Acta Pædiatrica ISSN 0803-5253
EDITORIAL DOI:10.1111/apa.12667
Mitochondrial DNA and sudden infant death syndrome €er et al. (1) present data In this issue of the journal, La indicating that mitochondrial DNA (mtDNA) variations may play a role in at least a subset of sudden infant death syndrome (SIDS) cases. The authors investigate commonly observed mtDNA polymorphisms, originally used to characterise the major European haplogroups, in 365 SIDS cases and 409 controls. It is interesting that even though there were no differences in assigned haplogroups between the SIDS cases and the controls, the authors found age- and gender-specific correlations of allele frequencies for six of the single nucleotide polymorphisms that they investigated. The most predominant result was in the male SIDS cases, which demonstrated a higher frequency of both 14470A and 3010A than the controls. This is very interesting and might be a small step towards understanding the male excess in SIDS. mtDNA is a 16 569-bp closed circular genome that is located within the mitochondrion and inherited through the maternal line. mtDNA encodes for 13 polypeptides involved in the electron transport chain and oxidative phosphorylation, as well as the 22 tRNAs and 12s and 16s rRNA genes needed for mitochondrial protein synthesis. The displacement loop (D-loop) consists of the origin of replication, as well as a terminator-associated sequence. The base composition of the D-loop differs within the population, but about 20% of humans have a specific sequence known as the Cambridge sequence. Due to a lack of histone protection, an insufficient repair mechanism and the highly compact structure of the mtDNA, mtDNA genes have a 10- to 20-fold higher mutation rate than nuclear DNA genes. The most important function of the mitochondrion is generating cellular energy in the form of adenosine triphosphate (ATP), but the organelle is also involved in the regulation of calcium and apoptosis. Mitochondrial diseases are heterogeneous and often multisystemic. They display a diverse range of age at onset and may manifest in infants, children and adults. Because the mitochondrion provides much of the energy for the cell, mitochondrial disorders tend to affect tissue with high energy demands, including the brain, muscle, heart and endocrine system. Mutations in mRNA genes, which result in amino acid substitutions, are often associated with ophthalmological and neurological disease. Mutations in tRNA genes have more systemic phenotypic consequences and are associated with mitochondrial myopathy, ragged red muscle fibres and abnormal mitochondria. In addition, there are diseases associated with mtDNA deletion and mtDNA depletion. Epidemiological studies have concluded that the frequency of mtDNA diseases is around one in 5000 live births, and known pathogenic mtDNA mutations
have been detected in the core blood of one in 200 live births (2). To date, nearly 300 disease-causing mtDNA mutations have been described (www.mitomap.org). Several studies have been performed in an attempt to disclose the role of mtDNA in SIDS, and a number of coding region mtDNA polymorphisms and mutations have been observed in several genes in cases of sudden unexpected infant death. These include alterations in the genes encoding 16s rRNA, tRNALeu(UUR), tRNAGly, tRNALeu(CUN), tRNAThr, ND1, ND4, ND5, ND6, Co1, Co2, Co3 and Cytb. However, many of the mutations have only been reported in one or a few SIDS victims, and many of them are relatively common in controls as well. So far, no predominant mtDNA mutation has been found associated with SIDS. The most common mtDNA point mutation is A3243G, which causes mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). The mutation is situated within the gene encoding tRNALeu(UUR), which is a hotspot in mitochondrial disease and has a high incidence of mutations. This is of particular interest with regard to SIDS, as mutations in this gene have been associated with excess mortality rates. A study by Majamaa-Voltti et al. (3) reported that 26% of A3243G carriers and first-degree relatives of such carriers dyed sudden and unexpectedly during their early years or young adulthood. So far, three different mutations in the tRNALeu(UUR) gene have been detected in families with SIDS. The mutation T3250C was detected in a family in which a sister and maternal uncle of the proband died of SIDS and C3303T was detected in a family in which an older brother of the proband died of SIDS (4,5). The tRNALeu(UUR) gene has been sequenced in 180 Norwegian SIDS cases and the mutation T3290C was detected in a 3-month-old female infant who was found dead in her cot one morning (6). These mutations might, in common with other tRNA mutations, disrupt the threedimensional structure, which in turn may lead to partial impairment of mitochondrial protein synthesis. In addition, possible additive or synergistic effects may be seen if such mutations are combined with other point mutations or major size rearrangements, in either mtDNA or nuclear DNA. Most cells contain multiple copies of mtDNA, with the copy number correlated with cellular respiratory demand. There may be thousands of mtDNA molecules inside highly energetic cells, and one cell may harbour a mixture of mutant and normal mtDNA. This gives rise to the concept of threshold expression, which states that in mtDNA disease the phenotype is a product of the nature of the mutation, the percentages of mutant mtDNA, and how dependent each organ system is on mitochondrial energy
