Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.

The immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disease characterized by targeted chromosome breakage, directly related to a genomic methylation defect. It manifests with phenotypic and clinical variability, with the most consistent features being developmental delay, facial anomalies, cytogenetic defects and immunodeficiency with a reduction in serum immunoglobulin levels. From the molecular point of view, ICF syndrome was always divided into ICF type I (ICF1) and ICF type 2 (ICF2). Mutations in DNMT3B gene are responsible for ICF1, while mutations in ZBTB24 have been reported to be responsible for ICF2. In this study, we describe a Lebanese family with three ICF2 affected brothers. Sanger sequencing of the coding sequence of ZBTB24 gene was conducted and revealed a novel deletion: c.396_397delTA (p.His132Glnfs*19), resulting in a loss-of-function of the corresponding protein. ZBTB24 belongs to a large family of transcriptional factors and may be involved in DNA methylation of juxtacentromeric DNA. Detailed molecular and functional studies of the ZBTB24 and DNMT3B genes are needed to understand the pathophysiology of ICF syndrome.

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The use of adipose-derived stem cells (ADSC) in regenerative medicine is rising due to their plasticity, capacity of differentiation and paracrine and trophic effects. Despite the large number of cells obtained from adipose tissue, it is usually not enough for therapeutic purposes for many diseases or cosmetic procedures. Thus, there is the need for culturing and expanding cells in-vitro for several weeks remain. Our aim is to investigate if long- term proliferation with minimal passaging will affect the stemness, paracrine secretions and carcinogenesis markers of ADSC. The immunophenotypic properties and aldehyde dehydrogenase (ALDH) activity of the initial stromal vascular fraction (SVF) and serially passaged ADSC were observed by flow cytometry. In parallel, the telomerase activity and the relative expression of oncogenes and tumor suppressor genes were assessed by q-PCR. We also assessed the cytokine secretion profile of passaged ADSC by an ELISA. The expanded ADSC retain their morphological and phenotypical characteristics. These cells maintained in culture for up to 12 weeks until P4, possessed stable telomerase and ALDH activity, without having a TP53 mutation. Furthermore, the relative expression levels of TP53, RB, and MDM2 were not affected while the relative expression of c-Myc decreased significantly. Finally, the levels of the secretions of PGE2, STC1, and TIMP2 were not affected but the levels of IL-6, VEGF, and TIMP 1 significantly decreased at P2. Our results suggest that the expansion of passaged ADSC does not affect the differentiation capacity of stem cells and does not confer a cancerous state or capacity in vitro to the cells.

250-mg challenge dose produced a 41% improvement in UPDRS-III with dyskinesia (Supporting Information Table S1). However, she developed FOG on gait initiation, straight walking, doorways, and turning. FOG was associated with rising up onto the toes during straight walking and onto the toe of the outer rotating foot when turning, raising the possibility of a dystonic phenomenon (Video 2). She was diagnosed with on-state FOG. L-dopa was changed to immediate release and fractionated, amantadine 200 mg daily added, and she commenced gait rehabilitation without improvement. Intermittent subcutaneous apomorphine injections were initiated; however, after 6 months' therapy, FOG severity was increased ( Fig. 1), leading to~20 falls a day. Based on previous observations, 4,5 she commenced a 16-hour LCIG infusion. During week 1 of LCIG titration, FOG persisted despite rates that improved parkinsonism while causing dyskinesia, reaffirming on-state FOG. We then performed a rapid infusion titration with hourly increments in the continuous rate of 0.1 to 0.2 mL over 5 hours, starting from 2.1 mL/h, and discovered a higher rate of 3.0 mL/h that led to near-complete resolution of FOG. At 6 months, FOG remained much improved with ≤1 fall per week; however, she still reported FOG when using LCIG extra doses. At 7 months, she converted to 24-hour LCIG with a nocturnal rate of 1.4 mL/h for treatment of nocturnal left foot dystonia. Nocturnal oral L-dopa was no longer required. She reduced her daytime rate from 3.0 to 2.9 mL/h. At 9 months (Video 3), FOG was further reduced, averaging 1 fall every 4 weeks. Pre-LCIG, she had used a wheelchair intermittently for 6 months. She now always walks without aids and no longer avoids escalators or misses lift doors. She experiences two to three occurrences of start hesitation daily and mild, nondisabling dyskinesia of the right leg. Extra doses for mild, nondisabling off periods sometimes trigger transient start hesitation. Hand function is excellent and she recently resumed playing piano.We explored LCIG as treatment for on-state FOG 3 because plasma L-dopa levels with an LCIG infusion are more predictable than oral L-dopa dosing. We surprisingly discovered an interaction between L-dopa infusion rates and FOG behavior that suggested the existence of another FOG subtype (Fig. 1). We suggest the term "triphasic-on" FOG, to denote its presence in both "on" and "supra-on" states, but also the presence of a narrow "on" therapeutic window in the transition between these two states where FOG improves. It is plausible that "triphasic-on" FOG may have been present, but obscured, in at least some of the patients reported on by Espay and colleagues 3 because of the use of a single supra-on challenge dose and the unpredictable plasma L-dopa levels following oral L-dopa. In conclusion, our case suggests that some PD patients with on-state FOG might be able to be treated successfully and implies the existence of additional FOG subtypes.