Progressive cerebellar atrophy in a patient with complex II and III deficiency and a novel deleterious variant in SDHA: A Counseling Conundrum.
SHDA
cerebellar atrophy
complex II
mitochondrial disease
novel mutation
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
08
03
2021
received:
02
10
2020
accepted:
19
03
2021
pubmed:
8
5
2021
medline:
1
2
2022
entrez:
7
5
2021
Statut:
ppublish
Résumé
Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes. Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder. We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.
Sections du résumé
BACKGROUND
Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes.
METHODS AND RESULTS
Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder.
CONCLUSION
We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.
Identifiants
pubmed: 33960148
doi: 10.1002/mgg3.1692
pmc: PMC8222855
doi:
Substances chimiques
Electron Transport Complex II
EC 1.3.5.1
SDHA protein, human
EC 1.3.5.1
Electron Transport Complex III
EC 7.1.1.8
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1692Investigateurs
Maria T Acosta
(MT)
Margaret Adam
(M)
David R Adams
(DR)
Pankaj B Agrawal
(PB)
Mercedes E Alejandro
(ME)
Justin Alvey
(J)
Laura Amendola
(L)
Ashley Andrews
(A)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Guney Bademci
(G)
Eva Baker
(E)
Ashok Balasubramanyam
(A)
Dustin Baldridge
(D)
Jim Bale
(J)
Michael Bamshad
(M)
Deborah Barbouth
(D)
Pinar Bayrak-Toydemir
(P)
Anita Beck
(A)
Alan H Beggs
(AH)
Edward Behrens
(E)
Gill Bejerano
(G)
Jimmy Bennet
(J)
Beverly Berg-Rood
(B)
Jonathan A Bernstein
(JA)
Gerard T Berry
(GT)
Anna Bican
(A)
Stephanie Bivona
(S)
Elizabeth Blue
(E)
John Bohnsack
(J)
Carsten Bonnenmann
(C)
Devon Bonner
(D)
Lorenzo Botto
(L)
Brenna Boyd
(B)
Lauren C Briere
(LC)
Elly Brokamp
(E)
Gabrielle Brown
(G)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
Peter Byers
(P)
William E Byrd
(WE)
John Carey
(J)
Olveen Carrasquillo
(O)
Ta Chen Peter Chang
(TCP)
Sirisak Chanprasert
(S)
Hsiao-Tuan Chao
(HT)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Laurel A Cobban
(LA)
Joy D Cogan
(JD)
Matthew Coggins
(M)
F Sessions Cole
(F)
Heather A Colley
(HA)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Andrew B Crouse
(AB)
Michael Cunningham
(M)
Precilla D'Souza
(P)
Hongzheng Dai
(H)
Surendra Dasari
(S)
Mariska Davids
(M)
Jyoti G Dayal
(JG)
Matthew Deardorff
(M)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Katrina Dipple
(K)
Daniel Doherty
(D)
Naghmeh Dorrani
(N)
Emilie D Douine
(ED)
David D Draper
(DD)
Laura Duncan
(L)
Dawn Earl
(D)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Cecilia Esteves
(C)
Tyra Estwick
(T)
Marni Falk
(M)
Liliana Fernandez
(L)
Carlos Ferreira
(C)
Elizabeth L Fieg
(EL)
Laurie C Findley
(LC)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Irman Forghani
(I)
Laure Fresard
(L)
William A Gahl
(WA)
Ian Glass
(I)
Rena A Godfrey
(RA)
Katie Golden-Grant
(K)
Alica M Goldman
(AM)
David B Goldstein
(DB)
Alana Grajewski
(A)
Catherine A Groden
(CA)
Andrea L Gropman
(AL)
Irma Gutierrez
(I)
Sihoun Hahn
(S)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Kelly Hassey
(K)
Nichole Hayes
(N)
Frances High
(F)
Anne Hing
(A)
Fuki M Hisama
(FM)
Ingrid A Holm
(IA)
Jason Hom
(J)
Martha Horike-Pyne
(M)
Alden Huang
(A)
Yong Huang
(Y)
Rosario Isasi
(R)
Fariha Jamal
(F)
Gail P Jarvik
(GP)
Jeffrey Jarvik
(J)
Suman Jayadev
(S)
