Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy

Abstract

Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.

Figure 1

Pedigrees of Investigated Families and Structure of TANGO2 (A) Pedigrees of three families with mutations in TANGO2. Mutation status of affected (closed symbols) and healthy (open symbols) family members shown. n.a., not available. (B) Gene structure of TANGO2 with known protein domains of the gene product and localization of the identified mutations. Intronic regions are not drawn to scale.

Figure 2

Neuroimaging Findings in TANGO2 Mutant Individuals (A–D) Brain MRIs of individuals F2:II.2 (A–C) and F3:II.1 (D). Although the individual MRI findings are nonspecific, the rather uniform pictures with widening of the ventricles should be noted when placing them side by side. (A) Brain MRI (T₁-weighted image, axial view) at the age of 2 11/12 years, demonstrating mild widening of the ventricles suggestive of a generalized brain atrophy. (B) Brain MRI (T₂-weighted image, axial view) at the age of 2 years, demonstrating mild widening of the ventricles and the bifrontal cerebrospinal fluid spaces. (C) Brain MRI (T₂-weighted image, axial view) at the age of 6 years, showing no relevant changes compared to the earlier investigation. (D) Diffusion-weighted imaging (axial view) at the age of 6 years during acute metabolic crisis and recurrent seizures showing extensive left-hemispheric cortical cytotoxic edema, possibly caused by prolonged focal status epilepticus. (E) Brain MRI (T₂-weighted image, axial view) at the age of 22 years, demonstrating widening of the ventricles as a sign of generalized brain atrophy.

Figure 3

Investigation of Palmitate-Dependent Mitochondrial Respiration Analysis of palmitate-dependent oxygen consumption rates (OCR) in fibroblast cell lines revealed impaired respiration in TANGO2-mutant cells in comparison to controls. A MCAD (medium-chain acyl-Coenzyme A dehydrogenase)-deficient cell line was used as a positive control. The experiment was performed several times with very similar results. The data are shown from one experiment performed with more than 12 replicates for each cell line grown and treated in parallel. Error bars indicate 1 SD from the mean. ^∗p < 0.001; two-tailed unpaired t test.