Genetics Genomics And Molecular Science

Clinical Description

Sengers syndrome (SS) was first described by Sengers et al. (1975) and is also known as cardiomyopathic mitochondrial DNA depletion syndrome-10 (MTDPS10) (Calvo et al., 2012). SS is a very rare genetic disorder; approximately 59 cases have been reported to date throughout the world. SS is inherited in an autosomal-recessive manner and characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis but normal mental development. SS might present in two forms, an infant lethal form or a chronic form, until fourth decade of life. In all the cases, the cause of mortality is heart failure due to hypertrophic cardiomyopathy. Abnormal structure of mitochondria and excessive storage of lipid and glycogen in both skeletal and heart muscle have been shown to be the main reason of hypertrophic cardiomyopathy. Interestingly, it’s still unclear whether mitochondria DNA depletion in muscle or heart is common feature of Sengers syndrome, as there are studies with contradictory findings.

Etiology

SS is caused in the majority of affected patients by homozygous or compound heterozygous mutation in the acylglycerol kinase (AGK) gene on chromosome 7q34. The mutations include: nonsense, frame-shift, start codon or splice site mutations, with all of them causing loss of function of the final protein. The AGK gene encodes the mitochondrial acylglycerol kinase, an enzyme which plays a key role in the recruitment of adenine nucleotide translocator (ANT), an essential component of the oxidative phosphorylation in mitochondria. AGK plays also a key role in cardiolipin biosynthesis, which is a fundamental component for the structural mitochondrial maintenance.

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However, mutations in the solute carrier family 25-member 4 (SLC25A4) gene have been reported to be a secondary disease-causing mutation. SLC25A4 gene is located on chromosome 4q35.1 and encodes the heart and muscle specific isoform 1 of the mitochondrial ANT. In particularly, the product of this gene functions as a gated pore mediating the transportation of ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm.

AGK function

AGK is located in mitochondria and involved in the conversion of monoacylglycerol (MAG) and diacylglycerol (DAG) to lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively through phosphorylation. The formation of LPA and PA molecules can either participate in the synthesis of phospholipids such as cardiolipin (CL) or act as signaling molecules regulating many cell processes. There are two hypothetical pathways of how the defective AGK is associated with the Sengers’ symptoms such as cataract, respiratory chain dysfunction and mitochondrial deficiency, as shown in figure 1.

Lipid peroxidation and increased free radical production, have been hypothesized to be the cause of congenital cataract and cardiovascular disfunction, as this type of tissue contains high numbers of mitochondria and respiratory chain components where superoxide radicals are produced. The production of mitochondrial antioxidant enzymes, and particularly manganese superoxide dismutase (SOD2), is induced in response to increased superoxide radical production. SOD2 converts superoxide radicals to H2O2 which is more stable and diffusible but still toxic for the cell. H2O2 is further converted to H2O and O2 by other mitochondria originated enzymes. If H2O2 molecules not removed promptly, it can lead to the production of oxidize [Fe–S] free iron cations, causing damage to the respiratory chain (Figure 1).

The serine/threonine kinase protein kinase D1 (PKD1) is a reactive oxygen species (ROS) sensor which is present in the downstream signaling pathways and induces cellular detoxification and cell survival. PKD1 needs to be transferred inside the mitochondria and bind to DAG in order to regulate those actions. The transportation of PKD1 is activated in response to H2O2. In patients suffering from SS, the AGK functional levels are reduced in their mitochondria which then leads to excessive amounts of DAG present in the cell. The later affects the mitochondria's response to superoxide free radicals, resulting in oxidative damage to mitochondrial DNA, lipids and proteins, and stimulation of cellular detoxification pathways.

The formation of LPA and PA molecules by AGK, can either participate in phospholipid synthesis of phospholipids such as cardiolipin (CL) or act as signaling molecules regulating many cell processes. Cardiolipin plays an important role in structural maintenance of mitochondria and regulating the permeability of the inner membrane. Loss of those two lipids, will cause changes in the lipid composition of the inner mitochondrial membrane. The later, results in cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue. PA and CL, are also both found in crystals of ANT, the most abundant mitochondrial protein, which is severely decreased in the muscle tissue of individuals with Sengers syndrome.

