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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.

ABSTRACT: 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.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.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.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.

SUBMITTER: Haghighi A

PROVIDER: S-EPMC4167147 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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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.

Haghighi Alireza A Haack Tobias B TB Atiq Mehnaz M Mottaghi Hassan H Haghighi-Kakhki Hamidreza H Bashir Rani A RA Ahting Uwe U Feichtinger René G RG Mayr Johannes A JA Rötig Agnès A Lebre Anne-Sophie AS Klopstock Thomas T Dworschak Andrea A Pulido Nathan N Saeed Mahmood A MA Saleh-Gohari Nasrollah N Holzerova Eliska E Chinnery Patrick F PF Taylor Robert W RW Prokisch Holger H

Orphanet journal of rare diseases 20140820

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Sequence ...[more]

PMID: 25208612

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Project description:BackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

Dataset Information

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

Publications

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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