Leigh syndrome in an infant: autopsy and histopathology findings

Leigh syndrome is an inherited neurodegenerative disorder of infancy that typically manifests between 3 and 12 months of age. The common neurological manifestations are developmental delay or regression, progressive cognitive decline, dystonia, ataxia, brainstem dysfunction, epileptic seizures, and respiratory dysfunction. Although the disorder is clinically and genetically heterogeneous, the histopathological and radiological features characteristically show focal and bilaterally symmetrical, necrotic lesions in the basal ganglia and brainstem. The syndrome has a characteristic histopathological signature that helps in clinching the diagnosis. We discuss these unique findings on autopsy and radiology in a young infant who succumbed to a subacute, progressive neurological illness suggestive of Leigh syndrome. Our case highlights that Leigh syndrome should be considered in the differential diagnosis of infantile-onset, subacute neuroregression with dystonia and seizures, a high anion gap metabolic acidosis, normal ketones, elevated lactates in blood, brain, and urine, and bilateral basal ganglia involvement.

A case of overlap myoclonic epilepsy with ragged-red fibers-Leigh syndrome associated with mitochondrial DNA 8344A>G mutation / 中华神经科杂志

Overlap myoclonic epilepsy with ragged-red fibers (MERRF)-Leigh syndrome is a rare mitochondrial encephalomyopathy. A case of MERRF-Leigh syndrome associated with mitochondrial DNA 8344A>G (m.8344A>G) mutation was reported in this article. The patient has suffered from the disease since 15-year old with myoclonus, exercise intolerance, ataxia, limb weakness, dysphasia, dyspnea, blurred vision and hearing loss. Magnetic resonance imaging revealed lesions on right thalamus, bilateral medulla and lumbar spinal cord and atrophy of cervical spinal cord. Electromyography showed predominantly axonal damage of both sensory nerve and motor nerve. Histochemical analyses revealed ragged red fibers, ragged blue fibers, succinate dehydrogenase-stronghly reactive vessels and decreased cytochrome oxidase activity. Gene tests demonstrated a high level of m.8344A>G mutation and m. 14484T>C mutation. MERRF-Leigh overlap syndrome with m.8344A>G mutation was rare. Bulbar paralysis following myoclonus is the main clinical symptom.

Clinical and genetic characteristics of children with Leigh syndrome / 中华儿科杂志

Objective@#To investigate the clinically and genetic characteristics of children with Leigh syndrome.@*Method@#Patients with clinically diagnosed Leigh syndrome(LS)in the department of Neurology, Beijing Children′s Hospital from January 2013 to February 2016 underwent the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) detecting with next generation sequencing (NGS) technology. The clinical data of gene confirmed cases were retrospectively collected and analyzed. The differences in the onset age, clinical manifestations, lactic acid level and MRI results between the mtDNA variation and nDNA variation were compared and analyzed.t test, Chi-square test and Fisher′s exact test were used for statistical analysis.@*Result@#Thirty-five cases were diagnosed by gene detection, including 20 males and 15 females. The median onset age was 1 year (ranging from the neonatal period to 4.4 years old). The age of onset within 2 years accounted for 74%(26 cases). The onset age of initial symptoms, including developmental delay, developmental regression, and seizures, were 6 (4, 12) months, 12 (8, 14) months, and 6 (1, 23) months respectively. The onset age of ptosis, extrapyramidal symptoms and ataxia were 26 (18, 44) months, 28 (23, 40) months and 28 (19, 35) months, respectively. There were significant differences in the onset age between the three groups (H=21.919, P=0.01). Within the 35 cases, 29 were manifested with developmental delay (83%), 26 with dystonia (74%), 18 with growth retardation, 15 with myasthenia, 13 with developmental regression, 11 with dysphagia, 10 with feeding difficulties, 4 with skeletal dysplasia, and 2 with digestive tract symptoms; nystagmus and respiratory abnormalities were observed in 9 cases respectively; extrapyramidal symptoms, peripheral nerve injury, ptosis, seizures were observed in 8 cases respectively; and ataxia, ophthalmoplegia and hypertrichiasis were found in 5 cases respectively.The blood lactic acid was measured in 32 LS patients, within which 23 cases (72%) had increased results; 8 out of 11 cases who underwent were cerebrospinal fluid lactic acid test had increased results. The results of neuroimaging revealed that all the patients were involved in the brainstem and (or) basal ganglia, of whom 27 (77%) had brainstem involvement, 24 (69%) had basal ganglia involvement. Thirteen out of 14 patients who had medulla oblongata involvement had nDNA variation; while 7 out of 8 patients with cerebellar involvement had nDNA variation. Genetic etiology was confirmed in all patients, among whom there were 17 cases (49%) with mtDNA mutation, including 8993T>C/G (n=5), 14487T>C (n=4), 13513G>A (n=2), 9176T>C, 10158T>C, 3697G>A, 10191T>C, 14459A>G and 11777C>A (n=1) respectively. Remaining 18 cases(51%) had nDNA mutation, including SURF1 gene(n=10), PDHA1 gene(n=3) and one case each of NDUFV1, NDUFAF6, NDUFAF5, NDUFS1 and COQ7 genes. In this study, 27 types of mutations were founded, 15 of which had not been previously reported. Respiratory chain gene mutations have been found in 31 cases(89%); 3 cases had PDHc gene mutations, and 1 case had other mutation.@*Conclusion@#LS usually occurs in infants. The most common primary symptoms are age-dependent abnormal movements, ocular symptoms, and seizures. Respiratory chain defects is the most common causes of LS.SURF1 is the most common variation, followed by 8993T>C/G, 14487 T>C and 13513G>A mutation.

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil / Escala Pediátrica de Doença Mitocondrial de Newcastle: tradução e adaptação cultural para uso no Brasil

ABSTRACT Objective The aim of this study was to translate and adapt the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to Portuguese for use in Brazil. Methods The scale was applied in 20 pediatric patients with mitochondrial disease, in three groups: myopathy (n = 4); Leigh syndrome (n = 8); and encephalomyopathy (n = 8). Scores were obtained for the various dimensions of the NPMDS, and comparisons were drawn between the groups. Results There was a statistically significant difference between the myopathy group and the Leigh syndrome group (p = 0.0085), as well as between the myopathy and encephalomyopathy groups (p = 0.01). Conclusions The translation of the NPMDS, and its adaptation to the socioeconomic and cultural conditions in Brazil, make the NPMDS score useful as an additional parameter in the evaluation and monitoring of pediatric patients with MD in Brazil.

RESUMO Objetivo O objetivo do presente estudo foi realizar a tradução e adaptação da escala NPMDS para a população brasileira. Métodos A escala foi aplicada em 20 crianças e adolescentes com doença mitocondrial (DM) divididos em três grupos: miopatia (n=4), síndrome de Leigh (n=8) e encefalomiopatia (n=8). Obteve-se os escores separados das dimensões da escala NPMDS, foram realizadas comparações entre os escores da NPMDS nos diferentes grupos. Conclusão A tradução da escala NPMDS e sua adequação as condições socioeconômicas e culturais de nossa população tornam este instrumento um parâmetro adicional na avaliação e acompanhamento de pacientes pediátricos com DM.

Identification of causative mutations in patients with Leigh syndrome and MERRF by mitochondrial DNA-targeted next-generation sequencing

PURPOSE: Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make their exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mitochondrial DNA (mtDNA) mutations in 2 Korean families with myoclonic epilepsy with ragged-red fibers (MERRF) and Leigh syndrome, respectively. MATERIALS AND METHODS: Whole mtDNAs were sequenced by the method of mtDNA-targeted next-generation sequencing (NGS). RESULTS: Two causative mtDNA mutations were identified from the NGS data. An m.8344A>G mutation in the tRNA-Lys gene (MT-TK ) was detected in a MERRF patient (family ID: MT132), and an m.9176T>C (p.Leu217Pro) mutation in the mitochondrial ATP6 gene (MT-ATP6) was detected in a Leigh syndrome patient (family ID: MT130). Both mutations, which have been reported several times before in affected individuals, were not found in the control samples. CONCLUSION: This study suggests that mtDNA-targeted NGS will be helpful for the molecular diagnosis of genetically heterogeneous mitochondrial diseases with complex phenotypes.

Current status of pyruvate dehydrogenase complex deficiency / 国际儿科学杂志

Pyruvate dehydrogenase complex (PDHc)deficiency is a genetic disorder of mitochondrial energy metabolism.Most cases result from mutations in gene encoded PDHc.The clinical presentation of patients with PDHc deficiency is extremely variable.Diagnosis of PDHc deficiency remains challenging,which depends on definitive enzymatic assays and DNA analysis.We review the relevant literature of recent domestic and international research results,in order to enhance our awareness of this disease and reduce misdiagnosis and missed diagnosis.It is helpful to improve prognosis and quality of life of patients by earlier and essential treatment.

Abordagem anestésica em paciente pediátrico com síndrome de Leigh / Anesthetic management of a pediatric patient with Leigh syndrome / Abordaje anestésico en paciente Pediátrico con el síndrome de Leigh

JUSTIFICATIVA E OBJETIVOS: A síndrome de Leigh (SL) é uma doença rara causada por anomalias na produção de energia mitocondrial. O sistema nervoso central é afetado com mais frequência, com retardo psicomotor, convulsões, nistagmo, oftalmoparesia, atrofia óptica, ataxia, distonia ou insuficiência respiratória. Os procedimentos cirúrgicos e anestésicos provocam irritabilidade traqueal e podem exacerbar os riscos de aspiração, sibilação, dificuldade respiratória, respiração ofegante, hipoventilação e apneia. RELATO DE CASO: Apresentamos uma abordagem anestésica usada em um menino de seis anos com a forma grave de SL que envolve reparação de uma fratura de fêmur. Propofol e remifentanil foram infundidos para anestesia geral. O paciente foi atentamente monitorado durante a anestesia e sua permanência na unidade de terapia intensiva no período pós-operatório inicial. CONCLUSÕES: Uma atenta monitoração intraoperatória dos pacientes, que inclui pressão arterial invasiva e mensurações frequentes da gasometria, glicose e lactato, faz esse procedimento transcorrer sem problemas. A terapia intensiva e a assistência respiratória ao paciente com SL sob sedação, com uma combinação de analgésicos durante o período pós-operatório inicial, minimizaram a resposta ao estresse causado pela dor pós-cirúrgica.

BACKGROUND AND OBJECTIVES: Leigh syndrome (LS) is a rare disease caused by abnormalities of mitochondrial energy generation. The central nervous system is most frequently affected, with psychomotor underdevelopment, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Surgical and anesthetic procedures stimulate the tracheal irritability, and could exacerbate risks of aspiration, wheezing, breathing difficulties, gasping, hypoventilation, and apnea. CASE REPORT: We present the anesthetic management for a six-year-old boy with severe form of LS, involving repair of a femur fracture. Propofol and remifentanil were infused for general anesthesia. The patient was closely monitored during anesthesia and in the intensive care unit in the early postoperative period. CONCLUSIONS: Close intraoperative monitoring of patients, including invasive arterial blood pressure monitoring and frequently measuring the levels of blood gases, glucose, and lactate, made this procedure run smoothly. Intensive care and breathing support for the patient with LS, under sedation with an analgesic combination during the early postoperative period, minimized the stress response due to pain after surgery.

JUSTIFICATIVA Y OBJETIVOS: El síndrome de Leigh (SL) es una enfermedad rara causada por anomalías en la producción de energía mitocondrial. El sistema nervioso central está afectado más a menudo, con el retardo psicomotor, convulsiones, nistagmo, oftalmoparesia, atrofia óptica, ataxia, distonía o insuficiencia respiratoria. Los procedimientos quirúrgicos y anestésicos provocan irritabilidad traqueal y pueden exacerbar los riesgos de aspiración, sibilancias, dificultad respiratoria, respiración extenuante, hipoventilación y apnea. RELATO DE CASO: Presentamos un abordaje anestésico usado en un niño de 6 años, con la forma grave de SL que nos ocupa con la reparación de una fractura de fémur. El propofol y el remifentanilo se infundieron para la anestesia general. El paciente fue monitoreado con mucho cuidado durante la anestesia y durante su permanencia en la unidad de cuidados intensivos en el período postoperatorio inicial. CONCLUSIONES: Una meticulosa monitorización intraoperatória de los pacientes, que incluye monitorización de presión arterial invasiva y mensuraciones frecuentes de la gasometría, glucosa y lactato, posibilita el perfecto transcurso del procedimiento. Los cuidados intensivos y la asistencia respiratoria al paciente con SL bajo sedación con una combinación de analgésicos durante el período postoperatorio inicial, minimizaron la respuesta al estrés causado por el dolor postquirúrgico.

Phenotype in 6 patients with mitochondrial DNA G13513A mutation / 中华神经科杂志

Objective To report 6 Chinese patients with mitochondrial encephalomyopathy caused by mitochondrial DNA(mtDNA)G13513A mutation and discuss the mitochondrial phenotype associated with this mutation based on the data of our patient series as well as the reports by others.Methods Direct sequencing of polymerase chain reaction(PCR)products or PCR-RFLP analysis Was performed to screen mtDNA G13513A mutation in 35 cases with mitoehondrial encephalomyopathy.who carried no mtDNA common mutations(1arge 8eale deletion,A3243G,T3271 C,A8344G,or T8993G/C).The clinical features,MRI changes were retrospectively collected and analyzed.Published studies of all patients with mtDNA G13513A mutation were also reviewed.Results Six patients were identified carrying mtDNA G13513A mutation.All patients presented stroke-like episodes with hemianopsia.hemiparesis or hemiparesthesia.Three adult patients presented clinical and radiological features of adult-onset mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),including stroke-like episodes,epilepsy,headache,short stature,sensorineural deafness,multifocal lesions on parietal,occipital and temporal lobes on cranial MRI scans.Three iuvenile.onset patients presented the clinical and brain MRI features of MELAS-Leigh syndrome(LS)overlap syndrome.In addition to the stroke-like episodes,they also showed brain stem lesions with dysarthria,ataxia,and ophthalmopJegia. Brain MRI revealed asymmetrical lesions in the cortex of the oecipital and temporal lobes,as well as symmetrical lesions in the bilateral basal ganglia and brainstem.Muslce biopsy showed ragged redfibem in 5 patients.The infant-onset LS or Leigh-like syndrome with mtDNA G135 13A was described in the English literature.Conclusions mtDNA G13513A mutation is a common pathogenic mutmion for mitochondrial encephalomyopathy,which can result in Leigh syndrome,MELAS-LS overlap syndrome and adult MELAS.The onset of various phenotypes is relatively age-dependent.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes/Leigh overlap syndrome caused by mutation of mitochondrial DNA G13513A / 中华神经科杂志

Objective To describe the chnical, neuroimagine, pathological and genetic features in a case with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)/Leigh overlap syndrome.Methods The ease was a 22-year-old woman with recurrent headache, loss of visual acuity and general seizures over 11 years.MRI demonstrated symmetrical high T2-weighted signals in occipital and parietal lobes, in the late stage of the disease, the above imagine changes on MRJ were also shown in the bilateral basal ganglion and brainstem.She died of status epilepticus at age of 22.Brain autopsy and mitochondrial DNA (mtDNA) analysis were performed in the patient.Results The main neuropathological findings were muhifocal and lamilar spongiform in the cortex of the whole brain, the basal ganglion and middle brain.Gliosis, macrophagie reaction and capillary endothelial proliferation were observed in these areas.All 6 layers of the cortex and subcortical white matter in occipital and parietal lobes were severely affected.GI3513A mutation was found in the gene of mitochondria encoded NADH dehydrogenase subunit 5 (MTNDS).Conclusions MELAS/Leigh overlap syndrome presents the symptoms predominantly affecting the cerebral cortex.Neuroimagines suggested that the lesion initially involves the cerebral cortex and in the late stage implicates the basal ganglion and the brainstem, possibly caused by pathological changes of spongiform with capillary proliferation in these areas.

Síndrome de Leigh: relato de caso / Leigh syndrome: case report

Os autores descrevem pela primeira vez no país um caso de criança do sexo feminino, com 10 anos de idade, atendida no ambulatório de Oftalmologia do Hospital Universitário Clementino Fraga Filho - UFRJ, portadora da síndrome de Leigh, que faz parte de um grupo de enfermidades metabólicas conhecidas como encefalomiopatias mitocondriais. É doença hereditária transmitida por diferentes modos de herança: mitocondrial, autossômica recessiva e recessiva ligada ao X. O início das manifestações clínicas é variado, ocorrendo em geral, dentro dos primeiros dois anos de vida, com evolução insidiosa, progressiva e com períodos de exacerbações. O diagnóstico é difícil pelo pleomorfismo de sua apresentação, sendo baseado nos achados clínicos e estudos complementares relacionados à deficiência na produção mitocondrial de ATP e da citocromo C oxidase. Como não há tratamento específico, este é baseado em medidas paliativas, portanto a identificação desta síndrome é importante como diagnóstico correto permitindo condutas adequadas à melhor qualidade de vida de seus portadores.

The authors describe for the first time in the Country a case of a 10-year-old female child, assisted at the Ophthalmology Clinic of the Hospital Universitário Clementino Fraga Filho UFRJ, with Leigh's syndrome that is part of a metabolic disease group known as mitochondrial encephalomyopathies. It is an hereditary disease transmitted by a different mode of inheritance: mitochondrial, X-linked recessive and autosomal recessive. The beginning of clinical manifestations is varied and occurs usually in the first two years of life, with progressive and insidious evolution and exacerbation periods. Diagnosis is difficult because pleomorphic presentation, based on clinical findings and complementary study related to mitochondrial production of ATP and cytochrome c oxidase deficiencies. Considering that there is no specific treatment, this is based on a palliative procedure. So, the identification of this syndrome is very important to keep it under control, since its evolution is progressive.

MRI findings in Leigh syndrome with SURF-1 gene 604G→C mutations / 中华放射学杂志

Objective To determine the MR phenotype of Leigh syndrome (IS) with SURF-1 gene mutation.Methods The cranial MR examination of eight patients with the diagnosis of Leigh syndrome associated with SURF-1 gene 604G→C mutations were reviewed retrospectively.Comparison was made with typical LS patients' MRI.Observation was made regarding lesions in basal ganglia,subthalamic nuclei,substantia nigra,and dentate nuclei,involvement of white matter,and brain atrophy.Results The MR findings of LS in the study included the following:3 cases exhibited involvement of brain stem and subthalamic nuclei,2 of these 3 cases also had basal ganglia abnormalities.3 cases showed abnormality in the white matter without any involvement of the deep nuclei.Cerebral atrophy was observed in all cases in the group,and was the only finding in two cases.Conclusion The imaging findings in LS with SURF-1 604G→C gene mutation were variable.

Two Cases of Leigh Disease in Siblings

Leigh disease is a familial and degenerative disorder characterized by focal, bilateral, and usually symmetric lesions of the both gray and white matter in the brain and the spinal cord. The clinical course is variable, but in most cases, the prognosis is poor with subacute progression leading to death within months or years of life. The pathogenesis was known as mitochondrial enzyme defects of the respiratory chain system. We experienced 2 cases of Leigh diseases in a brother and sister. The brother had general weakness at 43 months of life and the sister had ataxic gait and tachypnea at 34 months of life. Their MRI revealed low signal intensity in the midbrain and pons at T1 weighted imaging. They died at 43 months and 41 months of life, respectively. We report these cases with a brief review of the related literature.

Mitochondrial DNA mutation analysis in Leigh syndrome / 中华神经科杂志

Objective To investigate the characteristics of mitochondrial DNA mutations in Chinese patients with Leigh syndrome Methods Screening mtDNA T8993G,T8993C,T9176C,A8344G,A3243G point mutations and deletion in 12 patients with Leigh syndrome by PCR restriction analysis and Southern blotting Results Four patients were identified as harboring mtDNA point mutations:1 with T8993G,1 with T8993C,and 2 with A8344G The proportion of mutant mtDNA was high,ranging from 87 2% to 97 8% T9176C,A3243G point mutations or large scale deletions were not detected Conclusion There is extensive genetic heterogeneity in LS;There may be some subtle differences in clinical presentation of LS patients depending on their etiology

