RESUMEN
BACKGROUND: Cyclic vomiting syndrome (CVS) is a common, frequently disabling, 'functional' condition characterized by recurring, stereotypical attacks of intense nausea, vomiting, and lethargy, with the essential absence of these symptoms between episodes. Although the pathogenesis of CVS is yet unexplained, evidence has accumulated which suggest pathogenic roles for stress-related, autonomic, neuroendocrine, and mitochondrial factors. The objective of this pilot study was to elucidate mechanism(s) by identifying genes involved in the presumed multifactorial pathogenesis of CVS. METHODS: In this pilot study, DNA from 75 unrelated CVS cases and 60 healthy controls were assayed by Courtagen Life Science's next-generation sequencing platform (nucSEEK(™) ), including over 1100 nuclear-encoded genes involved with mitochondria, metabolism, or ion channels. Significant sequence variants were defined as evolutionary conservation at least to Xenopus (frog) per the UCSC Genome Browser. KEY RESULTS: The RYR2 gene, encoding a stress-induced calcium channel present in many neurons, was the only gene demonstrating a statistically significant difference in the proportion of conserved sequence variants among the groups (18/75 CVS, 24%, vs 3/60 controls, 5%; p = 0.0018, OR = 6.0, 95% CI = 1.7-22). CONCLUSIONS & INFERENCES: We propose a mechanism in which RYR2 sequence variants result in aberrant stress-induced calcium release into the mitochondria of autonomic neurons, resulting in an increased risk to develop autonomic/functional disease such as CVS, and related conditions such as migraine and gut dysmotility. This model incorporates the existing hypotheses regarding CVS pathogenesis into a cohesive mechanism, and might have treatment implications.
Asunto(s)
Variación Genética , Mutación , Canal Liberador de Calcio Receptor de Rianodina/genética , Vómitos/genética , Adolescente , Adulto , Sistema Nervioso Autónomo/metabolismo , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Vómitos/metabolismo , Adulto JovenRESUMEN
Pediatric cyclic vomiting syndrome (CVS) is associated with a high prevalence of co-morbid migraine and other functional disorders, and with two adult migraine-associated mitochondrial DNA (mtDNA) polymorphisms: 16519T and 3010A. These potential associations have not been studied in adult CVS. The objective of this study is to determine the prevalence of 16519T and 3010A mtDNA polymorphisms and other functional disorders in adult CVS patients. Adults with CVS recruited from the University of Kansas meeting Rome III criteria and a population control group completed a self-reported survey that included questions relating to the diagnostic criteria for several functional disorders. DNA was isolated from blood or saliva and genotyping was performed by standard methodologies. Adult CVS subjects, compared to controls, had significantly more symptoms consistent with several other functional disorders. 16519T was present in 22/31 cases (71%) of child-onset (<12 years) and 9/31 (29%) cases of adult-onset (18+ years) CVS (P = 0.01), vs 27% of controls. Among subjects with 16519T, 3010A was present in 30% of child-onset vs 0% of adult-onset CVS (P = 0.05) and 2% of controls. The conclusions drawn were: (i) unlike pediatric CVS, adult CVS is not associated with the 16519T and 3010A mtDNA polymorphisms, suggesting a degree of genetic distinction and (ii) similar to the pediatric setting, adult CVS is associated with a substantial burden of co-morbid functional disorders.
Asunto(s)
ADN Mitocondrial/genética , Trastornos Migrañosos/complicaciones , Polimorfismo Genético/genética , Vómitos/etiología , Vómitos/genética , Adolescente , Adulto , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Síndrome , Vómitos/epidemiología , Adulto JovenRESUMEN
Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of migraine without aura (MoA, 'common migraine') and the related condition of cyclic vomiting syndrome (CVS). In this study, the entire mitochondrial genome was sequenced in 20 haplogroup-H CVS patients, a subject group studied because of greater genotypic and phenotypic homogeneity. Sequences were compared against haplogroup-H controls. Polymorphisms of interest were tested in 10 additional CVS subjects and in 112 haplogroup-H adults with MoA. The 16519C-->T polymorphism was found to be highly disease associated: 21/30 CVS subjects [70%, odds ratio (OR) 6.2] and 58/112 migraineurs (52%, OR 3.6) vs. 63/231 controls (27%). A second polymorphism, 3010G-->A, was found to be highly disease associated in those subjects with 16519T: 6/21 CVS subjects (29%, OR 17) and 15/58 migraineurs (26%, OR 15) vs. 1/63 controls (1.6%). Our data suggest that these polymorphisms constitute a substantial proportion of the genetic factor in migraine pathogenesis, and strengthen the hypothesis that there is a component of mitochondrial dysfunction in migraine.
Asunto(s)
ADN Mitocondrial/genética , Predisposición Genética a la Enfermedad , Trastornos Migrañosos/genética , Vómitos/genética , Adulto , Niño , Femenino , Humanos , Masculino , Trastornos Migrañosos/complicaciones , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Síndrome , Vómitos/etiologíaRESUMEN
OBJECTIVE: To examine maternal parenting behaviors, child temperament and their potential interactions in families of obese children and demographically similar families of nonoverweight children. DESIGN: A total of 77 obese youth (M body mass index (BMI) z-score values, zBMI=2.4; ages 8-16, 59% female, 50% African American) and their parents were recruited from a pediatric weight management clinic and compared to 69 families of nonoverweight youth (M zBMI=-0.03). Comparison youth were classmates of each obese participant matched on gender, race and age. MEASUREMENTS: Maternal report of child temperament, parenting style and anthropometric assessments were obtained. RESULTS: Compared to nonoverweight youth, mothers of obese youth described their child as having a more difficult temperament and their parenting style as lower in behavioral control. A logistic regression model indicated that difficult temperament, lower behavioral control and the interaction of low maternal warmth and difficult child temperament were associated with increased odds of a child being classified as obese. CONCLUSIONS: Treatment-seeking obese youth and their parents are characterized by different parent and child factors when compared to nonoverweight comparison families. These findings direct investigators to test more complex models of the relation between parent and child characteristics and their mutual role in the weight-related behavior change process.
Asunto(s)
Obesidad/psicología , Responsabilidad Parental , Temperamento , Adolescente , Adulto , Factores de Edad , Estatura/fisiología , Índice de Masa Corporal , Peso Corporal/fisiología , Niño , Femenino , Humanos , Masculino , Relaciones Madre-Hijo , Obesidad/etnología , Obesidad/terapia , Aceptación de la Atención de Salud , Análisis de Regresión , Caracteres SexualesAsunto(s)
ADN Mitocondrial/genética , Genes Mitocondriales , Trastornos Migrañosos/genética , Modelos Genéticos , Distribución por Sexo , Femenino , Fibromialgia/genética , Enfermedades Gastrointestinales/genética , Predisposición Genética a la Enfermedad , Hormonas Esteroides Gonadales/fisiología , Humanos , Masculino , Trastornos Migrañosos/epidemiología , Enfermedades Mitocondriales/genética , PrevalenciaRESUMEN
Cyclic vomiting syndrome (CVS) was initially described in children but can occur in all age groups. Cyclic vomiting syndrome is increasingly recognized in adults. However, the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and a paucity of published data on the causes, diagnosis and management of CVS in adults. This article is a state-of-knowledge overview on CVS in adults and is intended to provide a framework for management and further investigations into CVS in adults.
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Vómitos/diagnóstico , Vómitos/fisiopatología , Vómitos/terapia , Adulto , Niño , Humanos , SíndromeRESUMEN
OBJECTIVE: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited mitochondrial disease, an association not previously published. METHODS: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria. RESULTS: CRPS-I was present in eight children in seven families, each of which also had additional functional/dysautonomic conditions, the most common (> or = 4 cases per condition) being gastrointestinal dysmotility, migraine, cyclic vomiting and chronic fatigue. All seven probands studied met Nijmegen (2002) diagnostic criteria for definite mitochondrial disease on the basis of the clinical signs and symptoms and biochemical analyses. Six of the seven families met our pedigree-based criteria for probable maternal inheritance. CONCLUSION: In one tertiary-care paediatric genetics practice, children meeting the CRPS-I diagnostic criteria frequently had additional autonomic-related conditions secondary to maternally inherited mitochondrial disease, suggesting that mitochondrial DNA sequence variants can predispose children towards the development of CRPS-I and other dysautonomias. CRPS-I should be considered in patients with mitochondrial disease who complain of idiopathic pain. Maternally inherited mitochondrial disease may not be a rare cause of CRPS-I, especially in children who present with other manifestations of dysautonomia.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades Mitocondriales/complicaciones , Adolescente , Enfermedades del Sistema Nervioso Autónomo/genética , Estudios de Casos y Controles , Niño , Preescolar , ADN Mitocondrial/genética , Herencia Extracromosómica/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/genética , Distrofia Simpática Refleja/etiología , Distrofia Simpática Refleja/genética , Estudios RetrospectivosRESUMEN
Inherited disorders of energy metabolism are increasingly being recognized as important causes of cardiomyopathy in children. We previously reported that heteroplasmic point substitutions in the mitochondrial DNA D-loop were found in 15 of 75 children at risk for mitochondrial disease (vs 0/95 controls). Four of these cases presented with severe cardiomyopathy in congestive failure in addition to other anomalies and are presented here. In each case, myocardial dysfunction greatly improved following supportive therapy aimed at reversing both congestive failure and catabolism. D-loop point heteroplasmy may be a marker for severe, reversible, infantile multisystem disease that can present with cardiomyopathy.
