PEDIATRICS Vol. 122 No. 5 November 2008, pp. 1003-1008 (doi:10.1542/peds.2007-3502)
ARTICLE |
Mitochondrial Oxidative Phosphorylation Disorders Presenting in Neonates: Clinical Manifestations and Enzymatic and Molecular Diagnoses
a Metabolic Service, Genetic Health Services Victoria, Victoria and Royal Children's Hospital, Melbourne, Australia
b Departments of Public Health Genetics
d Mitochondrial Research, Murdoch Children's Research Institute, Melbourne, Australia
c Department of Paediatrics, University of Melbourne, Melbourne, Australia
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ABSTRACT |
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OBJECTIVES. The goals were to examine the frequency of perinatal manifestations of mitochondrial oxidative phosphorylation disorders within a population-based cohort, to characterize these manifestations, to identify a possible association between these manifestations and diagnoses at a later age, and to identify possible associations between perinatal complications and specific disorders.
METHODS. We conducted a retrospective review of clinical and laboratory records for all patients with definitive oxidative phosphorylation disorders who were diagnosed and treated at the Royal Children's Hospital in Melbourne between 1975 and 2006 (N = 107; male/female ratio: 1.41).
RESULTS. Neonatal presentation was recorded for 32 of 107 patients (male/female ratio: 1:1), including 19 who presented on day 1 of life. Prematurity (gestational age of <37 weeks) was noted for 12.6% of the 107 patients. Of the 85 infants with known birth weights, 24 were in the 
10th percentile for gestational age (11 with complex I deficiency), and 9 of those (6 with complex I deficiency) were in the <3rd percentile. The most common presenting neonatal symptoms after the first day of life were poor feeding, recurrent vomiting, and failure to thrive. We noted 3 main clinical neonatal forms of oxidative phosphorylation disorders (encephalomyopathic, hepatointestinal, and cardiac). Of the 32 infants, 28 died (13 in the neonatal period). Complex I deficiency was identified for 15 neonates, combined complexes I, III, and IV deficiency for 7 neonates, and combined complexes I and IV deficiency for 3 neonates. No neonates had complex IV deficiency. Six neonates had nuclear mutations, and 2 neonates had the mitochondrial DNA 8993T>G mutation.
CONCLUSIONS. Oxidative phosphorylation disorders present commonly in the neonatal period. The combination of nonspecific manifestations such as prematurity and intrauterine growth retardation with early postnatal decompensation or poor feeding or vomiting and persistent lactic acidosis should suggest the possibility of an oxidative phosphorylation disorder.
Key Words: oxidative phosphorylation • mitochondrial respiratory chain • neonate • failure to thrive • intrauterine growth retardation • neonatal morbidity • neonatal mortality
Abbreviations: OXPHOS—oxidative phosphorylation
Mitochondria are essential organelles found in all nucleated mammalian cells. They function to provide the energy required for normal cell function through oxidative phosphorylation (OXPHOS). The OXPHOS system comprises the mitochondrial respiratory chain complexes (complexes I–IV) and adenosine triphosphatase (complex V). Defects of the OXPHOS system are increasingly being shown to underlie a wide variety of clinical presentations in any organ or system,1 ranging from prenatal complications through acute neonatal decompensation and death to adult-onset disorders.
Prenatal abnormalities were reported in a large series of patients diagnosed as having OXPHOS disorders, including intrauterine growth retardation (in 68 of 300 patients) and a variety of fetal abnormalities.2 Several "neonatal syndromes" that may be caused by a primary OXPHOS perturbation have been recognized, such as lethal infantile mitochondrial disease.3 In some of these syndromes, such as severe liver disease caused by hepatic mitochondrial DNA depletion,4 an association between the clinical presentation and the enzymatic or molecular defect has been established. The neonatal presentation profiles of OXPHOS disorders that also may present at a later age, such as disorders involving coenzyme Q10 deficiency5 or disorders involving liver dysfunction,6 have been described. We recently reported the poor outcomes of patients presenting with primary cardiac manifestations at an early age.7 In addition, neonatal renal manifestations as presenting symptoms of OXPHOS disorders have been documented.8 However, the frequency of these "neonatal syndromes" and possible associations between perinatal manifestations attributable to OXPHOS disorders and later morbidity or death have not been reported.
