AD form with different disease mechanism
FAR1 should be considered as a candidate gene for HSP according to the conclusions of this huge multinational study of autosomal dominant HSP in 12 people with sporadic mutations in the FAR1 gene.
Autosomal recessive mutations in this gene have a different disease mechanism with the exact opposite effect on certain lipid levels (lower versus higher in the AD form).
Purpose: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).
Methods: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.
Results: All patients had spastic paraparesis and bilateral congenital / juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.
Conclusion: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
SOURCE: Genet Med. 2020 Nov 26. doi: 10.1038/s41436-020-01027-3. Online ahead of print. PMID: 33239752
An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
Sacha Ferdinandusse 1 , Kirsty McWalter 2 , Heleen Te Brinke 3 , Lodewijk IJlst 3 , Petra M Mooijer 3 , Jos P N Ruiter 3 , Alida E M van Lint 3 , Mia Pras-Raves 3 4 5 , Eric Wever 3 4 5 , Francisca Millan 2 , Maria J Guillen Sacoto 2 , Amber Begtrup 2 , Mark Tarnopolsky 6 , Lauren Brady 6 , Roger L Ladda 7 , Susan L Sell 7 , Catherine B Nowak 8 , Jessica Douglas 8 , Cuixia Tian 9 , Elizabeth Ulm 10 , Seth Perlman 11 , Arlene V Drack 12 , Karen Chong 13 , Nicole Martin 13 , Jennifer Brault 14 , Elly Brokamp 14 , Camilo Toro 15 , William A Gahl 15 , Ellen F Macnamara 15 , Lynne Wolfe 15 , Undiagnosed Diseases Network; Quinten Waisfisz 16 , Petra J G Zwijnenburg 16 , Alban Ziegler 17 , Magalie Barth 17 , Rosemarie Smith 18 , Sara Ellingwood 18 , Deborah Gaebler-Spira 19 , Somayeh Bakhtiari 20 , Michael C Kruer 20 , Antoine H C van Kampen 5 21 , Ronald J A Wanders 3 , Hans R Waterham 3 , David Cassiman 22 , Frédéric M Vaz 23
Undiagnosed Diseases Network: Mercedes E Alejandro, Mahshid S Azamian, Carlos A Bacino, Ashok Balasubramanyam, Lindsay C Burrage, Hsiao-Tuan Chao, Gary D Clark, William J Craigen, Hongzheng Dai, Shweta U Dhar, Lisa T Emrick, Alica M Goldman, Neil A Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R Lalani, Brendan H Lee, Richard A Lewis, Ronit Marom, Paolo M Moretti, David R Murdock, Sarah K Nicholas, James P Orengo, Jennifer E Posey, Lorraine Potocki, Jill A Rosenfeld, Susan L Samson, Daryl A Scott, Alyssa A Tran, Tiphanie P Vogel, Michael F Wangler, Shinya Yamamoto, Christine M Eng, Pengfei Liu, Patricia A Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C Smith, Rebecca C Spillmann, Jennifer A Sullivan, Queenie K-G Tan, Nicole M Walley, Pankaj B Agrawal, Alan H Beggs, Gerard T Berry, Lauren C Briere, Laurel A Cobban, Matthew Coggins, Cynthia M Cooper, Elizabeth L Fieg, Frances High, Ingrid A Holm, Susan Korrick, Joel B Krier, Sharyn A Lincoln, Joseph Loscalzo, Richard L Maas, Calum A MacRae, J Carl Pallais, Deepak A Rao, Lance H Rodan, Edwin K Silverman, Joan M Stoler, David A Sweetser, Melissa Walker, Chris A Walsh, Cecilia Esteves, Emily G Kelley, Isaac S Kohane, Kimberly LeBlanc, Alexa T McCray, Anna Nagy, Surendra Dasari, Brendan C Lanpher, Ian R Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A Colley, Jyoti G Dayal, David J Eckstein, Laurie C Findley, Donna M Krasnewich, Laura A Mamounas, Teri A Manolio, John J Mulvihill, Grace L LaMoure, Madison P Goldrich, Tiina K Urv, Argenia L Doss, Maria T Acosta, Carsten Bonnenmann, Precilla D’Souza, David D Draper, Carlos Ferreira, Rena A Godfrey, Catherine A Groden, Ellen F Macnamara, Valerie V Maduro, Thomas C Markello, Avi Nath, Donna Novacic, Barbara N Pusey, Camilo Toro, Colleen E Wahl, Eva Baker, Elizabeth A Burke, David R Adams, William A Gahl, May Christine V Malicdan, Cynthia J Tifft, Lynne A Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M Hisama, Martha Horike-Pyne, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A Ashley, Gill Bejerano, Jonathan A Bernstein, Devon Bonner, Terra R Coakley, Liliana Fernandez, Paul G Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N Kohler, Elijah Kravets, Marta M Majcherska, Beth A Martin, Shruti Marwaha, Colleen E McCormack, Archana N Raja, Chloe M Reuter, Maura Ruzhnikov, Jacinda B Sampson, Kevin S Smith, Shirley Sutton, Holly K Tabor, Brianna M Tucker, Matthew T Wheeler, Diane B Zastrow, Chunli Zhao, William E Byrd, Andrew B Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J Butte, Esteban C Dell’Angelica, Naghmeh Dorrani, Emilie D Douine, Brent L Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K Loo, Bryan C Mak, Martin G Martin, Julian A Martínez-Agosto, Elisabeth McGee, Stanley F Nelson, Shirley Nieves-Rodriguez, Christina G S Palmer, Jeanette C Papp, Neil H Parker, Genecee Renteria, Rebecca H Signer, Janet S Sinsheimer, Jijun Wan, Lee-Kai Wang, Katherine Wesseling Perry, Jeremy D Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H Newman, John A Phillips 3rd, Lynette Rives, Amy K Robertson, Emily Solem, Joy D Cogan, F Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel
1 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
2 GeneDx, Gaithersburg, MD, USA.
3 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
4 Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands.
5 Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
6 Department of Pediatrics, McMaster University Children’s Hospital, Hamilton, ON, Canada.
7 Department of Pediatrics, Penn State Children’s Hospital, Hershey, PA, USA.
8 The Feingold Center for Children, Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.
9 Division of Neurology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
10 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
11 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
12 Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
13 Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.
14 Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.
15 NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
16 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
17 Genetic department, University Hospital Angers, Angers, France.
18 Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
19 Feinberg Northwestern University School of Medicine, Shirley Ryan Ability Lab, Chicago, IL, USA.
20 Barrow Neurological Institute, Phoenix Children’s Hospital and University of Arizona College of Medicine, Phoenix, AZ, USA.
21 Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
22 Department of Gastroenterology-Hepatology, Metabolic Center, University Hospitals Leuven, Leuven, Belgium.
23 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
My daughter’s genes have undergone this mutation，c.1439G>A: p.R480H，I would like to know the treatment plan for her with the needle。
Editor’s note: Please try asking your question a different way. Perhaps it has not translated well into English – not sure what you mean when you say “the needle”. Given that your medical professionals have detected the causative genetic variant, I am not sure if there is anything that we can add to what they have already told you.