Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

PURPOSE: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

Non-invasive, multimodal analysis of cortical activity, blood volume and neurovascular coupling in infantile spasms using EEG-fNIRS monitoring.

Although infantile spasms can be caused by a variety of etiologies, the clinical features are stereotypical. The neuronal and vascular mechanisms that contribute to the emergence of infantile spasms are not well understood. We performed a multimodal study by simultaneously recording electroencephalogram and functional Near-infrared spectroscopy in an intentionally heterogeneous population of six children with spasms in clusters. Regardless of the etiology, spasms were accompanied by two phases of hemodynamic changes; an initial change in the cerebral blood volume (simultaneously with each spasm) followed by a neurovascular coupling in all children except for the one with a large porencephalic cyst. Changes in cerebral blood volume, like the neurovascular coupling, occurred over frontal areas in all patients regardless of any brain damage suggesting a diffuse hemodynamic cortical response. The simultaneous motor activation and changes in cerebral blood volume might result from the involvement of the brainstem. The inconstant neurovascular coupling phase suggests a diffuse activation of the brain likely resulting too from the brainstem involvement that might trigger diffuse changes in cortical excitability.

Effects of Methylphenidate on Default-Mode Network/Task-Positive Network Synchronization in Children With ADHD.

OBJECTIVE: A failure of the anti-phase synchronization between default-mode (DMN) and task-positive networks (TPN) may be involved in a main manifestation of ADHD: moment-to-moment variability. The study investigated whereby methylphenidate may improve TPN/DMN synchronization in ADHD. METHOD: Eleven drug-naive ADHD children and 11 typically developing (TD) children performed a flanker task during functional magnetic resonance imaging. The ADHD group was scanned without and 1 month later with methylphenidate. The signal was analyzed by independent component analysis. RESULTS: The TD group showed anti-phase DMN/TPN synchronization. The unmedicated ADHD group showed synchronous activity in the posterior DMN only, which was positively correlated with response time variability for the flanker task. Methylphenidate initiated a partial anti-phase TPN/DMN synchronization, reduced variability, and abolished the variability/DMN correlation. CONCLUSION: Although results should be interpreted cautiously because the sample size is small, they suggest that a failure of the TPN/DMN synchronization could be involved in the moment-to-moment variability in ADHD. Methylphenidate initiated TPN/DMN synchronization, which in turn appeared to reduce variability.

Molecular characterization of a cohort of 73 patients with infantile spasms syndrome.

Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhythmia EEG pattern and a developmental arrest or regression. Aetiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n = 3) and STXBP1 (n = 3), 3 microdeletions (10 Mb in 2q24.3, 3.2 Mb in 5q14.3 including the region upstream to MEF2C, and 256 kb in 9q34 disrupting EHMT1), and 2 microduplications (671 kb in 2q24.3 encompassing SCN2A, and 11.93 Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs.