Subacute Necrotizing Encephalomyelopathy (Leigh's Disease): a Consideration of Clinical Features and Etiology

Abstract

SUMMARY Eighty‐six cases of subacute necrotizing encephalomyelopathy (sne) have been reviewed in order to establish as accurately ab possible the natural course and characteristic symptomatology of the disease. In most cases the diagnosis was confirmed by autopsy, which introduces a bias toward a poor prognosis. Laboratory tests have not usually been helpful diagnostically, but low blood CO2 content, elevated lactate and pyruvate and mild pH changes have been reported in several cases. These abnormalities may be related to the hyperventiltion which results from neurogenic respiratory disturbances which have been seen in a high proportion of reported cases. The finding that the urine of affected patients contains an inhibitor of the enzyme which catalyzes thiamine triphosphate (ttp) formation may be the basis of a specific diagnostic test. ttp was either totally absent or was present in abnormally low concentrations in the brains of six children who died of sne and these findings have led to therapeutic trials with high doses of thiamine, thiamine propyldisulfide and thiamine tetrafurfuryldisulfide. Initial results of therapy have been encouraging and further clinical trials seem justified. Ultimately, however, elimination of the inhibitor is likely to prove to be the only completely successful mode of therapy. RÉSUMÉ Encephalomyélopathie nécrosante subaigue (maladie de Leigh): Considérations sur les symptomes cliniques et l'étiologie 86 cas d'encéphalomyélopathie nécrosante subaigue (sne) ont été revus dans la litterature pour établir 1'évolution et les caractéristiques de la maladie. Dans la plupart des cas rapportés, le diagnostic a été confirmé par l'autopsie, ce qui indique un tendence á un mauvais pronostic. Les examens de laboratoire n'ont pas été d'une grande aide pour le díagnostic mais dans plusieurs cas, il a été signalé une faible pression partielle de CO2 dans le sang, des taux élevés de lactate et de piruvate et de légères modifications du pH. Ces anomalies peuventstre reliées à I'hyperventilation qui provient de troubles respiratoires neurogèes, observés dans une forte proportion de cas. Un test spécifique de diagnostic peut reposer sur la découverte que l'urine des malades contient un inhibiteur de l'enzyme qui catalyse la formation de la thiamine triphosphate (ttp). La ttp était totalement absente ou présente à des concentrations anormalement basses dans les cerveaux de 6 enfants morts de sne, et ces découvertes ont conduit à des essais thérapeutiques avec de fortes doses de thiamine, de thiamine propyldisulfide et thiamine tetrafurfuryldisulfide. Les premiers résultats de ce traitement sont encourageants et justifient d'autres essais cliniques. ZUSAMMENFASSUNG Subakute nekrotisierende Encephalomyelopathie (Leigh'sche Erkrankung): klinische Merkmale und Atiologie 86 Fälle mit subakuter nekrotisierender Encephalomyelopathie (sne) wurden aus der Literatur zusammengetragen, um den Verlauf und die charakteristischen Merkmale der Krankheit festzustellen. Bei den meisten beschriebenem Fällen wurde die d...

Fatal breathing dysfunction in a mouse model of Leigh syndrome

“…We noted previously (23) that KO mice resemble humans with LS with regard to a large range of phenotypes and we now extend that to breathing. Respiratory abnormalities affect many LS patients (8,9,35,36) and virtually all patients with mutations in the NDUFS4 gene (16-21, 37); however, the link between mitochondrial dysfunction and breathing could not be investigated without an animal model.…”

Autonomic Dysfunction Presenting as Orthostatic Intolerance in Patients Suffering From Mitochondrial Cytopathy

“…Autonomic nervous system dysfunction can be severe enough to overshadow the myopathic features of the disorder and might delay the definitive diagnosis of mitochondrial cytopathy 8. Autonomic features that include gastrointestinal dysmotility, impaired respiratory control, and cardiac arrhythmias have been observed with both Leigh syndrome and Kerns‐Sayre syndrome and in myoneurogastrointestinal disorders with encephalopathy 9–12. In addition, cardiac conduction defects or hypothermia and feeding problems might occasionally occur in other mitochondrial diseases, including Leber hereditary optic neuropathy and X‐linked recessive kinky hair disease 12, 13.…”

Hypokinesia and Rigidity as Clinical Manifestations of Mitochondrial Encephalomyopathy: Report of Three Cases

“…Familial dystonia with optic atrophy is excluded in our patients because of the exclusive dystonic syndrome in such patients. Infantile bilateral striatal necrosis may also be -3 4 L associated with hypokinesia, rigidity, or a mixture of extrapyramidal symptoms (Miyoshi et al 1969, Roessmann and Schwartz 1973, Roytta et al 1981. Goutikres and Aicardi (1982) divided the syndrome of infantile bilateral striatal necrosis into three subgroups: (1) those of definite or probable Leigh syndrome; (2) cases of familial degeneration of the striatum with an insidious onset and a slow progressive course; and (3) cases which present with abrupt neurological dysfunction following an acute systemic illness.…”

“…Representatives of this group are the syndromes of Leigh (Hommes et al 1968, Farmer et al 1973, Willems et al 1977, Van Erven et al 1985 and Alpers (Gabreels et al 1984), dysmyelination (Sengers et al 1984), Kearns-Sayre syndrome (Karpati et al 1973), myoclonus epilepsy with 'ragged-red fibres' (MERRF) (Fukuhara et al 1980), and the MELAS syndrome, an acronym which stands for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (Pavlakis et al 1984). These syndromes vary considerably in clinical signs and symptoms, but they all show cerebral spongiosis, although to a varying extent and with different localization (Walter 1983 Antemortem diagnosis of probable Leigh syndrome can be made when clinical signs and symptoms indicate involvement of the above-mentioned parts of the central nervous system (Pincus 1972) and when pyruvate metabolism is disturbed (Van Erven et al 1987). The presence of bilateral hypodensities in the basal ganglia on CT scans, or abnormal signal intensities on magnetic resonance imaging (Hall and Gardner-Medwin 1978), can further support the clinical diagnosis.…”