Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene

Abstract

Sengers syndrome (OMIM #212350) is a rare autosomal recessive disorder due to mutations in acylglycerol kinase (AGK) gene. We report two cases that were diagnosed clinically and confirmed genetically. Both infants had typical clinical features characterized by hypertrophic cardiomyopathy, bilateral cataracts, myopathy, and lactic acidosis, and heart failure was the most severe manifestation. Genetic testing of a boy revealed a homozygous pathogenic variant for Sengers syndrome in AGK (c.1131+2T>C) which was classified as likely pathogenic according to the ACMG guideline; besides, his skeletal muscle biopsy and transmission electron microscope presented obvious abnormity. One girl had compound heterozygous (c.409C>T and c.390G>A) variants of AGK gene that was identified in the proband and further Sanger sequencing indicated that the parents carried a single heterozygous mutation each. After the administration of “cocktail” therapy including coenzyme Q10, carnitine, and vitamin B complex, as well as ACEI, heart failure and myopathy of the boy were significantly improved and the condition was stable after 1-year follow-up, while the cardiomyopathy of the girl is not progressive but the plasma lactate acid increased significantly. We present the first report of two infants with Sengers syndrome diagnosed via exome sequencing in China.

Long term follow-up in two siblings with Sengers syndrome: Case report

“…A clear-cut genotype-phenotype correlation for SS has not been clearly defined yet, probably due to the few cases so far reported. However, a more severe phenotypes have been described in homozygous or compound heterozygous carriers of nonsense variants [ 8 ], whether all patients who survived the first decade, retained at least one splice site variant [ 7 , 9 ]. Our patients harbored a homozygous splicing variant on the AGK gene, already described in compound heterozygosity with the nonsense c.1213 C > T/ p.Gln405* (see case 62,218 in [ 2 ]).…”

“…Clinical course ranges from a severe fatal form, leading to death within the third year of age in around 86% of cases [ 8 ], to a more benign form with survival into adulthood [ 7 ], to an isolated form of congenital cataract [ 9 ]. To date, only 2/44 genetically reported patients [ 2 – 23 ] have survived the second decade at their latest examination [ 10 , 11 ], and no natural history data are available for the disease.…”

Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease

“…In addition to the increased levels of blood lactic acid and pyruvate, liver injury and abnormal myocardial enzymes are also common in laboratory examination ( 90 ). Two out of twelve MDS children were reported to have elevated myocardial enzymes ( 91 ).…”

“…The main clinical features of Sengers syndrome are hypertrophic cardiomyopathy, bi-sided cataracts, myopathy, and lactic acidosis. Hypertrophic cardiomyopathy can eventually contribute to the development of heart failure ( 91 ).…”