Bridging Over the Troubled Heterogeneity of SPG-Related Pathologies: Mechanisms Unite What Genetics Divide.

The hereditary spastic paraplegias (HSP) are characterized by spastic gait with weakness in the legs and additional neurological or extra-neurological signs in "complicated" forms. The past two decades have witnessed major advances in our understanding of their molecular bases with the identification of a plethora of loci and the cloning of several SPG genes. Combined genetic and clinical information has permitted a modern, molecularly-driven classification and an improved diagnosis, with several new data on the possible disease mechanisms. Further heterogeneity will rapidly emerge with the diffusion of next-generation sequencing platforms and, under the shadow of common themes in the pathogenesis, new therapeutic options will likely emerge for a great number of patients.

Pontocerebellar hypoplasia: clinical, pathologic, and genetic studies.

BACKGROUND: Mutations in genes encoding subunits of the tRNA-splicing endonuclease (TSEN) complex were identified in patients with pontocerebellar hypoplasia 2 (PCH2) and pontocerebellar hypoplasia 4 (PCH4). OBJECTIVE: We report molecular genetic findings in 12 Italian patients with clinical and MRI findings compatible with PCH2 and PCH4. METHODS: We retrospectively selected a cohort of 12 children from 9 Italian families with MRI of hypoplastic pontocerebellar structures and clinical manifestations suggesting either PCH2 or PCH4 and submitted them to direct sequencing of the genes encoding the 4 subunits of the TSEN complex, namely TSEN54, TSEN34, TSEN15, and TSEN2. RESULTS: In a cohort of 12 children, we detected the common p.A307S mutation in TSEN54 in 9/12 available patients from nine unrelated families. We also detected a novel c.1170_1183del (p. V390fs39X) in compound heterozygosity with the common p.A307S in a child with a severe PCH4 phenotype. In another severely affected patient, the second mutant allele was not identified. Two sibs without mutations in the TSEN complex were unlinked to the PCH3 locus. In addition to typical clinical and neuroradiologic features of PCH2, both children were affected by a tubulopathy resembling Bartter syndrome. CONCLUSIONS: We confirm that the common p.A307S mutation in TSEN54 is responsible for most of the patients with a PCH2 phenotype. The presence of a heterozygous in/del variant correlates with a more severe phenotype as PCH4. In addition, we describe a new clinical form of PCH in 2 sibs with clinical and MRI features of PCH2.

Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity.

Hereditary spastic paraplegias (HSP) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. We performed the first clinical, epidemiological and genetic study of HSP in Southern Tunisia. We investigated 88 patients belonging to 38 unrelated Tunisian HSP families. We could establish the minimal prevalence of HSP in the district of Sfax at 5.75/100,000. Thirty-one percent of the families had a pure HSP, whereas 69% had a complicated form. The mode of inheritance was almost exclusively compatible with an autosomal recessive trait (97%, 37/38). Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each. The linkage results could be validated through the identification of two recurrent truncating mutations (R2034X and M245VfsX246) in the SPG11 gene, three different mutations (Q493X, F683LfsX685 and the novel S2004T/r.?) in the SPG15 gene, the recurrent R499C mutation in the SPG4 gene as well as the new R112X mutation in the SPG5 gene. SPG11 and SPG15 are the major responsible HSP genes in Tunisia.

SPG11--the most common type of recessive spastic paraplegia in Norway?

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity with additional neurological symptoms and signs in complicated forms. Among the many autosomal recessive forms, SPG11 appears to be one of the most frequent. OBJECTIVE: Our objective was to select potential SPG11 patients based on phenotypes in our material, identify eventual disease-causing variants with the collaboration of laboratories abroad, estimate the frequency and spectrum of SPG11-mutations and describe their associated phenotypes. MATERIAL AND METHODS: Two isolated cases and two affected members of one family with cognitive impairment and confirmed thin corpus callosum on magnetic resonance imaging were selected from our database for inclusion into a multicenter study. Results - Mutations were found in the two isolated cases but not in the proband of the family. CONCLUSION: We present the first SPG11-HSP in the Norwegian population. SPG11 should be suspected in patients with isolated or recessive HSP, thin corpus callosum and mental retardation.

Oxytocin modulates nitric oxide generation by human fetal membranes at term pregnancy.

PROBLEM: Nitric oxide (NO), an important mediator of the inflammatory response, is involved in several reproductive processes including pregnancy and labor. Uterus, placenta and fetal membranes are significant sources of NO. Presently, there is no information on factors regulating NO production by fetal membranes. METHOD OF STUDY: Human fetal membranes at term gestation were cultured for 24 hr in the presence of oxytocin. The concentrations of NO metabolites nitrites in culture medium were determined by the Griess reaction. The presence of inducible nitric oxide synthase (iNOS) was determined by reverse transcriptase-polymerase chain reaction and Western blot. RESULTS: Oxytocin increased nitrite release by fetal membranes. Messenger ribonucleic acid iNOS expression was also enhanced by oxytocin. These effects were more marked in tissues obtained after labor than before labor. CONCLUSIONS: Oxytocin exerts an overall stimulatory effect on NO release by fetal membranes. This action might be of relevance in the biomolecular processes leading to parturition.