The high energy demands of labor, delivery, and the early neonatal period increase the vulnerability of infants with impaired energy production. Patients with mitochondrial OXPHOS disorders may thus be compromised at birth or in the first days of life, although more-specific clinical signs and symptoms that lead clinicians to suspect an OXPHOS diagnosis may be delayed. The aims of the present study were (1) to examine the frequency of perinatal manifestations of mitochondrial OXPHOS disorders within a population-based cohort of patients, (2) to characterize these manifestations and to identify a possible association between these manifestations and more-specific clinical diagnoses at a later age, and (3) to identify possible associations between perinatal complications and specific defects in the OXPHOS system.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We reviewed all clinical and laboratory records of all patients who were residents of Victoria, had OXPHOS disorders diagnosed between 1975 and 2006 in the Mitochondrial Research Laboratory at the Murdoch Children's Research Institute, Royal Children's Hospital (Melbourne, Australia), and were treated at that hospital. Ascertainment was through a computer-based database of all patients evaluated by the laboratory, which serves as a reference laboratory for the study of mitochondrial disorders in Australasia. We included in this study only patients who received definitive diagnoses according to our previously published diagnostic criteria.9 Some patients with mitochondrial respiratory chain enzyme activities not low enough to be considered diagnostic of an OXPHOS defect were recently found to have mutations in the polymerase
(POLG) gene and were included in this review (the significance of mutations in this gene, which plays a crucial role in mitochondrial DNA replication, has been elucidated in recent years). The clinical, enzymatic, and molecular data were collected for the whole cohort.
Mitochondrial enzyme studies were performed in 
1 of skeletal muscle, liver, heart, or cultured fibroblasts.10 Mutation analyses were performed by the molecular diagnostic laboratory of the Victorian Clinical Genetics Service, the Mitochondrial Research Laboratory at the Murdoch Children's Research Institute, or overseas laboratories of international collaborators.
We divided the patients into 2 groups according to their age at presentation, that is, neonatal (first 28 days of life) and postneonatal (>28 days). Perinatal data for patients in each group were analyzed separately. Observational data regarding the frequency of perinatal complications for patients with OXPHOS defects were compared with corresponding data for the general newborn population in Victoria by using annual reports from the Victorian Perinatal Data Collection Unit, where mandatory notifications of all births of 20 weeks of gestation are held within the Department of Human Services of the government of Victoria. Because of the small numbers, no statistical analyses were performed.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Group
There were 107 patients, including 63 male patients and 44 female patients (male/female ratio: 1.4:1). Neonatal presentation was recorded for 32 (29%) of 107 patients, including 10 who presented at birth and 9 who presented on day 1 of life. There were 16 male and 16 female patients in the neonatal group (male/female ratio: 1:1). It should be noted that one half of the patients in our study who presented in the neonatal period were diagnosed in 2001-2006. To identify possible associations between clinical, enzymatic, and molecular diagnoses and clinical manifestations, the data were organized in Tables 1 to 3 according to age at presentation, with special attention to day 1 of life and the neonatal period.
