TUFM variants lead to white matter abnormalities mimicking multiple sclerosis

Background and purpose: Defects in the mitochondrial respiratory chain (MRC) can lead to combined MRC dysfunctions (COXPDs) with heterogenous genotypes and clinical features. We report a patient carrying heterozygous variants in the TUFM gene who presented with clinical features compatible with COXPD4 and radiological findings mimicking multiple sclerosis (MS).

Methods: A 37-year-old French Canadian woman was investigated for recent onset of gait and balance problems. Her previous medical history included recurrent episodes of hyperventilation associated with lactic acidosis during infections, asymptomatic Wolff-Parkinson-White syndrome, and nonprogressive sensorineural deafness.

Results: Neurological examinations revealed fine bilateral nystagmus, facial weakness, hypertonia, hyperreflexia, dysdiadochokinesia, dysmetria, and ataxic gait. Brain magnetic resonance imaging (MRI) showed multifocal white matter abnormalities in cerebral white matter as well as cerebellar hemispheres, brainstem, and middle cerebellar peduncles, some of which mimicked MS. Analysis of native-state oxidative phosphorylation showed a combined decrease in CI/CII, CIV/CII, and CVI/CII. Exome sequencing detected two heterozygous TUFM gene variants. Little clinical progression was noted over a 5-year follow-up. Brain MRI remained unchanged.

Conclusions: Our report broadens the phenotypic and radiological spectrum of TUFM-related disorders by adding milder, later onset forms to the previously known early onset, severe presentations. The presence of multifocal white matter abnormalities can be misinterpreted as due to acquired demyelinating diseases, and thus TUFM-related disorders should be added to the list of mitochondrial MS mimickers.