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Cardiomiopatías/genética , ADN Mitocondrial , Preescolar , Femenino , Humanos , Masculino , MutaciónRESUMEN
Mitochondrial DNA (mtDNA) depletion refers to a quantitative defect in mtDNA and is heterogeneous with regard to causal genotypes and the associated clinical phenotypes. We report two unrelated infants with mtDNA depletion. A diagnosis of methylmalonic aciduria was initially raised in both on the basis of high urine methylmalonic acid and related organic acids and elevated propionylcarnitine and methylmalonylcarnitine. Carboxylase assay with skin fibroblasts revealed low propionyl-CoA and 3-methylcrotonyl-CoA carboxylase and normal pyruvate carboxylase activities. Quantitative Southern blot analysis of mitochondrial and nuclear DNA with muscle tissues revealed the patients' mtDNA to be depleted to 24% and 39% of normal controls. Our two patients showed multiple mitochondrial dysfunction including respiratory chain defects and deficiencies in the two nuclear DNA encoded carboxylases resulting in abnormal urine organic acids. To our knowledge, there is no obvious connection between the defective pathways other than their mitochondrial locations. These two cases may represent a new entity of mitochondrial disease that might be due to a defective common mechanism, such as assembly, maintenance and transport, affecting various mitochondrial enzymes and functions. Mitochondrial depletion should be considered in infants with atypical organic aciduria that may resemblemethylmalonicaciduria, propionicacidaemia, or 3-methylcrotonyl-CoA carboxylase deficiency.
Asunto(s)
Ligasas de Carbono-Carbono/deficiencia , ADN Mitocondrial/genética , Eliminación de Gen , Ácido Metilmalónico/orina , Enfermedades Mitocondriales/genética , Acidemia Propiónica , Preescolar , Femenino , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Fenotipo , SíndromeRESUMEN
A 9-month-old boy with presented generalised hypotonia, severe cardiomyopathy, and massive liver enlargement following 10 days of viral gastroenteritis. He was diagnosed with very long-chain acyl-CoA dehydrogenase deficiency and has been successfully treated.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Hepatomegalia/enzimología , Cardiomiopatías/complicaciones , Carnitina/uso terapéutico , Dieta , Gastroenteritis/complicaciones , Hepatomegalia/dietoterapia , Hepatomegalia/patología , Humanos , Lactante , Masculino , Hipotonía Muscular/complicaciones , Tomografía Computarizada por Rayos X , Triglicéridos/uso terapéutico , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
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Densidad Ósea/genética , Anomalías del Ojo/genética , Ojo/embriología , Osteoblastos/metabolismo , Osteoporosis/genética , Receptores de LDL/fisiología , Factor de Crecimiento Transformador beta , Proteínas de Pez Cebra , Proteínas Adaptadoras Transductoras de Señales , Adulto , Animales , Animales no Consanguíneos , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/farmacología , Células COS , Niño , Preescolar , Chlorocebus aethiops , Cromosomas Humanos Par 11/genética , Medios de Cultivo Condicionados/farmacología , ADN Complementario/genética , Proteínas Dishevelled , Femenino , Genes Recesivos , Heterocigoto , Humanos , Proteínas Relacionadas con Receptor de LDL , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Masculino , Mesodermo/citología , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Fosfoproteínas/genética , Fosfoproteínas/fisiología , Proteínas/genética , Proteínas/fisiología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Receptores de LDL/deficiencia , Receptores de LDL/genética , Proteínas Recombinantes de Fusión/fisiología , Proteínas Recombinantes , Transducción de Señal , Cráneo/citología , Especificidad de la Especie , Células del Estroma/citología , Células del Estroma/efectos de los fármacos , Síndrome , Transfección , Proteínas Wnt , Proteína Wnt-5a , Proteína wnt2 , Proteína Wnt3 , Proteína Wnt4RESUMEN
A child with controlled human immunodeficiency virus infection presented with neurologic deterioration, lactic acidosis, and organic aciduria. Muscle biopsy revealed abnormal mitochondrial (mt) morphology, reduced mt enzyme activities, and mtDNA depletion. After adjustment of antiretroviral therapy to a regimen free of nucleoside analogs, marked improvement was seen in clinical status and mt abnormalities.
