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

Alireza Haghighi,Mahmood A Saeed,Hassan Mottaghi,Nathan Pulido,Agnès Rötig,Thomas Klopstock,Andrea Dworschak,Hamidreza Haghighi-Kakhki,Mehnaz Atiq,Uwe Ahting,Holger Prokisch,Patrick F Chinnery ,Nasrollah Saleh‐Gohari ,Johannes A Mayr ,René G Feichtinger ,Anne-Sophie Lèbre ,Tobias B Haack ,Rani A Bashir ,Eliška Holzerová ,Robert W Taylor

doi:10.1186/s13023-014-0119-3

Abstract

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

Highlights

Sengers syndrome is a rare autosomal recessive condition. It was first described by Sengers and colleagues in 1975 with the clinical features of congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy and lactic acidosis after exercise [1]
Clinical investigation Altogether, we report 8 new cases of Sengers syndrome with predicted loss-of-function mutations in all affected individuals with no hot-spot region in acylglycerol kinase (AGK) gene
Cardiomyopathy occurred at birth in 5 out of 8 cases and in two cases within the first 5 months of life

Summary

Introduction

Sengers syndrome is a rare autosomal recessive condition It was first described by Sengers and colleagues in 1975 with the clinical features of congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy and lactic acidosis after exercise [1]. Two forms of this syndrome have been described, a severe neonatal form that causes infantile death and a more benign form with a longer survival into the fourth decade [2,3]. Mutations in the acylglycerol kinase (AGK) gene have been recently described as the cause of Sengers syndrome in nine families

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Conclusion