Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern

Behnam, M

Houlden, H

Kaiyrzhanov, R

Maroofian, R

Salehi, M

Salpietro, V

English

St George's Online Research Archive

CLINICAL/SCIENTIFIC NOTES OPEN ACCESSFurther supporting evidence for REEP1phenotypic and allelic heterogeneityReza Maroofian, PhD,* Mahdiyeh Behnam, MD, PhD,* Rauan Kaiyrzhanov, MD, Vincenzo Salpietro, MD,Mansour Salehi, PhD, and Henry Houlden, MD, PhDNeurol Genet 2019;5:e379. doi:10.1212/NXG.0000000000000379CorrespondenceDr. Kaiyrzhanovrauan.kaiyrzhanov.14@ucl.ac.ukHeterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomaldominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondriaand endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition tothe HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type ofCharcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratorydistress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygousmutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) withdiaphragmatic paralysis, expanding the phenotype frommild autosomal dominant HSP throughto severe recessive distal SMA pattern.Clinical reportThe proband is a 14-year-old girl who is the product of a normal full-term pregnancy. Her parentsare healthy first-cousin Iranians in their mid-thirties. At birth, she presented with proximal anddistal muscle weakness in all the limbs with flexion contractures at the knees and elbows, footdrop, and progressive wrist drop (figure1, B–F, Video 1). She could crawl, hold her head erect atnormal age, and sit at the age of 5 months. Afterward, there has been a marked regression inneurologic development, resulting in permanent inability to stand up and/or walk and in severerecurrent contractions in hands and feet despite surgery being started from the age of 2.5 years.She developed progressive muscular atrophy starting from the lower limbs and progressing to theupper limbs. At the age of 3 years, she was diagnosed with diaphragmatic palsy, resulting in fever-associated breathing difficulties. She was also diagnosed with esophageal sphincter palsy, whichwas corrected by surgery. Her cognition and speech are preserved, and she does not have visual orhearing impairment.On neurologic examination, she hadmarked plantar flexion contractures in the ankles and flexioncontractions in the wrists, brisk deep tendon reflexes in the knees, absent Achilles reflex, noBabinski sign, and normal reflexes in the upper limbs. There was low muscle tone and wasting inthe limbs. Neurophysiology studies showed signs of severe sensory and moderate motor axonaldegeneration, fibrillations, and marked reduction in the motor unit interference pattern with anincrease in amplitude and duration of motor unit action potentials in the right and left tibialisanterior muscles. The latter change was also observed to a lesser degree in the right biceps and leftdeltoid. Sural nerve biopsy was compatible with chronic demyelinating neuropathy with sec-ondary focal axonal and nerve fibers loss. Brain MRI was unremarkable. Dosage and Sangersequencing of the SMN1 gene was performed and resulted negative. The clinical diagnosis ofdistal SMA with diaphragmatic paralysis was made. Single-nucleotide polymorphism array*These authors contributed equally to the manuscript.From the Department of Neuromuscular Disorders Institute of Neurology (R.M., R.K., V.S., H.H.), University College London, Queen Square; and Medical Genetics Laboratory ofGenome (M.B., M.S.), Isfahan, Iran.Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by Wellcome Trust and MRC UK.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.MORE ONLINEVideoCopyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1genotyping in combination with exome sequencing revealeda homozygous pathogenic missense variant in REEP1 (NM_022912: c.124T > C; p.Trp42Arg) within a 59 Mb homozy-gosity region (figure1A).DiscussionThe p.Trp42Arg REEP1 variant has been previously reportedas pathogenic in autosomal dominant hereditary spasticparaplegia.5 The mutation leads to haploinsufficiency andinterferes with the integrity of the N-terminus of REEP1 andimpairs normal ER targeting and shaping.6 It has been specu-lated in a Drosophila model that REEP1-associated disorderscould be ER stress diseases expressing variable phenotypesdepending on the type of impaired function in the ER.4 Fur-thermore, REEP1 could have a direct role in the control ofmitochondrial network morphology through interaction withthe crucial protein involved in mitochondrial fission, namedDRP1. It has been shown that important alterations take placein the mitochondrial morphology in the primary fibroblasts ofpatients with REEP1 HSP compared with control cells.7To date, only 1 homozygous mutation has been reported inREEP1; this affects a splice donor site (p.Phe62Lysfs23*) andwas found in a Lebanese patient presenting with a SMARD1-like phenotype which included distal arthrogryposis, congenitalaxonal neuropathy, hyperreflexia, and respiratory distress, butwithout any cognitive or language impairment.4 Although therewas a significant phenotypic overlap between this reportedindividual and our patient, arthrogryposis involving proximaland