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Acidosis/etiología , Terapia Antirretroviral Altamente Activa/efectos adversos , ADN Mitocondrial/metabolismo , Fallo Hepático/inducido químicamente , Músculo Esquelético/patología , Terapia Antirretroviral Altamente Activa/métodos , Biopsia , Preescolar , ADN Mitocondrial/genética , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , EspectrofotometríaRESUMEN
Temporal temperature gradient gel electrophoresis was used to screen 70% of the mtDNA, including all 22 tRNA genes, for heteroplasmy in 75 children with neuromuscular and/or multi-system dysfunction and elevated lactate levels, and in 95 controls. Standard PCR/ASO (allele specific oligonucleotide) and Southern analyses were also employed. Excluding common length variants, heteroplasmy was found in 22 patients and two controls (P < 0.001), with four patients demonstrating heteroplasmy in two locations each. Of the 23 heteroplasmic variants sequenced among the patients, 17 were novel point variants in the control region (CR) and only two involved tRNA genes. Heteroplasmy is highly associated with the disease group, and is predominately found in the CR, an area rarely studied in patient populations. These variants may be pathological mutations or disease markers.
RESUMEN
Diagnosis by newborn screening and the implementation of a phenylalanine-restricted diet have resulted in normal neurological development in approximately 10,000 persons with phenylketonuria (PKU) in the United States. While it is accepted that a phenylalanine-restricted diet is necessary in childhood, the recommended concentration of phenylalanine in the blood varies. Clinicians now must make recommendations for adults with PKU who probably tolerate higher levels of phenylalanine than children. This factor, quality of life issues, the expense of the diet, and varying genetic and socioeconomic backgrounds, make the choice of dietary recommendations difficult. Molecular analysis of the mutations in PKU has provided insight but has not resulted in clear recommendations for phenylalanine concentration in the blood. Magnetic resonance imaging has provided the recognition that white-matter changes are present in PKU. However, owing to poor correlation of white-matter changes with clinical factors, analysis of white-matter changes has not proved useful. We hypothesize that measurement of brain phenylalanine directly will aid in clinical decision making. Twenty-one subjects with PKU had blood and brain phenylalanine measured simultaneously. Fifteen were randomly selected, 2 were examined for clinical reasons and 4 exceptional patients were chosen because they had maintained high IQs, despite having high historic blood concentrations and having been off the diet for at least 10 years. The correlation of blood and brain phenylalanine is in general poor. However, the four exceptional patients all had relatively low concentrations of phenylalanine in their brains compared to their blood. We suggest that their good clinical status, despite high historic blood levels, is due to their comparatively low brain levels of phenylalanine. We further suggest that measurement of brain phenylalanine concentration is useful in the management of PKU patients.
Asunto(s)
Química Encefálica , Fenilalanina/análisis , Fenilcetonurias/terapia , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Fenilalanina/sangre , Fenilcetonurias/metabolismoRESUMEN
Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism.
