Introduction

Leigh syndrome (LS) or subacute necrotizing encephalomyelopathy is a progressive neurological disease with specific neuropathological lesions to the brainstem and basal ganglia. Birth prevalence is approximately 1 in 36,000. Symptom onset occurs within the first 12 months, but in rare cases, the disease onset occurs during adolescence or early adult life.

Leigh syndrome can be caused by variants in one of more than 85 different genes. Recurrent, structural subunit mutations including m.10158T>C,12 m.10191T>C,13 and m.10197G>A14 in the MTND3 gene; m.12706T>C,15 m.13513G>A,16 and m.13514A>G17 in the MTND5 gene, and m.14459G>A18 and m.14487T>C19 in the MTND6 gene all contribute to the broad clinical spectrum of disease phenotypes. One such mutation, m.10191T>C in MTND3 variant causes a mitochondrial complex I deficiency NADH: ubiquinone oxidoreductase, the largest of the five multimeric enzyme complexes of the oxidative phosphorylation system, comprising seven mitochondrial-encoded subunits and at least 38 nuclear-encoded subunits. The NADH transfer electrons to ubiquinone using this complex via a series of protein-coupled redox centers and the translocation of protons across the inner mitochondrial membrane, contributing to the synthesis of adenosine triphosphate. The alteration of this metabolic pathway results in variable phenotypes from organ-specific to multisystem disease [1].

Here, we describe a patient with an alteration of this metabolic pathway and a review of similar cases from the literature.

Case Presentation

A 36-year-old African male presenting to the Emergency Department after falling over. On neurological examination, he showed ideomotor slowness and mild spastic gait due to a mild right hemiparesis with Babinski sign. He also showed dysarthria, down-gaze impairment, and loss of convergence. Temperature and pain sensation in the right leg was reduced. Tendon reflexes were reduced at the upper and absent at the lower limbs. There was no muscle atrophy or fasciculations. His relatives later revealed a progressive walking impairment with falls since the age of 25, as well as speech difficulties in the last 3 years. The family history was mute. He was a metal worker and denied any medication or abuse.

Investigations

At first, the clinical evaluation depicted a slowly progressive disease with dysarthria, gaze palsy, right hemiparesis with Babinski sign, and walking difficulties. This picture may well suggest brainstem damage. Secondly, features such as diffuse tendon hypo/areflexia and superficial hypoesthesia of the right leg would suggest a concurrent involvement of the peripheral nervous system.

In the Emergency Department, a computerized tomography (CT) scan of the head showed discrete hypodense areas around the third ventricle, the lenticular nuclei, and the right caudate nucleus. Initially, we considered it an infective/inflammatory or demyelinating disease. The patient then underwent magnetic resonance imaging (MRI) (Fig. 1), showing multiple white matter hyperintense lesions on fluid-attenuated inversion recovery (FLAIR) sequences. These lesions appeared to be symmetrically located: around the third ventricle, to the anterior putamen and the head of caudate nuclei (restricted on diffusion-weighted imaging or DWI), and in the posterior part of the caudate nuclei and medulla oblongata (not restricted to DWI). No lesions displayed gadolinium enhancement. Spectroscopy documented alteration with increased lactate, choline, and creatine and reduced n-acetyl-aspartate peaks, suggesting a mitochondrial disorder. Serum creatine kinase level was slightly increased (359 U/L; normal range: 38–174). Unremarkable blood tests included erythrocyte sedimentation rate, C-reactive protein, lupus anti-coagulant, anti-double strand deoxyribonucleic acid and extractable-nuclear antibodies, vitamin B12 and folate, Treponema, Borrelia, tuberculosis, and human immunodeficient virus, anti-oligodendrocyte myelinated glycoprotein and anti-aquaporin4 antibodies. Cerebrospinal fluid (CSF) analysis showed no cells, normal protein (39 mg/dL) and glucose (84 mg/dL), slightly increased lactate (2.1 mMol/l if compared to the serum value of 0.9), and no oligoclonal bands. CSF rapid bacterial and viral antigens were negative. Nerve conduction studies showed mild sensitive axonal neuropathy at the lower limbs. Optic fundoscopy and visually evoked potentials were normal. We excluded a covert alcohol abuse, denied by the patient, with normal carbohydrate-deficient transferrin (and normal mammillary bodies on MRI). Serum levels of lead, copper, and manganese were normal.

