Sudden Infant Death Syndrome Group Research Articles

Sudden infant death syndrome: deletions of glutathione-S-transferase genes M1 and T1 and tobacco smoke exposure

In developed countries, sudden infant death syndrome (SIDS) is the leading cause of death in infants in their first year of life. The risk of SIDS is increased if parents smoked during pregnancy and in presence of the child. Glutathione S-transferases (GSTs) catalyse the conjugation of glutathione with electrophilic compounds and toxins, making them less reactive and easier to excrete. As a gene dose effect was observed for GSTM1 and GSTT1, the aim of this study was to investigate whether there is a connection between homozygous or heterozygous gene deletions of GSTM1 or GSTT1 and the occurrence of SIDS. We found that heterozygous deletion of GSTM1 occurred significantly more frequently in the SIDS case group compared to the control group. A homozygous deletion of GSMT1 was slightly more frequently in the control group. A homozygous gene deletion of GSTT1 showed no significant difference between the SIDS group and the control group. We also found that in the SIDS group, the number of victims that were exposed to cigarette smoke was significantly higher than the number of victims without cigarette smoke exposure and that the mean lifetime of children whose mothers smoked was shorter in comparison with non-smoking mothers. In SIDS cases with homozygous gene deletions of GSTM1, the median life span of children with tobacco smoke exposure was 60 days shorter than without smoke exposure. In conclusion, the absence of these two genes is not the only trigger for SIDS but could be a critical aspect of SIDS aetiology, particularly in SIDS cases with smoking parents.

Aquaporin-1 and aquaporin-9 gene variations in sudden infant death syndrome

Several studies have indicated that a vulnerability in the development and regulation of brain function is involved in sudden infant death syndrome (SIDS). The aim of this study was to investigate the genes encoding the brain aquaporins (AQPs) AQP1 and AQP9 in SIDS. The hypothesis was that specific variants of these genes are part of the genetic vulnerability predisposing infants to sudden unexpected death. The study included 168 SIDS cases with a median age of 15.5 (range 2–52) weeks and 372 adolescent/adult deceased controls with a median age of 44 (range 11–91) years. In the AQP1 gene, the rs17159702 CC/CT genotypes were found to be associated with SIDS (p = 0.02). In the AQP9 gene, the combination of a TT genotype of rs8042354, rs2292711 and rs13329178 was more frequent in SIDS cases than in controls (p = 0.03). In the SIDS group, an association was found between genetic variations in the AQP1 gene and maternal smoking and between the 3xTT combination in the AQP9 gene and being found lifeless in a prone position. In conclusion, this study adds further evidence to the involvement of brain aquaporins in SIDS, suggesting that specific variants of AQP genes constitute a genetic predisposition, making the infant vulnerable to sudden death together with external risk factors and probably other genetic factors.

Immunohistochemical diagnosis of myocarditis on (infantile) autopsy material: Does it improve the diagnosis?

The standard for the histopathologic diagnosis of myocarditis has been the Dallas criteria. Recently, immunohistochemical studies that include the specification and quantification of interstitial inflammatory cells have been proposed as the diagnostic approach for myocarditis. Cut-off limits regarding inflammatory cell numbers for the positive diagnosis of myocarditis have been recommended. However, it is unclear whether these can be applied to postmortem tissues or to infants, as they were established from endomyocardial biopsies and for adults. Nevertheless, cut-off limits for the postmortem diagnosis of myocarditis in the first year of life have been proposed. Studies using these cut-off limits identified myocarditis in a high percentage of presumed sudden infant death syndrome (SIDS) cases. These results were re-evaluated by the present study, which examined heart specimens from infants less than 1 year of age. The study had a test group of 92 SIDS cases and a control group of 15. Myocardial tissue was examined from eight standardized locations, stained with hematoxylin-eosin and for three different immunohistochemical reagents (LCA for leukocytes, CD68 for macrophages, CD45-RO for T-lymphocytes). Histopathological assessment of the number of inflammatory cells was carried out on an aggregate of 80 mm(2) of myocardial tissue per case. Myocarditis, based on the Dallas criteria, was histologically diagnosed in only two cases. Immunohistochemical quantification revealed elevated cell counts in the SIDS group for LCA and CD45-RO. However, those differences were neither statistically significant nor clinically relevant as the mean cell counts per mm(2) were low. The density of inflammatory cells differed considerably from section to section and even within single sections. Therefore the commonly used arithmetic mean value was not diagnostically relevant, suggesting cut-off values based on the arithmetic mean value as recommended in the literature, cannot be regarded as valid. At least in infants, the diagnosis of myocarditis from autopsy tissues still requires application of the Dallas criteria. Immunohistochemical methods cannot replace the conventional diagnosis of myocarditis.