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 685–686
685
Editorial
Editorial
production. As a rule, the higher the percentage of mutated mtDNA, the more severe the phenotype of the disorder. Usually, at least 70% of mtDNA has to be mutated for disease symptoms to be displayed. It would, therefore, have been of great interest to know the percentage of mutated €er et al., as this mtDNA in the SIDS cases investigated by La would have given us an even deeper insight into the relevance that these mutations might play in SIDS. Mitochondrial dysfunction and disease can also be caused by mutations in nuclear DNA, as the majority of mitochondrial proteins are encoded in the nucleus. It is also clear that disease can result from the incompatible interaction of otherwise functional mtDNA and nuclear DNA genes (2). One example of the latter is two affected males with a virtually complete absence of Complex I in their skeletal muscle. Gene analysis revealed a nuclear DNA variant in the X-linked Complex I NDUFA1 gene, which resulted in a reduction of about 40% in Complex I activity, and two mtDNA mutations – one in ND1 and one in ND5 – that were associated with a reduction of around 30% in Complex I activity (7). These nuclear DNA and mtDNA variants were incompatible and resulted in a complete Complex I deficiency in these patients. This example highlights the fact that we should also investigate nuclear €er genes coding for mitochondrial proteins in SIDS, as La et al. (1) point out in this issue of the journal. If mtDNA mutations are involved in some SIDS cases, it is most likely that they provide a genetic predisposition and are not a cause of death. This is intriguing and fits well with the concept of a fatal triangle in SIDS, which implies that an infant only dies of SIDS when three conditions occur at the same time: a genetic predisposition, a vulnerable developmental stage of the central nervous system and the immune system, and a trigger event (8). There are a number studies that support the view that there are genetic risk factors for SIDS, consisting of polymorphisms that may be suboptimal in critical situations, even when they are normal gene variants (9). Genetic variations in mtDNA may very well be one of several genetic predisposing factors, by causing a slight ATP deficiency that increases the child’s vulnerability when they are exposed to trigger events, such as sleeping in the prone position, overheating or a slight
686
infection. However, it is not likely that there exists one, or a few, mtDNA mutations that will cause SIDS by themselves.
Siri H. Opdal ([email protected])1,2 1.Department of Forensic Pathology, Norwegian Institute of Public Health, Oslo, Norway 2.Department of Pathology, Oslo University Hospital, Oslo, Norway
References €er K, Vennemann M, Rothamel T, Klintschar M. 1. La Mitochondrial deoxyribonucleic acid may play a role in a subset of sudden infant death syndrome cases. Acta Paediatr 2014; 103: 775–9. 2. Wallace DC. Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 2010; 51: 440–50. 3. Majamaa-Voltti K, Turkka J, Kortelainen ML, Huikuri H, Majamaa K. Causes of death in pedigrees with the 3243A>G mutation in mitochondrial DNA. J Neurol Neurosurg Psychiatry 2008; 79: 209–11. 4. Ogle RF, Christodoulou J, Fagan E, Blok RB, Kirby DM, Seller KL, et al. Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin. J Pediatr 1997; 130: 138–45. 5. Silvestri G, Santorelli FM, Shanske S, Whitley CB, Schimmenti LA, Smith SA, et al. A new mtDNA mutation in the tRNA(Leu (UUR)) gene associated with maternally inherited cardiomyopathy. Hum Mutat 1994; 3: 37–43. 6. Opdal SH, Rognum TO, Torgersen H, Vege A. Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome. Acta Paediatr 1999; 88: 957–60. 7. Potluri P, Davila A, Ruiz-Pesini E, Mishmar D, O’Hearn S, Hancock S, et al. A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease. Mol Genet Metab 2009 April; 96: 189–95. 8. Rognum TO, Saugstad OD. Biochemical and immunological studies in SIDS victims. Clues to understanding the death mechanism. Acta Paediatr Suppl 1993 June; 82(Suppl 389): 82–5. 9. Opdal SH, Rognum TO. Gene variants predisposing to SIDS: current knowledge. Forensic Sci Med Pathol 2011 March; 7: 26–36.