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Proteínas de Transporte de Monosacáridos/deficiencia , Niño , Grasas de la Dieta/administración & dosificación , Electroencefalografía/métodos , Glucosa/metabolismo , Humanos , Discapacidad Intelectual/etiología , Cetosis , Masculino , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/dietoterapia , Convulsiones/diagnóstico , Convulsiones/etiología , Convulsiones/terapiaRESUMEN
Mutations of mitochondrial DNA are being increasingly recognized as a cause of human disease. Six unrelated children have been evaluated with cyclic vomiting syndrome and a strong maternal family history suggesting a mitochondrial DNA mutation. Manifestations suggestive of migraine were present in each child. Additional clinical findings present in all cases include: developmental delay (3/6 cases), seizures (3/6), and poor growth (3/6). The age of onset for vomiting episodes was < or = 1 year in five cases. An elevated body fluid lactate (lactic acid) was found in 5/6 cases. A mitochondrial DNA mutation was confirmed in one child with the finding of a large rearrangement. These cases suggest that mitochondrial DNA mutations can cause cyclic vomiting syndrome. Mitochondrial disease should be considered in cases of cyclic vomiting, especially those with additional pathology or possible maternal inheritance. Initial screening should include plasma lactate and urine organic acids obtained during an episode.
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Mitocondrias/fisiología , Periodicidad , Vómitos/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Femenino , Humanos , Lactante , Ácido Láctico/sangre , Masculino , Trastornos Migrañosos/genética , Trastornos Migrañosos/fisiopatología , Linaje , Síndrome , Vómitos/genéticaRESUMEN
BACKGROUND: A unique requirement for the molecular diagnosis of mitochondrial DNA (mtDNA) disorders is the ability to detect heteroplasmic mtDNA mutations and to distinguish them from homoplasmic sequence variations before further testing (e.g., sequencing) is performed. We evaluated the potential utility of temporal temperature gradient gel electrophoresis (TTGE) for these purposes in patients with suspected mtDNA mutations. METHODS: DNA samples were selected from patients with known mtDNA mutations and patients suspected of mtDNA disorders without detectable mutations by routine analysis. Six regions of mtDNA were PCR amplified and analyzed by TTGE. Electrophoresis was carried out at 145 V with a constant temperature increment of 1.2 degrees C/h. Mutations were identified by direct sequencing of the PCR products and confirmed by PCR/allele-specific oligonucleotide or PCR/restriction fragment length polymorphism analysis. RESULTS: In the experiments using patient samples containing various amounts of mutant mtDNA, TTGE detected as little as 4% mutant heteroplasmy and identified heteroplasmy in the presence of a homoplasmic polymorphism. In 109 specimens with 15 different known mutations, TTGE detected the presence of all mutations and distinguished heteroplasmic mutations from homoplasmic polymorphisms. When 11% of the mtDNA genome was analyzed by TTGE in 104 patients with clinically suspected mitochondrial disorders, 7 cases of heteroplasmy ( approximately 7%) were detected. CONCLUSIONS: TTGE distinguishes heteroplasmic mutation from homoplasmic polymorphisms and appears to be a sensitive tool for detection of sequence variations and heteroplasmy in patients suspected of having mtDNA disorders.
Asunto(s)
ADN Mitocondrial/genética , Alelos , ADN Mitocondrial/sangre , Electroforesis en Gel de Poliacrilamida/métodos , Humanos , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Eliminación de Secuencia , TemperaturaRESUMEN
A case is presented of a female with cleft palate, digital anomalies and mental retardation. The case is compared with one already reported and possible diagnoses discussed. These cases appear to present a new syndrome or a variant of distal arthrogryposis.
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Artrogriposis/patología , Blefaroptosis/patología , Fisura del Paladar/patología , Dedos/patología , Deformidades Congénitas de la Mano/patología , Discapacidad Intelectual/patología , Niño , Femenino , Humanos , Masculino , SíndromeRESUMEN
UNLABELLED: Kearns Sayre syndrome (KSS) is a multisystem disorder with a confounding variety of clinical manifestations, including ocular myopathy, pigmentary retinopathy, heart block and ataxia. Endocrinopathies are common in KSS, including growth hormone deficiency, hypogonadism, diabetes mellitus and hypoparathyroidism. A variety of deletions of mitochondrial DNA (mtDNA) are found in most cases. We report on a 5-year-old boy with Addison disease in whom further investigation revealed a 4.9 kilobase mtDNA deletion and KSS. Later he developed severe lactic acidosis and expired. CONCLUSION: The degree of mutant mtDNA heteroplasmy in various tissues on autopsy did not correlate well with the clinical manifestations, although this may be due at least in part to replacement with other tissue types. Our report is the first of non-autoimmune Addison disease in KSS and patients with KSS should be evaluated for adrenal insufficiency. Early recognition of adrenal insufficiency is crucial to prevent mortality from this cause.