Leigh syndrome followed by parkinsonism in an adult with homozygous c.626C>T mutation in MTFMT

Discussion

LS is usually reported as infantile subacute necrotizing encephalomyelopathy, a neurodegenerative disorder clinically characterized by variable neurologic signs. Bilateral lesions in the striatum are typically seen on brain imaging studies. The onset of symptoms in infancy or early childhood is usually triggered by metabolic or infectious stress, followed by rapid neurologic deterioration, often leading to death.⁷ Long-term survival after early-onset LS and atypical late-onset variants has been reported.⁸ The number of patients with late-childhood–, adolescent-, or adult-onset LS is limited, and only in a few, the genetic defect was identified. The MTFMT gene product is essential for efficient mitochondrial translation initiation and function. The protein is involved in formylation of a portion of the Met-tRNA^Met pool to generate formylmethionyl-tRNA needed for initiation of protein synthesis in mitochondria.^4,9 We report here the oldest patient so far with a homozygous pathogenic mutation in MTFMT who developed adult-onset LS.

Pathogenic mutations in the MTFMT gene were first reported in 2 children, aged 5 and 9 years, with LS and combined OXPHOS deficiency.⁴ To date, 22 patients with MTFMT mutations were reported in the literature. The age at onset varied between birth and 17 years. Most of them presented with ataxia, muscular hypotonia, and cognitive impairment, but recently reported cases support an expanding phenotypical spectrum, including MRI features mimicking demyelinating disease, cardiomyopathy, and even an association with renal dysplasia and moyamoya disease in a 4-year-old child.^6,9,–,12 Recently, a girl was reported with mild neurologic phenotype at age 7 years and involvement of the visual pathways starting at the age of 18 years.¹³ MTFMT-patients with adolescent-onset symptoms are rare. They have developmental delay already present in childhood, slight intellectual disability, and behavioral problems.^6,14

In the proband, molecular workup by WES and in silico analysis of the genes involved in mitochondrial transcription and translation revealed a homozygous missense mutation (c.626C>T, p.(Ser209Leu)) in the gene encoding MTFMT. This mutation is predicted to eliminate 2 overlapping exonic splicing enhancers (GTCAA and TCAAGA) and to generate an exonic splicing suppressor (GTTGTT) causing loss of function through altered splicing, leading to skipping of exon 4 and introduction of a premature stop codon resulting in truncation of the protein (p.Arg181Serfs*5) as reported earlier.^4,15 The c.626C>T variant is present in the heterozygous state in 0.1% of the European population, making it a strong candidate gene for patients presenting with LS in combination with combined OXPHOS deficiencies involving complexes I and IV.⁶

The clinical course of LS in the proband initially seemed to be self-limiting and benign. Of interest, the proband developed an extrapyramidal syndrome within 2 years after onset of LS characterized by symmetrical parkinsonism signs with limited levodopa responsiveness, distinguishing it from classical Parkinson disease (PD). Parkinsonian symptoms in MTFMT-deficient patients have not been reported so far. In most of the cases with adult-onset LS, EPS were limited to dystonia.¹⁶ In only 1 report, extrapyramidal rigidity was described in an adult with LS. However, the molecular defect was not specified.¹⁷ In the reported participant, EPS developed after stabilization of the symptoms attributed to LS, as was the case in the proband reported here. Juvenile parkinsonism with beneficial effect of treatment with levodopa was reported in an adolescent with Leigh-like phenotype caused by a point mutation in the mitochondrial tRNA^Ile (m.4296G>A).¹⁸

To evaluate the dopaminergic system in the proband, FP-CIT SPECT and C-11 raclopride PET were performed. Symmetrical decreased density of presynaptic dopamine transporter terminals with bilaterally reduced FP-CIT binding was found. C-11 raclopride PET labeling of dopamine D2 receptors showed severe bilateral neostriatal reduction of C-11 raclopride, revealing postsynaptic dopaminergic impairment. This result is similar to that seen in the atypical parkinsonian syndromes, such as multiple system atrophy or progressive supranuclear palsy.¹⁹

Limited evidence on dopamine transport imaging in LS is available. A study on ¹²³I-FP-CIT striatal binding in 14 patients (age 35–69 years, median 48 years) with mitochondrial disorders and complex I deficiency failed to demonstrate dopaminergic cell loss. However, none of these patients suffered from LS or showed clear signs of parkinsonism.²⁰ In the participant reported here, cystic lesions in the neostriatum reflecting basal ganglia degeneration caused by mitochondrial dysfunction are likely to be involved in EPS. Of interest, a recent study on the etiologic role of epigenetic influences in PD showed a role of several microRNAs involved in a network of genes associated with PD. It was shown that the expression of MTFMT (influenced by miR-488) was downregulated in the cingulate gyrus of patients with PD as compared to healthy controls. Dysregulation of 1 or more of the genes in the PD-genetic network, including MTFMT, might interfere with extrapyramidal neuronal integrity and function.²¹ The findings in the participant described here provide additional clinical evidence for the hypothesis that MTFMT is involved in PD-related genetic network and that MTFMT dysregulation might be an etiologic factor in parkinsonism.

We cannot rule out that the older age of the proband as compared to other reported patients may have played a role in the development of atypical parkinsonism. At present, it is unclear whether parkinsonism is part of the MTFMT phenotype. Natural history data on patients with MTFMT mutations and advanced age are lacking. Our data suggest that dopaminergic neurons in patients with LS caused by pathogenic MTFMT mutations may be more susceptible to PD because of the impaired OXPHOS system, ultimately leading to a clinically significant extrapyramidal syndrome.

Adult-onset LS can be seen in patients with c.626C>T mutation in MTFMT. We showed that the affected patient had a defect in the dopaminergic system associated with atypical parkinsonism. Further research on the natural history of patients with pathogenic MTFMT mutations is needed to clarify the full clinical spectrum and underlying physiopathologic mechanisms.