Biallelic variants in the MTFMT gene have been associated with Leigh syndrome (LS) and mitochondrial multiple respiratory chain deficiencies, or a separate entity of MTFMT‐related mitochondrial disease. More than 80 genes have been associated with LS with variable presentations; MTFMT variants are associated with a milder form. 1 LS attributed to a methionyl‐tRNA formyl transferase MTFMT gene mutation was found by Tucker and colleagues in 2011. 2
Mitochondrial disorders are associated with a variety of movement disorders, such as dystonia, ataxia, myoclonus, spasticity, parkinsonism, tremor, tics, and restless leg syndrome. 3 , 4 MTFMT gene variant–associated LS may present with various movement disorders and neurological symptoms. We document a case report of the MTFMT gene variant showing a milder form of LS, or rather MTFMT gene‐related mitochondrial disorder with nonprogressive mobile dystonia and abnormal gait with a choreoathetosis‐like presentation.
Sustained muscle contractions in dystonia can cause repetitive twisting movements (“mobile” dystonia) or abnormal gait. Dystonic movements can be distinguished from chorea by their nonflowing characteristics along with increased tone. Dystonic movements may resemble myoclonus if they are fast, which has been termed amyoclonic dystonia. On the other hand, if they are slow, they resemble athetosis. 5 Mobile dystonia is found in dyskinetic cerebral palsy involving the basal ganglia. 6
Case Report
A 6‐year‐old Caucasian boy was brought to the clinic for abnormal gait and global developmental delay noted from 1 year of age. He was born at 38 weeks gestational age by vaginal delivery from nonconsanguineous parents. The family history was negative for neurological diseases other than a history of learning difficulties in a maternal grandfather.
He continues to develop slowly but has involuntary dance‐like hand and leg movements. He can walk and run, but while walking he usually uses his toes and clenches his fists. He has no history of seizures, muscle weakness/atrophy, visual impairment, or symptoms of peripheral neuropathy. He had no cardiac, gastrointestinal, or other systemic involvement, nor intermittent progression of symptoms attributed to infection, trauma, or stress. On examination, it was found that he mostly walks on his tiptoes, and when he runs, he flexes his upper extremity, which stiffens and curls up. He has mobile dystonia of his hands, legs, foot, and tongue along with a characteristic gait (see Video 1). Brain magnetic resonance imaging (MRI) at 6 years of age showed T2 prolongation with patchy areas of diffusion restriction in the bilateral posterior putamen and head of caudate nucleus without contrast enhancement, suggestive of LS (Fig. 1A,B). Magnetic resonance spectroscopy (Fig. 1E–G) revealed lactate peak and serum lactate; pyruvate and other metabolic testing were normal. Biochemical testing for mitochondrial complex I deficiency was not done.
Video 1.
Mobile dystonia of the neck, right hand, and in the first segment on the right foot with characteristic gait in a developmentally delayed 6‐year‐old boy.
FIG 1.
(A–D) Brain diffusion‐weighted magnetic resonance imaging (A, at 6 years of age; C, at 9 years of age) showing diffusion restriction and T2 fluid‐attenuated inversion recovery image (B, at 6 years of age; D, at 9 years of age) showing signal abnormality (Yellow Arrow) in the bilateral posterior putamen and caudate head. (E–G) Brain magnetic resonance spectroscopy at 6 years of age showing lactate peak (Yellow Arrow): (E) short echo with positive lipid lactate peak, (F) intermediate echo with inverted lactate peak, and (G) long echo with positive lipid lactate peak. (H) Sanger sequencing confirms the mutation detected by next‐generation sequencing.
Whole exome sequencing (WES) and mitochondrial testing were pursued. WES is a genetic method that sequences coding regions of the genome that analyzes nuclear genes inherited from both parents. On the other hand, mitochondrial genomic testing looks at DNA located in the mitochondria, which is inherited from the mother.
Mitochondrial testing was negative. WES testing was only pertinent for a homozygous mutation, c.626 C > T (p.S209L), in the gene MTFMT that was confirmed through Sanger sequencing (Fig. 1H). Segregation analysis of both parents confirmed the presence of the mutation in heterozygosity. This variant is predicted to cause exon 4 skipping due to the elimination of the 2 exonic splicing enhancers that results in a frameshift and premature stop codon. 2 Functional studies demonstrate reduced mitochondrial methionyl‐tRNA formyl transferase protein activity. 7 The presence of this biallelic variant in the MTFMT gene confirms the patient's diagnosis of MTFMT‐related mitochondrial disease. He was followed up for 3 years, and overall he did well with no change in MRI findings (Fig. 1C,D). His mobile dystonia was present but improved without any treatment (Video 2). He continues to suffer from intellectual disability and learning disorders but has no cognitive deterioration.
Video 2.
Mobile dystonia of the hands, legs, foot, and tongue along with a characteristic gait was still present in the same patient at 8 years of age; interestingly, symptoms had improved without treatment.
Discussion
In general, MTFMT‐related mitochondrial disease has a better prognosis with a milder clinical phenotype and disease progression. 8 MTFMT variant‐related LS is mostly present from birth to 17 years of age, with developmental delay and motor symptoms. In the current case report, the patient had a milder form of MTFMT‐related mitochondrial disease with developmental delay, intellectual disability, nonprogressive or rather improved mobile dystonia, and characteristic gait. A total of 16 pathogenic variants of MTFMT gene mutations are identified, of which c.626C > T is the most common. MRI findings in MTFMT pathogenic variants included basal ganglia changes, periventricular and subcortical white matter abnormalities, and brainstem lesions. 9
Differential diagnoses include Wilson's disease, PANK2 and PKAN mutations related disorders, biotin‐responsive basal ganglia disease, pyruvate dehydrogenase deficiency diseases, and disorders of the Oxydative Phosphorylation pathway. Cerebellar ataxia, myoclonus, dystonia, parkinsonism, and spasticity are reported in MTFMT gene‐related mitochondrial disorders; however, to our knowledge, presentation of the c.626C > T variant with video of nonprogressive or rather improved mobile dystonia and characteristic gait are not available. 9 , 10 Thus, this case expands the phenotypical presentation of MTFMT‐related mitochondrial disease.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.
K.S.: 1A, 1B, 1C, 2A, 2B
K.D.: 1C, 2A, 2B
Disclosures
Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Verbal and written consent was obtained from the patient for the publication of this case study. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Acknowledgments
The authors acknowledge the Radiology Department at Dayton Children's Hospital for performing and providing brain magnetic resonance imaging. The authors also acknowledge Genedx/Sema4 for performing the genetic testing and providing the Sanger sequencing image.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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