distal joints was more pronounced in our patient, whereasdiaphragmatic palsy seems to be more severe in the homozy-gous p.Phe62Lysfs23* carrier. In addition, our case adds data onpeculiar electromyographic changes that were not reported inthe former report. Of interest, parents were carriers of the var-iant in the heterozygous state, already associated with complexautosomal dominant hereditary spastic paraplegia, and neithergait problems nor family history of HSP was reported by them.REEP1 heterozygous mutations express incomplete penetrancepredominantly manifesting before the age of 20 years or afterthe age of 30 years.8 Unfortunately, the parents did not haveneurologic and electrophysiologic examinations to exclude thesubclinical or mild forms of HSP. The incomplete penetrance ofthe p.Trp42Arg variant in the heterozygous state could beexplained by the effects of modifying genes and stochasticprocesses during development.4The identification of 2 different biallelic REEP1 mutations inpatients with SMARD1-like phenotypes and respiratory Dis-tress expand the phenotypic spectrum associated to this geneand demonstrates the loss-of-function dosage effect and impli-cations of the same allele in distinct neurologic phenotypes.Study fundingThis study was funded by Wellcome Trust and the MedicalResearch Council.DisclosureDisclosures available: Neurology.org/NG.Publication historyReceived by Neurology: Genetics April 8, 2019. Accepted in final formOctober 15, 2019.Figure Clinical images and molecular genetic findings ofthe case(A) DNA chromatograms. The top row is a sequence from the father, themiddle row is from the mother, and the bottom row is from the proband.The blue arrow points at A > G substitution, which is heterozygous in theparents and homozygous in the proband. (B–E) Distal and proximalarthrogryposis. Wasted limbmuscles. (F) X-ray of the arms. Deformity of themiddle phalanges and lateroflexion of the hand. (G) Family tree.Appendix AuthorsName Location Role ContributionRezaMaroofian,PhDQueen Square,London, UKAuthor Designed andconceptualized thestudy. Analyzed NGSand SNP array data.Drafted themanuscript.MahdiyehBehnam, PhDMedical GeneticsLaboratory ofGenome, Isfahan,IranAuthor Designed andconceptualized thestudy. Recruited andinvestigated thefamily. Validated theresults of the WES.Performed andanalyzed the Sangersequencing.RauanKaiyrzhanov,MDQueen Square,London, UKAuthor Drafted themanuscript forintellectual content.Literature review andanalyzed clinical andgenetic data.Manuscriptsubmission2 Neurology: Genetics | Volume 5, Number 6 | December 2019 Neurology.org/NGReferences1. Zu¨chner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrialprotein REEP1 cause hereditary spastic paraplegia type 31. Am JHumGenet 2006;79:365–369.2. Lim Y, Cho IT, Schoel LJ, Cho G, Golden JA. Hereditary spastic paraplegia-linkedREEP1 modulates endoplasmic reticulum/mitochondria contacts. Ann Neurol 2015;78:679–696.3. Bock A, Gu¨nther S, Mohr J, et al. A nonstop variant in REEP1 causes peripheralneuropathy by unmasking a 39UTR-encoded, aggregation-inducing motif. HumMutat 2018;39:193–196.4. Schottmann G, SeelowD, Seifert F, et al. Recessive REEP1mutation is associated withcongenital axonal neuropathy and diaphragmatic palsy. Neurol Genet 2015;1:e32.5. Goizet C, Depienne C, Benard G, et al. REEP1 mutations in SPG31: frequency,mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Hum Mutat 2011;32:1118–1127.6. Falk J, Rohde M, Bekhite M, et al. Functional mutation analysis provides evidence fora role of REEP1 in lipid droplet biology. Hum Mutat 2014;35:497–504.7. Lavie J, Serrat R, BellanceN, et al. Mitochondrial morphology and cellular distributionare altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. HumMol Genet 2017;26:674–685.8. Beetz C, Schule R, Deconinck T, et al. REEP1mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 2008;131:1078–1086.Appendix (continued)Name Location Role ContributionVincenzoSalpietro, MDQueen Square,London, UKAuthor Drafted themanuscript forintellectual content.Revised themanuscript forintellectual contentMansourSalehi, MDMedical GeneticsLaboratory ofGenome, Isfahan,Iran. IsfahanUniversity of MedicalSciences, Isfahan, IranAuthor Recruited,investigated, andphenotyped thefamily. Revised themanuscript forintellectual contentHenryHoulden, MD,PhDQueen Square,London, UKAuthor Supervised the workand obtained fundingsupportNeurology.org/NG Neurology: Genetics | Volume 5, Number 6 | December 2019 3DOI 10.1212/NXG.00000000000003792019;5; Neurol Genet Reza Maroofian, Mahdiyeh Behnam, Rauan Kaiyrzhanov, et al.  phenotypic and allelic heterogeneityREEP1Further supporting evidence for This information is current as of November 15, 2019ServicesUpdated Information & http://ng.neurology.org/content/5/6/e379.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/5/6/e379.full.html##ref-list-1This article cites 8 articles, 1 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/spastic_paraplegiaSpastic paraplegia http://ng.neurology.org//cgi/collection/all_geneticsAll Geneticsfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2019 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Maroofian, Reza

