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Background: Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs., Objective and Methods: To document neuroimaging data in six patients with PNPT1 highlighting novel findings., Results: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection., Conclusion: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Leigh Syndrome (LS) is a mitochondrial disorder defined by progressive focal neurodegenerative lesions in specific regions of the brain. Defects in NDUFS4, a subunit of complex I of the mitochondrial electron transport chain, cause LS in humans; the Ndufs4 knockout mouse (Ndufs4(KO)) closely resembles the human disease. Here, we probed brain region-specific molecular signatures in pre-symptomatic Ndufs4(KO) to identify factors which underlie focal neurodegeneration. Metabolomics revealed that free amino acid concentrations are broadly different by region, and glucose metabolites are increased in a manner dependent on both region and genotype. We then tested the impact of the mTOR inhibitor rapamycin, which dramatically attenuates LS in Ndufs4(KO), on region specific metabolism. Our data revealed that loss of Ndufs4 drives pathogenic changes to CNS glutamine/glutamate/α-ketoglutarate metabolism which are rescued by mTOR inhibition Finally, restriction of the Ndufs4 deletion to pre-synaptic glutamatergic neurons recapitulated the whole-body knockout. Together, our findings are consistent with mTOR inhibition alleviating disease by increasing availability of α-ketoglutarate, which is both an efficient mitochondrial complex I substrate in Ndufs4(KO) and an important metabolite related to neurotransmitter metabolism in glutamatergic neurons., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Leigh syndrome by definition is (1) a neurodegenerative disease with variable symptoms, (2) caused by mitochondrial dysfunction from a hereditary genetic defect and (3) accompanied by bilateral central nervous system lesions. A genetic etiology is confirmed in approximately 50% of patients, with more than 60 identified mutations in the nuclear and mitochondrial genomes. Here we review the clinical features and imaging studies of Leigh syndrome and describe the neuroimaging findings in a cohort of 17 children with genetically confirmed Leigh syndrome. MR findings include lesions in the brainstem in 9 children (53%), basal ganglia in 13 (76%), thalami in 4 (24%) and dentate nuclei in 2 (12%), and global atrophy in 2 (12%). The brainstem lesions were most frequent in the midbrain and medulla oblongata. With follow-up an increased number of lesions from baseline was observed in 7 of 13 children, evolution of the initial lesion was seen in 6, and complete regression of the lesions was seen in 3. No cerebral white matter lesions were found in any of the 17 children. In concordance with the literature, we found that Leigh syndrome follows a similar pattern of bilateral, symmetrical basal ganglia or brainstem changes. Lesions in Leigh syndrome evolve over time and a lack of visible lesions does not exclude the diagnosis. Reversibility of lesions is seen in some patients, making the continued search for treatment and prevention a priority for clinicians and researchers.

Leigh syndrome (LS) is the most common pediatric presentation of a defined mitochondrial disease. This progressive encephalopathy is characterized pathologically by the development of bilateral symmetrical lesions in the brainstem and basal ganglia that show gliosis, vacuolation, capillary proliferation, relative neuronal preservation, and by hyperlacticacidemia in the blood and/or cerebrospinal fluid. Understanding the molecular mechanisms underlying this unique pathology has been challenging, particularly in view of the heterogeneous and not yet fully determined genetic basis of LS. Moreover, animal models that mimic features of LS have only been created relatively recently. Here, we review the pathology of LS and consider what might be the molecular mechanisms underlying its pathogenesis. Data from a wide range of sources, including patient samples, animal models, and studies of hypoxic-ischemic encephalopathy (a condition that shares features with LS), were used to provide insight into the pathogenic mechanisms that may drive lesion development. Based on current data, we suggest that severe ATP depletion, gliosis, hyperlacticacidemia, reactive oxygen species, and potentially excitotoxicity cumulatively contribute to the neuropathogenesis of LS. An intimate understanding of the molecular mechanisms causing LS is required to accelerate the development of LS treatments.

We report a pedigree of adult-onset Leigh syndrome (LS) with mitochondrial mutation 8344 A>G. A 38-year-old woman presented with optic neuropathy, weakness and cognitive impairment. Family history of optic neuropathy and systemic involvement was suggestive of mitochondrial encephalopathy. Genetic and radiologic studies showed m.8344 A>G mutation with characteristics of LS. To our knowledge this is the first case of adult-onset LS demonstrating the m.8344 A>G mutation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Mutation in the SURF1 is one of the most common nuclear mutations associated with Leigh syndrome and cytochrome c oxidase deficiency. This study aims to describe the phenotypic and imaging features in four patients with Leigh syndrome and novel SURF1 mutation., Methods: The study included four patients with Leigh syndrome and SURF1 mutations identified from a cohort of 25 children with Leigh syndrome seen over a period of six years (2006-2012). All the patients underwent a detailed neurological assessment, muscle biopsy, and sequencing of the complete mitochondrial genome and SURF1., Results: Three patients had classical presentation of Leigh syndrome. The fourth patient had a later age of onset with ataxia as the presenting manifestation and a stable course. Hypertrichosis, facial dysmorphism and hypopigmentation were the additional phenotypic features noted. On magnetic resonance imaging all patients had brainstem and cerebellar involvement and two had basal ganglia involvement in addition. The bilateral symmetrical hypertrophic olivary degeneration in these patients was striking. The SURF1 analysis identified previously unreported mutations in all the patients. On follow-up three patients expired and one had a stable course., Conclusions: Patients with Leigh syndrome and SURF1 mutation often have skin and hair abnormalities. Bilateral symmetrical hypertrophic olivary degeneration was a consistent finding on magnetic resonance imaging in these patients., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Although the "face of the giant panda" sign on magnetic resonance imaging (MRI) is traditionally considered to be characteristic of Wilson disease, it has also been reported in other metabolic disorders. This study describes the characteristic "giant panda" sign on MRI in a child with Leigh disease. The diagnosis was based on the history of neurological regression; examination findings of oculomotor abnormalities, hypotonia, and dystonia; raised serum lactate levels; and characteristic brain stem and basal ganglia signal changes on MRI. The midbrain and pontine tegmental signal changes were consistent with the "face of the giant panda and her cub" sign. In addition to Wilson disease, metabolic disorders such as Leigh disease should also be considered in the differential diagnosis of this rare imaging finding., (© The Author(s) 2013.)

The authors describe a newborn with postnatal myopathy who subsequently developed feeding difficulties, ophthalmoplegia, ptosis, encephalopathy, and seizures. She became ventilator dependent after sudden apnea. The myopathy was without ragged red fibers in the muscle biopsy. An electron transport chain study showed a markedly generalized low level of enzyme activity, particularly in complexes I, I + III, and IV. An initial electroencephalogram finding was normal; subsequent electroencephalograms showed suppression bursts. The mitochondrial copy number in skeletal muscle was 2% of normal.

Objective: To investigate the value of functional magnetic resonance imaging (MRI) in sequential evaluation of patients with Leigh syndrome., Methods: Two patients with Leigh syndrome underwent diffusion weighted imaging (DWI), perfusion weighted imaging (PWI) and proton magnetic resonance spectroscopy ((1)H-MRS)., Results: The brain lesions showed hyperintensity on DWI, lactate doublet peak on MRS and hyperperfusion in the patients at baseline, and maintained a hyperintensity on DWI and hyperperfusion in the absence of lactate doublet peak on MRS at follow-up 1 year later. DWI still revealed persistent hyperintensity in the brain lesions in one patient 2 years later., Conclusion: Functional MRI can sensitively highlight the characteristics of brain lesions in patients with Leigh syndrome, and can therefore be used to evaluate the sequential changes of the brain lesions.

Aims: Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction., Results: At 3(1/2) months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh's encephalopathy., Conclusion: The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions., (Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

The 13513G>A mutation in the ND5 gene of mitochondrial DNA (mtDNA) is usually associated with mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS), or Leigh syndrome (LS). In this study, we describe three young Chinese patients with MELAS/LS overlap syndrome who carried the m.13513G>A mutation. Clinical and MRI features were characteristic of both MELAS and LS. Interestingly, the clinical presentation of this overlap syndrome could be variable depending on the degree of relative contribution of MELAS and LS, that is, MELAS as the initial presenting syndrome, LS as the predominant syndrome, or both MELAS and LS appearing at the same time. The final brain MRI showed findings characteristic of both MELAS and LS, with asymmetrical lesions in the cortex and subcortical white matter of the occipital, temporal, and frontal lobes (MELAS), and bilateral and symmetrical lesions in the basal ganglia and brainstem (LS). Brain autopsy in one case revealed infarct-like lesions in the cerebral cortex, basal ganglia and brainstem, providing further insight into the distribution of the pathological lesions in MELAS/LS overlap syndrome. This is the first report of the brain pathological changes in a patient with m.13513G>A mutation. The spatial distribution of infarct-like lesions in the brain could explain the symptoms in MELAS/LS overlap syndrome., (© 2010 Japanese Society of Neuropathology.)

Purpose: Ohtahara syndrome is one of the most severe and earliest forms of epilepsy and is frequently associated with brain malformations, such as hemimegalencephaly. Recently, longer expansion of the first polyalanine tract of ARX was found to be causative for Ohtahara syndrome without brain malformation, whereas premature termination mutations of ARX were found to cause severe brain malformations, such as lissencephaly or hydranencephaly. Both are designated as ARX-related interneuronopathies., Methods: We investigated the molecular basis of Ohtahara syndrome in two families, comprising six male patients in two generations demonstrating X-linked inheritance., Results: Novel frameshift mutations in the terminal exon of the ARX gene (Ala524fsX534 and E536fsX672) were identified in two patients (2 and 13 years, each) from both families. Two patients developed West syndrome, and one of these later developed Lennox-Gastaut syndrome. Brain magnetic resonance imaging (MRI) of all patients showed no brain malformations in contrast to the patients with a premature termination mutation in other exons of ARX., Discussion: The etiology of Ohtahara syndrome is heterogeneous; however, the molecular analysis of ARX should be considered in sporadic or familial male patients with Ohtahara syndrome., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by approximately 7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.

We report on a preterm Japanese male baby with Leigh syndrome, i.e., intrauterine growth restriction, central apnea, and feeding difficulty. These signs improved at 41 weeks of corrected age. At that time, brain magnetic resonance imaging revealed increased signal in diffusion-weighted imaging in the parietal white matter, bilaterally and symmetrically not respecting vascular territory or boundaries. However, clinical improvement deterred us from further investigation. About 3 months later, he manifested frequent ictal apnea with myoclonic seizures and deterioration of consciousness to semicoma. Subsequent diffusion-weighted imaging revealed increased signal in the bilateral symmetric thalamus, internal segments of the globus pallidus, substantia nigra, and pontine tegmentum. Laboratory investigation indicated remarkable elevation of lactate levels in cerebrospinal fluid. The diagnosis was of Leigh syndrome. We think this is the first reported case of Leigh encephalopathy with transient abnormality of diffusion-weighted imaging of the white matter before apparent clinical onset. Leigh syndrome should be included in the differential diagnosis of abnormality of diffusion-weighted imaging in white matter without apparent clinical signs.

Brain magnetic resonance spectroscopy in two patients with Leigh syndrome revealed the presence of lactate in gray and white matter brain tissue and relatively high choline levels in the white matter. The latter observation, most probably related to an ongoing demyelination process, underlines specific involvement of white matter metabolism in Leigh syndrome even in cases without involvement of the white matter as visualized on MRI. Magnetic resonance spectroscopy might thus be of help in differentiating Leigh syndrome from a range of other mitochondrial diseases, such as ophthalmoplegia and Kearns-Sayre syndrome, showing lack of lactate in brain tissues appearing normal on MRI.

Leigh syndrome (also termed subacute, necrotizing encephalopathy) is a devastating neurodegenerative disorder, characterized by almost identical brain changes, e.g., focal, bilaterally symmetric lesions, particularly in the basal ganglia, thalamus, and brainstem, but with considerable clinical and genetic heterogeneity. Clinically, Leigh syndrome is characterized by a wide variety of abnormalities, from severe neurologic problems to a near absence of abnormalities. Most frequently the central nervous system is affected, with psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also present with peripheral nervous system involvement, including polyneuropathy or myopathy, or non-neurologic abnormalities, e.g., diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). In the majority of cases, onset is in early childhood, but in a small number of cases, adults are affected. In the majority of cases, dysfunction of the respiratory chain (particularly complexes I, II, IV, or V), of coenzyme Q, or of the pyruvate dehydrogenase complex are responsible for the disease. Associated mutations affect genes of the mitochondrial or nuclear genome. Leigh syndrome and Leigh-like syndrome are the mitochondrial disorders with the largest genetic heterogeneity.

Acute necrotizing encephalopathy was initially reported in Japanese children. The rapid evolution and symmetrical brain lesions seen in the brainstem, cerebellum and specially in the thalamus characterize the disease. We studied a 7-month-old-girl, who presented with two episodes of rapid loss of consciousness and paresis without metabolic disturbances. At the first time she had a rapid improvement, but at the second episode the course was fulminant and in two days she lapsed into a clinical state of brain death. The magnetic resonance studies showed symmetrical lesions in the thalamus and additional lesions involving the brainstem and the cerebellum.

A 21-year-old previously-well woman who was undergoing medical investigations for problems with balance and suspected multiple sclerosis, developed a headache and breathing difficulties, and died suddenly and unexpected at home. The autopsy was unremarkable except for pulmonary and cerebral oedema. However, subsequent microscopy of the brain revealed characteristic features of Leigh syndrome with multifocal areas of astrogliosis, capillary proliferation, and parenchymal vacuolation. While Leigh syndrome is more commonly diagnosed in infancy, manifestations may occur throughout early life into adulthood. Sudden and unexpected death is a rare presentation that may be associated with cerebral necrosis and oedema. An awareness of the variable manifestations of Leigh syndrome is necessary in forensic practice as not all cases will present in a typical manner and sudden death may occur before a diagnosis has been established. The heritable nature of this condition makes accuracy of diagnosis essential.

Leigh syndrome is a mitochondrial disease of infancy and early childhood and is rare in adults. We report an autopsy case of adult Leigh syndrome of 15 years duration in a 32-year-old man with a familial history of the disease. His initial symptom was clumsiness followed by dullness, and dysphasia and dysarthria appeared in the last 3 months. His brother had similar symptoms and died at the age of 27 years. His sister is also demented. Cranial MRI revealed abnormal signals in the bilateral putamen and tegmentum of the brainstem. Neuropathologically, there were symmetrical, well-demarcated necrotizing lesions with proliferation of capillaries in the putamen, caudate nucleus and thalamus, as well as in the periaqueductal gray matter of the midbrain and tegmentum of the pons. It seems that the lesions in the putamen were more severe and older than those of the brainstem, the latter having numerous macrophage infiltrations. Neuronal loss and gliosis were also observed in the substantia nigra and cerebellar cortex. This is the first autopsy-confirmed familial adult Leigh syndrome in China. The clinicopathological features are presented together with a literature review.

We retrospectively analyzed a case of a 7-month-old infant with a delay of psychomotor development, slow pupillary light reflexes, horizontal nystagmus, spasticity and bilateral optic nerve atrophy. At the end of life there were problems with swallowing. Ventriculography showed widening of the lateral ventricles and atrophy in the frontal lobes. EEG revealed generalized changes. Clinically, leucodystrophy was diagnosed. General autopsy revealed cardiac hypertrophy. Neuropathological picture showed orthochromatic leucodystrophy with some features characteristic of neuropathology of mitochondrial disease: capillary hyperplasia and hypertrophy, spongiosis and symmetrical, bilateral damage of brain stem structures. The last one is characteristic of Leigh syndrome. Electron microscopic evaluation showed abnormal mitochondria, myelin and neurofibrils destruction. Hypertrophy of the heart may be also connected with mitochondrial disease.

Objective: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME)., Methods: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect., Results: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or "overlapping" characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome., Conclusions: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.

A 4-year-old boy showed two episodes of encephalitis/encephalopathy involving disturbed consciousness, convulsion, and paresis associated with the elevated levels of protein and myelin basic protein of the cerebrospinal fluid. MRI studies of the brain revealed symmetrical lesions in the brain stem and thalami at the first episode, and additional lesions were found in the cerebellum involving both the gray and white matter in the second episode. The intensities of MRI lesions were low in T I and high in T2. These episodes were followed by an elevation of the anti-viral antibody titers, for influenza A virus during the first episode and for adenovirus during the second. In the second episode, intravenous methylprednisolone therapy resulted in rapid improvement of his neurological signs.

We report clinical, radiological and pathological findings in a 5-year-old girl who died of subacute necrotizing encephalomyelopathy (SNE) after 4 weeks of illness. Autopsy revealed endothelial swelling and vacuolar degeneration of the neuropil in the brain, brain stem and cerebellum. In addition, the affected areas showed degeneration of the neurons which was different from anoxic nerve cell damage both with regard to morphological picture and topographical distribution. This neuronal degeneration was probably due to the underlying metabolic defect in SNE per se and resembled in several aspects the nerve cell changes seen in the thalami and inferior olives in active Wernicke's encephalopathy. It is our opinion that more attention should be paid to the nerve cell degeneration in SNE rather than focusing on the relative preservation of these cells.

In a search for pathogenic factors that might play roles in the selective vulnerability of brain regions to the lesions of Leigh's disease, archival material from 20 cases of this condition, dying between 1975 and 1992 and aged from 4 days to 11.75 years at death, have been examined. Attention was paid to the topography of the lesions, their nature and timing in the evolution of the disease, the clinico-pathological correlations and the ages of the subjects at onset and at death. The following observations would appear to be explicable in terms of the present understanding that impairment of cellular energy generation is known to be defective in some, and probably all, cases. (i) The characteristic lesion of this disease is symmetrical vasculonecrotic damage affecting several brainstem centres, the topography of which is variable and may partly depend upon the age of the individual. (ii) Early features of this lesion are indistinguishable from a small partial infarction and progress similarly. The size of the damaged area is generally related to the size of the region affected. There is no haemorrhagic component and haemosiderin is not at any time found, unlike the lesions of Wernicke's disease. (iii) The process is episodic and total tissue damage is thus cumulative. More than one episode of damage may be seen in a region, changes of clearly different ages being often present together. (iv) In some regions the lesions appear to be age dependent, e.g. inferior olivary nuclei, and may be related to behavioral development and neuronal activity. Other regions show damage at any age, e.g. substantia nigra. (v) Myelin and sometimes axon loss in optic pathways is usually central, the periphery being spared. This occurred in more than half the cases and may represent a partial infarct-like change. (vi) The characteristic dorsal spinal column degeneration is always associated with focal necrosis of central grey and white matter; this also resembles a partial infarction with secondary ascending degeneration. (vii) Massive myelin loss in the centra semiovalia occurred in one-third of the cases, with or without cavitation, often in association with spongy myelin changes elsewhere. A mild general spongy change in myelin alone occurred in two cases. The massive lesions are focal, infarct-like and analogous to Binswanger's disease. (viii) Selective neuronal loss, common in some mitochondrial disorders, is not a major feature of Leigh's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

We report 2 sisters with a degenerative neurological disorder presenting clinically as a leukodystrophy. CT scan and MRI demonstrated small symmetrical foci of necrosis in the substentia nigra and in the basal ganglia typical of Leigh syndrome and diffuse cerebral white matter abnormalities. In these patients a deficiency in complex II of the respiratory chain was demonstrated in isolated mitochondria from muscle, as well as in fibroblasts and lymphocytes.

Pearson's syndrome is a disease of refractory sideroblastic anemia and exocrine pancreatic dysfunction due to abnormal mitochondrial DNA (mtDNA). A male infant with Pearson's syndrome developed necrosis of both thalami and basal ganglia when he suffered from gastroenteritis at 1 year and 11 months of age. He died of sepsis at the age of 2 years and 4 months. Analysis of mtDNA from various organs revealed abnormal mtDNA with deletion by 5 kbp, confirming the diagnosis. At autopsy, the brain had symmetrical cavities in putamen, caudate nuclei and medial nuclei of the thalami. Ferruginous granules in nerve cells in medial thalamic nuclei, and scattered round bodies with neuronophagia in lateral nuclei were found at light microscopic observation. Electron microscopy showed that these granules were composed of radiating spicules and a dense layer containing packed cytoplasmic organelles, respectively. The macroscopic distribution of brain lesions was very similar to and characteristic of Leigh's disease. This similarity leads to the supposition that defective intracellular energy utilization common to Leigh's disease could be responsible for brain lesions in this case. Although the histological appearance was somewhat atypical for Leigh's disease, very acute formation of brain lesions in this case was thought to have caused the histological difference.

A case of Leigh disease in a 3-year-old girl is reported. The child had regression of the psychomotor development, muscular hypotonia, weak tendinous reflexes, opsoclonus, tremor of the whole body, hypertrichosis, autonomic system disturbances. Laboratory investigations demonstrated raised serum lactic acid level. Postmortem histological examination of the brain confirmed the diagnosis of Leigh disease established before death.

We report the cases of 2 siblings with progressive encephalopathy. The first symptoms were noted when they were 6 years old. The full clinical picture included myoclonus, seizures, cerebellar ataxia, blindness due to optic atrophy and retinal degeneration, deafness, swallowing difficulties with relatively spared intellectual functions. The course was progressive and led to death within 8 years. The pathological findings included bilateral and almost symmetrical lesions involving the thalami, the colliculi, and the pontine and medullar tegmentum, similar to the changes described in Leigh disease. Neuronal loss and gliosis were noted in the dentate nucleus and in the inferior olive, as in MERRF syndrome. Laminar necrosis of the cerebral cortex could have been due to episodes of severe hypotension before death. Cytochrome c oxidase deficiency was found in case 2. The enzyme deficiency was present in muscle and in fibroblasts in culture.

Leigh's disease, also known as subacute necrotizing encephalomyelopathy, is a rare progressive neurological disorder of childhood that was first described by Leigh in 1951. Diagnosis of this disease can be difficult because onset is usually insidious and can present with a number of different focal findings, however diagnostic imaging has been shown to be of benefit in this regard. We present a patient with Leigh's disease in whom serial MR imaging studies helped to make the diagnosis and also demonstrated the dynamic characteristic of this disease process.

We report the morphological, biochemical, immunological, and genetic findings in a patient with the clinical characteristics of Leigh's disease due to multisystemic cytochrome c oxidase (CCO) deficiency. Muscle biopsy at 2 years and 5 months of age showed markedly decreased CCO and cytochrome a + a3, moderately decreased NADH-cytochrome c reductase to 46.3%, and generalized loss of immunologically detectable CCO subunits, but other respiratory chain enzyme proteins were normal. All the tissues examined at autopsy showed decreased activity of all respiratory chain enzymes except complex II. The decrease in cytochromes b and a + a3 were in harmony with decreased enzyme activities in complex III and IV (CCO), respectively. All immunologically detectable subunits of CCO in immunoprecipitation were uniformly decreased in the cardiac and skeletal muscles, but subunits 1 and 4 were selectively decreased in other organs except liver. No large deletion could be detected in the cardiac muscle mtDNA after digestion with restriction enzymes. These results suggest that the respiratory chain enzymes are variable in their activity and the amount of enzyme proteins decreases as the disease progresses.

