Current Care and Investigational Therapies in Achondroplasia.

The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications

Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development

Urinary pyridinoline cross-links as biomarkers of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of genetic heterogeneous connective tissue disorders characterized by increased bone fragility and susceptibility to fractures. Laboratory diagnosis relies on time-consuming and cost-intensive biochemical and molecular genetics analyses. Therefore, it is desirable to identify and establish new diagnostic markers for OI that are reliable, cost-effective and easily accessible. In our study we have identified the ratio of the urinary pyridinoline cross-links lysyl-pyridinoline and hydroxylysyl-pyridinoline as a promising, time- and cost-effective biomarker for osteogenesis imperfecta, that could be used furthermore to investigate cases of suspected non-accidental injury in infants

Congenital disorder of glycosylation type Id (CDG Id): phenotypic, biochemical and molecular characterization of a new patient

Summary: Congenital disorders of glycosylation (CDG) are a family of multisystem inherited disorders caused by defects in the biosynthesis of N- or O-glycans. Among the many different subtypes of CDG, the defect of a mannosyltransferase encoded by the human ALG3 gene (chromosome 3q27) is known to cause CDG Id. Six patients with CDG Id have been described in the literature so far. We further delineate the clinical, biochemical, neuroradiological and molecular features of CDG Id by reporting an additional patient bearing a novel missense mutation in the ALG3 gene. All patients with CDG Id display a slowly progressive encephalopathy with microcephaly, severe psychomotor retardation and epileptic seizures. They also share some typical dysmorphic features but they do not present the multisystem involvement observed in other CDG syndromes or any biological marker abnormalities. Unusually marked osteopenia is a feature in some patients and may remain undiagnosed until revealed by pathological fractures. Serum transferrin screening for CDG should be extended to all patients with encephalopathy of unknown origin, even in the absence of multisystem involvemen

Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder - an alternative therapeutic approach.

Multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder is a rare inherited progressive skeletal disorder caused by mutations in the matrix metalloproteinase 2 (MMP2) gene. Treatment options are limited. Herein we present successful bisphosphonate therapy in three affected patients. Patients were treated with bisphosphonates (either pamidronate or zoledronate) for different time periods. The following outcome variables were assessed: skeletal pain, range of motion, bone densitometry, internal medical problems as well as neurocognitive function. Skeletal pain was dramatically reduced in all patients soon after initiation of therapy and bone mineral density increased. Range of motion did not significantly improve. One patient is still able to walk with aids at the age of 14 years. Neurocognitive development was normal in all patients. Bisphosphonate therapy was effective especially in controlling skeletal pain in MONA spectrum disorder. Early initiation of treatment seems to be particularly important in order to achieve the best possible outcome

Brain damage in methylmalonic aciduria: 2-methylcitrate induces cerebral ammonium accumulation and apoptosis in 3D organotypic brain cell cultures

ABSTRACT: BACKGROUND: Methylmalonic aciduria is an inborn error of metabolism characterized by accumulation of methylmalonate (MMA), propionate and 2-methylcitrate (2-MCA) in body fluids. Early diagnosis and current treatment strategies aimed at limiting the production of these metabolites are only partially effective in preventing neurological damage. METHODS: To explore the metabolic consequences of methylmalonic aciduria on the brain, we used 3D organotypic brain cell cultures from rat embryos. We challenged the cultures at two different developmental stages with 1 mM MMA, propionate or 2-MCA applied 6 times every 12 h. In a dose--response experiment cultures were challenged with 0.01, 0.1, 0.33 and 1 mM 2-MCA. Immunohistochemical staining for different brain cell markers were used to assess cell viability, morphology and differentiation. Significant changes were validated by Western blot analysis. Biochemical markers were analyzed in culture media. Apoptosis was studied by immunofluorescence staining and Western blots for activated caspase-3. RESULTS: Among the three metabolites tested, 2-MCA consistently produced the most pronounced effects. Exposure to 2-MCA caused morphological changes in neuronal and glial cells already at 0.01 mM. At the biochemical level the most striking result was a significant ammonium increase in culture media with a concomitant glutamine decrease. Dose--response studies showed significant and parallel changes of ammonium and glutamine starting from 0.1 mM 2-MCA. An increased apoptosis rate was observed by activation of caspase-3 after exposure to at least 0.1 mM 2-MCA. CONCLUSION: Surprisingly, 2-MCA, and not MMA, seems to be the most toxic metabolite in our in vitro model leading to delayed axonal growth, apoptosis of glial cells and to unexpected ammonium increase. Morphological changes were already observed at 2-MCA concentrations as low as 0.01 mM. Increased apoptosis and ammonium accumulation started at 0.1 mM thus suggesting that ammonium accumulation is secondary to cell suffering and/or cell death. Local accumulation of ammonium in CNS, that may remain undetected in plasma and urine, may therefore play a key role in the neuropathogenesis of methylmalonic aciduria both during acute decompensations and in chronic phases. If confirmed in vivo, this finding might shift the current paradigm and result in novel therapeutic strategies