A Case of Leigh's Disease Accompanied by Limitation of Bilateral Ocular Movement

PURPOSE: Leigh's disease is a mainly autosomal recessive inherited progressive disorder, with onset in the first 2 years of life, and has ocular signs such as nystagmus, gaze palsy, nuclear ophthalmoplegia and various neurologic signs. This disease finally results in death due to respiratory difficulty after repeated fever, dehydration, poor oral intake, lethargy, and convulsion. Leigh's disease is one of central nervous diseases considered in case infants or children who have paralytic esotropia or rapidly progressive limitation of ocular movement. METHODS: Authors experienced a case of 35-month-old male who had had 15 of right esotrophia and limitation of ocular movement in abduction for 1 month. At first visit, we diagnosed as a right 6th nerve palsy. However, the patient showed rapidly progressive limitation of ocular movement in all direction except in adduction and esotropia in both eyes. RESULTS: The patient presented ocular signs earlier than other neurologic symptoms and signs. He was consulted to the department of pediatric neurology and radiology, and diagnosed as Leigh's disease.

Two Cases of Leigh Disease

Leigh Disease, or subacute necrotizing encephalopathy (SNE), is a degenerative disorder characterized by lesions of the gray and white matter in the bran and spinal cord. The pathogenesis was known as mitochondrial enzyme defect of the respiratory chain system. We experienced 2 cases of Leigh disease. The first case, a seven-month old girl who was presented with weak respiration and failure to thrive, showed lactic acidemia and increased lactic acid in CSF fluid, high signal intensity in the bilateral putamen and head of caudate of nucleus at T2 weighted MR imaging. The second case, a 3-year-old girl with ataxic gait and bilateral ptosis also showed lactic acidemia, increased lactic acid in CSF fluid and high signal intensity in the bilateral basal ganglia. Respiratory difficuly developed in both cases and died within 1 month after visiting our hospital. The diagnosis was made by lactic acidosis and specific MRI finding. We report these cases with a brief review of its related literature.

MRI evaluation of cerebral perfusion change in pediatric patients with Leigh's syndrome / 中华放射学杂志

Objective To detect the change of cerebral perfusion in pediatric patients with Leigh's syndrome (LS)by using MR perfusion technique.Methods Twelve patients with Leigh's syndrome and thirteen normal children were scanned with the sequence of flow-sensitive alternating inversion recovery exempting separate T_1 measurement (FAIREST).Their relative cerebral blood flow(rCBF)values were obtained in regions of bilateral basilar nuclei and bilateral thalami.Student t-test was used to compare them between the two groups and receiver operating characteristic(ROC)curve analysis was carried out.Results Statistical analysis revealed significant difference between two groups in the regions of bilateral basilar nuclei and right thalamus(t =3.26,P =0.002;t =2.25 ,P =0.018 ;t =2.88 ,P =0.004,respectively).The rCBF values for LS group and control group were 0.432?0.158 and 0.619?0.125 for right basilar nuclear, 0.478?0.186 and 0.621?0.123 for left basilar nuclear,0.630?0.189 and 0.833?0.160 for right thalamus,respectively.The areas under the ROC curves were 0.833 and 0.756 for the rCBF of right and left basilar nuclear,respectively.Conclusion Relative CBF maps may reveal changes of cerebral blood flow in some specific brain regions in patients with Leigh's syndrome.It can provide additional information to the clinicians in the evaluation of the disease.

Leigh's disease involving multiple organs

Leigh's disease is a rare progressive neurological disorder that is characterized light microscopically by focal spongy necrosis in the brain and electron microscopically by mitochondriopathy. We report an autopsy case of Leigh's disease that showed abnormalities in the liver, kidney and skeletal muscle as well as the central nervous system. The patient was an 18-month-old girl who has carried a diagnosis of cerebral palsy ever since her birth to a 20-year-old mother. The baby was generally hypertonic and mentally retarded. She died of severe metabolic acidosis. Postmortem examination showed growth retardation, fatty liver, fatty kidney and soft brain. Brain section showed multifocal softenings in the brainstem, basal ganglia and periventricular areas. Microscopically increased capillaries with endothelial proliferation, vacuolar degeneration and mild gliosis were seen in the brain. The axons were relatively preserved. Liver and kidneys showed microvesicular fatty change. Myofiber degeneration of the skeletal muscle was also noted. Electron microscopic examination showed markedly increased mitochondria in the parenchymal cells of the brain, liver and kidney. The mitochondria showed round to ovoid ballooned appearance including electron-dense core-like structures and pseudoinclusions of glycogen granules.