Heat stress and sudden infant death syndrome—Stress gene expression after exposure to moderate heat stress

The aim of the present study was to investigate stress gene expression in cultured primary fibroblasts established from Achilles tendons collected during autopsies from sudden infant death syndrome (SIDS) cases, and age-matched controls (infants dying in a traumatic event). Expression of 4 stress responsive genes, HSPA1B, HSPD1, HMOX1, and SOD2, was studied by quantitative reverse transcriptase PCR analysis of RNA purified from cells cultured under standard or various thermal stress conditions. The expression of all 4 genes was highly influenced by thermal stress in both SIDS and control cells. High interpersonal variance found in the SIDS group indicated that they represented a more heterogeneous group than controls. The SIDS group responded to thermal stress with a higher expression of the HSPA1B and HSPD1 genes compared to the control group, whereas no significant difference was observed in the expression of SOD2 and HMOX1 between the two groups. The differences were related to the heat shock treatment as none of the genes were expressed significantly different in SIDS at base levels at 37°C. SOD2 and HMOX1 were up regulated in both groups, for SOD2 though the expression was lower in SIDS at all time points measured, and may be less related to heat stress. Being found dead in the prone position (a known risk factor for SIDS) was related to a lower HSPA1B up-regulation in SIDS compared to SIDS found on their side or back.The study demonstrates the potential usefulness of gene expression studies using cultured fibroblasts established from deceased individuals as a tool for molecular and pathological investigations in forensic and biomedical sciences.

Association between polymorphisms in the P2RY1 and SSTR2 genes and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is a multifactorial syndrome and we believe that an inefficient respiratory response to certain homeostatic stressors, such as hypoxia and hypercapnia, is a key factor in the etiology of SIDS. Hence, we genotyped two single nucleotide polymorphisms (SNPs) in genes of importance for respiratory control: P2RY1 (adenosine diphosphate/adenosine triphosphate receptor) and SSTR2 (somatostatin receptor). Two SNPs, Rs1466113 (C > G dimorphism in SSTR2) and rs701265 (A > G dimorphism in P2RY1), were typed in 175 SIDS cases and 195 controls and 275 SIDS cases and 338 controls, respectively. Genotyping was performed using TaqMan technology. The determined genotype frequencies were SSTR2: CC (14.4%), CG (49.7%), GG (35.9%) in controls and CC (17.1%), CG (49.1%), and GG (33.8%) in SIDS; P2RY1: AA (70.6%), AG (28.7%), GG (0.7%) in SIDS and AA (68.3%), AG (27.9%), and GG (3.8%) in the control group. For rs701265 in P2RY1, homozygous G carriers were significantly more frequent in the control group (p = 0.02). We think that allele G provides a protective effect in events of ventilatory stress. Moreover, the significant lack of P2Y1 G allele homozygotes in the SIDS group shows that respiratory response plays an important role in the etiology of SIDS. Thus, we believe it is worthwhile to further investigate functional polymorphisms within genes that are involved in respiratory control in the future.

The evidential value of intra-alveolar haemosiderin-macrophages in cases of sudden infant death syndrome (SIDS)

Intra-alveolar deposits of haemosiderin have repeatedly been brought into connection with some diagnostic value, such as markers for previous imposed suffocation, smothering due to Munchausen syndrome by proxy or sudden infant death syndrome (SIDS). This study is based on 104 SIDS cases and 14 controls (causes of death, e.g. inflammatory changes, internal haemorrhages, asphyxia, blunt force trauma or acute toxicity). The SIDS group comprised 44 females (aged 7 days to 12 months) and 60 males (aged 12 days to 16 months 8 days) with the ages of the controls ranging from 2 months 3 days to 47 months. Routine histology samples from the lungs were stained with Prussian blue and haemosiderin foci were counted in 20 hpf for each lung lobe by a pathologist blinded to the cause of death. Results were assigned to one of five categories for haemosiderin positivity. Data were analysed by the Levene-test revealing identical variances in both groups and with a two-sample t-test showing the mean values for haemosiderin counts not being significantly different between SIDS and control groups. Although the sizes of both samples differed considerably it is our opinion that the haemosiderin counts did not show sufficient diagnostic value. This outcome supports the latest results of other comparable investigations. Furthermore, it highlights the necessity to assess carefully positive haemosiderin findings to avoid false suspicion.

