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Background: Wernicke encephalopathy is rare in children and is caused by thiamine deficiency. It is characterized by acute or subacute ataxia, altered consciousness, and ophthalmoparesis. Gastroenterological surgery, total parenteral nutrition for short bowel syndrome, and alcoholism are common risk factors for Wernicke encephalopathy. Typical magnetic resonance imaging features include selective symmetrical signal changes in the mammillary bodies, medial thalamus, tectum, periaqueductal region, cranial nerves, cerebellum, red nucleus, dentate nucleus, fornix, splenium, cerebral cortex, and putamen. If left undiagnosed and untreated, the disease may be fatal., Patient Description: We describe a 13-year-old boy who developed acute cerebellar findings while receiving total parenteral nutrition after gastroduodenostomy for duodenal stenosis., Results: The diagnosis of Wernicke encephalopathy was based on his clinical history, neurological examination, and imaging results. We immediately started intravenous thiamine replacement therapy. Two weeks later, the patient's clinical signs had resolved except for mild clumsiness, which was observed during his tandem gait examination., Conclusion: Our report emphasizes the importance of clinical and magnetic resonance imaging pattern recognition in timely diagnosis, as well as the importance of prompt thiamine replacement therapy. We also demonstrate the importance of thiamine supplementation during total parenteral nutrition after gastrointestinal surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cataplexy is a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions such as anger, laugh, humor or surprise and it is considered to represent the physiologic atonia of rapid eye movement sleep. On the other hand, Niemann-Pick type C is a neurodegenerative lysosomal storage disease, characterized by the accumulation of cholesterol and glycosphingolipids. Cataplexy is a relatively specific and common neurologic sign seen in almost 50% of all patients with Niemann-Pick type C. The aim of this report is to demonstrate the successful treatment of cataplexy with the use of a tricyclic antidepressant imipiramine, in two patients between the ages 6-9, with mild to moderate mental retardation, molecularly diagnosed as Niemann-Pick type C 1 and currently under miglustat treatment and to discuss the possible mechanisms of drug action in the light of cataplexy and Niemann-Pick type C pathophysiology., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid phosphatase. To increase our understanding of MTM1 function, we conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, we identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Intellectual disability (ID) has a prevalence of 3% and is classified according to its severity. An underlying etiology cannot be determined in 75-80% in mild ID, and in 20-50% of severe ID. After it has been shown that copy number variations involving short DNA segments may cause ID, genome-wide SNP microarrays are being used as a tool for detecting submicroscopic copy number changes and uniparental disomy. This study was performed to investigate the presence of copy number changes in patients with ID of unidentified etiology. Affymetrix(®) 6.0 SNP microarray platform was used for analysis of 100 patients and their healthy parents, and data were evaluated using various databases and literature. Etiological diagnoses were made in 12 patients (12%). Homozygous deletion in NRXN1 gene and duplication in IL1RAPL1 gene were detected for the first time. Two separate patients had deletions in FOXP2 and UBE2A genes, respectively, for which only few patients have recently been reported. Interstitial and subtelomeric copy number changes were described in 6 patients, in whom routine cytogenetic tools revealed normal results. In one patient uniparental disomy type of Angelman syndrome was diagnosed. SNP microarrays constitute a screening test able to detect very small genomic changes, with a high etiological yield even in patients already evaluated using traditional cytogenetic tools, offer analysis for uniparental disomy and homozygosity, and thereby are helpful in finding novel disease-causing genes: for these reasons they should be considered as a first-tier genetic screening test in the evaluation of patients with ID and autism., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

GRID2 is a member of the ionotropic glutamate receptor family of excitatory neurotransmitter receptors. GRID2 encodes the glutamate receptor subunit delta-2, selectively expressed in cerebellar Purkinje cells. The phenotype associated with loss of GRID2 function was described only in mice until now, characterized by different degrees of cerebellar ataxia and usually relatively mild abnormalities of the cerebellum. This work describes for the first time the human phenotype associated with homozygous partial deletion of GRID2 in 3 children in one large consanguineous Turkish family. Homozygous deletion of exons 3 and 4 of GRID2 (94 153 589-94 298 037 bp) in the proband and similarly affected cousins, and heterozygous deletions in parental DNA were shown using Affymetrix® 6.0 single-nucleotide polymorphism array, confirmed by real-time polymerase chain reaction. The phenotype includes nystagmus, hypotonia with marked developmental delay in gross motor skills in early infancy followed by a static encephalopathy course with development of cerebellar ataxia, oculomotor apraxia, and pyramidal tract involvement.

