Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

Abstract

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism

“…The severity of TANGO2 ‐related disease is highly variable, both in our patient group and those previously described . This is not simply due to genotype‐phenotype correlations, as siblings carrying the same causative variants can present with dramatically different severity of symptoms.…”

“…Population‐based studies have shown that heterozygous loss of this region is found in white Europeans with an allele frequency of between 0.062% and 0.11%, with homozygous deletions being absent in large control datasets. In a consanguineous of Arab origin (family 3), the patient was homozygous for a deletion encompassing exons 4 to 6, which has previously been described in a consanguineous family from Saudi Arabia …”

“…The variants were absent or extremely rare (<0.002%) in the gnomAD database, and homozygous carriers were lacking. In three European families without known consanguineous descent (families 1, 5, and 7), five patients were homozygous for the previously described approximately 34‐kb deletion encompassing exons 3 to 9, likely reflecting an ancestral variant in Europeans . Population‐based studies have shown that heterozygous loss of this region is found in white Europeans with an allele frequency of between 0.062% and 0.11%, with homozygous deletions being absent in large control datasets.…”

“…The pattern of biochemical abnormalities found during crises with hypoglycaemia, hyperlacticacidaemia (and hyperammonaemia in one patient) followed by rhabdomyolysis is similar to previously described patients . It is unclear at present why some patients do not present with the metabolic derangements above and instead have rhabdomyolysis only.…”

“…Urine organic acids and acylcarnitine profiles have shown varying abnormalities with no consistent metabolic signature. Seizures have been found in 75% of patients and primary hypothyroidism in 40% …”