Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients

Orphanet Journal of Rare Diseases

Holger Prokisch⁸  Robert W Taylor⁵  Patrick F Chinnery¹  Eliska Holzerova⁸  Nasrollah Saleh-Gohari^1,12  Mahmood A Saeed^1,10  Nathan Pulido^1,11  Andrea Dworschak⁹  Thomas Klopstock³  Anne-Sophie Lebre⁷  Agnès Rötig⁷  Johannes A Mayr^1,13  René G Feichtinger^1,13  Uwe Ahting⁸  Rani A Bashir^1,10  Hamidreza Haghighi-Kakhki²  Hassan Mottaghi⁶  Mehnaz Atiq^1,14  Tobias B Haack⁸  Alireza Haghighi⁴ 

[1] Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK;Faculty of Medicine, Mashhad Azad University, Mashhad, Iran;Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität München, Munich, Germany;Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women¿s Hospital, Boston, MA, USA;Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK;Department of Pediatrics, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran;Inserm UMR 1163, Imagine Institute, Paris Descartes University, Paris, France;Institute of Human Genetics, Technische Universität München, Trogerstrasse 22, München 81675, Germany;Department of Pediatric Cardiology, University Hospital, Aachen University of Technology, Aachen, Germany;Department of Paediatrics and Neonatology, Ahmadi Hospital, Kuwait Oil Company, Al Ahmadi, Kuwait;Pediatric Department, Hospital Dr. Gustavo Fricke, Viña del Mar, Chile;Department of Genetics, Medical School, Kerman University of Medical Sciences, Kerman, Iran;Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria;Department of Pediatrics, Aga Khan University, Karachi, Pakistan

关键词: Genotype-Phenotype Correlation;    Mutation;    Acylglycerol Kinase;    AGK;    Sengers syndrome;   

Others  :  1149999
DOI  :  10.1186/s13023-014-0119-3

 received in 2014-04-09, accepted in 2014-07-17,  发布年份 2014

【 摘 要 】

Background

Sengers syndrome is an autosomal recessive condition characterized by congenital cataract, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families.

Methods

We investigated the clinical and molecular features of Sengers syndrome in seven new families; five families with the severe and two with the milder form.

Results

Sequence analysis of AGK revealed compound heterozygous or homozygous predicted loss-of-function mutations in all affected individuals. A total of eight different disease alleles were identified, of which six were novel, homozygous c.523_524delAT (p.Ile175Tyrfs*2), c.424-1G?>?A (splice site), c.409C?>?T (p.Arg137*) and c.877?+?3G?>?T (splice site), and compound heterozygous c.871C?>?T (p.Gln291*) and c.1035dup (p.Ile346Tyrfs*39). All patients displayed perinatal or early-onset cardiomyopathy and cataract, clinical features pathognomonic for Sengers syndrome. Other common findings included blood lactic acidosis and tachydyspnoea while nystagmus, eosinophilia and cervical meningocele were documented in only either one or two cases. Deficiency of the adenine nucleotide translocator was found in heart and skeletal muscle biopsies from two patients associated with respiratory chain complex I deficiency. In contrast to previous findings, mitochondrial DNA content was normal in both tissues.

Conclusion

We compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism.