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 685–686
EDITORIAL DOI:10.1111/apa.12667
Mitochondrial DNA and sudden infant death syndrome €er et al. (1) present data In this issue of the journal, La indicating that mitochondrial DNA (mtDNA) variations may play a role in at least a subset of sudden infant death syndrome (SIDS) cases. The authors investigate commonly observed mtDNA polymorphisms, originally used to characterise the major European haplogroups, in 365 SIDS cases and 409 controls. It is interesting that even though there were no differences in assigned haplogroups between the SIDS cases and the controls, the authors found age- and gender-specific correlations of allele frequencies for six of the single nucleotide polymorphisms that they investigated. The most predominant result was in the male SIDS cases, which demonstrated a higher frequency of both 14470A and 3010A than the controls. This is very interesting and might be a small step towards understanding the male excess in SIDS. mtDNA is a 16 569-bp closed circular genome that is located within the mitochondrion and inherited through the maternal line. mtDNA encodes for 13 polypeptides involved in the electron transport chain and oxidative phosphorylation, as well as the 22 tRNAs and 12s and 16s rRNA genes needed for mitochondrial protein synthesis. The displacement loop (D-loop) consists of the origin of replication, as well as a terminator-associated sequence. The base composition of the D-loop differs within the population, but about 20% of humans have a specific sequence known as the Cambridge sequence. Due to a lack of histone protection, an insufficient repair mechanism and the highly compact structure of the mtDNA, mtDNA genes have a 10- to 20-fold higher mutation rate than nuclear DNA genes. The most important function of the mitochondrion is generating cellular energy in the form of adenosine triphosphate (ATP), but the organelle is also involved in the regulation of calcium and apoptosis. Mitochondrial diseases are heterogeneous and often multisystemic. They display a diverse range of age at onset and may manifest in infants, children and adults. Because the mitochondrion provides much of the energy for the cell, mitochondrial disorders tend to affect tissue with high energy demands, including the brain, muscle, heart and endocrine system. Mutations in mRNA genes, which result in amino acid substitutions, are often associated with ophthalmological and neurological disease. Mutations in tRNA genes have more systemic phenotypic consequences and are associated with mitochondrial myopathy, ragged red muscle fibres and abnormal mitochondria. In addition, there are diseases associated with mtDNA deletion and mtDNA depletion. Epidemiological studies have concluded that the frequency of mtDNA diseases is around one in 5000 live births, and known pathogenic mtDNA mutations
have been detected in the core blood of one in 200 live births (2). To date, nearly 300 disease-causing mtDNA mutations have been described (www.mitomap.org). Several studies have been performed in an attempt to disclose the role of mtDNA in SIDS, and a number of coding region mtDNA polymorphisms and mutations have been observed in several genes in cases of sudden unexpected infant death. These include alterations in the genes encoding 16s rRNA, tRNALeu(UUR), tRNAGly, tRNALeu(CUN), tRNAThr, ND1, ND4, ND5, ND6, Co1, Co2, Co3 and Cytb. However, many of the mutations have only been reported in one or a few SIDS victims, and many of them are relatively common in controls as well. So far, no predominant mtDNA mutation has been found associated with SIDS. The most common mtDNA point mutation is A3243G, which causes mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). The mutation is situated within the gene encoding tRNALeu(UUR), which is a hotspot in mitochondrial disease and has a high incidence of mutations. This is of particular interest with regard to SIDS, as mutations in this gene have been associated with excess mortality rates. A study by Majamaa-Voltti et al. (3) reported that 26% of A3243G carriers and first-degree relatives of such carriers dyed sudden and unexpectedly during their early years or young adulthood. So far, three different mutations in the tRNALeu(UUR) gene have been detected in families with SIDS. The mutation T3250C was detected in a family in which a sister and maternal uncle of the proband died of SIDS and C3303T was detected in a family in which an older brother of the proband died of SIDS (4,5). The tRNALeu(UUR) gene has been sequenced in 180 Norwegian SIDS cases and the mutation T3290C was detected in a 3-month-old female infant who was found dead in her cot one morning (6). These mutations might, in common with other tRNA mutations, disrupt the threedimensional structure, which in turn may lead to partial impairment of mitochondrial protein synthesis. In addition, possible additive or synergistic effects may be seen if such mutations are combined with other point mutations or major size rearrangements, in either mtDNA or nuclear DNA. Most cells contain multiple copies of mtDNA, with the copy number correlated with cellular respiratory demand. There may be thousands of mtDNA molecules inside highly energetic cells, and one cell may harbour a mixture of mutant and normal mtDNA. This gives rise to the concept of threshold expression, which states that in mtDNA disease the phenotype is a product of the nature of the mutation, the percentages of mutant mtDNA, and how dependent each organ system is on mitochondrial energy
