piperidines and Craniofacial-Abnormalities

There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh) signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf), but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Benzophenones; Body Patterning; Cell Differentiation; Cholesterol; Chondrocytes; Craniofacial Abnormalities; Embryo, Nonmammalian; Enzyme Inhibitors; Gene Expression Regulation, Developmental; Hedgehog Proteins; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Synthase; Neural Crest; Piperidines; Pyridines; Signal Transduction; Terpenes; Zebrafish; Zebrafish Proteins; Zinc Finger Protein GLI1

Topics: Anesthesia, Intravenous; Cataract; Child; Craniofacial Abnormalities; Humans; Male; Nervous System Diseases; Piperidines; Propofol; Rare Diseases; Remifentanil

Topics: Abnormalities, Multiple; Airway Management; Airway Obstruction; Anesthesia, Inhalation; Bone Diseases, Developmental; Catheters, Indwelling; Child; Contraindications; Craniofacial Abnormalities; Female; Humans; Laryngeal Masks; Methyl Ethers; Neuromuscular Blocking Agents; Piperidines; Radiology Department, Hospital; Radiology, Interventional; Remifentanil; Septo-Optic Dysplasia; Sevoflurane; Subclavian Vein

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A, is a rare congenital myopathy and dysplasia characterised by multiple contractures, abnormalities of the head and face, defective development of the hands and feet and skeletal malformations. The facial muscle contracture produces the typical 'whistling face' appearance. Anaesthetic issues include difficult intravenous access, difficult airway and postoperative pulmonary complications. Although an association with malignant hyperthermia has been suggested, this has not been confirmed. We report the management of a seven-year-old girl with Freeman-Sheldon syndrome undergoing anterior and posterior spinal surgery and describe a successful anaesthetic regimen based on a total intravenous anaesthesia technique with remifentanil and propofol without neuromuscular blocking agents. The child had an uneventful anaesthetic and postoperative course. We believe the presence of the myopathy warranted the use of a 'non-triggering' anaesthetic, as suxamethonium and volatile agents may be associated with significant complications such as muscle rigidity and rhabdomyolysis in myopathic patients, even in the absence of malignant hyperthermia.

Topics: Abnormalities, Multiple; Anesthesia, General; Anesthetics, Intravenous; Arthrogryposis; Blood Pressure; Child; Craniofacial Abnormalities; Electroencephalography; Female; Heart Rate; Humans; Monitoring, Intraoperative; Orthopedic Procedures; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Respiration, Artificial; Scoliosis; Spine; Syndrome