title: Pontocerebellar hypoplasia type 2D and optic nerve atrophy further expand the spectrum associated with selenoprotein biosynthesis deficiency.
abstract: BACKGROUND
  The term Pontocerebellar hypoplasias collectively refers to a group of rare, heterogeneous and progressive disorders, which are frequently inherited in an autosomal recessive manner and usually have a prenatal onset. Mutations in the SEPSECS gene, leading to deficiency in selenoprotein biosynthesis, have been identified in recent times as the molecular etiology of different pre/perinatal onset neurological phenotypes, including cerebello-cerebral atrophy, Pontocerebellar hypoplasia type 2D and progressive encephalopathy with elevated lactate. These disorders share a similar spectrum of central (e.g., brain neurodegeneration with grey and white matter both involved) and peripheral (e.g., spasticity due to axonal neuropathy) nervous system impairment.
  
  
  METHODS
  We hereby describe a 9-year-old boy with (i) a typical Pontocerebellar hypoplasia type 2D phenotype (e.g. profound mental retardation, spastic quadriplegia, ponto-cerebellar hypoplasia and progressive cerebral atrophy); (ii) optic nerve atrophy and (iii) mild secondary mitochondrial myopathy detected by muscle biopsy and respiratory chain enzyme analysis. We performed whole exome sequencing which identified a homozygous mutation of the SEPSECS gene (c.1001T > C), confirming the clinical suspect of Pontocerebellar hypoplasia type 2D.
  
  
  CONCLUSIONS
  This report further corroborates the notion of a potential secondary mitochondrial dysfunction in the context of selenoprotein biosynthesis deficiency and also adds optic nerve atrophy as a new potential clinical feature within the SEPSECS-associated clinical spectrum. These findings suggest the presence of a possible shared genetic etiology among similar clinical entities characterized by the combination of progressive cerebello-cerebral and optic nerve atrophy and also stress the biological importance of selenoproteins in the regulation of neuronal and metabolic homeostasis.
authors.affiliation: Department of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom. Electronic address: efterpi.pavlidou@gmail.com.
authors.forename: Efterpi
authors.initials: E
authors.lastname: Pavlidou
authors.affiliation: Department of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom; Department of Molecular Neurosciences, University College of London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: salpietroenzo@yahoo.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Salpietro
authors.affiliation: Department of Molecular Neurosciences, University College of London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: r.phadke@ucl.ac.uk.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: Department of Molecular Neurosciences, University College of London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: iain.hargreaves@uclh.nhs.uk.
authors.forename: Iain P
authors.initials: IP
authors.lastname: Hargreaves
authors.affiliation: The Doctors Laboratory, Bupa Cromwell Hospital Pathology Department, 1-3 Pennant Mews, London, SW5 0TU, United Kingdom. Electronic address: leigh.batten@tdlpathology.com.
authors.forename: Leigh
authors.initials: L
authors.lastname: Batten
authors.affiliation: Human Developmental Genetics, Institute Pasteur, 25-28 Rue du Docteur Roux, 75015, Paris, France. Electronic address: kenneth.mcelreavey@pasteur.fr.
authors.forename: Kenneth
authors.initials: K
authors.lastname: McElreavy
authors.affiliation: The Portland Hospital for Women and Children, 205-209 Great Portland St, London, W1W 5AH, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond St, London, WC1N 3JH, United Kingdom. Electronic address: Matthew.Pitt@gosh.nhs.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pitt
authors.affiliation: The Portland Hospital for Women and Children, 205-209 Great Portland St, London, W1W 5AH, United Kingdom; Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond St, London, WC1N 3JH, United Kingdom. Electronic address: kshitij.mankad@gosh.nhs.uk.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Mankad
authors.affiliation: Department of Paediatric Ophthalmology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom. Electronic address: clarewil25@yahoo.com.
authors.forename: Clare
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Unit of Genetics and Paediatric Immunology, Department of Paediatrics, University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy. Electronic address: mcutrupi@libero.it.
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Cutrupi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi "Nesima" - Via Palermo, 636, I-95122, Catania, Italy. Electronic address: m.ruggieri@unict.it.
authors.forename: Martino
authors.initials: M
authors.lastname: Ruggieri
authors.affiliation: The Portland Hospital for Women and Children, 205-209 Great Portland St, London, W1W 5AH, United Kingdom; Department of Paediatrics, King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom. Electronic address: davidmccormick@nhs.net.
authors.forename: David
authors.initials: D
authors.lastname: McCormick
authors.affiliation: The Portland Hospital for Women and Children, 205-209 Great Portland St, London, W1W 5AH, United Kingdom; St George's Hospital, NHS Foundation Trust, Blackshaw Rd, Tooting, SW17 0QT, London, United Kingdom. Electronic address: a.saggar@hspg.org.uk.
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.affiliation: Department of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom; The Portland Hospital for Women and Children, 205-209 Great Portland St, London, W1W 5AH, United Kingdom. Electronic address: m.kinali@imperial.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Kinali
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D001284:Atrophy; D002526:Cerebellar Diseases / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D009900:Optic Nerve / Q000473:pathology*; D010641:Phenotype; D051140:Selenoproteins / Q000172:deficiency*
chemical_list: D051140:Selenoproteins; D000604:Amino Acyl-tRNA Synthetases; C542370:O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, human
keywords: Mitochondrial myopathy; Optic nerve atrophy; Pontocerebellar hypoplasia; SEPSECS; Selenoprotein biosynthesis deficiency