Restrictive dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.

Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different heterozygous splicing mutations in the LMNA gene, leading to the production and accumulation of truncated Prelamin A. In other patients, a single nucleotide insertion was identified in ZMPSTE24. This variation is located in a homopolymeric repeat of thymines and introduces a premature termination codon. ZMPSTE24 encodes an endoprotease essential for the post-translational cleavage of the Lamin A precursor and the production of mature Lamin A. However, the autosomal recessive inheritance of RD suggested that a further molecular defect was present either in the second ZMPSTE24 allele or in another gene involved in Lamin A processing. Here, we report new findings in RD linked to ZMPSTE24 mutations. Ten RD patients were analyzed including seven from a previous series and three novel patients. All were found to be either homozygous or compound heterozygous for ZMPSTE24 mutations. We report three novel 'null' mutations as well as the recurrent thymine insertion. In all cases, we find a complete absence of both ZMPSTE24 and mature Lamin A associated with Prelamin A accumulation. Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9. The accumulation of truncated or normal length Prelamin A is, therefore, a shared pathophysiological feature in recessive and dominant RD. These findings have an important impact on our knowledge of the pathophysiology in Progeria and related disorders and will help direct the development of therapeutic approaches.

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OBJECTIVE The supplementary motor area (SMA) syndrome is a well-studied lesional model of brain plasticity involving the sensorimotor network. Patients with diffuse low-grade gliomas in the SMA may exhibit this syndrome after resective surgery. They experience a temporary loss of motor function, which completely resolves within 3 months. The authors used functional MRI (fMRI) resting state analysis of the sensorimotor network to investigate large-scale brain plasticity between the immediate postoperative period and 3 months' follow-up. METHODS Resting state fMRI was performed preoperatively, during the immediate postoperative period, and 3 months postoperatively in 6 patients with diffuse low-grade gliomas who underwent partial surgical excision of the SMA. Correlation analysis within the sensorimotor network was carried out on those 3 time points to study modifications of its functional connectivity. RESULTS The results showed a large-scale reorganization of the sensorimotor network. Interhemispheric connectivity was decreased in the postoperative period, and increased again during the recovery process. Connectivity between the lesion side motor area and the contralateral SMA rose to higher values than in the preoperative period. Intrahemispheric connectivity was decreased during the immediate postoperative period and had returned to preoperative values at 3 months after surgery. CONCLUSIONS These results confirm the findings reported in the existing literature on the plasticity of the SMA, showing large-scale modifications of the sensorimotor network, at both inter- and intrahemispheric levels. They suggest that interhemispheric connectivity might be a correlate of SMA syndrome recovery.