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Clinical Enzymatic and Molecular Diagnoses
The most common diagnoses were Leigh disease or Leigh-like disease (29 of 107 patients) and mitochondrial cytopathy (22 of 107 patients), defined as a multisystemic disorder affecting the muscular, central nervous system, visual, and auditory systems and possibly the kidneys and liver. The most common clinical diagnoses in the neonatal group, as noted in the patients' records, were neonatal lactic acidemia (8 of 32 patients), cardiomyopathy (5 of 32 patients), and mitochondrial cytopathy (5 of 32 patients). Of the 4 patients with lethal infantile mitochondrial disease, 3 presented in the neonatal period and 2 of those presented with hepatopathy. An OXPHOS enzyme complex defect was found for 83 (78%) of 107 patients. Complex I deficiency (40 of 83 patients; 15 neonates) and combined deficiencies involving complexes I, III, and IV (16 of 83 patients; 7 neonates) were the most common findings. Combined deficiency of complexes I and IV was found for 6 of 83 patients (3 neonates), and complex IV deficiency was found for 12 of 83 patients (no neonates) (Table 1). The others had various combinations of complex deficiencies, and 1 patient had complex III deficiency. Two patients had normal enzyme activity (1 with a high mutant load of the mitochondrial T8993G mutation, which was found subsequently, and 1 with cytochrome oxidase-negative fibers in an enzyme histochemical analysis of a skeletal muscle biopsy sample, as well as increases in mitochondrial density and subsarcolemmal collection of lipid in an electron microscopic evaluation). Molecular diagnoses were available for 55 of 107 patients and included nuclear mutations (29 of 55 patients; 9 neonates) and mitochondrial DNA deletions, point mutations, or rearrangements (25 of 55 patients; 2 neonates with a 8993T>G mutation). Histopathologic changes were found for 6 patients.
Pregnancy, Gestation, and Delivery
Details about pregnancy history were recorded in the notes for 77 patients, and abnormalities were recorded for 21. The main gestational observations (usually with >1 in a pregnancy) were intrauterine growth retardation (6 patients), paucity of movements (6 patients), polyhydramnios (3 patients) or oligohydramnios (2 patients), and maternal hypertension or (pre)eclampsia (5 pregnancies). Fetal hydrops was noted for 3 infants (1 suspected of having Barth syndrome, in view of an older affected sibling, and 1 stillborn at 20 weeks). Fetal cardiac abnormalities were noted in 4 pregnancies, including hypertrophic cardiomyopathy (1 patient), combined dilated left ventricle and hypertrophic right ventricle (1 patient), an episode of fetal tachyarrhythmia documented on fetal monitoring and presenting as supraventricular tachycardia on day 1 of life (1 patient), and a ventricular septal defect in an infant who also had a 22q11 deletion.
We aimed to identify possible associations of gestational age, delivery, and birth weight with age at presentation (Table 2). Information on gestational age was available in the notes for 95 of 107 patients. Prematurity (gestational age of <37 weeks) was noted for 12 (12.6%) of 95 patients and specifically for 8 of 31 patients who presented in the neonatal period. Preterm delivery rates in Victoria have been recorded since 1983 and had increased from 
6% to 8% by 2005.11–13 There was no association between prematurity and a particular clinical, enzymatic, or molecular defect.
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Information regarding delivery was available for 88 patients (and 1 stillborn infant) (Table 2). Normal delivery was noted for 50 patients, including 9 cases of induction and 4 "precipitate" deliveries. Three infants were delivered by using ventouse extraction and 9 by using forceps. Cesarean section was performed for 20 (23%) of 88 patients, including emergency cesarean section for 9 (10.2%) of 88 patients. These rates did not differ from those for all deliveries in Victoria during the study period.11–13
Birth weight data were available for 85 patients; birth weight data were missing in the notes of patients with a variety of deficiencies or mutations, mostly born in the 1970s and 1980s, with no predominance of a particular diagnosis except for 3 of 6 patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Of the 85 infants with known birth weights, 24 (28%) were of 10th percentile, 43 (50%) were of >10th percentile but 50th percentile, 15 (18%) were of >50th percentile but 90th percentile, and 3 (4%) were of >90th percentile. Of the 24 infants with birth weights of 10th percentile, 11 had complex I deficiency and 3 had complex IV deficiency (including 1 with deficiency only in the liver). All 3 infants with complex IV deficiency presented after the neonatal period. Two infants had complex I plus IV deficiency, 3 had complex I plus III plus IV deficiency, 6 had mutations in the POLG gene, 2 had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, and 1 had abnormal histologic and histochemical analysis results for a muscle biopsy sample. Of those 24 infants, 9 infants had birth weights of <3rd percentile, 6 of whom had complex I deficiency.
