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

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.

Figure 1

Electrocardiogram, echocardiogram and chest X-ray of a Sengers patient. a. ECG of Case-1 showing left ventricular hypertrophy and T wave inversion in limb and chest leads. b. 2D echocardiogram of in parasternal long axis projection showing severe left ventricular hypertrophy in (Case-1). c. Chest X-ray revealing significant cardiomegaly in (Case-3).

Figure 2

Echocardiography of a Sengers patient. a. M-Mode of LV in short axis showing dilated LV for age of (Case-3) at 6 days (LVEDD 2.04). b. moderate mitral valve regurgitation with left atrial contraction in systole. c. moderate tricuspid regurgitation with right atrial contraction envelope in systole.

Figure 3

Gene structure of AGK and localization of identified mutations. Boldface type indicates newly reported mutations.

Figure 4

Western blot analysis of heart and muscle samples. The blots were decorated with antibodies (all from Mitosciences/Abcam (Eugene, OR, USA)) against adenine nucleotide translocator (ANT), subunit NDUFS4 of complex I, and subunit SDHA of complex II. Intensities were quantified by the Image J software (National Institutes of Health, Bethesda, MD) and relative intensities were calculated for the patient sample in each tissue in relation to the two controls. P1stands for PC-8 and P2 stands for Case 5 in the Table 1.