Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50%...
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2020-02-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2020.00041/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sergio Aguilera-Albesa Sergio Aguilera-Albesa Ana Belén de la Hoz Ana Belén de la Hoz Nekane Ibarluzea Nekane Ibarluzea Andrés R. Ordóñez-Castillo Olivia Busto-Crespo Olatz Villate Olatz Villate Olatz Villate María Asunción Ibiricu-Yanguas María Asunción Ibiricu-Yanguas María E. Yoldi-Petri María E. Yoldi-Petri Iñaki García de Gurtubay Iñaki García de Gurtubay Guiomar Perez de Nanclares Arrate Pereda María Isabel Tejada María Isabel Tejada María Isabel Tejada |
spellingShingle |
Sergio Aguilera-Albesa Sergio Aguilera-Albesa Ana Belén de la Hoz Ana Belén de la Hoz Nekane Ibarluzea Nekane Ibarluzea Andrés R. Ordóñez-Castillo Olivia Busto-Crespo Olatz Villate Olatz Villate Olatz Villate María Asunción Ibiricu-Yanguas María Asunción Ibiricu-Yanguas María E. Yoldi-Petri María E. Yoldi-Petri Iñaki García de Gurtubay Iñaki García de Gurtubay Guiomar Perez de Nanclares Arrate Pereda María Isabel Tejada María Isabel Tejada María Isabel Tejada Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis Frontiers in Neurology intellectual disability hereditary spastic paraplegia SPG 31 copy number variants dual genetic etiology |
author_facet |
Sergio Aguilera-Albesa Sergio Aguilera-Albesa Ana Belén de la Hoz Ana Belén de la Hoz Nekane Ibarluzea Nekane Ibarluzea Andrés R. Ordóñez-Castillo Olivia Busto-Crespo Olatz Villate Olatz Villate Olatz Villate María Asunción Ibiricu-Yanguas María Asunción Ibiricu-Yanguas María E. Yoldi-Petri María E. Yoldi-Petri Iñaki García de Gurtubay Iñaki García de Gurtubay Guiomar Perez de Nanclares Arrate Pereda María Isabel Tejada María Isabel Tejada María Isabel Tejada |
author_sort |
Sergio Aguilera-Albesa |
title |
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis |
title_short |
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis |
title_full |
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis |
title_fullStr |
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis |
title_full_unstemmed |
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis |
title_sort |
hereditary spastic paraplegia and intellectual disability: clinicogenetic lessons from a family suggesting a dual genetics diagnosis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neurology |
issn |
1664-2295 |
publishDate |
2020-02-01 |
description |
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50% of the patients remain without molecular diagnosis. We present a Spanish family with autosomal dominant HSP and intellectual disability (ID) in which we found a possible dual genetic diagnosis with incomplete penetrance and variable expressivity in the parents and three siblings: a heterozygous duplication of 15q11.2–q13.1 found by array CGH and a novel missense heterozygous change in REEP1 [c.73A>G; p.(Lys25Glu)] found by whole exome sequencing (WES). Following the standard genetic diagnosis approach in ID, array CGH analysis was first performed in both brothers affected by spastic paraparesis and ID from school age, and a heterozygous duplication of 15q11.2–q13.1 was found. Subsequently, the duplication was also found in the healthy mother and in the sister, who presented attention deficit/hyperactivity disorder (ADHD) symptoms from school age and pes cavus with mild pyramidal signs at 22 years of age. Methylation analysis revealed that the three siblings carried the duplication unmethylated in the maternal allele, whereas their mother harbored it methylated in her paternal allele. Functional studies revealed an overexpression of UBE3A and ATP10A in the three siblings, and the slightest cognitive phenotype of the sister seems to be related to a lower expression of ATP10A. Later, searching for the cause of HSP, WES was performed revealing the missense heterozygous variant in REEP1 in all three siblings and the father, who presented subtle pyramidal signs in the lower limbs as well as the sister. Our findings reinforce the association of maternally derived UBE3A overexpression with neurodevelopmental disorders and support that a spectrum of clinical severity is present within families. They also reveal that a dual genetic diagnosis is possible in patients with presumed complex forms of HSP and cognitive impairment. |
topic |
intellectual disability hereditary spastic paraplegia SPG 31 copy number variants dual genetic etiology |
url |
https://www.frontiersin.org/article/10.3389/fneur.2020.00041/full |