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 685–686
685
Editorial
Editorial
production. As a rule, the higher the percentage of mutated mtDNA, the more severe the phenotype of the disorder. Usually, at least 70% of mtDNA has to be mutated for disease symptoms to be displayed. It would, therefore, have been of great interest to know the percentage of mutated €er et al., as this mtDNA in the SIDS cases investigated by La would have given us an even deeper insight into the relevance that these mutations might play in SIDS. Mitochondrial dysfunction and disease can also be caused by mutations in nuclear DNA, as the majority of mitochondrial proteins are encoded in the nucleus. It is also clear that disease can result from the incompatible interaction of otherwise functional mtDNA and nuclear DNA genes (2). One example of the latter is two affected males with a virtually complete absence of Complex I in their skeletal muscle. Gene analysis revealed a nuclear DNA variant in the X-linked Complex I NDUFA1 gene, which resulted in a reduction of about 40% in Complex I activity, and two mtDNA mutations – one in ND1 and one in ND5 – that were associated with a reduction of around 30% in Complex I activity (7). These nuclear DNA and mtDNA variants were incompatible and resulted in a complete Complex I deficiency in these patients. This example highlights the fact that we should also investigate nuclear €er genes coding for mitochondrial proteins in SIDS, as La et al. (1) point out in this issue of the journal. If mtDNA mutations are involved in some SIDS cases, it is most likely that they provide a genetic predisposition and are not a cause of death. This is intriguing and fits well with the concept of a fatal triangle in SIDS, which implies that an infant only dies of SIDS when three conditions occur at the same time: a genetic predisposition, a vulnerable developmental stage of the central nervous system and the immune system, and a trigger event (8). There are a number studies that support the view that there are genetic risk factors for SIDS, consisting of polymorphisms that may be suboptimal in critical situations, even when they are normal gene variants (9). Genetic variations in mtDNA may very well be one of several genetic predisposing factors, by causing a slight ATP deficiency that increases the child’s vulnerability when they are exposed to trigger events, such as sleeping in the prone position, overheating or a slight
686
infection. However, it is not likely that there exists one, or a few, mtDNA mutations that will cause SIDS by themselves.
Siri H. Opdal ([email protected])1,2 1.Department of Forensic Pathology, Norwegian Institute of Public Health, Oslo, Norway 2.Department of Pathology, Oslo University Hospital, Oslo, Norway
References €er K, Vennemann M, Rothamel T, Klintschar M. 1. La Mitochondrial deoxyribonucleic acid may play a role in a subset of sudden infant death syndrome cases. Acta Paediatr 2014; 103: 775–9. 2. Wallace DC. Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 2010; 51: 440–50. 3. Majamaa-Voltti K, Turkka J, Kortelainen ML, Huikuri H, Majamaa K. Causes of death in pedigrees with the 3243A>G mutation in mitochondrial DNA. J Neurol Neurosurg Psychiatry 2008; 79: 209–11. 4. Ogle RF, Christodoulou J, Fagan E, Blok RB, Kirby DM, Seller KL, et al. Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin. J Pediatr 1997; 130: 138–45. 5. Silvestri G, Santorelli FM, Shanske S, Whitley CB, Schimmenti LA, Smith SA, et al. A new mtDNA mutation in the tRNA(Leu (UUR)) gene associated with maternally inherited cardiomyopathy. Hum Mutat 1994; 3: 37–43. 6. Opdal SH, Rognum TO, Torgersen H, Vege A. Mitochondrial DNA point mutations detected in four cases of sudden infant death syndrome. Acta Paediatr 1999; 88: 957–60. 7. Potluri P, Davila A, Ruiz-Pesini E, Mishmar D, O’Hearn S, Hancock S, et al. A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease. Mol Genet Metab 2009 April; 96: 189–95. 8. Rognum TO, Saugstad OD. Biochemical and immunological studies in SIDS victims. Clues to understanding the death mechanism. Acta Paediatr Suppl 1993 June; 82(Suppl 389): 82–5. 9. Opdal SH, Rognum TO. Gene variants predisposing to SIDS: current knowledge. Forensic Sci Med Pathol 2011 March; 7: 26–36.
ª2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 685–686