Behnam, Mahdiyeh

Kaiyrzhanov, Rauan

Salpietro, Vincenzo

Salehi, Mansour

Houlden, Henry

Archivio istituzionale della ricerca - Università di Genova

Further supporting evidence for REEP1 phenotypic and allelic heterogeneity

UCL Discovery

CLINICAL/SCIENTIFIC NOTES OPEN ACCESSFurther supporting evidence for REEP1phenotypic and allelic heterogeneityReza Maroofian, PhD,* Mahdiyeh Behnam, MD, PhD,* Rauan Kaiyrzhanov, MD, Vincenzo Salpietro, MD,Mansour Salehi, PhD, and Henry Houlden, MD, PhDNeurol Genet 2019;5:e379. doi:10.1212/NXG.0000000000000379CorrespondenceDr. Kaiyrzhanovrauan.kaiyrzhanov.14@ucl.ac.ukHeterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomaldominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondriaand endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition tothe HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type ofCharcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratorydistress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygousmutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) withdiaphragmatic paralysis, expanding the phenotype frommild autosomal dominant HSP throughto severe recessive distal SMA pattern.Clinical reportThe proband is a 14-year-old girl who is the product of a normal full-term pregnancy. Her parentsare healthy first-cousin Iranians in their mid-thirties. At birth, she presented with proximal anddistal muscle weakness in all the limbs with flexion contractures at the knees and elbows, footdrop, and progressive wrist drop (figure1, B–F, Video 1). She could crawl, hold her head erect atnormal age, and sit at the age of 5 months. Afterward, there has been a marked regression inneurologic development, resulting in permanent inability to stand up and/or walk and in severerecurrent contractions in hands and feet despite surgery being started from the age of 2.5 years.She developed progressive muscular atrophy starting from the lower limbs and progressing to theupper limbs. At the age of 3 years, she was diagnosed with diaphragmatic palsy, resulting in fever-associated breathing difficulties. She was also diagnosed with esophageal sphincter palsy, whichwas corrected by surgery. Her cognition and speech are preserved, and she does not have visual orhearing impairment.On neurologic examination, she hadmarked plantar flexion contractures in the ankles and flexioncontractions in the wrists, brisk deep tendon reflexes in the knees, absent Achilles reflex, noBabinski sign, and normal reflexes in the upper limbs. There was low muscle tone and wasting inthe limbs. Neurophysiology studies showed signs of severe sensory and moderate motor axonaldegeneration, fibrillations, and marked reduction in the motor unit interference pattern with anincrease in amplitude and duration of motor unit action potentials in the right and left tibialisanterior muscles. The latter change was also observed to a lesser degree in the right biceps and leftdeltoid. Sural nerve biopsy was compatible with chronic demyelinating neuropathy with sec-ondary focal axonal and nerve fibers loss. Brain MRI was unremarkable. Dosage and Sangersequencing of the SMN1 gene was performed and resulted negative. The clinical diagnosis ofdistal SMA with diaphragmatic paralysis was made. Single-nucleotide polymorphism array*These authors contributed equally to the manuscript.From the Department of Neuromuscular Disorders Institute of Neurology (R.M., R.K., V.S., H.H.), University College London, Queen Square; and Medical Genetics Laboratory ofGenome (M.B., M.S.), Isfahan, Iran.Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by Wellcome Trust and MRC UK.