CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.

METAP1 mutation is a novel candidate for autosomal recessive intellectual disability.

Intellectual disability (ID) is a genetic and clinically heterogeneous common disease and underlying molecular pathogenesis can frequently not be identified by whole-exome/genome testing. Here, we report four siblings born to a consanguineous union who presented with intellectual disability and discuss the METAP1 pathway as a novel etiology of ID. Genomic analyses demonstrated that patients harbor a novel homozygous nonsense mutation in the gene METAP1. METAP1 codes for methionine aminopeptidase 1 (MetAP1) which oversees the co-translational excision of the first methionine remnants in eukaryotes. The loss-of-function mutations to this gene may result in a defect in the translation of many essential proteins within a cell. Improper neuronal function resulting from this loss of essential proteins could lead to neurologic impairment and ID.

Psychiatric symptoms and health-related quality of life in children with epilepsy and their mothers.

PURPOSE: This study evaluated the psychiatric symptoms and health-related quality of life (HRQL) of children with epilepsy and psychiatric symptoms of their mothers, and compared them to those of healthy children and their mothers. This study also explored the influence of the child-related and maternal psychiatric variables and seizure-specific factors on the HRQLs of children with epilepsy according to both the children's and parents' perspectives. METHOD: Ninety-nine children with epilepsy (8 to 17years old), their mothers, and a control group (n=51) participated in this study. The depression and anxiety symptoms of the children were assessed using the Child Depression Inventory (CDI) and the Screen for Child Anxiety-Related Emotional Disorders (SCARED), respectively. The severities of the attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms were assessed via the mother-rated Turgay DSM-IV-Based Child and Adolescent Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S). In addition, the mothers completed the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) to assess their depression and anxiety symptoms, respectively. Child-reported and parent-reported Pediatric Quality of Life Inventories were used to evaluate the HRQLs of the children. RESULTS: The patients exhibited higher inattention and ODD scores than the controls did. With the exception of the child-reported physical health scores, all of the child- and parent-reported HRQL scores were significantly lower in the patient group. According to the regression analysis, the child-related psychiatric and seizure-specific factors, but not the maternal psychiatric factors, were associated with the child's HRQL. The explained variances for the overall HRQL and HRQL subscales were similar between the child-reported (0.373 to 0.654) and parent-reported (0.499 to 0.682) questionnaires. The largest contributors to the total variance were the child-related psychiatric factors for both the child-reported and parent-reported HRQLs by far. CONCLUSION: Epilepsy is associated with a poor psychiatric status and HRQL in childhood. The impact of epilepsy on the HRQL occurs mainly through child-related psychiatric factors. Both the child-reported and parent-reported questionnaires seem to be useful for the evaluation of the HRQL in pediatric epilepsy cases.

Pediatric Sialadenosis Due to Valproic Acid.

Sialadenosis is a rare entity characterized by bilateral diffuse, painless swelling of the parotid glands. Its etiology is not clear; however, it may occur due to adverse effects of some drugs. To our knowledge, sialadenosis due to valproic acid has not been reported in the literature up to date in any child. In this article, the authors presented a child who developed sialadenosis due to valproic acid, and improved after stopping use of the drug.

Brain magnetic resonance imaging and magnetic resonance spectroscopy findings of children with kernicterus.

BACKGROUND: The term kernicterus, or bilirubin encephalopathy, is used to describe pathological bilirubin staining of the basal ganglia, brain stem, and cerebellum, and is associated with hyperbilirubinemia. Kernicterus generally occurs in untreated hyperbilirubinemia or cases where treatment is delayed. Magnetic resonance imaging (MRI)-based studies have shown characteristic findings in kernicterus. The objective of our study was to describe the role of (1)H magnetic resonance spectroscopy (MRS) in demonstrating these metabolic changes and to review conventional MRI findings of kernicterus. MATERIAL/METHODS: Forty-eight pediatric cases with kernicterus were included in this study. MRI and MRS examinations were performed on variable dates (10-29 days after birth). NAA, Cr, Cho, NAA/Cr, NAA/Cho, and Cho/Cr values were evaluated visually and by computer analysis. RESULTS: There was no statistically significant difference between the NAA and Cho levels in the acute kernicterus patients and the control group (healthy patients), whereas both were significantly elevated in the chronic kernicterus patients. Both the mean NAA/Cr and Cho/Cr ratio values were significantly higher in the acute and chronic cases compared to the control group. The NAA/Cho ratio value was statistically lower in the acute cases than in the control group while it was similar in the chronic cases. CONCLUSIONS: Conventional MR imaging and (1)H-MRS are important complementary tools in the diagnostics of neonatal bilirubin encephalopathy. This study provided important information for applying these MR modalities in the evaluation of neonates with bilirubin encephalopathy.

Cerebral atrophy in a vitamin B12-deficient infant of a vegetarian mother.

In developed countries, vitamin B12 (cobalamin) deficiency usually occurs in children, exclusively breastfed ones whose mothers are vegetarian, causing low body stores of vitamin B12. The haematologic manifestation of vitamin B12 deficiency is pernicious anaemia. It is a megaloblastic anaemia with high mean corpuscular volume and typical morphological features, such as hyperlobulation of the nuclei of the granulocytes. In advanced cases, neutropaenia and thrombocytopaenia can occur, simulating aplastic anaemia or leukaemia. In addition to haematological symptoms, infants may experience weakness, fatigue, failure to thrive, and irritability. Other common findings include pallor, glossitis, vomiting, diarrhoea, and icterus. Neurological symptoms may affect the central nervous system and, in severe cases, rarely cause brain atrophy. Here, we report an interesting case, a 12-month old infant, who was admitted with neurological symptoms and diagnosed with vitamin B12 deficiency.