The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.
SSADH deficiency
evolving phenotype
genetic spectrum
in silico analyses
long-term follow-up
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
18 Mar 2024
18 Mar 2024
Historique:
revised:
15
02
2024
received:
04
12
2023
accepted:
20
02
2024
medline:
19
3
2024
pubmed:
19
3
2024
entrez:
19
3
2024
Statut:
aheadofprint
Résumé
The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Instituto de Salud Carlos III
ID : FIS P118/00111
Organisme : Instituto de Salud Carlos III
ID : FI21/0073
Organisme : Medical Faculty of the Ruprecht Karl University of Heidelberg
ID : F.206871
Organisme : Dietmar Hopp Foundation
Organisme : German SSADH-Defizit e.V
Organisme : De Neu. Asociación de Enfermedades de Los Neurotransmisores
Informations de copyright
© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
Références
Gupta M, Hogema BM, Grompe M, et al. Murine succinate semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54(S6):S81-S90. doi:10.1002/ana.10625
Lakhani R, Vogel KR, Till A, et al. Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition. EMBO Mol Med. 2014;6(4):551-566. doi:10.1002/emmm.201303356
Walters DC, Lawrence R, Kirby T, et al. Postmortem analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD): II. Histological, lipid, and gene expression outcomes in regional brain tissue. J Child Neurol. 2021;36(13-14):1177-1188. doi:10.1177/0883073820987742
Knerr I, Gibson KM, Jakobs C, Pearl PL. Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients. CNS Spectr. 2008;13(7):598-605.
Pearl PL, Gibson KM, Acosta MT, et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology. 2003;60(9):1413-1417. doi:10.1212/01.wnl.0000059549.70717.80
DiBacco ML, Pop A, Salomons GS, et al. Novel ALDH5A1 variants and genotype: phenotype correlation in SSADH deficiency. Neurology. 2020;95(19):e2675-e2682. doi:10.1212/WNL.0000000000010730
Pearl PL, Novotny EJ, Acosta MT, Jakobs C, Gibson KM. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol. 2003;54(Suppl 6):S73-S80. doi:10.1002/ana.10629
Tokatly Latzer I, Bertoldi M, DiBacco ML, et al. The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency. Epilepsia. 2023;64(6):1516-1526. doi:10.1111/epi.17592
Tokatly Latzer I, Hanson E, Bertoldi M, et al. Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency. Dev Med Child Neurol. 2023;65(12):1596-1606. doi:10.1111/dmcn.15659
Gupta M, Jansen EEW, Senephansiri H, et al. Liver-directed adenoviral gene transfer in murine succinate semialdehyde dehydrogenase deficiency. Mol Ther. 2004;9(4):527-539. doi:10.1016/j.ymthe.2004.01.013
Vogel KR, Ainslie GR, Walters DC, et al. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. J Inherit Metab Dis. 2018;41(4):699-708. doi:10.1007/s10545-018-0153-8
Lee HHC, McGinty GE, Pearl PL, Rotenberg A. Understanding the molecular mechanisms of succinic semialdehyde dehydrogenase deficiency (SSADHD): towards the development of SSADH-targeted medicine. Int J Mol Sci. 2022;23(5):2606. doi:10.3390/ijms23052606
Lee HHC, Pearl PL, Rotenberg A. Enzyme replacement therapy for succinic semialdehyde dehydrogenase deficiency: relevance in γ-aminobutyric acid plasticity. J Child Neurol. 2021;36(13-14):1200-1209. doi:10.1177/0883073821993000
Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem. 2005;38(12):1051-1058. doi:10.1016/j.clinbiochem.2005.09.012
Opladen T, Cortès-Saladelafont E, Mastrangelo M, et al. The international working group on neurotransmitter related disorders (iNTD): a worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Rep. 2016;9:61-66. doi:10.1016/j.ymgmr.2016.09.006
Spong CY. Defining “term” pregnancy: recommendations from the defining “term” pregnancy workgroup. JAMA. 2013;309(23):2445-2446. doi:10.1001/jama.2013.6235
Leviton A, Holmes LB, Allred EN, Vargas J. Methodologic issues in epidemiologic studies of congenital microcephaly. Early Hum Dev. 2002;69(1-2):91-105. doi:10.1016/s0378-3782(02)00065-8
Sharma D, Shastri S, Sharma P. Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr. 2016;10:67-83. doi:10.4137/CMPed.S40070
Keller M, Brennenstuhl H, Kuseyri Hübschmann O, et al. Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: data from the iNTD registry. J Inherit Metab Dis. 2021;44(6):1489-1502. doi:10.1002/jimd.12416
Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 2013;13:59. doi:10.1186/1471-2431-13-59
Hahsler M, Grün B, Hornik K. Arules - a computational environment for mining association rules and frequent item sets. J Stat Softw. 2005;14(15):1-25. doi:10.18637/jss.v014.i15
Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;76:7.20.1-7.20.41. doi:10.1002/0471142905.hg0720s76
Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99(4):877-885. doi:10.1016/j.ajhg.2016.08.016
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310-315. doi:10.1038/ng.2892
Kim YG, Lee S, Kwon OS, et al. Redox-switch modulation of human SSADH by dynamic catalytic loop. EMBO J. 2009;28(7):959-968. doi:10.1038/emboj.2009.40
Abraham MJ, Murtola T, Schulz R, et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1-2:19-25. doi:10.1016/j.softx.2015.06.001
PyMOL | pymol.org. Accessed December 11, 2020. https://pymol.org/2/
Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812-3814. doi:10.1093/nar/gkg509
