Distinct Imaging Markers of Leigh’s Disease Linked to Mutation: A Pediatric Case Study

Introduction

Leigh disease (LD) is a genetic disorder that is commonly inherited with an autosomal recessive pattern and homogeneous or compound heterogeneous genetic mutation defects. The most common gene mutations associated with LD are located in the mitochondrial DNA [1]. However, nuclear mutations result in rare Cytochrome C Oxidase Assembly Factor (SURF1) gene defects, which show signal abnormalities at characteristic locations on magnetic resonance imaging (MRI). The progression of LD with the SURF1 mutation is typically rapid and can lead to severe disability or death, usually within a few years of onset [2,3]. Diagnosis is usually made based on characteristic clinical symptoms and neuroimaging findings. Genetic testing can confirm the diagnosis by identifying the specific gene mutation. Treatment primarily focuses on managing symptoms and providing supportive care, which may include physical therapy, speech therapy, and respiratory support. We report a case of a 2-year-old boy with developmental delay, hypotonia, involuntary movements, shortness of breath, and reduced activity since age 6 months.

Case Report

A 2-year-old first born male child born at term to consanguineous parents presented with developmental delay, hypotonia, involuntary movements, and shortness of breath, with reduced activity since age 6 months. The family history was insignificant, with no similar cases noted. The generalized symmetrical hypotonia showed markedly reduced deep tendon reflexes.

Laboratory investigations revealed mildly elevated blood lactate levels (37 mg/dL; normal 10–24 mg/dL) at rest with an increased lactate-o -pyruvate ratio of 35.9 (normal: 10–20). Cerebrospinal fluid analysis showed a mild increase in lactate levels.

On MRI of the brain, symmetrical hyperintense lesions were observed in the posterior lentiform nucleus, subthalamic nucleus, midbrain (substantia nigra, periaqueductal gray matter), posterolateral pons, and olivary nucleus of the medulla, extending into the cervical cord and bilateral dentate nucleus of the cerebellum on T2-weighted (T2W) MRI (Figure 1A–1F), with corresponding areas of non-enhancing hypointensities on T1-weighted (T1W) MRI (Figure 2A–2D). Diffusion-weighted MRI showed areas of restriction with a reduced apparent diffusion coefficient (ADC) in the periphery and within the lesion (Figure 3A, 3B). Magnetic resonance spectroscopy (MRS) demonstrated elevated choline, reduced N-acetylaspartate, and mild prominence of the lactate peak (Figure 4). Further targeted gene sequencing showed defects in the SURF1 gene with heterogenous single-base pair insertion at exon 9 and two-base pair deletion in exon 6 of the SURFI gene – OMIM 185620 an intranuclear type 1 mutation (MC4DN1 and OMIM 220110).

The patient was given supportive treatment with Co-enzyme A, L-carnitine, thiamine, biotin, and other vitamin supplementation, and the child’s parents were advised to return for follow-up care. On follow-up there was slight improvement in the tone and involuntary movements and breathing of the patient.

Discussion

LD (aka subacute necrotizing encephalopathy) is a rare progressive neurodegenerative disorder characterized by symmetrical spongiform lesions in the brain. The disorder is caused by mitochondrial mutation, whereas the SURF1 variant is caused by mitochondrial and intranuclear mutations, which lead to extensive neurodegeneration and MRI signal abnormalities at characteristic locations. The brainstem and subthalamic nuclei are the most affected sites, but the spinal cord also may be affected. Spinal cord involvement is a rare feature of LD and has been infrequently reported [4]. The most consistent imaging findings are midbrain involvement, including hyper-intense signals on T2W and FLAIR and non-enhancing hypoin-tense lesions on T1W-MRI in the substantia nigra and subthalamic nuclei, periaqueductal region, pons, medulla, and dentate nuclei of the cerebellum [5,6]. Diffusion imaging shows areas of complete or peripheral restrictions with reduced ADC and MRS, which may show a mild increase in lactate peak at 1.33 ppm, an increase in choline, and reduction in the N-acetyl aspartate peak [7]. Very few case reports of cervical spinal cord involvement in patients with the SURF1 mutation have been reported in the literature. Brainstem abnormalities are linked to respiratory failure. Various genetic mutations are described for Leigh disease (Figure 5) [8].

Conclusions

LD is a rare metabolic neurodegenerative disease with spongiform degeneration in the brain. The possibility of a SURF1 mutation should be considered when lesions are present in characteristic locations, including the dentate nuclei of the cerebellum, inferior olivary nucleus of the medulla, substantia nigra, subthalamic nuclei, and posterior lentiform nuclei, as well as spinal cord involvement with a minimal increase in the lactate peak. These imaging findings should be further evaluated by performing genetic studies to look for a possible SURF1 mutation among the various other genetic mutations described.