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.MORE ONLINEVideoCopyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1genotyping in combination with exome sequencing revealeda homozygous pathogenic missense variant in REEP1 (NM_022912: c.124T > C; p.Trp42Arg) within a 59 Mb homozy-gosity region (figure1A).DiscussionThe p.Trp42Arg REEP1 variant has been previously reportedas pathogenic in autosomal dominant hereditary spasticparaplegia.5 The mutation leads to haploinsufficiency andinterferes with the integrity of the N-terminus of REEP1 andimpairs normal ER targeting and shaping.6 It has been specu-lated in a Drosophila model that REEP1-associated disorderscould be ER stress diseases expressing variable phenotypesdepending on the type of impaired function in the ER.4 Fur-thermore, REEP1 could have a direct role in the control ofmitochondrial network morphology through interaction withthe crucial protein involved in mitochondrial fission, namedDRP1. It has been shown that important alterations take placein the mitochondrial morphology in the primary fibroblasts ofpatients with REEP1 HSP compared with control cells.7To date, only 1 homozygous mutation has been reported inREEP1; this affects a splice donor site (p.Phe62Lysfs23*) andwas found in a Lebanese patient presenting with a SMARD1-like phenotype which included distal arthrogryposis, congenitalaxonal neuropathy, hyperreflexia, and respiratory distress, butwithout any cognitive or language impairment.4 Although therewas a significant phenotypic overlap between this reportedindividual and our patient, arthrogryposis involving proximaland distal joints was more pronounced in our patient, whereasdiaphragmatic palsy seems to be more severe in the homozy-gous p.Phe62Lysfs23* carrier. In addition, our case adds data onpeculiar electromyographic changes that were not reported inthe former report. Of interest, parents were carriers of the var-iant in the heterozygous state, already associated with complexautosomal dominant hereditary spastic paraplegia, and neithergait problems nor family history of HSP was reported by them.REEP1 heterozygous mutations express incomplete penetrancepredominantly manifesting before the age of 20 years or afterthe age of 30 years.8 Unfortunately, the parents did not haveneurologic and electrophysiologic examinations to exclude thesubclinical or mild forms of HSP. The incomplete penetrance ofthe p.Trp42Arg variant in the heterozygous state could beexplained by the effects of modifying genes and stochasticprocesses during development.4The identification of 2 different biallelic REEP1 mutations inpatients with SMARD1-like phenotypes and respiratory Dis-tress expand the phenotypic spectrum associated to this geneand demonstrates the loss-of-function dosage effect and impli-cations of the same allele in distinct neurologic phenotypes.Study fundingThis study was funded by Wellcome Trust and the MedicalResearch Council.DisclosureDisclosures available: Neurology.org/NG.Publication historyReceived by Neurology: Genetics April 8, 2019. Accepted in final formOctober 15, 2019.Figure Clinical images and molecular genetic findings ofthe case(A) DNA chromatograms. The top row is a sequence from the father, themiddle row is from the mother, and the bottom row is from the proband.The blue arrow points at A > G substitution, which is heterozygous in theparents and homozygous in the proband. (B–E) Distal and proximalarthrogryposis. Wasted limbmuscles. (F) X-ray of the arms. Deformity of themiddle phalanges and lateroflexion of the hand. (G) Family tree.Appendix AuthorsName Location Role