Fig. 1
figure 1

Magnetic resonance imaging (MRI) showed A–C axial-sagittal fluid-attenuated inversion recovery (FLAIR) sequences with bilateral lesions around the third ventricle, to the anterior putamen and the head of caudate nuclei, and in the posterior part of the caudate nuclei and medulla oblongata (blue arrows); D, E axial-sagittal diffusion-weighted imaging (DWI) showing bilateral restriction to the anterior putamen and the head of caudate nuclei (not to the posterior part of the caudate nuclei) (red arrows; E–G) axial-sagittal T1 sequences after gadolinium revealed no contrast enhancement

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Meanwhile, the patient’s respiratory function worsened, and he underwent a tracheostomy. We decided to focus on the MRI findings and considered a biotin-thiamine-responsive basal ganglia disease, supplementing thiamine and biotin with no improvement [2]. There was no history of carbon monoxide or methanol intoxication, and normal serum ceruloplasmin was against Wilson’s disease. We then searched for mitochondrial disorders [3, 4] and performed a muscle biopsy on the left quadriceps femoris showing mild, nonspecific myopathic changes with no “ragged red” fibers. Subsequently, we performed genetic testing for point mutations in the genes of the mitochondrial oxidative phosphorylation complex, which was negative. Finally, PCR amplification of the mitochondrial genes, followed by direct sequencing, found a 10191T>C variant, which is reported as pathogenic for LS [5, 6]. To identify any point mutations in the mitochondrial DNA, a Sanger sequencing was carried out starting from DNA extracted from a muscle biopsy. The m.10191T>C mutation was subsequently studied by restriction fragment length polymorphism analysis to identify the percentage of heteroplasmy in muscle and lymphocytes, resulting respectively 45% and 8%.

Clinical Course and Management

The patient started with acetylcarnitine 1500 mg and ubidecarenone 50 mg daily, then was transferred to the rehabilitation unit. His respiratory function improved and the tracheostomy was removed. He is still alive 2 years after diagnosis.

Discussion

Adult-onset LS (later than 15 years old) has been reported extremely rarely with these cardinal features: seizures, ataxia/dystonia, external ophthalmoplegia, and spastic weakness. Serum and CSF may reveal lactic acidosis [4, 6-10]. Suspicion relies mainly on MRI/spectroscopy findings: hallmarks are bilateral, symmetric necrotizing lesions in the basal ganglia, thalamus, brainstem, and spinal cord, with spared mammillary bodies [11, 12]. Spectroscopy might be of help in differentiating Leigh syndrome from a range of other mitochondrial diseases, such as ophthalmoplegia and Kearns-Sayre syndrome, showing a lack of lactate in brain tissues appearing normal on MRI. Deficits in pyruvate dehydrogenase complex and mitochondrial respiratory chain complexes I, II, and IV are related to necrotizing lesions on T2-weighted MRI and FLAIR [12]. It is not known to what extent the degree of heteroplasmy correlates with the severity of the disease, as far as possible in relation to the case presented it is possible to say that the absence of symptoms till adulthood could be correlated with the low degree of heteroplasmy found (45% muscle and 8% % lymphocytes).

Conclusion

LS is genetically heterogeneous since pathogenic mutations were found in over 85 genes [3]. Only 8 adult-onset cases share the same mutation as ours (Table 1). The majority presented with seizures (7 patients), myoclonus (3 patients), and optic atrophy (2 patients). These features were absent in our patient who showed a predominant respiratory involvement and failure (Table 1). MRI was confirmed as the most informative investigation in the cohort, while muscle biopsy was not.

Table 1 Clinical features of late-onset Leigh syndrome due to m.10191T>C variant. C current case, CSF cerebro-spinal fluid, EPC epilepsia partialis continua, NA not available, NCS nerve conduction studies, RRF ragged red fibers, VEP visually evoked potential; +, altered/present; −, normal/absent; m muscle, b blood
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