title: Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene.
abstract: Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.
authors.affiliation: Department of Paediatric Neurology-Neuromuscular Service, Evelina Children's Hospital, Guy's & St. Thomas' NHS Foundation Trust, UK. nomazulu.dlamini@gstt.nhs.uk
authors.forename: Nomazulu
authors.initials: N
authors.lastname: Dlamini
authors.forename: Dragana J
authors.initials: DJ
authors.lastname: Josifova
authors.forename: Simon M L
authors.initials: SM
authors.lastname: Paine
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Stefan
authors.initials: S
authors.lastname: Buk
authors.forename: Frances
authors.initials: F
authors.lastname: Smith
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D001176:Arthrogryposis / Q000235:genetics*; D017809:Fatal Outcome; D050172:Genes, X-Linked / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D055532:SMN Complex Proteins / Q000235:genetics*; D014897:Spinal Muscular Atrophies of Childhood / Q000150:complications / Q000175:diagnosis / Q000503:physiopathology*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*
chemical_list: D055532:SMN Complex Proteins; C471538:UBA1 protein, human; D044764:Ubiquitin-Activating Enzymes