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1.
Brain ; 137(Pt 3): 683-92, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24459106

ABSTRACT

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies.


Subject(s)
Bone Diseases/genetics , Endoplasmic Reticulum/genetics , GTP Phosphohydrolases/genetics , Hereditary Sensory and Autonomic Neuropathies/genetics , Adult , Age of Onset , Bone Diseases/etiology , Bone Diseases/physiopathology , Cohort Studies , Cough/genetics , Cough/pathology , Cough/physiopathology , Endoplasmic Reticulum/pathology , Exome/genetics , Female , Fractures, Bone/genetics , Fractures, Bone/pathology , Gastroesophageal Reflux/genetics , Gastroesophageal Reflux/pathology , Gastroesophageal Reflux/physiopathology , Genes, Dominant/genetics , Haplotypes/genetics , Hereditary Sensory and Autonomic Neuropathies/complications , Hereditary Sensory and Autonomic Neuropathies/pathology , Hereditary Sensory and Autonomic Neuropathies/physiopathology , Humans , Intracellular Space/genetics , Male , Mutation , Mutation, Missense/genetics , Pedigree , Phenotype , Young Adult
2.
J Orthop Trauma ; 21(5): 285-94, 2007 May.
Article in English | MEDLINE | ID: mdl-17485992

ABSTRACT

OBJECTIVES/DESIGN: To assess the functional outcome after treatment of proximal humeral fractures with a new antegrade nail that provides angular and sliding stability. INTERVENTION/PATIENTS: Ninety-seven patients were treated during a 4-year period between April 2000 and March 2004. All patients were followed for 6 months, 51 patients (53%) for 12 months, and 31 patients (32%) for 24 months. This study focuses mainly on the patients with a follow up of 1 year. Their mean age was 68 years (range: 33 to 90); 22% were more than 80 years of age. MAIN OUTCOME MEASUREMENTS: All fractures were radiologically graded by the Neer and AO/ASIF classifications. Clinical assessment was performed at all follow-up visits using the Constant-Murley and Neer scores, and complications were recorded. RESULTS: There were 26.8% 2-part, 66% 3-part, and 7.2% 4-part fractures. The relative Constant-Murley score improved significantly (P < 0.001) from 72% at 6 months to 82% at 12 months after operation. No further improvement regarding functional outcome was observed after 24 months. Patients younger than 60 years of age had better results. No significant functional differences were found among 2-, 3- or 4-part fractures. Complications included backing out of the proximal screws (9.8%), secondary dislocation (1.9%), complete osteonecrosis (1.9%), and partial osteonecrosis (5.8%). CONCLUSION: Treatment with this nail provides sufficient fixation of the fragments to allow early mobilization. The good functional results in the majority of the patients indicate that this nail can be used, even in complex fractures and elderly patients.


Subject(s)
Bone Nails , Fracture Fixation, Internal/methods , Shoulder Fractures/surgery , Adult , Aged , Aged, 80 and over , Arthroscopy , Equipment Design , Female , Humans , Male , Middle Aged , Treatment Outcome
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