Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias.

Hereditary spastic paraplegias (HSP) are a group of inherited, neurodegenerative disorders characterized by progressive gait impairment, lower extremity spasticity and increased patellar reflexes. More than 80 types of HSP have been defined to date. In complicated forms, lower limb spasticity and gait impairment is accompanied by an additional neurological finding. Autosomal recessive (AR) HSPs are usually identified in complicated forms and occur more frequently in countries where consanguineous marriage is more widespread. Next generation sequencing techniques, developed in the last decade, have led to the identification of many new types of HSP and reduced the "diagnostic odyssey." Whole exome sequencing (WES) can diagnose up to 75% of undiagnosed HSP patients. Targeted genetic analysis with good clinical phenotyping gives the best diagnostic yields for rare diseases. Clinical heterogeneity is prominent in AR complicated HSP. However, some clinical features complicating the disease or magnetic resonance imaging findings, including thin corpus callosum or white matter abnormalities, can help to distinguish some types. AR spastic paraplegia type 64 (SPG64) is a very rare HSP, caused by a mutation in the ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) gene, first described in 2014. To date only nine patients from five families have been reported. We present two siblings with a novel pathogenic variant in ENTPD1, diagnosed by WES, as the sixth published family. We propose that early onset in childhood, cognitive impairment, dysarthria/anarthria, dystonia and areflexia may be the distinctive features of SPG64 and more clinical evidence from families with pathogenic ENTPD1 variants is warranted.

Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations.

Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.

Dicentric Recombinant Chromosome 18 due to Maternal Paracentric Inversion Analyzed by Array CGH.

Introduction: Chromosomal abnormalities are mostly found in 0.5-0.8% of live-born infants with developmental and morphological defects. Paracentric inversions are structural intrachromosomal rearrangements resulting in a risk of chromosomally unbalanced gametes in carriers. Case Presentation: Herein, we report a patient with dicentric rearrangement of chromosome 18 due to maternal paracentric inversion of chromosome 18. The patient was a girl, aged 3 years and 11 months. She was referred due to multiple congenital abnormalities, severe intellectual disability, and motor retardation. She had microcephaly, prominent metopic suture, synophrys, epicanthic folds, telecanthus, wide-set alae nasi, wide columella, bilateral cleft lip and palate, pectus carinatum, umbilical hernia, pes planus, and anteriorly displaced anus. She had bilateral external auditory canal stenosis and mild right-sided and moderate left-sided sensorineural hearing loss. Echocardiography showed secundum-type atrial septal defect and mild tricuspid failure. Brain magnetic resonance imaging showed only thinning of posterior areas of the corpus callosum. Chromosome analysis showed 46,XX,dic rec(18) by GTG and C banding. Dicentric chromosome was confirmed by fluorescence in situ hybridization analysis. Paternal karyotype was normal 46,XY but maternal chromosome analysis showed a paracentric inversion in chromosome 18 with 46,XX,inv(18)(q11.2?q21.3?) karyotype. Array CGH was performed on a peripheral blood sample from the patient and showed duplication at 18p11.32p11.21 and 18q11.1q11.2, and deletion at 18q21.33q23. The patient's final karyotype is arr 18p11.32p11.21(64,847_15,102,598)×3,18q11.1q11.2(18,542,074_22,666,470)×3,18q21.33q23(59,784,364_78,010,032)×1. Discussion: To the best of our knowledge, this is the first report of a patient with dicentric chromosome 18 due to a parental paracentric inversion of chromosome 18. We present the genotype-phenotype correlation with literature review.

Neurobrucellosis developing unilateral oculomotor nerve paralysis.

