Elsevier

Brain and Development

Volume 21, Issue 3, 1 April 1999, Pages 200-204
Brain and Development

Case report
Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome

https://doi.org/10.1016/S0387-7604(98)00095-3Get rights and content

Abstract

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T→G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patient's spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.

Introduction

Leigh syndrome is a progressive neurodegenerative disorder in infancy or childhood with variable clinical presentations, lactic acidosis and characteristic pathological findings in the brain, i.e. symmetrical foci of necrosis in the basal ganglia, thalamus, brainstem, dentate nuclei and optic nerves 1, 2. This disease is due to a disturbance of aerobic metabolism. Defects in pyruvate dehydrogenase (PDH) and cytochrome c oxidase (COX) are often associated with Leigh syndrome, and are inherited as autosomal recessive or X-linked traits 3, 4. Recently, some patients with Leigh syndrome were reported to carry specific mitochondrial (mt) DNA point mutations: A8344G [5], T8993G [6]and T8993C [7]mutations. A T→G point mutation at nt 8993 in the ATPase 6 gene of mtDNA was initially described in a family with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) [8], and was later found to result in maternally inherited Leigh syndrome when present at a high level [6].

We performed localized proton magnetic resonance spectroscopy (MRS) to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T→G point mutation at nt 8993 of mtDNA. The patient was treated with thiamine and sodium dichloroacetate (DCA), which have lactate-lowering effects. Proton-MRS allows non-invasive measurement of brain metabolites, such as N-acetylaspartate (NAA), a choline-containing compound (Cho), creatine and phosphocreatine (Cr), and lactate (Lac). NAA is present in neurons and appears to be a possible indicator of neuronal function 9, 10. Choline is involved in the synthesis of a neurotransmitter, acetylcholine, and the synthesis and breakdown of membrane phospholipids [10]. The presence of lactate indicates the occurrence of anaerobic glycolysis in the brain. The aim of this study was to demonstrate a clinical usefulness of proton-MRS in evaluating an effectiveness of treatment in Leigh syndrome.

Section snippets

Case report

The patient was a Japanese boy born at term after an uncomplicated pregnancy. He was the second child of healthy and non-consanguineous parents. A 3-year-old sister was healthy. His birth weight was 2842 g and the Apgar scores were six and eight at 1 and 10 min, respectively. Generalized hypotonia was noted at birth. He developed apnea attacks and altered consciousness after upper respiratory infections at the ages of 2 and 4 months. At the age of 9 months, he was admitted to our hospital due

Discussion

We reported here the use of localized proton-MRS to study the metabolic changes in the brain of a patient with Leigh syndrome. This approach allowed us to examine various brain regions directly and non-invasively, and to correlate the regional metabolic changes with biochemical changes or lesions observed on MRI. Under normal conditions, the lactate concentration in the brain is at the limit of detectability on proton-MRS [13]. The presence of lactate indicates the occurrence of anaerobic

Acknowledgements

We wish to thank Dr. Teruo Kimura, Department of Neurosurgery, and Drs. Takumi Goto and Hidetoshi Ono, Department of Radiology, Asahikawa Medical College, for the helpful comments regarding the proton-MRS studies.

References (15)

  • S.R. Hammans et al.

    Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples

    Lancet

    (1991)
  • S. Takahashi et al.

    De novo mtDNA nt 8993 (T→G) mutation resulting in Leigh syndrome

    Am J Hum Genet

    (1998)
  • D. Leigh

    Subacute necrotizing encephalomyelopathy in an infant

    J Neurol Neurosurg Psychiatry

    (1951)
  • V.J. Montpetit et al.

    Subacute necrotizing encephalomyelopathy. A review and a study of two families

    Brain

    (1971)
  • H.A. Kretzschmar et al.

    Pyruvate dehydrogenase complex deficiency as a cause of subacute necrotizing encephalopathy (Leigh disease)

    Pediatrics

    (1987)
  • S. DiMauro et al.

    Cytochrome c oxidase deficiency in Leigh syndrome

    Ann Neurol

    (1987)
  • F.M. Santorelli et al.

    The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome

    Ann Neurol

    (1993)
There are more references available in the full text version of this article.

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