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Sengers Syndrome: Six Novel AGK Mutations in Seven New Families and Review of the Phenotypic and Mutational Spectrum of 29 Patients

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Sengers Syndrome: Six Novel AGK Mutations in Seven New Families and Review of the Phenotypic and Mutational Spectrum of 29 Patients Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Haghighi, A., T. B. Haack, M. Atiq, H. Mottaghi, H. Haghighi-Kakhki, R. A. Bashir, U. Ahting, et al. 2014. “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 9 (1): 119. doi:10.1186/s13023-014-0119-3. http:// dx.doi.org/10.1186/s13023-014-0119-3. Published Version doi:10.1186/s13023-014-0119-3 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987338 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Haghighi et al. Orphanet Journal of Rare Diseases 2014, 9:119 http://www.ojrd.com/content/9/1/119 RESEARCH Open Access Sengers syndrome: six novel AGK mutations in seven new families and review of the phenotypic and mutational spectrum of 29 patients Alireza Haghighi1,2*, Tobias B Haack3,4, Mehnaz Atiq5, Hassan Mottaghi6, Hamidreza Haghighi-Kakhki7, Rani A Bashir8, Uwe Ahting3,4, René G Feichtinger9, Johannes A Mayr9, Agnès Rötig11, Anne-Sophie Lebre10, Thomas Klopstock12, Andrea Dworschak13, Nathan Pulido14, Mahmood A Saeed8, Nasrollah Saleh-Gohari15, Eliska Holzerova3,4, Patrick F Chinnery16, Robert W Taylor17 and Holger Prokisch3,4* Abstract 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. Keywords: Sengers syndrome, AGK, Acylglycerol Kinase, Mutation, Genotype-Phenotype Correlation Introduction Two forms of this syndrome have been described, a se- Sengers syndrome is a rare autosomal recessive con- vere neonatal form that causes infantile death and a dition. It was first described by Sengers and colleagues more benign form with a longer survival into the fourth in 1975 with the clinical features of congenital cataract, decade [2,3]. The longer surviving patients had normal hypertrophic cardiomyopathy, mitochondrial myopathy developmental milestones. The cause of mortality in and lactic acidosis after exercise [1]. Sengers syndrome is heart failure as the result of hyper- trophic cardiomyopathy. Van Ekeren et al. investigated 16 clinically-diagnosed patients with Sengers syndrome * Correspondence: [email protected]; prokisch@helmholtz- in order to describe the course of these two forms [2,3]. muenchen.de 1Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, Although these authors did not observe any histopatho- Boston, MA 02115, USA logic distinction in muscle or heart samples between the 3Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, two forms, Perry described 3 cases of neonatal Sengers München, Germany Full list of author information is available at the end of the article with significant central nervous system involvement [4]. © 2014 Haghighi et al.; licensee Biomedcentral Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haghighi et al. Orphanet Journal of Rare Diseases 2014, 9:119 Page 2 of 12 http://www.ojrd.com/content/9/1/119 The cranial ultrasonography findings in the three sib- All members of families underwent a comprehensive lings included cerebellar hypoplasia and increased echo- clinical investigation including cardiac, metabolic, neu- genicity of the basal ganglia suggestive of calcification. rological, endocrinological, ophthalmological and neuro- Magnetic resonance imaging demonstrated hypoplasia muscular assessments. of both the brainstem and inferior cerebellar vermis, impaired myelination of the cerebral hemispheres and Methods brainstem, and cortical infarction [5]. These authors sug- Peripheral blood samples were collected from all family gested that the neonatal form of Sengers syndrome members. should be described as a mitochondrial encephalomyo- The causal mutation in Case 4 (Table 1) was identified pathy, because of involvement of the central nervous by exome sequencing as described previously [14] and system. However, the genetic cause of the disease in this subsequently confirmed by Sanger sequencing. In the family has not been reported. Siriwardena et al. investi- other individuals, testing for DNA sequence variations in gated two siblings with Sengers Syndrome and AGK mu- AGK was done by Sanger sequencing. Genomic DNA was tations using magnetic resonance imaging and showed amplified using intronic primers and the resulting PCR cortical infarction, however in a vascular pattern unlike products were sequenced in both directions. Primer se- metabolic strokes that do not respect any arterial distri- quences and PCR conditions are available upon request. bution [6]. The mtDNA content from 3 patient samples was mea- Recently, Mayr et al. investigated Caucasian Sengers sured in muscle or heart from three patients with samples patients from Germany, Italy, The Netherlands and available for testing according to published protocol [15]. Switzerland and, using whole exome sequencing, identi- Western blot analysis was performed from very small fied AGK as the disease-causing gene in Sengers syndrome amount of tissue samples from 2 patients, therefore only [4]. AGK encodes a mitochondrial transmembrane en- ANT and respiratory chain complexes I and II were zyme, acylglycerol kinase, a multisubstrate lipid with a determined as described in [4]. Biochemical analysis of likely role in cardiolipin biosynthesis. Acylglycerol kinase OXPHOS activity was done in 3 different research centers, catalyzes the formation of phosphatidic acid and lysopho- where the muscle biopsies were available (case-4, 5, 7 [4]). sphatidic acid [7] that can participate in phospholipid syn- thesis or act as signaling molecules regulating a number of Results cell processes [7–9]. Cardiolipin plays an important role Clinical investigation in structural maintenance of mitochondria and regulating Altogether, we report 8 new cases of Sengers syndrome the permeability of the inner membrane. Abnormal mito- with predicted loss-of-function mutations in all affected chondrial morphology has been seen in conditions with individuals with no hot-spot region in AGK gene. Six pa- cardiolipin impairment, like Sengers and Barth syndromes tients displayed onset of cataract at birth, one in the first [10–12]. Secondary to AGK mutations, a deficiency of the month of life. Cardiomyopathy occurred at birth in 5 adenine nucleotide translocator and impairment of ATP out of 8 cases and in two cases within the first 5 months synthesis has been reported and seems to play a central of life. For one case, the onset of cardiomyopathy role in the pathomechanism of Sengers syndrome [4,13]. remained unclear. Five patients with severe form or We present the clinical features and molecular basis of Sengers syndrome died in the first year of life, last pa- Sengers syndrome in seven new families of different eth- tient with severe form is alive with the age of 3 moths. nic origin, documenting for the first time a molecular Patients with milder form of disease survived the first study of Sengers syndrome patients of non-Caucasian decade of their life. Our data underline tachydyspnea descent. and isolated Complex I deficiency as additional phe- notypes of Sengers syndrome. Consistently to previous findings, blood
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