Biochemical, cytological and histopathological examination of sudden unexpected death in infancy

To evaluate the pathophysiological mechanisms underlying sudden infant death syndrome (SIDS), four sudden unexpected death in infancy (SUDI) and four sudden deaths in children over 1 year of age were examined. In the SUDI cases, increased numbers of scavenger receptor A positive (SRA(+) ) cells (4/4), numerous platelet aggregates (3/4), and tumor necrosis factor (TNF)-α(+) cells (4/4) were observed in the peripheral blood (PB) smear preparations. Macrophage colony stimulating factor, interleukin (IL)-6, IL-8, TNF-α and IL-1β all exceeded the normal levels. Minute foci of inflammatory lung injury (4/4), numerous platelet emboli in lungs and among cardiac myocytes (3/4) and appreciable contraction band necrosis (1/4) were observed. And neutrophils accumulated in the capillaries of injured organs and endothelial cells were extensively injured. From these findings, cytokine abnormality induced by SRA(+) cells in PB was considered to play an important role in the development of tissue injury, and platelet emboli or contraction band necrosis might have been the leading cause of death in our SUDI cases. Patients with characteristics thought to be similar to our SUDI cases were included in the SIDS group; cytokine abnormality was considered to be one of the underlying mechanisms in SIDS.

Cytokine gene polymorphisms and sudden infant death syndrome

Several studies indicate that the mucosal immune system is stimulated in cases of sudden infant death syndrome (SIDS), and our hypothesis is that this immune reaction is because of an unfavourable combination of functional polymorphisms in the cytokine genes. Thus, in this study, single nucleotide polymorphisms (SNPs) in the genes encoding IL-6, IL-8, IL-12, IL-13, IL-16, IL-18 and IFNgamma were investigated in 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death and 131 controls. Regarding genotype distribution, no differences between the investigated groups were found. However, in the SIDS group, the genotypes IL-8 -251AA/AT and IL-8 -781CT/TT were significantly more frequent in the SIDS cases found dead in a prone sleeping position, compared with SIDS cases found dead in other sleeping positions. In addition, there was an association between fever prior to death and the genotype IL-13 +4464GG in the cases of infectious death. This study indicates that specific interleukin genotypes are a part of a genetic make up that make infants sleeping prone at risk for SIDS.

IL-1 gene cluster polymorphisms and sudden infant death syndrome

Several studies indicate that interleukin gene polymorphisms are of importance to sudden infant death syndrome (SIDS), and so far it has been reported that associations between SIDS and polymorphism in the genes encoding tumor necrosis factor alpha, IL (interleukin)-6, and IL-10. IL-1 are important for the synthesis of acute phase proteins, and it is a pyrogen cytokine that may cause fever. The purpose of the present study was to investigate two polymorphisms in the IL-1α gene; a variable number of tandem repeat (VNTR) in intron 6 and a single nucleotide polymorphism in +4845G/T, as well as the −511C/T polymorphism in the gene encoding IL-1β, and a VNTR in intron 2 of the competitive antagonist IL-1Ra, in SIDS cases, cases of infectious death, and controls. Furthermore, the genotypes were correlated with known external risk factors for SIDS. When investigating each polymorphism separately, no differences in genotype distribution between the diagnosis groups and controls were found. However, when combining VNTR and single nucleotide polymorphism genotypes, an association between the gene combination IL-1α VNTR A1A1/IL-1β+ +4845TT and SIDS was disclosed ( p < 0.01). In the SIDS group it was also found that the genotypes IL-1β −511CC/CT were significantly more frequent in the SIDS victims found dead in a prone sleeping position, compared with SIDS victims found dead in other sleeping positions ( p = 0.004). The findings in the present study indicate that specific interleukin gene variants may be a predisposing factor for sudden unexpected infant death.

Pulmonary arterial medial smooth muscle thickness in sudden infant death syndrome: an analysis of subsets of 73 cases

Previous studies addressing pulmonary artery morphology have compared cases of sudden infant death syndrome (SIDS) to controls but none have compared demographic profiles, exposure to potentially hypoxic risk factors and other pathologic variables in SIDS cases grouped according to pulmonary artery medial smooth muscle thickness. Aims: To compare the relative medial thickness (RMT) in alveolar wall arteries (AW) in SIDS cases with that in age-matched controls and 2. Compare demographic, clinical, and pathologic characteristics among three subsets of SIDS cases based upon alveolar wall (AW) RMT. Retrospective morphometric planimetry of all muscularized arteries in standardized right apical lung sections in 73 SIDS cases divided into three groups based on increasing AW RMT as well as 19 controls age-matched to 19 of the SIDS cases. SIDS and age-matched control cases did not differ with respect to AW RMT or other demographic variables. The SIDS group with the thickest AW RMT had significantly more males and premature birth than the other groups, but the groups did not differ for known clinical risk factors that would potentially expose them to hypoxia. Pathologic variables, including pulmonary inflammation, gastric aspiration, intra-alveolar siderophages, cardiac valve circumferences, and heart and liver weights, were not different between groups. Age was not significantly correlated with RMT of alveolar wall and pre-acinar arteries but was significant at p = .018 for small intra-acinar arteries. The groups were different for RMT of small pre-acinar and intra-acinar arteries, which increased with increasing AW RMT. Statistical differences should not necessarily be equated with clinical importance, however future research incorporating more quantified historical data is recommended.

Infant and perinatal pulmonary hypoplasia frequently associated with brainstem hypodevelopment

Recent anatomo-pathological studies have revealed a frequent associated hypoplasia of both arcuate nucleus and lungs in stillbirths. The purpose of this study is to analyze the lung and brainstem development in sudden unexplained perinatal death and sudden infant death syndrome (SIDS). A total of 51 cases were investigated. A complete autopsy was performed in each case. Anatomo-pathologic examination of the central autonomic nervous system included an in-depth study on histological serial sections of the brains where the main structures participating in control of the vital functions are located. The stage of lung development was evaluated by macroscopic and microscopic criteria. In 52.9% of cases, a pulmonary hypoplasia was detected. The pulmonary hypoplasia was significantly more frequent in the SIDS group compared to the sudden perinatal unexplained death groups (p < 0.05). In 72.5% of cases, histological examination of the brainstem on serial sections showed hypodevelopment of the brainstem nuclei, particularly hypoplasia, of the arcuate nucleus (60.8%). In 47.1% of cases, pulmonary hypoplasia was associated with brainstem hypodevelopment.

Hypoxic–ischemic changes in SIDS brains as demonstrated by a reduction in MAP2-reactive neurons

Sudden infant death syndrome (SIDS) is characterized by a lack of any known morphological or functional organ changes that could explain the lethal process. In the present study we investigated the hypothesis of an association between hypoxic/ischemic injury and SIDS deaths. In a previous study, we could demonstrate by quantitative immunohistochemistry a distinct drop in microtubule-associated protein (MAP2) reactivity in neurons of adult, human brains secondary to acute hypoxic-ischemic injuries. Here we applied the same method on sections of the frontal cortex and hippocampus of 41 brains of infants younger than 1 year of age. For each brain area 100 selected neurons were evaluated for their MAP2 reactivity in the different layers of the frontal cortex and in the different segments of the hippocampus. Three groups were compared: (1) SIDS victims (n = 17), (2) infants with hypoxia/ischemia (control group one; n = 14), (3) infants without hypoxic/ischemic injury (control group two; n = 10). The SIDS group and hypoxic/ischemic group exhibited a general reduction in the number of MAP2 reactive neurons in comparison with the non-hypoxic/ischemic injury group. The SIDS group also had a significantly lower (P < 0.05) number of reactive neurons in the CA2 and CA3 areas of the hippocampus than did control group two. No difference was detected between the SIDS group and control group one. The SIDS brains were thus found to display hypoxic/ischemic features without however providing evidence as to the cause of the oxygen reduction.

