The Assessment and Management of Childhood Masturbation: An Analysis of 90 Cases.

AIM: The child's self-stimulating pleasure behavior is defined as childhood masturbation (CM). Diagnosis of CM is mainly based on behavior and analysis of video recordings. This study aims to investigate etiological factors, movement patterns, and treatment options.Medical records and video recordings of CM in our clinic between 2015 and 2020 were retrospectively reviewed. RESULTS: Ninety patients aged 8 months to 9 years were included in our study. The male-to-female ratio was 23/67. The mean age at onset of masturbation (mean ± standard deviation) was 21.42 ± 18.44 (6-107) months. Note that 27.7% (32) of the patients were taking antiepileptic drugs before admission.Eight of the 90 patients had abnormal electroencephalograms. The time of onset of CM was related to cessation of breast milk in 24.4%, separation from the mother in 43.3%, new siblings in 16.6%, initiation of toilet training in 7.7%, and parental divorce in 6.6%. Behavioral therapy was sufficient in 71.1%. Hydroxyzine hydrochloride in 19 (21.1%) and risperidone in 9 (10%) were given in the remaining cases. Overall, 23/28 of the cases receiving medication improved during follow-up. CONCLUSION: Physicians may have difficulty identifying repetitive movements in CM. Misdiagnosis or delayed diagnosis may lead to unnecessary use of antiepileptic drugs, delayed initiation of treatment, and prolonged treatment duration. Video recordings are important in the differential diagnosis of CM. CM may have psychosocial causes and can often be effectively treated with behavioral therapy. Pharmacological treatment (hydroxyzine hydrochloride and risperidone) may be considered in cases that do not respond to behavioral treatment.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study.

BACKGROUND: Various etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. METHODS: Cases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. RESULTS: The study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1-12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others". The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. CONCLUSION: Our results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri­ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Pediatric-Onset Chronic Inflammatory Demyelinating Polyneuropathy: A Multicenter Study.

BACKGROUND: To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey. METHODS: The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics. RESULTS: A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 44.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05). CONCLUSIONS: This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response.

Congenital Myasthenic Syndromes in Turkey: Clinical and Molecular Characterization of 16 Cases With Three Novel Mutations.

BACKGROUND: Congenital myasthenic syndromes (CMS) are composed of numerous hereditary disorders involving genetic mutations in proteins essential to the integrity of neuromuscular transmission. The symptoms of CMS vary according to the age at onset of symptoms, and the type and severity of muscle weakness. Effective treatment and genetic counseling depend upon the underlying pathogenic molecular mechanism and subtype of CMS. METHODS: A retrospective and cross-sectional study was performed with 16 patients with a genetically confirmed diagnosis of CMS to share our experience with clinical symptoms, demographic data, genetic variants, and treatments applied. RESULTS: Sixteen patients with a specific CMS genetic diagnosis (three novel mutations) were identified, including CHRNE (n = 7), DOK7 (n = 2), AGRN (n = 2), RAPSN (n = 1), CHRNA1 (n = 1), CHRNB1 (n = 1), CHAT (n = 1), and SCN4A (n = 1). Age at onset of symptoms ranged from the neonatal period to 12 years. Genetic diagnosis was confirmed between the ages of three months and 17 years. A significant delay was determined between the onset of symptoms and genetic diagnosis of the disease. CONCLUSIONS: This study highlights the importance of genetic testing in CMS. Due to the rarity of CMS, more cases will be recognized and reported as the use of laboratory and genetic testing accelerates. We hope that our experience will grow and contribute further to the literature as clinical follow-up and treatment increase.

Clinical and genetic studies of thiamine metabolism dysfunction syndrome-4: case series and review of the literature.

Thiamine metabolism dysfunction syndrome-4 (THMD-4) is an autosomal recessive inherited rare disease (OMIM #613710) characterized by febrile illness associated episodic encephalopathy, leading to transient neurological dysfunction and progressive polyneuropathy. We report three patients from two different families with normal development, episodic encephalopathy, gait disorder, progressive chronic polyneuropathy characterized by motor difficulties, distal weakness, and hoarseness (dysphonia). We identified a homozygous missense c.576G>C, p.(Gln192His) variant in the SLC25A19 gene in both families by whole-exome sequencing. Following genetic diagnosis, thiamine replacement therapy was started, and improvement was observed in all affected patients. We highlight the associated phenotypes of an SCL25A19 mutation leading to clinical features of THMD-4.

Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.

Evaluation of immunization status in patients with cerebral palsy: a multicenter CP-VACC study.

Children with chronic neurological diseases, including cerebral palsy (CP), are especially susceptible to vaccine-preventable infections and face an increased risk of severe respiratory infections and decompensation of their disease. This study aims to examine age-appropriate immunization status and related factors in the CP population of our country. This cross-sectional prospective multicentered survey study included 18 pediatric neurology clinics around Turkey, wherein outpatient children with CP were included in the study. Data on patient and CP characteristics, concomitant disorders, vaccination status included in the National Immunization Program (NIP), administration, and influenza vaccine recommendation were collected at a single visit. A total of 1194 patients were enrolled. Regarding immunization records, the most frequently administrated and schedule completed vaccines were BCG (90.8%), hepatitis B (88.9%), and oral poliovirus vaccine (88.5%). MMR was administered to 77.3%, and DTaP-IPV-HiB was administered to 60.5% of patients. For the pneumococcal vaccines, 54.1% of children received PCV in the scope of the NIP, and 15.2% of children were not fully vaccinated for their age. The influenza vaccine was administered only to 3.4% of the patients at any time and was never recommended to 1122 parents (93.9%). In the patients with severe (grades 4 and 5) motor dysfunction, the frequency of incomplete/none vaccination of hepatitis B, BCG, DTaP-IPV-HiB, OPV, and MMR was statistically more common than mild to moderate (grades 1-3) motor dysfunction (p = 0.003, p < 0.001, p < 0.001, p < 0.00, and p < 0.001, respectively). Physicians' influenza vaccine recommendation was higher in the severe motor dysfunction group, and the difference was statistically significant (p = 0.029).Conclusion: Children with CP had lower immunization rates and incomplete immunization programs. Clinicians must ensure children with CP receive the same preventative health measures as healthy children, including vaccines. What is Known: • Health authorities have defined chronic neurological diseases as high-risk conditions for influenza and pneumococcal infections, and they recommend vaccines against these infections. • Children with CP have a high risk of incomplete and delayed immunization, a significant concern given to their increased healthcare needs and vulnerability to infectious diseases. What is New: • Influenza vaccination was recommended for patients hospitalized due to pneumonia at a higher rate, and patients were administered influenza vaccine more commonly. • Children with CP who had higher levels of motor dysfunction (levels 4 and 5) were more likely to be overdue immunizations.

Analysis of genotype-phenotype correlation in Walker-Warburg syndrome with a novel CRPPA mutation in different clinical manifestations.

PURPOSE: Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy and severe brain and eye malformations. This study aims to analyze genotype-phenotype correlations in WWS with a novel cytidine diphosphate-l-ribitol pyrophosphorylase A (CRPPA) mutation in different clinical manifestations. CASE DESCRIPTION: We report a girl with a presentation of multiple brain and ocular anomalies. Her ophthalmological evaluation showed a shallow anterior chamber, cortical cataract, iris hypoplasia, persistent hyperplastic primary vitreous in the right eye, punctate cataract, iris hypoplasia, primary congenital glaucoma, and a widespread loss of fundus pigmentation in the left eye. She was hypotonic, and her deep tendon reflexes were absent. Laboratory investigations showed high serum levels of serum creatine kinase. Brain magnetic resonance imaging demonstrated hydrocephalus, agenesis of the corpus callosum, retrocerebellar cyst, cerebellar dysplasia and hypoplasia, cobblestone lissencephaly, and hypoplastic brainstem. Whole exome sequencing revealed a novel homozygous nonsense mutation in the first exon of the CRPPA gene (NM_001101426.4, c.217G>T, p.Glu73Ter). CONCLUSIONS: The study findings expand the phenotypic variability of the ocular manifestations in the CRPPA gene-related WWS. Iris hypoplasia can be a part of clinical manifestations of the CRPPA gene-related WWS. The uncovering of the genes associated with ocular features can provide preventative methods, early diagnosis, and improved therapeutic strategies.

Genotype-phenotype correlations in ocular manifestations of Marinesco-Sjögren syndrome: Case report and literature review.

