SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Ayman W El-Hattab, Fernando Scaglia, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya, Ayman W El-Hattab, Fernando Scaglia, Margaret P Adam, Jerry Feldman, Ghayda M Mirzaa, Roberta A Pagon, Stephanie E Wallace, Lora JH Bean, Karen W Gripp, Anne Amemiya

Excerpt

Clinical characteristics: SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood.

Diagnosis/testing: The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in SUCLA2 identified by molecular genetic testing.

Management: Treatment of manifestations: Appropriate early developmental support; physical therapy to maintain muscle function and prevent joint contractures; antiseizure medication for epileptic seizures; hearing aids / cochlear implantation for sensorineural hearing loss; gastrostomy tube placement as needed to assure adequate caloric intake; blepharoplasty for significant ptosis; low vision services as needed; chest physiotherapy, aggressive antibiotic treatment of chest infections, and consideration of respiratory aids; bracing to treat scoliosis or kyphosis.

Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures.

Genetic counseling: SUCLA2-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SUCLA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for SUCLA2-related mtDNA depletion syndrome are possible.

Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

References

    1. Alkhater RA, Ahonen S, Minassian BA. SUCLA2 Arg407Trp mutation can cause a nonprogressive movement disorder - deafness syndrome. Ann Clin Transl Neurol. 2021;8:252-8.
    1. Carrozzo R, Dionisi-Vici C, Steuerwald U, Lucioli S, Deodato F, Di Giandomenico S, Bertini E, Franke B, Kluijtmans LA, Meschini MC, Rizzo C, Piemonte F, Rodenburg R, Santer R, Santorelli FM, van Rooij A, Vermunt-de Koning D, Morava E, Wevers RA. SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain. 2007;130:862-74.
    1. Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E. Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients. J Inherit Metab Dis. 2016;39:243-52.
    1. El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta Mol Basis Dis. 2017;1863:1539-55.
    1. El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 2013;10:186-98.
    1. Fang F, Liu Z, Fang H, Wu J, Shen D, Sun S, Ding C, Han T, Wu Y, Lv J, Yang L, Li S, Lv J, Shen Y. The clinical and genetic characteristics in children with mitochondrial disease in China. Sci China Life Sci. 2017;60:746-57.
    1. Garone C, Gurgel-Giannetti J, Sanna-Cherchi S, Krishna S, Naini A, Quinzii CM, Hirano M. A novel SUCLA2 mutation presenting as a complex childhood movement disorder. J Child Neurol. 2017;32:246-50.
    1. Hiramatsu Y, Okamoto Y, Yoshimura A, Yuan JH, Ando M, Higuchi Y, Hashiguchi A, Matsuura E, Nozaki F, Kumada T, Murayama K, Suzuki M, Yamamoto Y, Matsui N, Miyazaki Y, Yamaguchi M, Suzuki Y, Mitsui J, Ishiura H, Tanaka M, Morishita S, Nishino I, Tsuji S, Takashima H. Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes. J Neurol. 2022;269:4129-40.
    1. Huang X, Bedoyan JK, Demirbas D, Harris DJ, Miron A, Edelheit S, Grahame G, DeBrosse SD, Wong LJ, Hoppel CL, Kerr DS, Anselm I, Berry GT. Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab. 2017;120:213-22.
    1. Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22.
    1. Kang L, Liu Y, Shen M, Liu Y, He R, Song J, Jin Y, Li M, Zhang Y, Dong H, Liu X, Yan H, Qin J, Zheng H, Chen Y, Li D, Wei H, Zhang H, Sun L, Zhu Z, Liang D, Yang Y. A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia. J Inherit Metab Dis. 2020;43:409-23.
    1. Linney M, Hain RDW, Wilkinson D, Fortune PM, Barclay S, Larcher V, Fitzgerald J, Arkell E. Achieving consensus advice for paediatricians and other health professionals: on prevention, recognition and management of conflict in paediatric practice. Arch Dis Child. 2019;104:413-6.
    1. Maas RR, Marina AD, de Brouwer AP, Wevers RA, Rodenburg RJ, Wortmann SB. SUCLA2 deficiency: a deafness-dystonia syndrome with distinctive metabolic findings (report of a new patient and review of the literature). JIMD Rep. 2016;27:27-32.
    1. Matilainen S, Isohanni P, Euro L, Lönnqvist T, Pihko H, Kivelä T, Knuutila S, Suomalainen A. Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion. Eur J Hum Genet. 2015;23:325-30.
    1. Morava E, Steuerwald U, Carrozzo R, Kluijtmans LA, Joensen F, Santer R, Dionisi-Vici C, Wevers RA. Dystonia and deafness due to SUCLA2 defect; Clinical course and biochemical markers in 16 children. Mitochondrion. 2009;9:438-42.
    1. Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain. 2007;130:853-61
    1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24.
    1. Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren