Dataset Information

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.

SUBMITTER: Lalani SR

PROVIDER: S-EPMC4746334 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Lalani Seema R SR Liu Pengfei P Rosenfeld Jill A JA Watkin Levi B LB Chiang Theodore T Leduc Magalie S MS Zhu Wenmiao W Ding Yan Y Pan Shujuan S Vetrini Francesco F Miyake Christina Y CY Shinawi Marwan M Gambin Tomasz T Eldomery Mohammad K MK Akdemir Zeynep Hande Coban ZH Emrick Lisa L Wilnai Yael Y Schelley Susan S Koenig Mary Kay MK Memon Nada N Farach Laura S LS Coe Bradley P BP Azamian Mahshid M Hernandez Patricia P Zapata Gladys G Jhangiani Shalini N SN Muzny Donna M DM Lotze Timothy T Clark Gary G Wilfong Angus A Northrup Hope H Adesina Adekunle A Bacino Carlos A CA Scaglia Fernando F Bonnen Penelope E PE Crosson Jane J Duis Jessica J Maegawa Gustavo H B GH Coman David D Inwood Anita A McGill Jim J Boerwinkle Eric E Graham Brett B Beaudet Art A Eng Christine M CM Hanchard Neil A NA Xia Fan F Orange Jordan S JS Gibbs Richard A RA Lupski James R JR Yang Yaping Y

American journal of human genetics 20160121 2

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 ...[more]

PMID: 26805781

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Project description:Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurological examinations and neurophysiological characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. Fifty-six individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. Twenty-eight participants had longitudinal data available. While there was no significant difference in the CMTES in those with protein truncating versus non-protein truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units, respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, these data will further define the natural history of the disease and inform study design in preparation for clinical trials.

Dataset Information

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

Publications

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

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