PURPOSE: This study aims to present a family with two children with MSS who presented with different ophthalmic features. We also aim to review MSS patients' ocular manifestations to provide a basis for future clinical trials and improve MSS patients' ophthalmologic care. CASE DESCRIPTION: Both patients presented with global developmental delay, microcephaly, cerebellar ataxia, and myopathy. The older sibling had developed bilateral cataracts at the age of six. Her 2 years younger sister interestingly showed bilateral hyperopic refractive error without cataracts yet. Mendeliome sequencing unraveled a novel homozygous frameshift mutation in the SIL1 gene (SIL1, NM_022464.5, c.1042dupG, p.E348Gfs*4), causing MSS. A systematic literature review revealed that cataracts appear in 96% of MSS cases with a mean onset at 3.2 years. Additional frequent ocular features were strabismus (51.6%) and nystagmus (45.2%). CONCLUSION: SIL1-related MSS is associated with marked clinical variability. Cataracts can develop later than neuromuscular features and cognitive signs. Since cataract is a relatively late finding, patients may refer to ophthalmologists for other reasons such as refractive errors, strabismus, or nystagmus. Molecular genetic testing for SIL1 is essential to facilitate early diagnosis in patients with suspected MSS.

Evaluating the brainstem in children with breath-holding spells.

OBJECTIVE: Breath-holding spells (BHSs) are a non-epileptic paroxysmal phenomenon characterized by frequent apnea episodes, loss of consciousness, and changes in skin tone and postural tone triggered by negative stimuli of childhood. The pathophysiology of the disease remains unclear; autonomic dysregulation caused by delayed myelination is believed to play a role. In this study, we aimed to evaluate the brainstems of children with BHS using diffusion tensor imaging (DTI) and investigate the etiology of this phenomenon. METHODS: The study group consisted of 16 children with a history of severe breath-holding episodes (accompanied by loss of consciousness and tonic contraction due to prolonged anoxic response) and 18 age-, gender-, and handedness-matched controls. All children underwent systemic, neurologic, and cardiologic evaluation, including complete blood count, blood biochemistry, serum iron and ferritin level, serum vitamin B12 level, electrocardiogram, and electroencephalograms. Magnetic resonance imaging was performed using a 1.5-Tesla Siemens Aera scanner (Siemens, Germany). RESULTS: Evaluation of brainstem (midbrain, pons, and medulla oblongata) volumes revealed no statistically significant differences between the BHS patient and control groups. In a voxel-wise analysis of DTI data, the BHS patient group had significantly lower fractional anisotropy (FA) values than the control group in the bilateral midbrain and medulla, right corticospinal tract, bilateral corpus callosum body and splenium, and left corpus callosum genu. In contrast, there were no significant differences in FA values in the pons, cerebellum, left corticospinal tract, and right corpus callosum genu. CONCLUSION: Based on our findings, we think that patients with BHS should be treated with an approach similar to other neurodevelopmental diseases and that this study may help elucidate the pathophysiology and establish the groundwork for future studies on its treatment.

The Spectrum of Underlying Diseases in Children with Torticollis.

AIM: To investigate the underlying conditions in children with torticollis. MATERIAL AND METHODS: Between May 2016 and December 2019, 24 patients (10 girls and 14 boys; mean age, 8 years) presenting with twisted neck, neck pain, weakness of extremities, imbalance, and gait disorder were evaluated retrospectively. RESULTS: Five of the patients had cranial pathologies (cerebellar anaplastic ependymoma and medulloblastoma, brain stem glioma, atypical teratoid rhabdoid tumor, and acute disseminated encephalomyelitis), and five of the patients had spinal pathologies (idiopathic intervertebral disc calcification, vertebral hemangiomatosis, compression fracture, multiple hereditary exostoses, and Langerhans cell histiocytosis at C4). Six of the patients had ocular pathologies (strabismus, Duane syndrome, and Brown syndrome each in two patients). Four patients had otorhinolaryngological infections (Sandifer syndrome, esophageal atresia, reflux, and spasmus nutans, with one patient each). Detailed clinical physical examination and necessary laboratory investigation were performed for all patients. CONCLUSION: Torticollis is a sign that is not always innocent and may herald an underlying severe disease. Misdiagnosis can lead to wrong and unnecessary surgical procedures and treatments, and sometimes, the results can be damaging due to underlying severe conditions if diagnosed late. In addition, we first report a case of vertebral hemangiomatosis and temporomandibular joint ankylosis that presented with torticollis in the English medical literature.

Shuddering attacks in children: A retrospective analysis of 19 cases from a single-center in Turkey.

BACKGROUND: Shuddering attacks (SA) are one of the most common childhood paroxysmal nonepileptic events (PNEs). These attacks usually start between the first 4th and 6th months of life with rapid tremors of the head and adduction of the arms and knees. A number of factors including eating, breastfeeding, and playing stimulating games have been shown to trigger the attacks; however, the exact pathogenesis remains unknown. It has been stated that there is no need for further research in patients diagnosed, and spontaneous regression is expected. PURPOSE: This study aimed to identify the causes, accompanying clinical conditions, possible differential diagnosis of SA, and the role of video-electroencephalogram (V-EEG) recording for accurate diagnosis. METHODS: Nineteen cases with SA have been collected from the database of Erciyes University Pediatric Neurology Clinic, where 52.6% are boys (n = 10) and 47.6% are girls (n = 9). The relationship between the onset and disappearance of SA symptoms and variables including family history, birth history, age, sleep, teething during SA, video-EEG recordings, brain imaging, and accompanying conditions such as epilepsy have been investigated by retrospective analysis. RESULTS: Four cases were found to have gastroesophageal reflux, one had epilepsy, and one had Marcus Gunn Jaw Winking Syndrome. No accompanying conditions could be identified for rest of the cases. It was observed that onset of symptoms in 15 (78.9%) of 19 cases coincided remarkably with the period of teething. CONCLUSION: We speculate that there might be an indirect link between SA and teething and teething may be a triggering or an aggravating factor for SA.

Long-Term Follow-Up of Patients with a Diagnosis of Posterior Reversible Encephalopathy Syndrome.

OBJECTIVE: The essential characteristics of posterior reversible encephalopathy syndrome (PRES) are the presence of acute onset neurologic symptoms, focal vasogenic edema at neuroimaging, and reversible clinical and/or radiologic findings. This study aimed to evaluate the clinical findings, causes, radiologic findings, and prognoses of patients with PRES. METHODS: Patients with PRES confirmed with clinical and radiologic findings by a pediatric neurologist were evaluated retrospectively. RESULTS: Seventeen patients with PRES were evaluated (mean age at onset, 10.23 ± 4.65 years; range, 2-17 years; girls, 29.4% [n = 5]). The mean length of follow-up was 6 ± 2.3 years (range, 3.4-10 years). Mortality due to primary disease occurred in 4 patients (23.5%) during follow-up. PRES was derived from renal diseases in 10 patients (58.8%), hematologic diseases in 6 patients (35.3%), and liver disease in one patient (5.9%). Hypertension was present in 16 patients (94.1%) at onset of PRES (>99th percentile). Seizure, the most frequent initial symptom, was observed in 82.4% (n = 14). Blurred vision and headache were the initial symptoms in 3 patients (17.6%). Sequelae were observed at magnetic resonance imaging (MRI) in 6 patients. Development of epilepsy was determined as a sequela in 4 patients (23.5%) and mental motor retardation in 2 patients (11.8%). CONCLUSION: Epilepsy is uncommon in patients who have recovered from PRES. The presence of gliosis on MRI and interictal epileptic discharges on electroencephalograms are major risk factors for the development of epilepsy. Antiepileptic treatment can be stopped in the early period in patients with normal MRI and electroencephalogram by eliminating the factors that trigger the seizures.

An analysis of 109 fetuses with prenatal diagnosis of complete agenesis of corpus callosum.

BACKGROUND: Agenesis of the corpus callosum (ACC) is the most frequent commissural malformation of the brain. It continues to be an important cause of the pregnancy termination associated with the central nervous system (CNS). OBJECTIVE: The aim of the study is to provide a comprehensive assessment of fetuses with diagnosis of complete ACC, as well as postnatal neurodevelopmental outcomes. METHODS: The data of 75,843 fetuses were screened for evaluation of complete ACC between 2003 and 2017, and a total of 109 cases with complete ACC were included in the study. ACC was considered isolated when no additional anomalies were detected, and ACC was considered complex when additional anomalies were present. RESULTS: The prevalence of complete ACC was 9.4 per 10,000 live births, and the incidence was ranged from 1.8 to 16.6 per 10,000 person-years. Patients with isolated ACC had a significantly higher survival when compared with patients with complex ACC (97.4%, n = 38/39 vs. 68.8%, n = 22/32, P = 0.001).The most important cause of death were congenital heart disease and/or respiratory failure during neonatal period. Developmental and intellectual disabilities were significantly higher in the complex ACC cases (P < 0.001). Postnatal neurodevelopmental outcomes were completely normal in 79.4% of cases with isolated ACC. CONCLUSIONS: Isolated complete ACC is usually associated with a favorable outcome. The most important prognostic factors are the presence or absence of associated congenital anomalies.