The IL6 −174G/C polymorphism and sudden infant death syndrome

The interleukin-6 genotype (IL6 -174GG) has been proposed to be associated with sudden infant death syndrome (SIDS). The aim of this study was to investigate the -174G/C polymorphism in 175 Norwegian SIDS cases and 71 controls. There were no differences in genotype distribution between these two groups (p = 1.0). This confirms the findings in a combined SIDS group compared with European Caucasian controls, but not findings in smaller cohorts of SIDS cases from Australia and England. The discrepancy may result from bias introduced when investigating only a few SIDS cases, differences in diagnostic criteria when diagnosing the cause of death as SIDS, and differences in the distribution of the -174G/C polymorphism in different ethnic groups. Findings of an activated immune system in SIDS indicate that genes involved in the immune response are of importance. However, because there are several polymorphisms in the IL6 gene promoter that could potentially regulate the expression of the gene, more than one polymorphism should be investigated to assess the involvement of the IL-6 gene in SIDS.

Maternal smoking and sudden infant death syndrome: epidemiological study related to pathology

Various risk factors have been postulated to be related to sudden infant death syndrome (SIDS). Despite its reduction, thanks to the "Back to Sleep" campaign, SIDS is still a major cause of infant mortality in the first year of life. The purpose of this study was to correlate the different risk factors with the autopsy results and thus to determine if one or more of these variables is really specific for SIDS. We collected 128 sudden infant death victims with clinical diagnosis of SIDS and performed a complete autopsy with in-depth histology on serial sections, particularly of the brainstem, in accordance with our necropsy protocol. Histopathologic and immunohistochemical examination of the central autonomic nervous system revealed, in 78 cases of the SIDS group, the following anomalies: hypodevelopment of the arcuate nucleus, somatostatin positive hypoglossus nucleus, tyrosine hydroxylase negativity in the locus coeruleus, gliosis, and hypoplasia of the hypoglossus nucleus. A significant relation was found between maternal smoke and brainstem alterations.

Pulmonary Intra-Alveolar Siderophages in SIDS and Suffocation: A San Diego SIDS/SUDC Research Project Report

Pulmonary intra-alveolar siderophages (PS) have been suggested as a marker of previous attempts at imposed suffocation in infants dying suddenly and unexpectedly. The aims of this study were to (1) compare PS counts between cases of sudden infant death syndrome (SIDS) and a control group comprised of infants whose deaths were attributed to accidental or inflicted suffocation, (2) compare clinical variables in SIDS and control suffocation cases, and (3) review individual cases irrespective of the cause and manner of death with an average PS count greater than 200 per 20 high-power fields (hpf) per lung lobe. Retrospective assessment of siderophages in available iron-stained lung sections was undertaken in 91 SIDS cases and 29 cases of death due to suffocation (27 accidents and 2 homicides) from the San Diego SIDS and Sudden Unexplained Death in Childhood (SUDC) Research Project (SDSSRP) database. Neither the means of the log-transformed PS counts nor the medians of the raw PS counts were significantly different between the SIDS and control suffocation groups. The distributions of the PS data were different, however-the range was wider in the SIDS group. Only 6% of each group had a history of prior apparent life-threatening events. Approximately three fourths of the families from both groups had no prior referral to Child Protective Services. The number of PS varies widely in cases of sudden infant death caused by SIDS and accidental or inflicted suffocation and cannot be used as an independent variable to ascertain past attempts at suffocation.

Serum tryptase levels in sudden infant death syndrome in forensic autopsy cases

An elevated serum tryptase concentration is considered to be a specific marker for systemic mast-cell activation, a central feature of anaphylaxis, which has been observed in some cases of sudden infant death syndrome (SIDS). However, it is still unclear whether anaphylaxis is involved in the etiology for SIDS. In the present study, we measured serum tryptase levels in 21 infants with SIDS, and 14 control infants from forensic autopsy cases by Uni-CAP TRYPTASE Fluoroenzyme immunoassay system, which detects both α- and β-tryptase. The assay did not show any significant elevation of tryptase levels in the SIDS group compared with controls. Additionally, increased concentrations of tryptase were not observed in any SIDS case. Our results indicated that anaphylaxis does not seem to be involved in the etiology of SIDS.