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doaj-928125b5ba684bcfa70ca9f0a961ddad2020-11-25T02:26:55ZengFrontiers Media S.A.Frontiers in Neurology1664-22952020-02-011110.3389/fneur.2020.00041495629Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics DiagnosisSergio Aguilera-Albesa0Sergio Aguilera-Albesa1Ana Belén de la Hoz2Ana Belén de la Hoz3Nekane Ibarluzea4Nekane Ibarluzea5Andrés R. Ordóñez-Castillo6Olivia Busto-Crespo7Olatz Villate8Olatz Villate9Olatz Villate10María Asunción Ibiricu-Yanguas11María Asunción Ibiricu-Yanguas12María E. Yoldi-Petri13María E. Yoldi-Petri14Iñaki García de Gurtubay15Iñaki García de Gurtubay16Guiomar Perez de Nanclares17Arrate Pereda18María Isabel Tejada19María Isabel Tejada20María Isabel Tejada21Paediatric Neurology Unit, Department of Paediatrics, Navarra Health Service Hospital, Pamplona, SpainNavarrabiomed Health Research Institute, Pamplona, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainClinical Group Affiliated With the Centre for Biomedical Research on Rare Diseases (CIBERER), Valencia, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainClinical Group Affiliated With the Centre for Biomedical Research on Rare Diseases (CIBERER), Valencia, SpainDepartment of Neurology, Navarra Health Service Hospital, Pamplona, SpainDepartment of Physical Medicine and Rehabilitation, Navarra Health Service, Pamplona, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainClinical Group Affiliated With the Centre for Biomedical Research on Rare Diseases (CIBERER), Valencia, SpainMolecular Genetics Laboratory, Genetics Service, Cruces University Hospital, Osakidetza Basque Health Service, Barakaldo, SpainNavarrabiomed Health Research Institute, Pamplona, SpainDepartment of Neurophysiology, Navarra Health Service Hospital, Pamplona, SpainPaediatric Neurology Unit, Department of Paediatrics, Navarra Health Service Hospital, Pamplona, SpainNavarrabiomed Health Research Institute, Pamplona, SpainNavarrabiomed Health Research Institute, Pamplona, SpainDepartment of Neurophysiology, Navarra Health Service Hospital, Pamplona, SpainRare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainRare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainBiocruces Bizkaia Health Research Institute, Barakaldo, SpainClinical Group Affiliated With the Centre for Biomedical Research on Rare Diseases (CIBERER), Valencia, SpainMolecular Genetics Laboratory, Genetics Service, Cruces University Hospital, Osakidetza Basque Health Service, Barakaldo, SpainHereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50% of the patients remain without molecular diagnosis. We present a Spanish family with autosomal dominant HSP and intellectual disability (ID) in which we found a possible dual genetic diagnosis with incomplete penetrance and variable expressivity in the parents and three siblings: a heterozygous duplication of 15q11.2–q13.1 found by array CGH and a novel missense heterozygous change in REEP1 [c.73A>G; p.(Lys25Glu)] found by whole exome sequencing (WES). Following the standard genetic diagnosis approach in ID, array CGH analysis was first performed in both brothers affected by spastic paraparesis and ID from school age, and a heterozygous duplication of 15q11.2–q13.1 was found. Subsequently, the duplication was also found in the healthy mother and in the sister, who presented attention deficit/hyperactivity disorder (ADHD) symptoms from school age and pes cavus with mild pyramidal signs at 22 years of age. Methylation analysis revealed that the three siblings carried the duplication unmethylated in the maternal allele, whereas their mother harbored it methylated in her paternal allele. Functional studies revealed an overexpression of UBE3A and ATP10A in the three siblings, and the slightest cognitive phenotype of the sister seems to be related to a lower expression of ATP10A. Later, searching for the cause of HSP, WES was performed revealing the missense heterozygous variant in REEP1 in all three siblings and the father, who presented subtle pyramidal signs in the lower limbs as well as the sister. Our findings reinforce the association of maternally derived UBE3A overexpression with neurodevelopmental disorders and support that a spectrum of clinical severity is present within families. They also reveal that a dual genetic diagnosis is possible in patients with presumed complex forms of HSP and cognitive impairment.https://www.frontiersin.org/article/10.3389/fneur.2020.00041/fullintellectual disabilityhereditary spastic paraplegiaSPG 31copy number variantsdual genetic etiology |