【 授权许可】

   
2014 Haghighi et al.; licensee Biomedcentral Ltd.

【 图 表 】

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【 参考文献 】

• [1]Sengers RC, Trijbels JM, Willems JL, Daniels O, Stadhouders AM: Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. J Pediatr 1975, 86:873-880.
• [2]van Ekeren GJ, Stadhouders AM, Smeitink JA, Sengers RC: A retrospective study of patients with the hereditary syndrome of congenital cataract, mitochondrial myopathy of heart and skeletal muscle and lactic acidosis. Eur J Pediatr 1993, 152:255-259.
• [3]Smeitink JA, Sengers RC, Trijbels JM, Ruitenbeek W, Daniels O, Stadhouders AM, Kock-Jansen MJ: Fatal neonatal cardiomyopathy associated with cataract and mitochondrial myopathy. Eur J Pediatr 1989, 148:656-659.
• [4]Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H: Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet 2012, 90:314-320.
• [5]Perry MS, Sladky JT: Neuroradiologic findings in Sengers syndrome. Pediatr Neurol 2008, 39:113-115.
• [6]Siriwardena K, Mackay N, Levandovskiy V, Blaser S, Raiman J, Kantor PF, Ackerley C, Robinson BH, Schulze A, Cameron JM: Mitochondrial citrate synthase crystals: novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations. Mol Genet Metab 2013, 108:40-50.
• [7]Bektas M, Payne SG, Liu H, Goparaju S, Milstien S, Spiegel S: A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells. J Cell Biol 2005, 169:801-811.
• [8]Kalari S, Zhao Y, Spannhake EW, Berdyshev EV, Natarajan V: Role of acylglycerol kinase in LPA-induced IL-8 secretion and transactivation of epidermal growth factor-receptor in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2009, 296:L328-336.
• [9]Waggoner DW, Johnson LB, Mann PC, Morris V, Guastella J, Bajjalieh SM: MuLK, a eukaryotic multi-substrate lipid kinase. J Biol Chem 2004, 279:38228-38235.
• [10]Claypool SM, Oktay Y, Boontheung P, Loo JA, Koehler CM: Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane. J Cell Biol 2008, 182:937-950.
• [11]Jiang F, Ryan MT, Schlame M, Zhao M, Gu Z, Klingenberg M, Pfanner N, Greenberg ML: Absence of cardiolipin in the crd1 null mutant results in decreased mitochondrial membrane potential and reduced mitochondrial function. J Biol Chem 2000, 275:22387-22394.
• [12]McKenzie M, Lazarou M, Thorburn DR, Ryan MT: Mitochondrial respiratory chain supercomplexes are destabilized in Barth Syndrome patients. J Mol Biol 2006, 361:462-469.
• [13]Jordens EZ, Palmieri L, Huizing M, van den Heuvel LP, Sengers RC, Dorner A, Ruitenbeek W, Trijbels FJ, Valsson J, Sigfusson G, Palmieri F, Smeitink JA: Adenine nucleotide translocator 1 deficiency associated with Sengers syndrome. Ann Neurol 2002, 52:95-99.
• [14]Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H: Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet 2012, 49:277-283.
• [15]Acham-Roschitz B, Plecko B, Lindbichler F, Bittner R, Mache CJ, Sperl W, Mayr JA: A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. Mol Genet Metab 2009, 98:300-304.
• [16]Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, Dimauro S, Thorburn DR, Mootha VK: Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Science translational medicine 2012, 4:118ra110.
• [17]Kozak M: Context effects and inefficient initiation at non-AUG codons in eucaryotic cell-free translation systems. Mol Cell Biol 1989, 9:5073-5080.
• [18]Aldahmesh MA, Khan AO, Mohamed JY, Alghamdi MH, Alkuraya FS: Identification of a truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomal recessive cataract locus. Hum Mutat 2012, 33:960-962.
• [19]Borchman D, Yappert MC: Lipids and the ocular lens. J Lipid Res 2010, 51:2473-2488.
• [20]Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, Martin RP, Tsai-Goodman B, Garratt V, Ashworth M, Bowen VM, McCurdy KR, Damin MK, Spencer CT, Toth MJ, Kelley RI, Steward CG: Barth syndrome. Orphanet J Rare Dis 2013, 8:23. BioMed Central Full Text
• [21]Karkucinska-Wieckowska A, Trubicka J, Werner B, Kokoszynska K, Pajdowska M, Pronicki M, Czarnowska E, Lebiedzinska M, Sykut-Cegielska J, Ziolkowska L, Jaron W, Dobrzanska A, Ciara E, Wieckowski MR, Pronicka E: Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome. J Inherit Metab Dis 2013, 36:929-937.