Jean M Johnston
(JM)
Lefkothea Karaviti
(L)
Emily G Kelley
(EG)
Jennifer Kennedy
(J)
Dana Kiley
(D)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Deborah Krakow
(D)
Donna M Krasnewich
(DM)
Elijah Kravets
(E)
Susan Korrick
(S)
Mary Koziura
(M)
Joel B Krier
(JB)
Seema R Lalani
(SR)
Byron Lam
(B)
Christina Lam
(C)
Brendan C Lanpher
(BC)
Ian R Lanza
(IR)
C Christopher Lau
(CC)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Hane Lee
(H)
Roy Levitt
(R)
Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Pengfei Liu
(P)
Xue Zhong Liu
(XZ)
Nicola Longo
(N)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Marta M Majcherska
(MM)
Bryan Mak
(B)
May Christine V Malicdan
(MCV)
Laura A Mamounas
(LA)
Teri A Manolio
(TA)
Rong Mao
(R)
Kenneth Maravilla
(K)
Thomas C Markello
(TC)
Ronit Marom
(R)
Gabor Marth
(G)
Beth A Martin
(BA)
Martin G Martin
(MG)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Jacob McCauley
(J)
Allyn McConkie-Rosell
(A)
Colleen E McCormack
(CE)
Alexa T McCray
(AT)
Elisabeth McGee
(E)
Heather Mefford
(H)
J Lawrence Merritt
(JL)
Matthew Might
(M)
Ghayda Mirzaa
(G)
Eva Morava
(E)
Paolo M Moretti
(PM)
Marie Morimoto
(M)
John J Mulvihill
(JJ)
David R Murdock
(DR)
Mariko Nakano-Okuno
(M)
Avi Nath
(A)
Stan F Nelson
(SF)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Deborah Nickerson
(D)
Shirley Nieves-Rodriguez
(S)
Donna Novacic
(D)
Devin Oglesbee
(D)
James P Orengo
(JP)
Laura Pace
(L)
Stephen Pak
(S)
J Carl Pallais
(JC)
Christina G S Palmer
(CGS)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
John A Phillips
(JA)
Jennifer E Posey
(JE)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Aaron Quinlan
(A)
Wendy Raskind
(W)
Archana N Raja
(AN)
Deepak A Rao
(DA)
Genecee Renteria
(G)
Chloe M Reuter
(CM)
Lynette Rives
(L)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Natalie Rosenwasser
(N)
Maura Ruzhnikov
(M)
Ralph Sacco
(R)
Jacinda B Sampson
(JB)
Susan L Samson
(SL)
Mario Saporta
(M)
C Ron Scott
(CR)
Judy Schaechter
(J)
Timothy Schedl
(T)
Kelly Schoch
(K)
Daryl A Scott
(DA)
Prashant Sharma
(P)
Vandana Shashi
(V)
Jimann Shin
(J)
Rebecca Signer
(R)
Catherine H Sillari
(CH)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kathy Sisco
(K)
Edward C Smith
(EC)
Kevin S Smith
(KS)
Emily Solem
(E)
Lilianna Solnica-Krezel
(L)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Nicholas Stong
(N)
Jennifer A Sullivan
(JA)
Kathleen Sullivan
(K)
Angela Sun
(A)
Shirley Sutton
(S)
David A Sweetser
(DA)
Virginia Sybert
(V)
Holly K Tabor
(HK)
Cecelia P Tamburro
(CP)
Queenie K-G Tan
(QK)
Mustafa Tekin
(M)
Fred Telischi
(F)
Willa Thorson
(W)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Brianna M Tucker
(BM)
Tiina K Urv
(TK)
Adeline Vanderver
(A)
Matt Velinder
(M)
Dave Viskochil
(D)
Tiphanie P Vogel
(TP)
Colleen E Wahl
(CE)
Stephanie Wallace
(S)
Nicole M Walley
(NM)
Chris A Walsh
(CA)
Melissa Walker
(M)
Jennifer Wambach
(J)
Jijun Wan
(J)
Lee-Kai Wang
(LK)
Michael F Wangler
(MF)
Patricia A Ward
(PA)
Daniel Wegner
(D)
Mark Wener
(M)
Tara Wenger
(T)
Katherine Wesseling Perry
(KW)
Monte Westerfield
(M)
Matthew T Wheeler
(MT)
Jordan Whitlock
(J)
Lynne A Wolfe
(LA)
Jeremy D Woods
(JD)
Shinya Yamamoto
(S)
John Yang
(J)
Guoyun Yu
(G)
Diane B Zastrow
(DB)
Chunli Zhao
(C)
Stephan Zuchner
(S)
Informations de copyright
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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