Neurological Findings and a Brief Review of the Current Literature in a Severe Case of Aicardi-Goutières Syndrome Due to an IFIH1 Mutation.

Aicardi-Goutières syndrome (AGS) is a rare genetic early-onset progressive encephalopathy with variable clinical manifestations. The IFIH1 mutation has been confirmed to be responsible for type I interferon production and activation of the Janus kinase signaling pathway. We herein stress neurological observations and neuroimaging findings in a severe case report of an infant with AGS type 7 due to an IFIH1 mutation who was diagnosed in the first month of life. We also review neurological characteristics of IFIH1 mutations through recent literature.

MKS1 regulates ciliary INPP5E levels in Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation 'the molar tooth sign'. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. METHODS: We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations. RESULTS: We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥ 1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. CONCLUSIONS: MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.

Specificity of human rhinovirus 2A(pro) is determined by combined spatial properties of four cleavage site residues.

The 2A proteinase (2A(pro)) of human rhinoviruses cleaves the virally encoded polyprotein between the C terminus of VP1 and its own N terminus. Poor understanding of the 2A(pro) substrate specificity of this enzyme has hampered progress in developing inhibitors that may serve as antiviral agents. We show here that the 2A(pro) of human rhinovirus (HRV) 1A and 2 (rhinoviruses from genetic group A) cannot self-process at the HRV14 (a genetic group B rhinovirus) cleavage site. When the amino acids in the cleavage site of HRV2 2A(pro) (Ile-Ile-Thr-Thr-Ala*Gly-Pro-Ser-Asp) were singly or doubly replaced with the corresponding HRV14 residues (Asp-Ile-Lys-Ser-Tyr*Gly-Leu-Gly-Pro) at positions from P3 to P2', HRV1A and HRV2 2A(pro) cleavage took place at WT levels. However, when three or more positions of the HRV1A or 2 2A(pro) were substituted (e.g. at P2, P1 and P2'), cleavage in vitro was essentially eliminated. Introduction of the full HRV14 cleavage site into a full-length clone of the HRV1A and transfection of HeLa cells with a transcribed RNA did not give rise to viable virus. In contrast, revertant viruses bearing cysteine at the P1 position or proline at P2' were obtained when an RNA bearing the three inhibitory amino acids was transfected. Reversions in the enzyme affecting substrate specificity were not found in any of the in vivo experiments. Modelling of oligopeptide substrates onto the structure of HRV2 2A(pro) revealed no appreciable differences in residues of HRV2 and HRV14 in the respective substrate binding sites, suggesting that the overall shape of the substrate is important in determining binding efficiency.

Pineal cysts - a benign consequence of mild hypoxia in a near-term brain?

BACKGROUND: Pineal cysts are benign glial uniloculated or multiloculated fluid-filled sacs located in the pineal gland region. Small pineal cysts are often found incidentally in healthy adults in 1.5-10.8%. Large cysts may cause neurological problems due to pressure exertion on adjacent structures. METHODS: We have used prospective, observational study of an inception cohort of 16 adolescents of mean age 21.69 years (SD=±0.87) with mild (68.7%) to moderate (31.3%) HIE: 7 girls (43.8%) and 9 (56.3%) boys, born with mean gestational age of 35.75 weeks (SD=±3.80) and mean birthweight of 2 644 g (SD=±815). HIE was confirmed by presence of abnormal CTG and/or meconium and/or Apgar scores less than 7 at 5 minutes and/or need for resuscitation and/or cord pH less than 7.2 and /or BE more than -15. The clinical assessment of HIE was done according to the Sarnat-Sarnat scoring. Neonatal data, including EEG and imaging data, were collected. Adolescents were scanned with 3T Magnetom Trio Tim, Siemens, head coil 12 channels, regular sequences and sagittal 3D magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence with voxel size 1 mm3. Neurological outcome was determined. RESULTS: In 1 patient we found cortical dysplasia and 1 had a panic attack hence their data were omitted. In the group of 14 we have incidentally found in 5 patients a larger, asymptomatic pineal cysts with the overall incidence of 36%. Other MR findings in the group were in 50% white matter injury, in 50% thinner corpus callosum. No statistically significant difference between neonatal cUS and late follow-up MRI (p=0.881) was found. Correlation was not significant with Spearman correlation coefficient 0.201. Presence of pineal cysts was linked to thinner corpus callosum (p=0.005). CONCLUSIONS: We propose that larger pineal cyst, in the absence of other imaging findings except for thinner corpus callosum, is a benign consequence of mild hypoxia in a near-term brain. Our findings warrant a larger study.

Polysomnogram changes in marijuana users who report sleep disturbances during prior abstinence.

BACKGROUND: Abrupt discontinuation of heavy marijuana (MJ) use is associated with self-reports of sleep difficulty. Disturbed sleep is clinically important because MJ users experiencing sleep problems may relapse to MJ use to improve their sleep quality. Few studies have used polysomnography (PSG) to characterize changes in sleep architecture during abrupt abstinence from heavy MJ use. METHODS: We recorded PSG measures on nights 1, 2, 7, 8, and 13 after abrupt MJ discontinuation in 18 heavy MJ users residing in an inpatient unit. RESULTS: Across abstinence, Total Sleep Time (TST), Sleep Efficiency (SEff), and amount of REM sleep declined, while Wake after Sleep Onset (WASO) and Periodic Limb Movements (PLM) increased. Furthermore, quantity (joints/week) and duration (years) of MJ use were positively associated with more PLMs. CONCLUSION: The treatment of sleep disturbance is a potential target for the management of cannabis use disorders since poor sleep could contribute to treatment failure in heavy MJ users.

Epidemiologic features of infantile spasms in Slovenia.

PURPOSE: To determine the epidemiologic features of infantile spasms (ISs) in Slovenia. METHODS: Medical records of all children with ISs in Slovenia in the period from 1985 to 1995, based on community pediatrician referrals to four hospitals, including all pediatric EEG laboratories, were retrospectively studied. The outcome was assessed by a follow-up study in 1998. RESULTS: Forty-seven children with ISs were identified over an 11-year interval. The cumulative incidence was 2.06 per 10,000 live births. Among 29 (61.7%) children with symptomatic etiology, 14 cases had prenatal etiology [tuberous sclerosis (TS), seven; vascular insult, three; cerebral malformations, three; Down syndrome, one child], 14 perinatal and one postnatal cause: anoxic brain damage after cardiac surgery. Cryptogenic and idiopathic etiology were diagnosed in 13 (27.6%) and five (10.6%) of 47 cases, respectively. The age of onset of ISs ranged from 2 to 10 months. As initial treatment, steroids were used in 19 children (remission in 10); vigabatrin in seven (remission in four), and other antiepileptic drugs (AEDs) in 20 children (remission in six). According to the follow-up study, 18 (38.3%) children were seizure free, and 14 of them had normal mental development. Among 29 mentally retarded children (14 severely), 26 belonged to the symptomatic group. Four children died. CONCLUSIONS: The incidence of ISs in Slovenia is similar to that in some parts of the United States, but lower than that in Finland or Sweden. The outcome depends mainly on etiology. Additional neuroimaging studies are needed for evaluation of cryptogenic cases.