Akaboshi S, Hogema BM, Novelletto A, et al. Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Hum Mutat. 2003;22(6):442-450. doi:10.1002/humu.10288
Hu C, Li X, Zhao L, et al. Clinical and molecular characterization of pediatric mitochondrial disorders in south of China. Eur J Med Genet. 2020;63(8):103898. doi:10.1016/j.ejmg.2020.103898
Akiyama T, Osaka H, Shimbo H, et al. SSADH deficiency possibly associated with enzyme activity-reducing SNPs. Brain and Development. 2016;38(9):871-874. doi:10.1016/j.braindev.2016.03.008
Jung R, Rauch A, Salomons GS, et al. Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity. Mol Genet Metab. 2006;88(3):256-260. doi:10.1016/j.ymgme.2006.02.003
Attri SV, Singhi P, Wiwattanadittakul N, et al. Incidence and geographic distribution of succinic semialdehyde dehydrogenase (SSADH) deficiency. JIMD Rep. 2017;34:111-115. doi:10.1007/8904_2016_14
Brennenstuhl H, Didiasova M, Assmann B, et al. Succinic semialdehyde dehydrogenase deficiency: in vitro and in silico characterization of a novel pathogenic missense variant and analysis of the mutational spectrum of ALDH5A1. Int J Mol Sci. 2020;21(22):8578. doi:10.3390/ijms21228578
Stessman HA, Xiong B, Coe BP, et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49(4):515-526. doi:10.1038/ng.3792
Didiasova M, Banning A, Brennenstuhl H, et al. Succinic semialdehyde dehydrogenase deficiency: an update. Cells. 2020;9(2):477. doi:10.3390/cells9020477
Martin K, McConnell A, Elsea SH. Assessing prevalence and carrier frequency of succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2021;36(13-14):1218-1222. doi:10.1177/08830738211018902
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7
Tokatly Latzer I, Roullet JB, Gibson KM, Pearl PL. Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2023;46(5):992-1003. doi:10.1002/jimd.12635
Lee ACC, Katz J, Blencowe H, et al. National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010. Lancet Glob Health. 2013;1(1):e26-e36. doi:10.1016/S2214-109X(13)70006-8
Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19(5):253-268. doi:10.1038/nrg.2017.116
DiBacco ML, Roullet JB, Kapur K, et al. Age-related phenotype and biomarker changes in SSADH deficiency. Ann Clin Transl Neurol. 2019;6(1):114-120. doi:10.1002/acn3.696
Lapalme-Remis S, Lewis EC, De Meulemeester C, et al. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology. 2015;85(10):861-865. doi:10.1212/WNL.0000000000001906
Pearl PL, Shukla L, Theodore WH, Jakobs C, Michael GK. Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. Brain and Development. 2011;33(9):796-805. doi:10.1016/j.braindev.2011.04.013
Colijn MA. The characterization of psychotic symptoms in succinic semialdehyde dehydrogenase deficiency: a review. Psychiatr Genet. 2020;30(6):153-161. doi:10.1097/YPG.0000000000000264
Afacan O, Yang E, Lin AP, et al. Magnetic resonance imaging (MRI) and spectroscopy in succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2021;36:1162-1168. doi:10.1177/0883073821991295
Yamakawa Y, Nakazawa T, Ishida A, et al. A boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency. Brain and Development. 2012;34(2):107-112. doi:10.1016/j.braindev.2011.05.003
Leuzzi V, Di Sabato ML, Deodato F, et al. Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency. Neurology. 2007;68(16):1320-1321. doi:10.1212/01.wnl.0000259537.54082.6d
Pearl PL, Wiwattanadittakul N, Roullet JB, Gibson KM. Succinic semialdehyde dehydrogenase deficiency. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews((R)). University of Washington; 1993.
Wang KY, Barker PB, Lin DD. A case of acute onset succinic semialdehyde dehydrogenase deficiency: neuroimaging findings and literature review. Childs Nerv Syst. 2016;32(7):1305-1309. doi:10.1007/s00381-015-2942-9
Zeiger WA, Sun LR, Bosemani T, Pearl PL, Stafstrom CE. Acute infantile encephalopathy as presentation of succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol. 2016;58:113-115. doi:10.1016/j.pediatrneurol.2015.10.009
Maitre M. The gamma-hydroxybutyrate signalling system in brain: organization and functional implications. Prog Neurobiol. 1997;51(3):337-361. doi:10.1016/s0301-0082(96)00064-0
Colombo G, Agabio R, Carai MA, et al. Characterization of the discriminative stimulus effects of gamma-hydroxybutyric acid as a means for unraveling the neurochemical basis of gamma-hydroxybutyric acid actions and its similarities to those of ethanol. Alcohol. 2000;20(3):237-245. doi:10.1016/s0741-8329(99)00087-7
Nava F, Carta G, Bortolato M, Gessa GL. Gamma-Hydroxybutyric acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABA(B) receptors. Eur J Pharmacol. 2001;430(2-3):261-263. doi:10.1016/s0014-2999(01)01163-3
Cutando L, Puighermanal E, Castell L, et al. Cerebellar dopamine D2 receptors regulate social behaviors. Nat Neurosci. 2022;25(7):900-911. doi:10.1038/s41593-022-01092-8
Kim KJ, Pearl PL, Jensen K, et al. Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance. Antioxid Redox Signal. 2011;15(3):691-718. doi:10.1089/ars.2010.3470
Pearl PL, DiBacco ML, Papadelis C, et al. Succinic semialdehyde dehydrogenase deficiency: review of the natural history study. J Child Neurol. 2021;36(13-14):1153-1161. doi:10.1177/0883073820981262