Leigh's disease is a subacute metabolic encephalopathy characterized by bilateral and symmetrical lesions of basal ganglia, mid-brain and pons. Lesions are related to an abnormal pyruvate metabolism which mechanisms remain still uncertain. This disease is rare and the authors present a case with complete anatomic study.

Leigh's disease, or subacute necrotizing encephalomyelopathy (SNE), in adults is rare, and its diagnosis has depended on the postmortem identification of characteristic lesions in a typical distribution. We observed an autopsy-proved case of SNE in which the diagnosis was established by the distribution and evolution of lesions documented by serial magnetic resonance imaging (MRI). A 21-year-old woman insidiously developed diplopia and gait disturbance, and subsequently deteriorated to a vegetative state over seven months. An initial MRI obtained one month after presentation showed increased signal intensity that surrounded the aqueduct of Sylvius and involved the tectum of the midbrain. Serial MRI scans showed these lesions to extend and symmetrically involve the tectum of the midbrain, caudate, putamen, globus pallidus, and substantia nigra, while sparing the mammillary bodies and red nuclei. Despite treatment with 2 g of thiamine administered intravenously daily, she continued to deteriorate and died. Results of an autopsy established the diagnosis of SNE and confirmed the MRI-identified distribution of lesions. To our knowledge, this case is the first report of MRI findings in an adult with autopsy-proved SNE, suggesting that MRI can be valuable in the early diagnosis of this disease.

Although Leigh's disease corresponds to a quite distinct histopathological complex, clinical and biochemical findings may be very divergent. By the description of classical and borderline cases and by the comparison with cases from the literature, it is suggested that Leigh's disease encompasses several nosological entities related to different disorders of the energy metabolism. They produce an identical histopathological complex. New evidence for a cerebral mitochondriopathy is also given.

The clinical and pathological findings of a 31-year-old woman, in whom the diagnosis of Leigh's disease was made, are reported. CT scan examination with contrast enhancement showed symmetrical areas of low density, in both thalami, anterior limbs of internal capsules and corpus callosum. Longstanding chronic lesions involved the optic chiasma and the cerebral peduncles and consisted of myelin loss, status spongiosus, astrocytic gliosis and marked capillary proliferation. The neurons were spared. In the basal ganglia, internal capsules and corpus callosum, these lesions were more recent and consisted of focal necrosis, perivascular oedema and few lymphocytic perivascular cuffings.

The simultaneous occurrence of multicystic encephalomalacia of the cerebral hemispheres, and symmetric necrotizing lesions of diencephalic and infratentorial structures is described in a 15 month-old infant. The baby developed clonic jerks of four limbs a few hours after delivery. She attained no developmental milestones, and remained bed-ridden with hypertonic posture until her death. Multicystic cavities of the cerebral hemispheres were well evident at CT scan when she was 7 months old. The topographic distributions of the different pathological pictures are described; their relationship to the regional properties of the developing brain are commented upon. Etiological aspects of this case are discussed according to present knowledge of the pathophysiological mechanisms leading either to multiple cyst formation or to necrotizing lesions.

The clinical and postmortem findings in three cases of encephalomyeloneuropathy are reported. Two patients presented with subacute sensory neuropathy and one with amnesia and confusion. In none of these cases was a tumour detected clinically or at autopsy. Neuropathological examination showed inflammatory lesions in the brain, spinal cord and posterior root ganglia indistinguishable from encephalomyeloneuropathy occurring as a remote effect of carcinoma.