The use of rapamycin in patients with tuberous sclerosis complex: Long-term results.

PURPOSE: The purpose of this study was to evaluate the long-term results of eight cases diagnosed with tuberous sclerosis complex (TSC) and receiving rapamycin therapy because of epileptic seizures and/or accompanying TSC findings. METHOD: Rapamycin therapy was initiated at a dose of 1.5 mg/m2. Seizure frequency, electroencephalographic (EEG) findings, renal and cranial imaging findings, and cutaneous lesions over 3- to 6-month periods during follow-up and treatment were evaluated. RESULTS: Four girls and four boys aged 4-16 years at the start of rapamycin therapy and now aged 9-24 years were evaluated. Duration of rapamycin therapy was 1-5 years, and the monitoring period after commencement of rapamycin therapy lasted 5-8 years. Positive effects were observed at 9-12 months in three out of six cases of renal angiomyolipoma (AML) and in the second year of treatment in one. An increase in AML dimensions was observed in three cases after treatment was stopped. Seizure control was established in the first year of rapamycin therapy in all cases. An increased frequency of seizures was observed in three cases after the second year of treatment. No seizure recurrence was determined in the second year of treatment with rapamycin in five out of eight cases. Recurrence of seizure was observed in 6-12 months after the discontinuation of rapamycin in three cases. CONCLUSION: Rapamycin therapy exhibits positive effects on epileptic seizures in cases of TSC in 1-2 years but these positive effects on seizure control of rapamycin therapy decline after the second year. Larger case series are still needed to determine the duration and effectiveness of treatment in childhood.

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

Increased vitamin D receptor gene expression and rs11568820 and rs4516035 promoter polymorphisms in autistic disorder.

Although there are a large number of sequence variants of different genes and copy number variations at various loci identified in autistic disorder (AD) patients, the pathogenesis of AD has not been elucidated completely. Recently, in AD patients, a large number of expression array and transcriptome studies have shown an increase in the expression of genes especially related to innate immune response. Antimicrobial effects of vitamin D and VDR are exerted through Toll-Like-Receptors (TLR) which have an important role in the innate immune response, are expressed by antigen presenting cells and recognize foreign microorganisms. In this study, age and gender matched 30 patients diagnosed with AD and 30 healthy controls were included in the study. Comparatively whole blood VDR gene expression and rs11568820 and rs4516035 SNP profile of the promoter region of the VDR gene were investigated by real time PCR. Whole blood VDR gene expression was significantly higher in the AD group compared to control subjects (p < 0.0001). There were no significant differences among allele and genotype distribution of rs11568820 and rs4516035 polymorphisms between AD patients and controls. The increase of VDR gene expression in patients with AD may be in accordance with an increase in the innate immune response in patients with AD. Furthermore, this study will stimulate new studies in order to clarify the relationship among AD, vitamin D, VDR, and innate immunity.

Brain susceptibility changes in neurologically asymptomatic pediatric patients with Wilson's disease: evaluation with quantitative susceptibility mapping.

Background Wilson's disease (WD) is a copper metabolism disorder that causes hepatolenticular degeneration. It is important to diagnose WD before central nervous system involvement. Purpose To demonstrate the early susceptibility changes associated with the copper accumulation in the brain of neurologically asymptomatic pediatric patients with WD using quantitative susceptibility mapping (QSM). Material and Methods Twelve patients with neurologically asymptomatic WD (mean age = 13.7 ± 3.3 years) and 14 age-matched controls were prospectively examined using a 1.5-T clinical scanner. Routine magnetic resonance (MR) sequences and a three-dimensional multi-echo spoiled gradient echo (GRE) sequence were used and QSM maps were reproduced. The quantitative susceptibility of corpus striatum, thalamus, substantia nigra, and pons were analyzed with the region of interest analysis on QSM maps. The susceptibility values of two groups were statistically compared using a two-sample t-test. Results Conventional MR images of the patients and control group were similar. However increased magnetic susceptibility in the thalamus, pons and left posterior putamen were observed in the patients compared to the control group ( p < 0.05). Conclusion We observed statistically increased susceptibility values in the brains of neurologically asymptomatic patients with WD although the conventional MR images were normal. This might be compatible with early brain impairment, before neurological symptoms occur.