectral measurements in common carotid artery (CCA), left and right internal CA (ICA) and external CA (ECA), anterior cerebral artery (ACA) and middle cerebral artery (MCA) were performed and the maximum velocity (VM), end-diastolic velocity (EDV), resistive index (RI), pulsatility index (PI) and flow rate (FR) were calculated. RESULTS: The mean age of drug and control groups were 9.33 plus or minus 2.11, and 9.74 plus or minus 2 years, respectively. Follow-up of patients was 17.7 plus or minus 3.2 months. The period of VPA treatment was 17.4 plus or minus 3.4 months. No statistically significant differences were found between control and VPA group for the VM, EDV, RI, PI, and FR values obtained from the bilateral ICA, ACA, and MCA. CONCLUSIONS: The results showed that VPA in therapeutic doses did not affect anterior cerebral blood flow. However according to result, it is still difficult to conclude that neurocognitive deterioration is not observed in patients receiving VPA.

Impact of COVID-19 on serum melatonin levels and sleep parameters in children

Background/aim: This study aimed to analyze the serum melatonin levels and changes in sleep patterns in pediatric patients with coronavirus disease 2019 (COVID-19). Materials and methods: This study was designed as a descriptive, cross-sectional study. Serum melatonin levels and sleep parameters of children with the diagnosis of COVID-19 who had mild and moderate disease (i.e., COVID-19 group) were compared with those of children admitted with non-COVID-19 nonspecific upper respiratory tract infection (i.e., control group). The sleep disturbance scale for children (SDSC) questionnaire was applied to the participants> primary caregivers to analyze their sleep patterns at present and six months before symptom onset and to investigate the impact of COVID-19 on sleep patterns. Results: The entire study cohort consisted of 106 patients. The COVID-19 group included 80 patients, while the control group consisted of 26 patients. The mean serum melatonin levels were 136.72 pg/mL and 172.63 pg/mL in the COVID-19 and control groups, respectively (p = 0.16). There was no significant difference between the groups in terms of 6 subcategories of the SDSC questionnaire regarding the present time and 6 months before symptom onset. The total SDSC scores were also similar in two different evaluation time points described above (p = 0.99) Conclusions: We conclude that COVID-19 did not impact the sleep parameters of children. Serum melatonin levels of all patients were higher than the reference range; however, they were higher in the non-COVID-19 patient group than the COVID-19 group. Since serum melatonin levels were higher than the reference values in children with COVID-19, and this disease is significantly less morbid in children, melatonin may have protective effects against COVID-19.

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.

Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Løken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.

Homozygous SLC20A2 mutations cause congenital CMV infection-like phenotype.

BACKGROUND: Idiopathic basal ganglia calcification, also known as Fahr's disease, it is a neurological disease characterized by intracranial calcification caused by heterozygous SLC20A2 mutations. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, tremor, dystonia, ataxia, and seizures. OBJECTIVES: The aim of this study was to investigating the clinical implications of the SLCA20A2 gene and identifying a new phenotype through a family. METHODS: Two siblings with growth retardation, bilateral cataracts, microcephaly, and convulsion were included in the study. The MRI showed cerebral atrophy, corpus callosum hypoplasia, microcalcifications. Chromosomal microarray analysis was performed to identify the existence of copy number variation. The whole exome sequencing analysis of the individual IV-I was performed, and Sanger sequencing was performed for segregation. RESULTS: Whole exome sequencing revealed a homozygous NM_006749.5:c.1794 + 1G > A of the SLC20A2 gene. The Sanger sequencing confirmed the affected siblings were homozygous and the parents were heterozygous. CONCLUSIONS: SLC20A2 gene heterozygous mutations were associated with the adult-onset phenotype, while homozygous SLC20A2 mutations in the two affected siblings we reported in our study resulted in a severe clinic including growth retardation, bilateral cataracts, microcephaly, and convulsion. We showed that biallelic mutations in the SLC20A2 gene that cause the Fahr's disease lead to more severe phenotypes contrary to what is known. The two siblings, showing similar phonotypic and genotypic characteristics, would be the youngest cases in the pediatric age group published in the literature.

CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.

The relationship between migraine and right-to-left shunt in children.

UNLABELLED: Migraine is the most common headache in childhood, and there are some reports that suggest the relationship between migraine and right-to-left shunt. The aim of this study was to evaluate the frequency of right-to-left shunt in children with migraine with aura and compare it with children with migraine without aura, and in healthy children. In a cross-sectional case-control study, we assessed 20 children with migraine with aura, 20 migraine without aura and 20 healthy age, and gender-matched control group. We determined the frequency of right-to-left shunt by transcranial doppler with contrast and transthoracic echocardiography without contrast. The dopplers and echocardiograms were performed blindly by the same examiners during headache-free periods. The presence of right-to-left shunt was found in 13/20 patients with migraine with aura compared with five of 20 migraine without aura and four of 20 control subjects. The frequency of right-to-left shunt in migraine with aura was statistically different from the other two groups (P < 0.005). There was no association between right-to-left shunt and frequency of attacks, duration and intensity of attacks, uni/bilateral occurence, familial occurrence, gender and age of patients. CONCLUSION: our findings suggest possible association of migraine with aura and right-to-left shunt. It seems that right-to-left shunt does not influence the clinical features of migraine.

Neurologic Manifestations of COVID 19 in Children: Prospective Study in a Single Center.

Background: The data related to the neurologic manifestations of coronavirus disease 2019 (COVID-19) in children are limited. The frequency of the neurologic manifestations and the risk factors in the development of these symptoms are not clear. Objectives: We aimed to determine the exact frequency of the neurological symptoms in pediatric patients with confirmed COVID-19 and to identify the risk factors for the development of neurological manifestations. Materials and Methods: We included pediatric Covid-19 patients admitted to the Children's Hospital of Ankara City Hospital between March 22 and June 1, 2020. Neurological findings were questioned by interviewing the patients and their families and detailed neurologic examinations were performed within protection measures. Results: A total of 312 pediatric patients with the diagnosis of COVID-19 were enrolled in the study. Sixty-six participants (21.15%) showed neurologic symptoms during COVID-19. Headache was the most common neurologic symptom and present in 14% (n: 44) of the cases. The other neurologic symptoms were myalgia (n: 30, 9.6%), anosmia/hyposmia (n: 6, 1.9%), ageusia (n: 2, 0.6%), and vertigo (n: 1, 0.3%). Neutrophil-to-lymphocyte ratio (NLR) (P = 0.002) and platelet-to-lymphocyte ratio (PLR) (P = 0.001) were significantly elevated in patients with neurological symptoms when compared to the patients without the symptoms. Conclusions: Physicians should be alert to the neurologic involvement of COVID-19 disease in children. NLR and PLR ratios could have a predictive value for the development of neurological manifestations.

SLC35A2-CDG: novel variants with two ends of the spectrum.

OBJECTIVES: Congenital disorders of glycosylation (CDGs) are rare inherited metabolic disorders associated with facial dysmorphism and in the majority of the patients, there is an important neurological impairment. Epilepsy was a main concern in rare forms of the disease. There are two groups of the disease: CDG-I results from the defects in glycan addition to the N-terminal and CDG-II occurs due to defects in the processing of protein bound glycans. SLC35A2-CDG is a rare form of CDG caused by mutations in the X-linked gene that encodes a UDP-Galactose transporter. The manifestations of the disease include seizures, failure to thrive, delayed myelination, and cerebral atrophy. CASE PRESENTATION: We describe herein a severe female child with intractable seizures, microcephaly, growth retardation, hypotonia, global developmental delay, facial dysmorphism, skeletal findings, cerebral/cerebellar atrophy, and thin corpus callosum, and a mildly affected male carrying a novel variant with seizures and mild global developmental delay who were found by whole exome sequencing (WES) for SLC35A2 mutations previously not reported. CONCLUSIONS: Our findings expand the number of reported cases and add novel variants to the repertoire of SLC35A2-CDG.

