title: Severe axonal neuropathy is a late manifestation of SPG11.
abstract: Complex hereditary spastic paraplegia (HSP) is a clinically heterogeneous group of disorders usually inherited in an autosomal recessive manner. In the past, complex recessive spastic paraplegias have been frequently associated with SPG11 mutations but also with defects in SPG15, SPG7 and a handful of other rare genes. Pleiotropy exists in HSP genes, exemplified in the recent association of SPG11 mutations with CMT2. In this study, we performed whole exome sequence analysis and identified two siblings with novel compound heterozygous frameshift SPG11 mutations. The mutations segregated with disease were not present in control databases and analysis of skin fibroblast derived mRNA indicated that the SPG11 truncated mRNA species were not degraded significantly by non-sense mediated mRNA decay. These siblings had severe early-onset spastic paraplegia but later in their disease developed severe axonal neuropathy, neuropathic pain and blue/black foot discolouration likely caused by a combination of the severe neuropathy with autonomic dysfunction and peripheral oedema. We also identified a similar late-onset axonal neuropathy in a Cypriot SPG11 family. Although neuropathy is occasionally present in SPG11, in our SPG11 patients reported here it was particularly severe, highlighting the association of axonal neuropathy with SPG11 and the late manifestation of axonal peripheral nerve damage.
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Andreea
authors.initials: A
authors.lastname: Manole
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Department of Neurology, Medical University N. Testemitanu, Chisinau, Republic of Moldova.
authors.forename: Viorica
authors.initials: V
authors.lastname: Chelban
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Nourelhoda A
authors.initials: NA
authors.lastname: Haridy
authors.affiliation: Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt.
authors.forename: Sherifa A
authors.initials: SA
authors.lastname: Hamed
authors.affiliation: Instituto de Neurociencias Conci Carpinella, Laboratorio de Neurobiologìa, Instituto de Investigaciónes Medicas "Mercedes y Martín Ferreyra", INIMEC-CONICET-UNC, Córdoba, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Berardo
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. h.houlden@ucl.ac.uk.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D001921:Brain / Q000503:physiopathology; D004252:DNA Mutational Analysis; D004576:Electromyography; D005192:Family Health; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009431:Neural Conduction; D010525:Peripheral Nerves / Q000503:physiopathology; D011115:Polyneuropathies / Q000235:genetics / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
keywords: Axonal neuropathy; CMT2; Gene; Genetics; SPG11; Spatacsin