Unlabelled: We report an infant diagnosed with Majewski osteodysplastic primordial dwarfism type II at age 8 months, who experienced cerebrovascular morbidities related to this entity. Molecular analysis identified c.2609+1 G>A, intron 14, homozygous splice site mutation in the pericentrin gene. At age 18 months, she developed recurrent strokes and hemiparesis. Brain magnetic resonance imaging and magnetic resonance angiography showed abnormal gyral pattern, cortical acute infarcts, bilateral stenosis of the internal carotid arteries and reduced flow on the cerebral arteries, consistent with moyamoya disease. In Majewski osteodysplastic primordial dwarfism type II, life expectancy is reduced because of high risk of stroke secondary to cerebral vascular anomalies (aneurysms, moyamoya disease). Periodic screening for vascular events is recommended in individuals with Majewski osteodysplastic primordial dwarfism type II every 12-18 months following diagnosis. Our patient was medically managed with low molecular weight heparin followed with aspirin prophylaxis, in addition to carbamazepine and physical rehabilitation., Conclusion: We report an infant with moyamoya disease and recurrent stroke presenting 10 months after diagnosis (at age 18 months), and discuss the outcome of nonsurgical medical management. The presented case is the second youngest case developing stroke and moyamoya disease.

Neurometabolic diseases diagnosed by cerebrospinal fluid (CSF) examination are GLUT1 deficiency, serine-deficiency syndromes, glycine encephalopathy, cerebral folate deficiency, neonatal vitamin-responsive epileptic encephalopathies, disorders of monoamine metabolism, and y-amino butyric acid (GABA) metabolism. We retrospectively analyzed and compared the demographic, clinical, laboratory, and neuroimaging features of 62 patients in whom CSF examination was performed. Of the 62 patients, 16 (25.8%) had a final diagnosis, including succinic semialdehyde dehydrogenase (SSADH) deficiency (n=4), aromatic amino acid decarboxylase (AADC) deficiency (n=4), L-dopa-responsive dystonia (n=3), glycine encephalopathy (n=2), pyridoxal-phosphate-dependent seizures (n=l), cerebral folate deficiency (n=1), and serine biosynthesi defect (n=1). Parental consanguinity was present in all patients except one Positive yield of a diagnostic lumbar puncture (LP) for the diagnosis of inherited neurotransmitter metabolism disorder was 25.8% overall. Oculogyric crisis (50%), diurnal variation (81.8%) and consanguinity (93.8%) were the only statistically significant variables between patients with and without a specific diagnosis. It is challenging to diagnose neurotransmitter defects, since there is no ideal set of clinical symptoms. In our cohort, consanguinity, diurnal variation and abnormal ocular movements were the most significant findings associated with a diagnosis of a specific neurometabolic disorder based on CSF examination. Early diagnosis is of great importance not only for specific treatment, but also for genetic counseling and prenatal diagnosis.

Monomelic amyotrophy (MMA) is a benign motor neuron disease characterized by neurogenic amyotrophy, which usually affects one of the upper or lower extremities. Progression is slow and symptoms are clinically stable. Symptoms are seen in the second or third decades of life. In this study, we present a seven-year-old girl who was diagnosed and directed to the Physiotherapy Department at the age of 5 years and had unilateral proximal upper limb involvement. Family history of the case was recorded. Neurologic evaluation was performed. Range of joint motion, muscle shortness and strength, posture, extremity lengths, gait, timed performance, arm function, and motor and mental maturation were assessed. The physiotherapy program was designed progressively as strengthening and resistive exercises. Motor and mental developmental milestones were normal. There was no limitation in active or passive motion of all joints. She had more flexible joints, scapula alata, asymmetry between shoulder levels, and weakness on proximal muscles of the right upper extremity. In the follow-up assessment at eight months, there was no asymmetry between shoulder levels and scapular symmetry began to improve. Female gender and involvement restricted to one proximal upper limb are rare in the literature. This patient demonstrates the positive effects of physical therapy with early diagnosis of MMA. The rapid recovery of muscle weakness shows the importance of strengthening and resistive exercises applied to specific muscles in the treatment.

Purpose: We performed a retrospective study in which we investigated malformations other than brainstem and vermian dysgenesis in Joubert syndrome-related disorders (JSRD). We investigated the frequency and type of structural abnormalities that coexist with the molar tooth sign (MTS) in JSRD., Materials and Methods: We searched our archive for the years 2002-2008 in order to find patients with the diagnosis of JSRD. Cranial magnetic resonance imaging studies of 20 patients with the diagnosis of JSRD were reviewed by two neuroradiologists., Results: In addition to known anomalies including callosal dysgenesis, heterotopia, polymicrogyria, atretic encephalocele, hypomyelination, and nonobstructive dilatation of lateral ventricles; malformations that have not been previously reported were determined, including cerebellar folial disorganization, hippocampal malformation, temporal lob hypoplasia, ambient cistern lipoma, and parenchymal cyst., Conclusion: Structural abnormalities associated with the MTS are not rare, and the additional imaging findings may help explain the neurological presentation in these patients.