Diagnostic methods and available tests

Serum and urine analysis for lactic acid at rest and during exercise, radiology and echocardiogram are mainly used for cardiomyopathy investigation.

Muscle biopsy from cardiac and skeletal muscle can provide evidences for storage of lipid and glycogen. Additional testing methods include tests for mitochondrial abnormalities, ANT deficiency and mild decrease of respiratory chain complexes I and IV.

Genetic testing for screening of the disease-causing, AGK and SLC25A4 mutations can be performed, in affected individuals and their parents.

Preimplantation genetic testing (PGT-M), is an alternative procedure for conception of non-diseased children and can be offered in couples with already affected children or parents with affected relatives, if only known specific mutations have been found. The process starts with in vitro fertilization (IVF) treatment and then embryonic cells are removed for genetic diagnosis for the disease-causing, AGK and SLC25A4 mutations. Only the disease-free embryos are transferred back to the woman.

References

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2. Atiq, M., Iqbal, S. and Ibrahim, S. (2004). Sengers disease: A rare association of hypertrophic cardiomyopathy and congenital cataracts. The Indian Journal of Pediatrics, 71(5), pp.437-440.
3. Calvo, S., Compton, A., Hershman, S., Lim, S., Lieber, D., Tucker, E., Laskowski, A., Garone, C., Liu, S., Jaffe, D., Christodoulou, J., Fletcher, J., Bruno, D., Goldblatt, J., DiMauro, S., Thorburn, D. and Mootha, V. (2012). Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing. Science Translational Medicine, 4(118), pp.118ra10-118ra10.
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6. Mayr, J., Haack, T., Graf, E., Zimmermann, F., Wieland, T., Haberberger, B., Superti-Furga, A., Kirschner, J., Steinmann, B., Baumgartner, M., Moroni, I., Lamantea, E., Zeviani, M., Rodenburg, R., Smeitink, J., Strom, T., Meitinger, T., Sperl, W. and Prokisch, H. (2012). Lack of the Mitochondrial Protein Acylglycerol Kinase Causes Sengers Syndrome. The American Journal of Human Genetics, 90(2), pp.314-320.
7. Omim.org. (2018). OMIM Entry - # 212350 - SENGERS SYNDROME. [online] Available at: https://www.omim.org/entry/212350 [Accessed 12 Dec. 2018].
8. Omim.org. (2018). OMIM Entry - * 103220 - SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ADENINE NUCLEOTIDE TRANSLOCATOR), MEMBER 4; SLC25A4. [online] Available at: https://www.omim.org/entry/103220 [Accessed 12 Dec. 2018].
9. Omim.org. (2018). OMIM Entry - * 610345 - ACYLGLYCEROL KINASE; AGK. [online] Available at: https://www.omim.org/entry/610345#6 [Accessed 12 Dec. 2018].
10. Sengers, R., Trijbels, J., Willems, J., Daniels, O. and Stadhouders, A. (1975). Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. The Journal of Pediatrics, 86(6), pp.873-880.
11. Siriwardena, K., MacKay, N., Levandovskiy, V., Blaser, S., Raiman, J., Kantor, P., Ackerley, C., Robinson, B., Schulze, A. and Cameron, J. (2013). Mitochondrial citrate synthase crystals: Novel finding in Sengers syndrome caused by acylglycerol kinase (AGK) mutations. Molecular Genetics and Metabolism, 108(1), pp.40-50.
12. Ncbi.nlm.nih.gov. (2018). SLC25A4 solute carrier family 25 member 4 [Homo sapiens (human)] - Gene - NCBI. [online] Available at: https://www.ncbi.nlm.nih.gov/gene/291 [Accessed 12 Dec. 2018].