Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function

Comparison of arthroscopic microfracture and cell-free scaffold implantation techniques in the treatment of talar osteochondral lesions.

This study aims to compare two single-step arthroscopic techniques, microfracture and cell-free scaffold implantation, in the treatment of talar osteochondral lesions (OCLs) clinically and radiologically

Comparison of arthroscopic microfracture and cell-free scaffold implantation techniques in the treatment of talar osteochondral lesions

Objectives: This study aims to compare two single-step arthroscopic techniques, microfracture and cell-free scaffold implantation, in the treatment of talar osteochondral lesions (OCLs) clinically and radiologically. Patients and methods: This retrospective study included 62 patients (35 males, 27 females; mean age 41 +/- 13 years; range, 15 to 65 years) diagnosed with talar OCLs between March 2007 and January 2015. Patients who were followed-up with a minimum of 24 months with lesions larger than 1 cm(2) were included. Pre- and postoperative clinical evaluations were performed according to the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale and radiological evaluations according to the magnetic resonance observation of cartilage repair tissue (MOCART) scale. Results: Patients were divided into microfracture (n=22) and scaffold (n=40) groups. The mean follow-up duration was 36.1 +/- 14.9 months. The mean preoperative AOFAS score increased from 60.6 +/- 13.9 to 82.1 +/- 11.8 in the microfracture group (p<0.001) and from 53.8 +/- 13.6 to 89.4 +/- 9.9 in the scaffold group (p<0.001). The scaffold group had superior results than the microfracture group clinically (p=0.011). Clinical results were superior in younger patients (<45 years) (p=0.018), male patients (p=0.020), and traumatic lesions (p=0.014). There was no significant difference between the two techniques according to the total MOCART scores (p=0.199). However, the scaffold technique was more successful in terms of lesion border and effusion subgoups of MOCART scale. Conclusion: Both single-step arthroscopic techniques are effective and safe in the treatment of talar OCLs. The scaffold technique showed superior clinical results than the microfracture technique in short-term follow-up. Age, trauma history and gender significantly affected the treatment outcomes. The scaffold technique can be considered as a safe and good alternative particularly in the treatment of large lesions