Serine deficiency disorders are a new group of neurometabolic diseases resulting from a deficiency in one of the three enzymes in the biosynthetic pathway of L-serine. Deficiency of the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH), which catalyzes the first step in the biosynthetic pathway, leads to congenital microcephaly, severe psychomotor retardation, and intractable seizures. We report a 4 1/2-year-old boy who presented with congenital microcephaly, psychomotor retardation, hypertonia, strabismus, and drug-resistant seizures due to 3-PGDH deficiency. His seizures responded to L-serine and glycine supplementation only. This potentially treatable disease should be borne in mind in patients with congenital microcephaly, psychomotor retardation and seizures. A timely diagnosis based on the detection of low cerebrospinal fluid levels of L-serine and glycine is expected to further increase the success of L-serine and glycine supplementation in these patients.

A seven-year-old boy admitted with the complaints of fever, weakness in legs, sensory loss in lower limb, and difficulty in voiding lasting for two weeks. His initial symptoms also included cough and fever. His spinal magnetic resonance imaging scan demonstrated acute transverse myelitis, and Mycoplasma pneumoniae-specific IgM and IgG antibodies were found to be positive in cerebrospinal fluid (CSF) and serum samples. He was treated with a single high-dose intravenous immunoglobulin (2 g/kg/dose) and clarithromycin. Mycoplasma pneumoniae is a frequent cause of upper and lower respiratory tract infections in children. Central nervous system (CNS) manifestations are among the most frequent extrapulmonary complications during the course of the disease. They occur most frequently in children, usually within three weeks after the onset of respiratory illness, with an incidence of approximately 1 in 1,000 patients. In this report, we present a seven-year-old boy with transverse myelitis during the course of Mycoplasma pneumoniae infection with serological confirmation both in serum and CSF samples.

Central nervous system infection of Herpes simplex virus (HSV) is the most common etiologic agent of the non-epidemic fatal form of encephalitis. Relapse of HSV encephalitis is rare in childhood. In this report, we present our experience in a 36-month-old child with relapse of HSV encephalitis after 14-day acyclovir therapy. A 36-month-old boy who was presented with deterioration in speech and motor functions and fluctuation of consciousness was treated with acyclovir for 14 days for HSV encephalitis. He was discharged since his cerebrospinal fluid findings returned to normal range and clinical improvement was seen. Ten days later, he was readmitted to our clinic with acute fever, focal convulsions and choreoathetoid movements, and altered consciousness. Acyclovir was started immediately, but he died on the 17th day because of respiratory failure. Relapses due to HSV encephalitis are rare and limited to a small number of case reports in the literature. Persistence of HSV, detection of high viral load or detection of HSV by polymerase chain reaction, prior corticosteroid therapy, low total dosage of acyclovir (especially for children under 2 years of age) and short duration of therapy were suspected risk factors. Even absence of pleocytosis and normal cerebrospinal fluid biochemistry in our patient after treatment did not indicate eradication of HSV. In our opinion, treatment duration of HSV encephalitis, especially in small children, must be at least 21 days. Clinical and experimental studies are required since only case reports on this topic exist.

Reduced serum levels of vitamin A affect morbidity and mortality in measles. The authors' newly diagnosed subacute sclerosing panencephalitis (n = 21) and age-matched control groups (n = 20) had mean serum beta-carotene levels of 1.12 +/- 0.56 and 1.50 +/- 0.52 microg/mL, respectively. Serum retinol <20 microg/dL was observed in 6 of 21 subacute sclerosing panencephalitis and 0 of 20 control cases (P < .05). Vitamin A deficiency can accompany subacute sclerosing panencephalitis: its contribution to the pathogenesis or course of the disease warrants further investigations.

L-2-hydroxyglutaric aciduria (L2HGA) is a chronic slowly progressive neurodegenerative disease characterized mainly by psychomotor developmental delay and cerebellar dysfunction. We report the clinical, biochemical, and neuroimaging features of 29 patients from 22 families. The mean age at the time of diagnosis was 13.4 years (2.5-32 years). The mean follow-up period of patients was four years (1.5-16 years). The main clinical findings were mental retardation and cerebellar involvement with ataxic gait and intentional tremor. Additional findings were mental retardation, macrocephaly and seizures. Diagnosis was confirmed by increased urinary excretion of L-2-hydroxyglutaric acid in all patients and highly specific magnetic resonance imaging (MRI) pattern showing subcortical leukoencephalopathy with bilateral high signal intensity in dentate nuclei and putamens. During the follow-up period, all patients had a static encephalopathy course. The underlying metabolic defect and the possible role of L-2-hydroxyglutaric acid are studied in a subgroup of these families and under evaluation for publication.