Cognitive functions in neurofibromatosis type 1 patients and unaffected siblings.

Attention, learning, and perceptual problems have been reported at various degrees and rates in neurofibromatosis type 1 (NF1). We aimed to define the cognitive profiles frequently associated with NF1. Children and adolescents with NF1 (n=58) were tested using Wechsler Intelligence Scales for Children-Revised (WISC-R), Judgment of Line Orientation, and Bender Visual-Motor Gestalt tests. Comparison groups were unaffected siblings of NF1 patients (n=20), children with attention deficit and hyperactivity disorder (ADHD, n=40), and normal children (n=40). No difference was found between familial or sporadic NF1 cases. Seventeen/58 (29%) of NF1 cases had a full scale IQ<70. The subgroup of NF1 patients with full scale IQ>80 (n=27) scored lower in WISC-R subtests measuring visual perception when compared to a healthy control group of similar intelligence, and lower in arithmetic but better in Bender-Gestalt and Judgment of Line Orientation tests when compared to an ADHD group of similar intelligence. These results indicate a high prevalence of mental retardation in a clinical NF1 series. NF1 patients who have normal intelligence may have impaired visual perception, but their visual perceptual problems are less than in ADHD. The tendency of unaffected siblings of NF1 patients to have mildly but consistently low test scores compared to healthy controls needs to be studied further for underlying genetic or environmental factors.

Quantitative assessment of muscular stiffness in children with cerebral palsy using acoustic radiation force impulse (ARFI) ultrasound elastography.

PURPOSE: To evaluate the feasibility of quantitative analysis of muscle stiffness in the medial gastrocnemius muscle (GCM) by acoustic radiation force impulse (ARFI) ultrasound elastography in children with spastic cerebral palsy (CP). METHODS: Seventeen children with spastic CP and 25 healthy children participated in the study between the years 2016-2017. The medial GCM in the CP group was assessed using the Modified Ashworth Scale (MAS) by a physiatrist. ARFI was used to measure the shear-wave velocities (SWVs) of the medial GCM. The mean SWV value for each MAS score was calculated and used for statistics. RESULTS: The mean SWV values of the medial GCM in the CP and healthy groups were 3.17 ± 0.81 m/s (mean ± SD) and 1.45 ± 0.25 m/s (mean ± SD), respectively. The SWV of the medial GCM significantly increased in the CP patients when compared with controls (p < 0.001). In addition, the SWV values were correlated with the MAS scores (p < 0.001). The interobserver agreement expressed as the interclass correlation coefficient was 0.65 (95% CI 0.33-0.84, p < 0.001). CONCLUSIONS: ARFI imaging demonstrated a difference in muscle stiffness in the medial GCM between the CP and healthy groups. This method is a feasible imaging modality for the noninvasive assessment of contracting muscles in children with CP.

Pyridoxine and pyridostigmine treatment in vincristine-induced neuropathy.

Vincristine is a commonly used antineoplastic drug and frequently causes neurotoxicity. Here the authors report a 4-year-old boy with acute lymphoblastic leukemia in whom vincristine-induced peripheral and cranial neuropathy developed during remission induction therapy. The patient seemed to benefit from pyridoxine and pyridostigmine therapy greatly and this therapy is recommended in patients with severe vincristine-induced neuropathy.

Prolonged acyclovir treatment in a child with opercular syndrome related to herpes simplex encephalitis.

HSV 1 encephalitis is the most common cause of sporadic and focal viral encephalitis. Opercular syndrome is characterized by swallowing and speech difficulties which are associated with deterioration of voluntary control of face, pharynx, tongue and chewing muscles. It can be developed in patients with Herpes simplex encephalitis (HSE). Here, a twelve-year-old boy who was diagnosed with HSE and Opercular syndrome, is presented. The patient recovered without sequela as a result of 30 days of intravenous and 10 days of oral acyclovir treatment. It might be important as well, to personalize and elongate the treatment in terms of prognosis.

