Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.

The aim of this cross‐sectional study was to determine the prevalence of cerebral palsy (CP) among children in Turkey between the ages of 2 and 16 years. Samples were selected from cities, towns, districts, and villages using the cluster sampling method; 41861 children were selected. Data was collected by parental interview and physical examination. One hundred and eighty‐six children were identified with CP. The prevalence of CP was determined as 4.4 per 1000 live births and included postnatally acquired CP. Origin of CP was classified as prenatal in 49 (26.6%), perinatal/neonatal in 34 (18.5%), postnatal in 11 (5.9%), and unclassifiable in 90 participants (48.9%; data was unobtainable for two individuals). Type of CP was diplegia in 39.8% of children, hemiplegia in 28%, tetraplegia in 19.9%, ataxia in 5.9%, and dyskinetic in 6.4%. Prenatal factors were seen more frequently in the groups with a high socioeconomic status while perinatal factors were encountered more often in those with a low socioeconomic status (p<0.05). Place of residence and sex had no significant effect on the prevalence of CP (p>0.05). This cross‐sectional study shows that the prevalence of CP in Turkey is higher than that in developed countries but the aetiology is probably similar. Although the high prevalence of CP in Turkey could originate from an increased level of obstetric and neonatal problems, the lack of a possible aetiological factor in approximately half the children suggests that the high level might also be due to other factors, such as genetic disorders.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.

Summary:Purpose: The aim of this study was to evaluate the effects of short-term oxcarbazepine (OXC) and valproate (VPA) monotherapy on thyroid functions in children.Methods: Fifty-five newly diagnosed epileptic children with normal thyroid functions (confirmed with the thyrotropin releasing hormone stimulation test) participated in this study. VPA treatment was started in 30 patients and OXC in 25 patients. Serum thyroxine (T 4 ), free thyroxine (fT 4 ), triiodothyronine (T 3 ), free triiodothyronine (fT 3 ), reverse T3 (rT 3 ), thyroid peroxidase antibodies (TPO-ab), and urine iodine levels were evaluated at baseline and at the third and sixth months of therapy.Results: In the OXC group, serum T 4 , fT 4 , T 3 , fT 3 , and rT 3 levels were found to be decreased at the third and sixth months, the differences were significant compared to the baseline values except for fT 3 levels at the third month and fT 4 and rT 3 levels at the sixth month (p < 0.05). At the sixth month, serum T 4 level dropped below the normal reference value in 8 (32%), fT 4 in 5 (20%), T 3 in 4 (16%), and fT 3 in 3 (12%) patients. In the VPA group, mean T 4 , fT 4 , T 3 , fT 3 , and rT 3 levels at 3 and 6 months remained similar compared to the baseline values (p > 0.05). Mean serum thyroid stimulating hormone levels increased significantly at the sixth month compared to the baseline values in the VPA group (p < 0.05) while it remained unchanged in the OXC group (p > 0.05). There was no effect of either drug on urinary iodine excretion and serum TPO-ab levels remained in normal ranges throughout the study.Conclusions: In this prospective study, it is documented that children under short-term OXC or VPA therapy showed altered thyroid functions similar to the changes observed after long-term treatment. Although, the clinical significance of these results need to be evaluated with future studies, this observation of altered thyroid functions points out that thyroid functions may need to be monitored closely in children receiving antiepileptic treatment, even in the short-time interval.

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