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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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Autores principales: Aguilera-Albesa, Sergio, de la Hoz, Ana Belén, Ibarluzea, Nekane, Ordóñez-Castillo, Andrés R., Busto-Crespo, Olivia, Villate, Olatz, Ibiricu-Yanguas, María Asunción, Yoldi-Petri, María E., García de Gurtubay, Iñaki, Perez de Nanclares, Guiomar, Pereda, Arrate, Tejada, María Isabel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033498/
https://www.ncbi.nlm.nih.gov/pubmed/32117010
http://dx.doi.org/10.3389/fneur.2020.00041
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author Aguilera-Albesa, Sergio
de la Hoz, Ana Belén
Ibarluzea, Nekane
Ordóñez-Castillo, Andrés R.
Busto-Crespo, Olivia
Villate, Olatz
Ibiricu-Yanguas, María Asunción
Yoldi-Petri, María E.
García de Gurtubay, Iñaki
Perez de Nanclares, Guiomar
Pereda, Arrate
Tejada, María Isabel
author_facet Aguilera-Albesa, Sergio
de la Hoz, Ana Belén
Ibarluzea, Nekane
Ordóñez-Castillo, Andrés R.
Busto-Crespo, Olivia
Villate, Olatz
Ibiricu-Yanguas, María Asunción
Yoldi-Petri, María E.
García de Gurtubay, Iñaki
Perez de Nanclares, Guiomar
Pereda, Arrate
Tejada, María Isabel
author_sort Aguilera-Albesa, Sergio
collection PubMed
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.
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spelling pubmed-70334982020-02-28 Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis Aguilera-Albesa, Sergio de la Hoz, Ana Belén Ibarluzea, Nekane Ordóñez-Castillo, Andrés R. Busto-Crespo, Olivia Villate, Olatz Ibiricu-Yanguas, María Asunción Yoldi-Petri, María E. García de Gurtubay, Iñaki Perez de Nanclares, Guiomar Pereda, Arrate Tejada, María Isabel Front Neurol Neurology 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. Frontiers Media S.A. 2020-02-14 /pmc/articles/PMC7033498/ /pubmed/32117010 http://dx.doi.org/10.3389/fneur.2020.00041 Text en Copyright © 2020 Aguilera-Albesa, de la Hoz, Ibarluzea, Ordóñez-Castillo, Busto-Crespo, Villate, Ibiricu-Yanguas, Yoldi-Petri, García de Gurtubay, Perez de Nanclares, Pereda and Tejada. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Aguilera-Albesa, Sergio
de la Hoz, Ana Belén
Ibarluzea, Nekane
Ordóñez-Castillo, Andrés R.
Busto-Crespo, Olivia
Villate, Olatz
Ibiricu-Yanguas, María Asunción
Yoldi-Petri, María E.
García de Gurtubay, Iñaki
Perez de Nanclares, Guiomar
Pereda, Arrate
Tejada, María Isabel
Hereditary Spastic Paraplegia and Intellectual Disability: Clinicogenetic Lessons From a Family Suggesting a Dual Genetics Diagnosis
title 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_short 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
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033498/
https://www.ncbi.nlm.nih.gov/pubmed/32117010
http://dx.doi.org/10.3389/fneur.2020.00041
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