Burden of proof in the postmortem diagnosis of mitochondrial disease: Leigh disease.
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Autopsy↗
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Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease).
Leigh disease is a disorder with great clinical variability and for which diverse biochemical causes have been proposed. Clarification requires rigorous correlation of biochemical abnormalities with strict morphologic diagnosis; such an unambiguous association is the subject of this report. A patient with well-documented clinical and biochemical pyruvate dehydrogenase complex deficiency is shown on postmortem examination to have the specific CNS pathology of Leigh disease. These findings, considered together with the aggregate data in the literature, suggest strongly that pyruvate dehydrogenase complex deficiency is the basic defect in a subgroup of patients with Leigh disease.
Acidosis, Lactic↗
Self-inflicted orodental injury in a child with Leigh disease.
Leigh disease is an inherited progressive mitochondrial neurodegenerative disease that affects the neurological, respiratory and cardiovascular systems and is associated with retardation of the intellectual and physical development. This report describes the case of a 4-year-old boy with Leigh disease who presented with self-inflicted traumatic injury to the teeth, alveolar bone, lips and tongue during repeated episodes of intense orofacial spasms. Conservative management of the injury included repositioning the fractured alveolar bone, splinting the traumatized teeth and planning for a mouthguard. However, after a second incident of severe self-induced injury to the teeth and alveolar bone, extraction of the anterior teeth became inevitable to protect the child from further self-mutilation and to allow healing of the injured tissues.
Alveolar Process↗
An adult case of Leigh disease.
Leigh's disease is a mitochondrial disease of infancy and early childhood, and is rare in adults. Following a febrile illness, a 21-year-old woman developed ataxic paraparesis and was originally diagnosed as multiple sclerosis. Her illness progressed to somnolence and quadriparesis. The unusual MR images, the discovery of elevated blood lactate and pyruvate levels, the results of muscle biopsy and the lack of response to corticosteroid treatment, led to the correct diagnosis of Leigh disease. Initiation of a ketogenic diet resulted in a rapid partial response. She recovered sufficiently to be able to walk after 6 months.
Adult↗
Subacute necrotizing encephalomyelopathy (Leigh disease): CT study.
Leigh disease, or subacute necrotizing encephalomyelopathy (SNE), is a familial, degenerative disorder characterized by lesions of the gray and white matter in the brain and spinal cord. Low attenuation in the putamina on computed tomography (CT) scans is considered to be characteristic of the disease. The authors used CT to study five patients, in three of whom the disease was confirmed histologically. In one of the patients with documented SNE, there was extensive gray matter lucency with normal basal ganglia. CT scans obtained in a second patient showed diffuse, diseased white matter with focal cortical extension and bilateral caudate involvement. In the other three cases, CT scans revealed the usual changes that occur in the basal ganglia. The appearance of SNE on CT scans thus reflects the variable and widespread distribution of the disease. The absence of radiologically detectable abnormalities in the basal ganglia should not deter one from the diagnosis of Leigh disease given in the appropriate clinical context.
Basal Ganglia↗
Ultrasonography and magnetic resonance imaging in Leigh disease.
An infant with Leigh disease, who was the younger sister of a similarly affected infant, had been examined before the onset of the disease. Ultrasonography revealed hyperechoic lesions in the putamen and caudate nucleus during the preclinical stage. At onset, these changes extended into the cerebral cortex and medulla. These lesions were also detected by T2-weighted magnetic resonance imaging (MRI) as areas of increased signal intensity. Her brother demonstrated the same ultrasonographic results; cranial computed tomography disclosed low-density areas in the basal ganglia which were detected as hyperechoic lesions by ultrasonography. These findings suggest that ultrasonography is useful in detecting early intracranial lesions in Leigh disease.
Basal Ganglia↗
Cytochrome c oxidase partial deficiency-associated Leigh disease presenting as an extrapyramidal syndrome.
Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We describe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2 1/2 years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually developed. Nystagmus, transient ptosis, and strabismus also appeared. Abnormal laboratory findings included elevated plasma and cerebrospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebellar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Muscle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase deficiency No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently receiving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced.
Adolescent↗
Pelizaeus-Merzbacher disease with thiamine deficiency or Leigh disease with extensive involvement of white matter? Case report.
We report on a case of a 30-month-old child who presented with a clinical syndrome compatible with leucodystrophy and in whom neuropathological features of both Pelizaeus-Merzbacher disease and subacute necrotizing encephalopathy were shown. The significance of the neuropathological findings is discussed in the light of a possible coexistence of both diseases which has not previously been reported.
Brain↗
Subacute necrotizing encephalomyelopathy (Leigh disease): report of a case with Lennox-Gastaut syndrome.
More than 100 cases of Leigh disease have been reported. None have shown Lennox-Gastaut syndrome. We report here the first known case of Leigh disease with Lennox-Gastaut syndrome, and discuss the clinical course in detail. A 3 1/2-year-old-boy was admitted with multiple symptoms and despite various therapies he died at age of ten years. Serial CT showed marked cerebral atrophy, ventricular dilatation, and an arachnoid cyst in the posterior fossa. Histopathological findings on autopsy of the brain and spinal cord were consistent with those characteristic of Leigh disease. In the chronic course of Leigh disease, the cerebral cortex was also involved and the Lennox-Gastaut syndrome might be complicated.
Brain Diseases, Metabolic↗
Leigh disease with mitochondrial DNA A8344G mutation: case report and brief review.
Leigh disease, subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder often seen in infancy or childhood but rarely reported in adults. Genetic heterogeneity is well recognized, and the associated etiologies include both mitochondrial and nuclear DNA defects. We describe an infant presenting with developmental delay and then progressive multisystem disorder and neuroradiologic features of Leigh disease. He and his maternal relatives all have the A8344G mitochondrial DNA mutation. However, only minor clinical features are seen in his maternal relatives, with migraine being the most common problem. Additionally the A8344G mitochondrial DNA mutation is associated with spinocerebellar degeneration, other nonspecific mitochondrial encephalomyopathies, atypical Charcot-Marie-Tooth disease, and progressive external ophthalmoplegia. The A8344G mitochondrial DNA mutation may present with Leigh disease or other different atypical clinical features without myoclonic epilepsy and ragged red fibers.
Brain↗
Cochlear degeneration in leigh disease: histopathologic features.
OBJECTIVE: To describe pathologic findings from temporal bones acquired from an infant with Leigh disease. STUDY DESIGN: Retrospective case review. MATERIALS AND METHODS: Temporal bones were taken at autopsy from an 8-month-old infant with Leigh disease. The right temporal bone was studied by microdissection. The middle ear was examined and the inner ear sensory organs dissected for study by light microscopy. The left temporal bone was embedded in celloidin, and sections were cut for microscopic examination. RESULTS: Middle ear structures were normal bilaterally. There was, however, evidence of otitis media in both middle ears, which was more severe on the left side. Inner and outer hair cell loss, patchy degeneration of organ of Corti, and loss of nerve fibers in the osseous spiral lamina were found in the basal and middle turns of both cochleas. Basophilic deposits in the stria vascularis were observed in the apical portion of the left cochlea. CONCLUSIONS: Inner ear sensorineural degeneration may occur in Leigh disease. Possible cochlear dysfunction caused by the degenerative changes needs to be considered in the hearing assessment of patients with Leigh disease.
Autopsy↗
Deficiency of respiratory chain complex I is a common cause of Leigh disease.
We reviewed the clinical features and etiologies of Leigh disease in 66 patients from 60 pedigrees. Biochemical or molecular defects were identified in 50% of all pedigrees, and in 74% of the 19 pedigrees with pathologically proved Leigh disease. Isolated deficiency of respiratory chain complex I was found in 7 patients, though the complex was only assayed in 25 patients, making this the second most common biochemical abnormality after complex IV deficiency. Mutations at residue 8993 of mitochondrial DNA were found in only 2 patients. No correlation was found between the clinical features and etiologies. No defects were identified in the 8 patients with normal lactate concentrations in the cerebrospinal fluid.
Blotting, Southern↗
Leigh disease associated with a novel mitochondrial DNA ND5 mutation.
Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation.
Adult↗
Electrophysiological brainstem dysfunction in a child with Leigh disease.
We evaluated brainstem dysfunction in a girl with Leigh disease. Neuroradiological and neurophysiological tests included brain magnetic resonance imaging, [123I]IMP single-photon emission computed tomography (SPECT), auditory brainstem responses (ABRs), short-latency somatosensory evoked potentials (SSEPs), electrically elicited blink reflexes (BRs) and all night polysomnography (PSG). The basal ganglia and midbrain contained areas of low accumulation on [123I]IMP SPECT images. Serial analysis of ABRs and SSEPs showed progressive disturbances of the brainstem wave components. The R2 components of the BRs were impaired. All night PSG revealed disturbances in both the tonic and phasic components of REM sleep. These findings suggested the multimodality tests in combination with neuroradiologic examinations are useful for assessing brainstem dysfunction in patients with Leigh disease.
Blinking↗
Mitochondrial abnormalities in choroid plexus of Leigh disease.
Morphological study of the choroid plexuses in three patients with Leigh disease revealed a marked increase in the number of mitochondria in almost all of the choroidal epithelial cells. This finding is considered the morphological expression of a biochemical defect in the mitochondrial metabolism underlying Leigh disease, and the probable explanation for increased CSF levels of lactate and pyruvate in this disease.
Brain Diseases, Metabolic↗
[Leigh disease in a 3-year-old girl].
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.
Brain↗
Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families.
Leigh disease can be caused by defects of both nuclear and mitochondrially encoded genes. One mitochondrial DNA mutation, G14459A, has been associated with both respiratory chain complex I deficiency and Leber's hereditary optic neuropathy, with or without dystonia. Here, we report the occurrence of this mutation in 3 complex I-deficient patients from 2 separate pedigrees who presented with Leigh disease, with no evidence or family history of Leber's hereditary optic neuropathy or dystonia.
Adolescent↗
Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations.
Mutations in the SURF1 gene are the most frequent causes of Leigh disease with cytochrome c oxidase deficiency. We describe four children with novel SURF1 mutations and unusual features: three had prominent renal symptoms and one had ragged red fibers in the muscle biopsy. We identified five pathogenic mutations in SURF1: two mutations were novel, an in-frame nonsense mutation (834G-->A) and an out-of-frame duplication (820-824dupTACAT). Although renal manifestations have not been described in association with SURF1 mutations, they can be part of the clinical presentation. Likewise, mitochondrial proliferation in muscle (with ragged red fibers) is most unusual in Leigh disease but might be part of an emerging phenotype.
Cytochrome-c Oxidase Deficiency↗