ContributionRezaMaroofian,PhDQueen Square,London, UKAuthor Designed andconceptualized thestudy. Analyzed NGSand SNP array data.Drafted themanuscript.MahdiyehBehnam, PhDMedical GeneticsLaboratory ofGenome, Isfahan,IranAuthor Designed andconceptualized thestudy. Recruited andinvestigated thefamily. Validated theresults of the WES.Performed andanalyzed the Sangersequencing.RauanKaiyrzhanov,MDQueen Square,London, UKAuthor Drafted themanuscript forintellectual content.Literature review andanalyzed clinical andgenetic data.Manuscriptsubmission2 Neurology: Genetics | Volume 5, Number 6 | December 2019 Neurology.org/NGReferences1. Züchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrialprotein REEP1 cause hereditary spastic paraplegia type 31. Am JHumGenet 2006;79:365–369.2. Lim Y, Cho IT, Schoel LJ, Cho G, Golden JA. Hereditary spastic paraplegia-linkedREEP1 modulates endoplasmic reticulum/mitochondria contacts. Ann Neurol 2015;78:679–696.3. Bock A, Günther S, Mohr J, et al. A nonstop variant in REEP1 causes peripheralneuropathy by unmasking a 39UTR-encoded, aggregation-inducing motif. HumMutat 2018;39:193–196.4. Schottmann G, SeelowD, Seifert F, et al. Recessive REEP1mutation is associated withcongenital axonal neuropathy and diaphragmatic palsy. Neurol Genet 2015;1:e32.5. Goizet C, Depienne C, Benard G, et al. REEP1 mutations in SPG31: frequency,mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Hum Mutat 2011;32:1118–1127.6. Falk J, Rohde M, Bekhite M, et al. Functional mutation analysis provides evidence fora role of REEP1 in lipid droplet biology. Hum Mutat 2014;35:497–504.7. Lavie J, Serrat R, BellanceN, et al. Mitochondrial morphology and cellular distributionare altered in SPG31 patients and are linked to DRP1 hyperphosphorylation. HumMol Genet 2017;26:674–685.8. Beetz C, Schule R, Deconinck T, et al. REEP1mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 2008;131:1078–1086.Appendix (continued)Name Location Role ContributionVincenzoSalpietro, MDQueen Square,London, UKAuthor Drafted themanuscript forintellectual content.Revised themanuscript forintellectual contentMansourSalehi, MDMedical GeneticsLaboratory ofGenome, Isfahan,Iran. IsfahanUniversity of MedicalSciences, Isfahan, IranAuthor Recruited,investigated, andphenotyped thefamily. Revised themanuscript forintellectual contentHenryHoulden, MD,PhDQueen Square,London, UKAuthor Supervised the workand obtained fundingsupportNeurology.org/NG Neurology: Genetics | Volume 5, Number 6 | December 2019 3DOI 10.1212/NXG.00000000000003792019;5; Neurol Genet Reza Maroofian, Mahdiyeh Behnam, Rauan Kaiyrzhanov, et al.  phenotypic and allelic heterogeneityREEP1Further supporting evidence for This information is current as of November 15, 2019ServicesUpdated Information & http://ng.neurology.org/content/5/6/e379.full.htmlincluding high resolution figures, can be found at:References http://ng.neurology.org/content/5/6/e379.full.html##ref-list-1This article cites 8 articles, 1 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/spastic_paraplegiaSpastic paraplegia http://ng.neurology.org//cgi/collection/all_geneticsAll Geneticsfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:reserved. Online ISSN: 2376-7839.Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rightsan open-access, online-only, continuous publication journal. Copyright Copyright © 2019 The Author(s). is an official journal of the American Academy of Neurology. Published since April 2015, it isNeurol Genet 

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Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

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