Intracranial aneurismal pulsatility as a new individual criterion for rupture risk evaluation: Biomechanical and numerical approach (IRRAs project).

International audienceThis study was designed to highlight by means of numerical simulations, the correlation between aneurism sac pulsatility and the risk of rupture through the mechanical properties of the wall. In accordance to previous work suggesting a correlation between the risk of rupture and the material properties of cerebral aneurysms, twelve fluid-structure interaction (FSI) computations were performed on 12 "patient-specific" cases, corresponding to typical shapes and locations of cerebral aneurysms. The variations of the aneurismal volume during the cardiac cycle (3V) are compared using wall material characteristics of either degraded and non-degraded tissues. Aneurysms were located on 7 different arteries: Middle Cerebral Artery (4), Anterior Cerebral Artery (3), Internal Carotid Artery (1), Vertebral Artery (1), Ophthalmic Artery (1) and Basilar Artery (1). Aneurysms presented different shapes (uniform or multi-lobulated) and diastolic volumes (from 18 to 392 mm3). The pulsatility (3V/V) was significantly larger for a soft aneurismal material (average of 26 %) than for a stiff material (average of 4 %). The difference between 3V, for each condition, was statistically significant: p = 0.005. The difference in aneurismal pulsatility as highlighted in this work might be a relevant patientspecific predictor of aneurysm risk of rupture

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis

Impact of Anesthetic Management on Safety and Outcomes Following Mechanical Thrombectomy for Ischemic Stroke in SWIFT PRIME Cohort

Background and purpose: The optimal anesthetic management of acute ischemic stroke patients during mechanical thrombectomy (MT) remains controversial. In this post-hoc analysis, we investigated the impact of anesthesia type on clinical outcomes in patients included in SWIFT PRIME trial.Methods: Ninety-seven patients treated with MT were included. Patients treated in centers with general anesthesia (GA) policy (n = 32) were compared with those treated in centers with conscious sedation (CS) policy (n = 65). Primary outcomes studied included times to treatment initiation (TTI), rates of successful recanalization (TICI 2b/3), and functional independence (mRS 0–2 at 90 days). Secondary outcomes were adverse events, lowest systolic and diastolic blood pressures (LSBP and LDBP) during MT. Univariate analysis and multivariate regression logistic modeling were conducted.Results: The GA-policy and CS-policy groups presented comparable TTI (94 ± 36 min vs. 102 ± 48 min; p = 0.44), rates of TICI 2b/3 recanalization (22/32 [68.8%] vs. 51/65 [78.5%]; p = 0.32). CS-policy was associated to higher rate of functional independence than GA-policy, but the difference was not significant (43/65 [66.2%] vs. 16/32 [50.0%]; p = 0.18). GA-policy patients had a higher rate of postoperative pneumonia (11/32 [34.4%] vs. 8/65 [12.3%]; p = 0.02) and lower LSBP (110 [30,160] mmHg vs. 119 [77,170] mmHg; p = 0.03) and LDBP (55 (15,75) mmHg vs. 67 [40,121]; p < 0.001). When corrected for differences in baseline characteristics, GA-policy was associated with lower rate of functional independence (OR 0.32; p = 0.05). A 10-point increase in perprocedural LDBP was associated with an increased likelihood of favorable outcome (OR 1.51; p = 0.01).Conclusions: GA-policy for MT presented comparable TTI and rates of successful revascularization to CS-policy. However, GA-policy was associated with lower rates of functional independence and with higher incidence of perprocedural hypotension and postoperative pneumonia.Clinical Trial Registration: URL—http://www.clinicaltrials.gov. Unique identifier: NCT0165746