Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants.

Autor:	Steel DBD; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Danti FR; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Abunada M; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Kamien B; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Malhotra S; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Topf M; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Kaliakatsos M; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Valentine J; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Nemeth AH; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Jayawant S; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Reid KM; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Mankad K; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Sudhakar S; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Ben-Pazi H; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Barwick K; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel., Kurian MA; From the Department of Developmental Neurosciences (D.B.D.S., K.M.R., M.A.K.), UCL Great Ormond Street Institute of Child Health; Departments of Neurology (D.B.D.S., F.R.D., M.K., K.B., M.A.K.) and Radiology (K.M., S.S.), Great Ormond Street Hospital, London, United Kingdom; Pediatric Neurology Department (M.A.), al-Rantisi Pediatric Hospital, Gaza; Department of Paediatrics (B.K., J.V.), University of Western Australia Medical School, Perth, Australia; Scientific Computing Department (S.M.), Science and Technology Facilities Council, Didcot, United Kingdom; Centre for Structural Systems Biology (M.T.), Leibniz-Institut für Experimentelle Virologie and Universitätsklinikum Hamburg-Eppendorf (UKE), Germany; Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford; Department of Paediatric Neurology (S.J.), Oxford Radcliffe Hospitals; and Neuropediatric Unit (H.B.-P.), Shaare Zedek Medical Centre, Jerusalem, Israel. manju.kurian@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Neurology [Neurology] 2023 May 23; Vol. 100 (21), pp. e2214-e2223. Date of Electronic Publication: 2023 Apr 11.
DOI:	10.1212/WNL.0000000000207241
Abstrakt:	Background and Objectives: Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities, and renal impairment. It has previously been reported in 2 families. We describe the clinical phenotype of 8 further individuals from 4 unrelated families with SLC30A9 -related disease. Method: Following detailed clinical phenotyping, 1 family underwent research whole-genome sequencing (WGS), 1 research whole-exome sequencing, and 2 diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modeling, and, where relevant, sequencing of complementary DNA (cDNA) for splicing effect. Results: In 2 unrelated families of Pakistani origin (1 consanguineous and 1 not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included 2 affected brothers, and family 2 one affected boy. In family 3, also consanguineous, there were 4 affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was nonconsanguineous: the 1 affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5, and c.1413A>G, p.Ser471=. Despite phenotypic variability between the 4 families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modeling. Its presence in 2 unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an effect on splicing was confirmed through cDNA analysis. Discussion: Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurologic syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognized. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze:	MEDLINE
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