Brucellosis is a zoonotic infectious disease that is common around the world. Its clinical course demonstrates great diversity as it can affect all organs and systems. However, the central nervous system is rarely affected in the pediatric population. Neurobrucellosis is most frequently observed with meningitis and has numerous complications, including meningocephalitis, myelitis, cranial nerve paralyses, radiculopathy, and neuropathy. Neurobrucellosis affects the second, third, sixth, seventh, and eighth cranial nerves. Involvement of the oculomotor nerves is a very rare complication in neurobrucellosis although several adult cases have been reported. In this article, we present the case of a 9-year-old girl who developed unilateral nerve paralysis as a secondary complication of neurobrucellosis and recovered without sequel after treatment. This case is notable because it is a very rare, the first within the pediatric population. Our article emphasizes that neurobrucellosis should be considered among the distinguishing diagnoses in every case that is admitted for nerve paralysis in regions where Brucella infection is endemic.

Risk of recurrence after drug withdrawal in childhood epilepsy.

OBJECTIVES: After a reasonable seizure-free period, discontinuation of antiepileptic drugs (AED) is usually decided in epileptic patients despite the risk of seizure recurrence. In children, risk of recurrence after discontinuation of AED is generally 20-40%; however, there is still no general agreement on the criteria to predict safe discontinuation. This study was designed to determine the risk of recurrence and related risk factors after drug withdrawal in epileptic children. METHODS: 200 epileptic patients between 1 month and 15 years of age who were followed at least 1 year after drug withdrawal at a child neurology center between January 1993 and December 2005 formed the study population of this retrospective study. Patients were classified into groups according to defined risk factors for recurrence. RESULTS: Of 200 patients (118 boys, 82 girls), overall recurrence rate was 27%. Girls were more likely to have a seizure recurrence than boys, with the difference approaching statistical significance (p=0.058). EEG recordings after withdrawal (post-withdrawal EEG) in the follow-up were significantly different in the patients with recurrence with respect to presence of an abnormality (p=0.05). In the multivariate Cox regression analysis, female gender and abnormal post-withdrawal EEG were the risk factors influencing seizure recurrence, with female gender identified as the main risk factor. CONCLUSIONS: Although the decision to discontinue AED treatment necessitates evaluation of each patient individually, our study suggests that female patients and those with abnormal EEG after withdrawal require more cautious follow-up because of the high risk of recurrence.

Serum retinol and beta-carotene levels in subacute sclerosing panencephalitis.

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.

Cerebrospinal fluid pressures in subacute sclerosing panencephalitis.

Increased intracranial pressure can rarely be the initial symptom in subacute sclerosing panencephalitis (SSPE). We examined cerebrospinal fluid (CSF) pressures and their correlation with clinical features in 58 patients with SSPE. CSF pressure varied between 50 and 500 mmH2O, mean 210.9+/-103.7 mmH2O. Twenty-five (42%) patients had pressures above 200 mmH2O and 15/58 (25%), above 250 mmH2O. There was no correlation between CSF pressure and neurological disability, spasticity, or clinical stage. Frequent myoclonia and shorter interval between measles and onset of SSPE were associated with CSF pressure >200 mmH2O (p=0.035). The causes of high pressure in certain SSPE patients is unknown but may include the effect of myoclonic jerks or inflammatory reaction. Because these patients may be unable to express symptoms, increased intracranial pressure should be considered in the presence of irritability or frequent myoclonia.

Panic disorder in a child with recurrent chest pain.

A 10-year-old boy was admitted to the Pediatric Cardiology Unit with complaints of chest pain and dizziness. Physical examination did not show any pathologic signs. Family history revealed no heart disease and diagnosis of panic disorder (PD) in one of his family members. On follow-up, he was admitted to the pediatric emergency department several times with the same complaint. Organic etiologies of chest pain were excluded by extensive diagnostic work-up. He was referred to the Child and Adolescent Psychiatry Department for further work-up, and PD was diagnosed. A few weeks after starting paroxetine therapy, the frequency and the intensity of the chest pain attacks began to diminish. Early diagnosis of PD will avoid unnecessary investigations and prevent utilization of expensive health services, especially those performed in the emergency department. Physicians should consider that chest pain may be related to psychiatric disorders and refer their patient to mental health professionals for further management. Pharmacological therapy and cognitive-behavioral interventions are successfully used in the management of PD in children and adolescents.

Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome.

Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p.[=,Asp11Profs*14]) causing deletion of all known functional domains of the protein. PLK4 is a master regulator of centriole biogenesis and its deficiency has recently been associated with Seckel syndrome. However, the role of PLK4 in genomic stability and the DNA damage response is unclear. Evaluation of the PLK4-Seckel fibroblasts obtained from patient revealed the expected impaired centriole biogenesis, disrupted mitotic morphology, G2/M delay, and extended cell doubling time. Analysis of the PLK4-Seckel cells indicated that PLK4 is also essential for genomic stability and DNA damage response. These findings provide mechanistic insight into the pathogenesis of the severe growth failure associated with PLK4-deficiency.

Cyclic vomiting with generalized epileptiform discharges responsive to topiramate therapy.

Cyclic vomiting syndrome is a disorder characterized by recurrent attacks of vomiting and intervals of normal health between vomiting episodes averaging 2-4 weeks. It has been described by a variety of names such as abdominal migraine, abdominal epilepsy, and periodic syndrome but now has been classified in the subgroup of childhood periodic syndromes that are commonly precursors of migraine. Topiramate is an antiepileptic drug used both in the treatment of epilepsy and in migraine prophylaxis. This report presents a child with cyclic vomiting syndrome with generalized epileptiform discharges who responded to topiramate therapy. The common features of epilepsy, migraine, and cyclic vomiting syndrome are discussed.

Alpha-mannosidosis and mutational analysis in a Turkish patient.

We present a case of alpha-mannosidosis with its mutational analysis. She was referred to our hospital with the provisional diagnosis of mucolipidosis. She was the first child of second-degree relative parents. She had a coarse face with flat and wide nasal bridge, hepatosplenomegaly, umbilical hernia, lumbar gibbus, motor and mental retardation and deafness. On peripheral blood smear, lymphocytes revealed vacuoles and neutrophils contained some granules resembling Reilly bodies seen in mucopolysaccharidosis (MPS). Based on these findings, the diagnosis of alpha-mannosidosis was suspected. Her urine oligosaccharide chromatography showed an abnormal pattern with a heavy trisaccharide band. Enzyme studies on white cells confirmed a deficiency of alpha-mannosidase activity, which was 2.6 micromol/g/hr. Her DNA analysis showed a S453Y mutation.

Agranulocytosis: A Rare Complication of Infectious Mononucleosis and Recovery After IVIG Therapy.

A six-year-old boy was admitted with acute agranulocytosis four weeks after the onset of infectious mononucleosis. His bone marrow aspiration revealed maturation arrest of myeloid series. He was hospitalized for agranulocytosis and he was put on intravenous immunoglobulin (IVIG) (400 mg/kg/day) on the third day of hospitalization for two days. His white blood cell count increased to 4200/mm3 (1176 PMNL absolutely) on the fifth day. This may suggest that IVIG therapy may be effective for early recovery from agranulocytosis which is a very rare complication of infectious mononucleosis.

Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia.

AIM: This study aimed to identify the underlying genetic defect responsible for anophthalmia/microphthalmia. METHODS: In total, two Turkish families with a total of nine affected individuals were included in the study. Affymetrix 250 K single nucleotide polymorphism genotyping and homozygosity mapping were used to identify the localisation of the genetic defect in question. Coding region of the ALDH1A3 gene was screened via direct sequencing. cDNA samples were generated from primary fibroblast cell cultures for expression analysis. Reverse transcriptase PCR (RT-PCR) analysis was performed using direct sequencing of the obtained fragments. RESULTS: The causative genetic defect was mapped to chromosome 15q26.3. A homozygous G>A substitution (c.666G>A) at the last nucleotide of exon 6 in the ALDH1A3 gene was identified in the first family. Further cDNA sequencing of ALDH1A3 showed that the c.666G>A mutation caused skipping of exon 6, which predicted in-frame loss of 43 amino acids (p.Trp180_Glu222del). A novel missense c.1398C>A mutation in exon 12 of ALDH1A3 that causes the substitution of a conserved asparagine by lysine at amino acid position 466 (p.Asn466Lys) was observed in the second family. No extraocular findings-except for nevus flammeus in one affected individual and a variant of Dandy-Walker malformation in another affected individual-were observed. Autistic-like behaviour and mental retardation were observed in three cases. CONCLUSIONS: In conclusion, novel ALDH1A3 mutations identified in the present study confirm the pivotal role of ALDH1A3 in human eye development. Autistic features, previously reported as an associated finding, were considered to be the result of social deprivation and inadequate parenting during early infancy in the presented families.