PCR-Based Diagnosis of Enterovirus and Parvovirus B19 in Paraffin-Embedded Heart Tissue of Children with Suspected Sudden Infant Death Syndrome

The diagnosis of viral myocarditis remains difficult and generally depends on clinical and histologic criteria. Viral cultures and serology are often unrewarding with low yields. The purpose of this study was to analyze the usefulness of PCR in the rapid diagnosis of myocarditis in children. PCR was used to analyze 120 myocardial tissue samples from 60 cases of sudden infant death syndrome (SIDS) and 56 myocardial tissue samples from 36 cases with well-known causes of sudden death (11 children younger than 1 year and 25 children 1–10 years old). The myocardial tissue samples were evaluated for the presence of enteroviruses and parvovirus B19 using PCR primers designed to consensus and unique sequences of these viral genomes. Enteroviruses could be detected in 14 cases of SIDS, whereas the detection of enteroviral nucleic acid within the control group was negative. Seven cases with myocardial infection caused by parvovirus B19 were found in the SIDS group. The detection of parvoviruses in the control group of the 11 children younger than 1 year was negative, whereas 3 positive cases of parvoviruses could be detected in the control group of children from 1 to 10 years old. In the myocardial sample of one SIDS case, both enteroviruses and parvovirus B19 could be detected. Our results emphasize the importance of modern molecular biologic methods in cases of sudden infant death even when conventional histologic examination revealed no serious findings in heart muscle tissue.

Risk Factors for Sudden Infant Death Syndrome Among Northern Plains Indians

Iyasu, Solomon; Randall, Leslie L.; Welty, Thomas K.; Hsia, Jason; Kinney, Hannah C.; Mandell, Frederick; McClain, Mary; Randall, Brad; Habbe, Don; Wilson, Harry; Willinger, Marian

Vascular endothelial growth factor in the cerebrospinal fluid of infants who died of sudden infant death syndrome: evidence for antecedent hypoxia.

Recurrent hypoxemia has been proposed as an important pathophysiological mechanism underlying sudden infant death syndrome (SIDS). However, conflicting results emerged when xanthines were used as markers for hypoxia. The vascular endothelial growth factor (VEGF) gene is highly sensitive to changes in tissue partial oxygen tension, and changes in genomic and protein expression occur even after changes in oxygenation within the physiologic range. For determining whether hypoxia precedes SIDS, VEGF levels were measured using an enzyme-linked immunosorbent assay in the cerebrospinal fluid (CSF) of 51 SIDS infants and in 33 additional control infants who died of an identifiable cause. In addition, 6 rats that had a chronically implanted catheter in the lateral ventricle were exposed to a short hypoxic challenge, and VEGF concentrations were measured in CSF at various time points for 24 hours. Another set of 6 rats were killed with a pentobarbital overdose, and VEGF CSF levels were obtained at different time points after death. Mean VEGF concentrations in CSF were 308.2 +/- 299.1 pg/dL in the SIDS group and 85.1 +/- 82.9 pg/dL in those who died of known causes. Mean postmortem delay averaged 22 hours for both groups. In rat experiments, hypoxic exposures induced time-dependent increases in VEGF, peaking at 12 hours and returning to baseline at 24 hours. Postmortem duration in the animals was associated with gradual increases in VEGF that reached significance only at 36 hours. We conclude that VEGF CSF concentrations are significantly higher in infants who die of SIDS. We postulate that hypoxia is a frequent event that precedes the sudden and unexpected death of these infants.

Possible role of mtDNA mutations in sudden infant death

Variation in hypervariable region I (HVR-I) and mutations in coding areas of mtDNA were studied in 257 patients of sudden infant death caused by infections, sudden infant death syndrome (SIDS), and borderline SIDS and in a control group of 102 living infants. Nine different point mutations were detected in the coding areas investigated: T3290C, T3308C, T3308G (three patients), A9299G (two patients), G9300A (two patients), T10034C (nine patients), A10042T, C10043T, and A10044G. An association was found between a high number of HVR-I substitutions and potentially pathogenic mtDNA point mutations in coding areas ( P = 0.024, odds ratio = 1.3). The mean number of substitutions in HVR-I was 3.28 in the infectious death group, 2.63 in the borderline SIDS group, 2.58 in the SIDS group, and 2.02 in the control group ( P = 0.005). In coding areas, 11.1% of the infectious death patients had a mutation, and the same was true for 9.8% of the borderline SIDS patients, 5.6% of the SIDS patients, and 2.9% of the control subjects ( P = 0.21). The results indicate that increased levels of HVR-I substitutions may be an indicator of mtDNA instability. Furthermore, mtDNA mutations may play a role in some patients with sudden unexpected infant death that was unexplained or thought to be caused by infection.