Given the large proportion of patients with complex I deficiency in this cohort, we analyzed their birth weights in more detail. Figure 1 depicts the birth weights of all patients with complex I deficiency. Of note, complex I deficiency only in the heart or liver was not associated with low birth weight, with the exception of 1 patient. The numbers of patients with particular mutations were too small to allow conclusions about any correlations, although there seemed to be a trend toward such a correlation (eg, mutations in the ND6 subunit, compared with mutations in the ND5 subunit).
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Neonatal Symptoms and Signs
Congenital malformations were noted in 4 neonates, including contractures (1 neonate), a short foreskin and dilated urinary meatus (1 neonate), bilateral talipes equinovarus, umbilical hernia, and hypospadias (1 neonate), and hypospadias (1 neonate). There was no association between any of these malformations and particular enzymatic or molecular defects.
Ten infants presented at birth and another 9 on day 1 of life. A "collapse" immediately after birth or later on day 1 was noted for 8 of 32 newborns. Full resuscitation was required for 8 of the 25 infants from this group for whom this information was available, 2 infants did not undergo resuscitation because of very poor condition, and 2 needed some support after delivery. Another infant underwent resuscitation on day 1 of life and was without symptoms until presentation at 9 months of age.
Patients usually presented with >1 symptom or sign in the neonatal period, and a summary is presented in Table 3. We noted 3 main clinical forms of OXPHOS disorders in the neonatal period. Most patients presented with an encephalomyopathic form, which included any of encephalopathy, seizures, hypotonia, or ophthalmologic manifestations, or a combination thereof. This group included 17 patients, of whom 8 had neonatal persistent lactic acidosis and 4 were later diagnosed as having Leigh disease. Of note, a newborn screening program for hearing deficiency has been in place for several years in Victoria, but we are not aware of any newborn in this cohort having sensorineural hearing loss. It is possible that some very sick infants were missed by the screening program, however, and prospective studies should be performed to explore the prevalence of sensorineural hearing loss in newborns with OXPHOS defects. A hepatointestinal form, presenting as cholestatic jaundice ("neonatal hepatopathy") with or without hypoglycemia, recurrent vomiting, or diarrhea or with intestinal dysmotility, was noted for 8 patients. This group included 5 patients who were later found to have a mutation in the POLG gene, 2 of whom had Alpers syndrome. A cardiac form, mainly early lethal cardiomyopathy, was noted for 5 patients. Two other patients, one with hydrops fetalis and the other with poor feeding and vomiting, were later diagnosed as having Barth syndrome. The most common, presenting, neonatal symptoms after the first day of life, noted in all 3 clinical forms, were poor feeding, recurrent vomiting, and failure to thrive, which were found for 9 of 31 infants. It is interesting to note that 5 of those infants were later found to have mutations in the POLG gene. Respiratory difficulties were found for 6 patients, from all clinical groups.
Outcomes
Of the 32 infants who presented in the neonatal period, 28 died (13 in the neonatal period), 2 were lost to follow-up monitoring, and 2 are alive. Of the 74 patients who presented at a later age, 46 died, 12 were lost to follow-up monitoring, and 16 are alive.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study aimed to examine the frequency and nature of perinatal complications in OXPHOS disorders and to identify potential associations between specific OXPHOS disorders and perinatal presentations or complications. A limitation of this study is the fact that data were retrieved retrospectively from patients' notes, and the lack of systematic comprehensive data on all patients prevented more-comprehensive analysis of symptoms and signs. However, this study has an important strength. Although complete ascertainment of all patients born in a given region and time period cannot be guaranteed, given the clinical and genetic diversity of OXPHOS disorders, we think that we are likely to have ascertainment of children with OXPHOS disorders as complete as is currently possible to achieve in any population. The availability of medical records and laboratory data for a single, large, pediatric population diagnosed and treated in 1 tertiary referral center that serves the whole state of Victoria enabled us to characterize the perinatal features of OXPHOS defects in this population.