[Two cases of rare cerebral hydatid cyst]. / Nadir Serebral Yerlesimli Hidatik Kist Olgusu.

Hydatid cyst disease (Echinococcosis) is a parasitic illness that is rarely located in the brain. Primary cerebral hydatid cyst disease is rarely seen. We report here rare two cases presenting with sixth cranial nerve palsy with increased intracranial pressure syndrome due to primary cerebral hydatid cyst. A 5-year-old female and a 13-year-old boy complained of headache, strabismus, nausea, and vomiting. Neurological examination revealed sixth nerve palsy and papilloedema. The diagnosis was cerebral hydatid cyst disease and was confirmed with radiological and pathological investigations. Both cases were operated on. The cysts were removed without rupture, and therapy was completed with albendazole for a period of six months. They were symptom-free during the follow-up period. In conclusion, cerebral hydatid cyst disease should be kept in mind in the differential diagnosis of increased intracranial pressure syndrome.

Serum zinc levels in children with acute gastroenteritis.

BACKGROUND: The aim of the present study was to determine the serum zinc levels on admission and 7-10 days after clinical recovery from acute gastroenteritis of <8 days' duration. METHODS: This prospective study included 82 infants aged 2-24 months who had no associated bacterial infection, chronic disease, prior antibiotic use, moderate or severe malnutrition or dysentery. Forty-one healthy children formed the control group. RESULTS: The mean serum zinc level on admission (Zn1) was 11.85 +/- 2.83 micromol/L and at 7-10 days after recovery (Zn2) was 10.92 +/- 2.17 micromol/L; mean serum zinc level of the control group was 11.81 +/- 3.45 micromol/L. Zn2 was significantly lower than Zn1, but there was no statistical difference between the mean of the control group and Zn1 and Zn2. When dehydrated patients were excluded from the patient group, Zn1 and Zn2 did not differ. Although asymptomatic, 39% of the control group had low zinc. Serum zinc levels were not affected by sex, age, clinical characteristics of the patients or severity of gastroenteritis. CONCLUSION: Serum zinc levels of the patients admitted with acute gastroenteritis without any other disease and without moderate or severe malnutrition were not affected by disease state. Gastroenteritis did not further decrease serum zinc levels in patients with asymptomatic or subclinical zinc deficiency.

Serum selenium levels in acute gastroenteritis of possible viral origin.

Selenium, as an essential micronutrient, is required for the proper functioning of the immune system and its deficiency affects the occurrence, virulence, or disease progression of some viral infections. We conducted a study to determine the serum selenium levels of children with acute gastroenteritis of possible viral origin and the effect of the serum selenium levels on the severity and the morbidity of the disease. The study was performed prospectively on 109 children aged 2-24 months with diarrhea of less than 8 days' duration admitted to the Diarrheal Disease Training and Treatment Unit. Blood samples were taken for selenium measurement on admission and 7-10 days after the end of the disease. Forty-three healthy children formed the control group. The mean serum selenium level on admission (62.41 +/- 13.06 microg/dl) was significantly lower than the mean of the second samples 7-10 days after the end of the diarrhea (81.73 +/- 17.10 microg/dl). The mean of the control group was 74.36 +/- 10.75 microg/dl, which was lower than the mean of the second samples but higher than the first sample. The frequency of vomiting and purging on admission and at the control visit, duration of diarrhea on admission, total duration of diarrhea, dehydration, breastfeeding, sex of the patients, and severity score of the disease did not alter the serum selenium levels. No correlation was detected between serum selenium levels and the parameters above. Further studies about the changes in selenium status during infectious diseases and the effect of selenium status on related mortality and morbidity are required to determine if there is need for supplementation.