Detection of gastroesophageal reflux in children with cerebral palsy using combined multichannel intraluminal impedance-ph procedure.

Gastroesophageal reflux (GER) is a very common condition in children with neurological impairment and this can influence nutritional and respiratory outcomes. The aim of this study was to investigate the presence of GER in children with cerebral palsy (CP) using multiple intraluminal impedance (MII)-pH monitoring. The use of combined MII-pH allows for the detection of both acid and non-acid reflux episodes. A total of 29 CP patients with symptoms suggesting GER, aged 2 to 10 years old, underwent 24-hour combined MII-pH monitoring. There were a total of 3899 reflux episodes, of which 29% were acid, 60% were weakly acid and 11% were alkaline. The number of non-acid reflux episodes was statistically significantly greater (p < 0.01). These findings confirm that GER disease is seen frequently in children with cerebral palsy and most of the reflux episodes are not acidic. Non-acid reflux can also influence the morbidity in patients with cerebral palsy. It can be concluded that 70% of the reflux episodes would not have been recognized by pH measurement alone.

Reversible posterior leukoencephalopathy syndrome: report of three cases.

Reversible posterior leukoencephalopathy syndrome is characterized clinically by headache, abnormalities of mental status and visual perception, and seizures. Despite its diverse causes, common precipitating factors are defined as abrupt elevations of blood pressure, renal decompensation, fluid retention, and immunosuppressive therapy. We report three children with reversible posterior leukoencephalopathy syndrome presenting with generalized seizures and headache. The causes of reversible posterior leukoencephalopathy syndrome were considered to be acute hypertension and immunosuppressive therapy in case 1 with systemic lupus erythematosus, chemotherapy (vincristine and/or actinomycin-D) and hyponatremia in case 2, and acute hypertension in case 3, admitted with a familial Mediterranean fever attack. In light of these cases, we review the literature for the etiology, clinical and laboratory findings, and pathogenetic mechanisms of the disease.

Repetitive EEG recordings are necessary for the diagnosis of early myoclonic encephalopathy.

Early myoclonic encephalopathy (EME) is a rare malignant epileptic syndrome. The erratic myoclonus with or without focal motor seizures, time of onset before 3 months of age, and suppression-burst (SB) pattern in EEG are accepted as the diagnostic criteria for EME. We report a 40-day-old infant with the diagnosis of non-ketotic hyperglycinemia (NKHG). The infant developed myoclonic and focal tonic seizures on the first day of life. His first sleep EEG recorded after onset of seizure was normal. Because of the diagnosis of NKHG and early developed myoclonic seizure, we thought the infant might be EME, and repeated sleep EEG on admission in which asymmetrical SB pattern was seen. We concluded that the absence of SB pattern in the first EEG recording does not exclude the diagnosis of EME, but repetition of EEG is necessary to demonstrate the presence of SB pattern to meet the diagnostic criteria for EME.

Absence of the lateral and third ventricles associated with holoprosencephaly.

We describe a 6-month-old boy suffering from motor and mental retardation. All radiological features were suggestive of holoprosencephaly with no identifiable lateral or third ventricles and fusion of the thalami.

Evaluation of Nerve Conduction Studies in Obese Children With Insulin Resistance or Impaired Glucose Tolerance.

The aim of the study was to investigate nerve conduction studies in terms of neuropathic characteristics in obese patients who were in prediabetes stage and also to determine the abnormal findings. The study included 69 obese adolescent patients between April 2009 and December 2010. All patients and control group underwent motor (median, ulnar, tibial, and peroneal) and sensory (median, ulnar, sural, and medial plantar) nerve conduction studies and sympathetic skin response test. Sensory response amplitude of the medial plantar nerve was significantly lower in the patients with impaired glucose tolerance and insulin resistance. To our knowledge, the present study is the first study demonstrating the development of sensory and autonomic neuropathy due to metabolic complications of obesity in adolescent children even in the period without development of diabetes mellitus. We recommend that routine electrophysiological examinations be performed, using medial plantar nerve conduction studies and sympathetic skin response test.