The term limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that, at the outset, affect primarily the muscles of the hip and shoulder girdle. Limb-girdle muscular dystrophy is genetically heterogeneous comprising autosomal dominant (types LGMD 1A-1E) as well as autosomal recessive forms (types LGMD 2A-2J known). A subgroup among the autosomal recessive forms comprises the sarcoglycanopathies (LGMD2C-2F), caused by mutations in the gamma (gamma-SG), alpha (alpha-SG), beta (beta-SG) and delta (delta-SG) sarcoglycan genes, respectively. The sarcoglycans form the sarcoglycan complex, part of the dystrophin-associated glycoproteins. Mutations in the beta-SG gene causes LGMD2E. Disease severity, in this form, varies from mild to severe phenotypes depending on the individual mutation. Homozygous missense mutations in critical locations may result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane and a phenotype as severe as null mutations. In the present study, through screening 80 unrelated LGMD2 families, we identified 13 families with LGMD2E. Mutations in the beta-SG gene were identified in 12 patients from nine families. One of these patients carried a previously reported truncating mutation (Q11X), while the other 11 carried novel missense/rameshift mutations (M1L, V89M, I92T, I92S, 739insA), some of which were seen in more than one patient and may, therefore, be more common in the Turkish population.

Purpose of Review: Congenital disorders of glycosylation are caused by defects in the synthesis of the glycan moiety of glycoproteins or other glycoconjugates. There has been a great explosion in the number of neuromuscular diseases caused by mutations in genes that affect carbohydrate metabolism or protein glycosylation. A common defect in these disorders is the defective processing of alpha-dystroglycan., Recent Findings: Recent advances demonstrating mutations in glycosyltransferases and dysfunction of the alpha-beta dystroglycan axis causing different forms of muscular dystrophy, especially with brain involvement, shows clearly that muscle integrity is dependent on glycosylation. We first review the newly identified muscular dystrophies, with a focus on the hypoglycosylation of alpha-dystroglycan, from a clinical, biochemical and genetic standpoint, and second hereditary inclusion body myopathies caused by mutations in the gene that encodes an enzyme responsible for the protein's posttranslational modification that cause sialidation defects. It is shown very recently that molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan. Gene transfer of LARGE into the cells of individuals with congenital muscular dystrophies restores alpha-dystroglycan function., Summary: The clinical spectrum of congenital disorders of glycosylation is becoming increasingly broad. A demonstration of mutations in glycosyltransferases will further help to design diagnostic tools and therapeutic approaches. Recent findings which show that molecular recognition by LARGE is essential for expression of functional dystroglycan and LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies, indicate a new therapeutic strategy.

Canavan disease (CD) is a rare autosomal recessive genetic disorder characterized by early onset progressive spongy degeneration of the brain involving the axon's myelin sheath. Patients with CD have leukoencephalopathy and megalencephaly; clinically they show a variable course ranging from slow neurodegenerative course to no neurological development or rapid regression. Current treatment is symptomatic including management of seizures and spasticity. Topiramate (TPM) is a novel antiepileptic drug for treatment of a broad spectrum of seizure types in adults and children. We used TPM in two of our patients diagnosed with CD at six months of age. At seven months and 15 months' follow-up, respectively, each patient showed a decrease in head growth velocity. We suggest that TPM can be used in patients with CD and possibly in other childhood neurodegenerative diseases with leukoencephalopathy and megalencephaly. Further studies are required to reveal the underlying mechanisms that lead to decreased head growth velocity, and to conclude whether this ameliorates the clinical course of CD.

Tuberous sclerosis is an autosomal dominant multisystem disorder characterized by hamartomatous growths in different organs. Disease determining genes are localized to 9q34 (TSC1) and 16p13.3 (TSC2). Two-thirds of the cases are sporadic and result from new mutations. The aim of this study was to determine TSC2 gene mutations by Single Stranded Conformation Polymorphism (SSCP) analysis and direct sequencing in 33 familial cases with tuberous sclerosis who were followed up in the Pediatric Neurology Departments of Hacettepe University Ihsan Doğramaci and Ankara Social Security Children's Hospitals. Forty-one exons of TSC2 gene were amplified and subjected to SSCP, and sequence analysis was performed when an abnormal SSCP pattern was observed. As a result, six new mutations and nine gene polymorphisms were detected. The new mutations are G-->T mutation in exon 20, 16bp deletion in exon 29, 18bp deletion in exon 40, 538 G-->A mutation in exon 29, T-->C mutation in exon 21 and G-->A splice site mutation in exon 5. Although further studies on larger groups are needed, these results do not indicate a common region or type of mutation in the Turkish population.