We found that a large proportion of patients with OXPHOS disorders presented in the neonatal period and that this presentation was associated with early death, as reported previously,3,14 regardless of the particular system or organ involved, gestational age, or birth weight. The greater number of neonates diagnosed as having these disorders in the past 6 years suggests that the true proportion of patients with OXPHOS disorders who present in the neonatal period is probably higher, and this indicates that increased awareness should lead to the diagnosis of more neonates with OXPHOS disorders. Given the high mortality rate in this patient population, it is likely that OXPHOS disorders are responsible for a significant proportion of neonatal deaths, but prospective research is needed to substantiate this hypothesis. The male/female ratio of 1:1 for patients presenting in the neonatal period was noted previously14 and is intriguing, in that it deviates considerably from the usual 1.5:1 male/female ratio found in large patient groups, including our own, when the whole cohort of patients is considered.3,15
Low birth weight was common in our cohort of patients, in agreement with the findings by von Kleist-Retzow et al,2 who suggested that OXPHOS disorders may underlie prematurity and prenatal growth and developmental anomalies in 1 system. In theory, these infants may be more susceptible to perinatal complications, either secondary to their prematurity and low birth weight or directly attributable to their primary OXPHOS disorders. The results shown in Table 2 suggest that these complications cannot be correlated with low birth weight, but the number of patients was too small to allow conclusions regarding a causal relationship between prematurity and complications in our cohort. Of particular note is the lack of apparent association between specific OXPHOS diagnoses and the type of delivery, although a relatively large proportion of patients were born after some intervention. Other nonspecific prenatal manifestations included congenital malformations and fetal hydrops, as well as prenatal seizures and cardiac arrhythmia, which were more specific to neurologic or cardiac dysfunction, respectively.
We identified some common nonspecific manifestations of OXPHOS disorders in the neonatal period, namely, poor feeding, recurrent vomiting, and failure to thrive, as well as 3 main clinical neonatal forms, namely, an encephalomyopathic form, an hepatointestinal form, and a cardiac form. A nephropathic form has been described8 but was not found in our patient population. The advantage of characterization of neonatal clinical manifestations as these clinical forms, compared with categorizations such as "neonatal lactic acidosis" or "lethal infantile mitochondrial disease," is in that the characterization better serves as a clinical guideline and may lead to more-specific enzymatic or molecular testing and, to a limited extent, prognostication.14 For example, early hepatic involvement has been associated with hepatic mitochondrial DNA depletion syndromes, such as those resulting from mutations in the deoxyguanosine kinase (DGUOK) gene16,17 (the product of which plays an important role in the maintenance of mitochondrial deoxyribonucleotide pools) or the POLG gene.18 In addition to these specific diagnoses, a severe form of hepatic involvement in the first days of life attributable to various enzymatic OXPHOS defects but no mitochondrial DNA depletion or deletion has been described.6 Early presentation was associated with poor outcomes. Similarly, we7 and others15,19 reported previously on the natural history of patients who present early in life with cardiac manifestations attributable to OXPHOS defects. It is important to note that the potentially specific finding of an OXPHOS defect in the liver or heart of neonates (and older patients) should prompt clinicians to consider biopsies of these organs for the diagnosis of OXPHOS disorders and not to rely only on skeletal muscle biopsies. In some circumstances, these biopsies could be taken as part of a metabolic postmortem protocol.
In a study focusing on the long-term outcomes of neonates with OXPHOS defects, Garcia-Cazorla et al14 categorized 57 patients according to clinical outcomes and according to plasma lactate levels. The clinical outcome categories included progression toward neurologic disease, hepatodigestive disease, myopathic disease, and multisystemic disease. The characteristics of our clinical groups were similar but not identical to those. The differences probably stem from the different purposes of the 2 studies. We categorized our patients according to their clinical findings in the neonatal period (hence, prospectively, with the aim of helping in the diagnostic process), rather than according to their clinical outcomes (hence, retrospectively, with the aim of helping in prognostication). Many patients who survive the neonatal period may gradually suffer from a multisystemic disorder, beyond the primary 3 forms described above. We did not include data on plasma and cerebrospinal fluid lactate levels in our study because of inconsistencies in the availability of these data over the years. Similarly, information regarding renal tubular function, which theoretically could be helpful, was not included in our study because of poor data quality.
Our results suggest possible specific associations between early clinical manifestations and particular OXPHOS disorders. For example, whereas higher rates of prematurity and intrauterine growth retardation leading to low birth weight were observed with complex I deficiency, there was no increase in any perinatal complications with complex IV deficiency, with or without a mutation in the SURF1 gene (which is involved in the assembly of complex IV), despite the rapid decline and early death that followed the onset of manifestations of this deficiency (an exception was a patient with complex IV deficiency in the liver but not in muscle). Moreover, as can be seen in Fig 1, it is possible that some specific molecular defects leading to complex I deficiency are not associated with low birth weight, but additional research with larger cohorts of patients is required to substantiate this finding. Similarly, whereas there was a high rate of neonatal presentation in complex I deficiency, there was none in complex IV deficiency. This difference perhaps reflects temporal or developmental stage-specific gene expression, tissue specificity of gene expression, or the changing energy demands of an infant over time. This theoretical explanation follows the suggestion that congenital malformations in OXPHOS defects result from the disease gene being expressed during early prenatal development and resulting in disturbed embryogenesis, either because of a leak of ATP or secondary to disturbed apoptotic processes.2 A possible association between neonatal presentation and mutations in nuclear genes responsible for OXPHOS structure and integrity is shown by the finding of only 2 neonates with a mitochondrial DNA mutation (T8993G), but additional research on larger patient cohorts is needed to substantiate this observation.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OXPHOS disorders lead to prenatal and postnatal manifestations in a large proportion of patients. We suggest that nonspecific observations such as prematurity and intrauterine growth retardation should be coupled with malformations, early postnatal decompensation, or poor feeding or vomiting and with persistent lactic acidosis to suggest the possibility of an OXPHOS disorder. We propose 3 clinical forms, that is, neonatal encephalopathy and/or seizures, intestinal dysmotility or liver disease, and cardiomyopathy, which may help direct more-specific diagnostic investigations.
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ACKNOWLEDGMENTS |
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This study was supported in part by a grant from the National Health and Medical Research Council of Australia (project grant 436901). Dr Kirby is a C. J. Martin postdoctoral fellow of the National Health and Medical Research Council (ID 334371). Dr Halliday is a senior research fellow (ID 436904) and Dr Thorburn is a principal research fellow (ID 436906) of the National Health and Medical Research Council.
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FOOTNOTES |
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Accepted Feb 6, 2008.
Address correspondence to Avihu Boneh, MD, PhD, Metabolic Service, Genetic Health Services Victoria, Royal Children's Hospital, Flemington Rd, Parkville, Melbourne, Victoria 3052, Australia. E-mail: avihu.boneh{at}ghsv.org.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Intrauterine growth retardation and prematurity have been reported in oxidative phosphorylation disorders. Poor prognosis for patients presenting in the neonatal period has been reported. One study dealt with neonatal lactic acidosis and provided clues for prognostication in these infants.
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| What This Study Adds This was a population-based study. We report a high incidence and poor prognosis of neonatal presentation of OXPHOS disorders, associations between particular OXPHOS complex deficiencies and intrauterine growth retardation and prematurity, and 3 main clinical forms of neonatal presentation.
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