Efterpi Pavlidou1, Vincenzo Salpietro2, Rahul Phadke3, Iain P Hargreaves4, Leigh Batten5, Kenneth McElreavy6, Matthew Pitt7, Kshitij Mankad8, Clare Wilson9, Maria Concetta Cutrupi10, Martino Ruggieri11, David McCormick12, Anand Saggar13, Maria Kinali14. 1. Department of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom. Electronic address: efterpi.pavlidou@gmail.com. 2. 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. 3. Department of Molecular Neurosciences, University College of London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: r.phadke@ucl.ac.uk. 4. Department of Molecular Neurosciences, University College of London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: iain.hargreaves@uclh.nhs.uk. 5. The Doctors Laboratory, Bupa Cromwell Hospital Pathology Department, 1-3 Pennant Mews, London, SW5 0TU, United Kingdom. Electronic address: leigh.batten@tdlpathology.com. 6. Human Developmental Genetics, Institute Pasteur, 25-28 Rue du Docteur Roux, 75015, Paris, France. Electronic address: kenneth.mcelreavey@pasteur.fr. 7. 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. 8. 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. 9. Department of Paediatric Ophthalmology, Chelsea and Westminster NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, United Kingdom. Electronic address: clarewil25@yahoo.com. 10. Unit of Genetics and Paediatric Immunology, Department of Paediatrics, University of Messina, Via Consolare Valeria 1, 98125, Messina, Italy. Electronic address: mcutrupi@libero.it. 11. 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. 12. 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. 13. 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. 14. 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.
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. CASE PRESENTATION: 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. CONCLUSION: 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.
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. CASE PRESENTATION: 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. CONCLUSION: 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: Vincenzo Salpietro; Massimo Zollo; Jana Vandrovcova; Mina Ryten; Juan A Botia; Veronica Ferrucci; Andreea Manole; Stephanie Efthymiou; Fuad Al Mutairi; Enrico Bertini; Marco Tartaglia; Henry Houlden Journal: Brain Date: 2017-08-01 Impact factor: 13.501