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• W4200540129 abstract "The TANGO2 (transport and golgi organization 2 homolog) gene mutation was initially identified in 2016 by exome sequencing in 15 patients with variable phenotypes.1 Homozygous inheritance produces metabolic crises associated with rhabdomyolysis and acute neurologic or cardiac symptoms.1, 2 This case describes multifocal combined dystonia as a novel phenotypic feature of TANGO2 mutations. A 27-year-old female presented to the movement disorders clinic at age 17 for a 3-year history of episodic left arm jerks. At 9 months, she developed episodes of weakness when her night feeds were stopped. Developmental delay, regression in speech, ptosis, and microcephaly were also noted. Between the ages of 18 months and 3 years, she developed recurrent episodes of lactic acidosis and rhabdomyolysis (CK > 64,000) with intercurrent illnesses, episodic feeding difficulties requiring a nasogastric tube, hypothyroidism, sensorineural hearing loss, intellectual disability, and seizures well-controlled with levetiracetam. By age 14, she developed jerky flexion-extension wrist tremor, worse in specific positions, with a “null point” when the tremor stopped. By age 19, she developed gait imbalance and falls associated with foot inversion. Neurologic exam was significant for dystonic posturing of the left arm and bilateral legs (left>right), intermittent left head tilt, facial hypotonia, markedly dysarthric speech, and disconjugate gaze. Sensation was normal, strength was 4/5, and reflexes were brisk with extensor plantar responses bilaterally. Gait was wide-based and lurching, with mixed dystonic and spastic features, feet inverting progressively the more she walked (Video 1 ). Her gait could be said to resemble dystonic pseudo foot drop, a rarely reported phenomenon in which dystonia mimics the steppage gait associated with true foot drop from weakness of the dorsiflexors.3 In contrast to true foot drop, however, dystonic pseudo foot drop does not have significant distal weakness, atrophy, sensory changes, or loss of reflexes.3 Extensive metabolic workup, brain MRI, and EEG were unremarkable. At age 4, a muscle biopsy confirmed an oxidative phosphorylation defect, leading to a suspected diagnosis of mitochondrial myopathy associated with complex 1 deficiency. When the patient's younger brother's night feeds were stopped, he developed hypoglycemic episodes associated with left-sided weakness and cervical dystonia, which led to additional genetic workup. Pedigree of family included consanguinity between the paternal grandmother and maternal grandfather (Fig. 1A). Blood samples were obtained from proband and parents for whole exome sequencing and variant segregation analysis. A homozygous deletion involving exons 3–9 of TANGO2 gene (NM_152906.4)arr[GRCh37] 22q11.21(20030782_20052415)x0 was found in both the patient and patient's brother (Fig. 1B). The mother and father were heterozygous for the partial deletion, which has previously been reported in TANGO2-related disorders.1, 2 Her dystonia was successfully treated with clonazepam and botulinum toxin injections (Fig. 1C). The TANGO2 gene resides on chromosome 22, encoding a protein with unknown function.4, 5 The TANGO2 mutation is rare with no more than 50 cases reported to date.4, 5 In more than 55% of cases, a deletion of exons 3–9 is the cause.2, 4 Although the mechanism is unknown, hypotheses include impacting secretory protein loading in the endoplasmic reticulum, with secondary inhibition of mitochondrial complexes such as flavin adenine dinucleotide (FAD)-dependent dehydration, leading to transient impairment during crises,1, 6 or reduction of crucial proteins in fibroblasts leading to defective mitochondrial fatty acid oxidation.5 Movement disorders, particularly dystonia, are well-established features of mitochondrial disorders.7 Oxidative phosphorylation dysfunction leads to accumulation of metabolic intermediates and the inability to generate appropriate energy levels, which results in dysfunction of tissues that require high energy levels, and ultimately leads to clinical manifestations of dystonia.7 Initially, TANGO2-related disorders were called “metabolic encephalomyopathic crises, recurrent with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration.”1, 2 Neurologic symptoms include developmental delay, intellectual disability in nearly all individuals, encephalopathy, ataxia, and seizures in up to 75% of individuals.2, 4 Cardiac symptoms include dilated cardiomyopathy and arrhythmias.1, 2 Patients may have optic atrophy, sensorineural hearing loss, dysphagia, gastric dysmotility, and 40%–60% have hypothyroidism.4, 6, 8 Symptom onset is typically between 4 and 27 months, with up to 86% presenting with global developmental delay.4 The phenotypic presentation is highly variable, with even affected siblings demonstrating dramatically different symptom severity.6 Hallmark features include metabolic crises, typically triggered by viral illnesses or fasting, with significant regression in developmental milestones following these crises.4 Management of TANGO2 includes avoidance of triggers for crises, and surveillance for cardiac, thyroid, and epileptic abnormalities.2 Some cases have reported spasticity or alternating hemiplegia of childhood (AHC) as clinical manifestations within the TANGO2 spectrum.4, 9 No genetic mutation is identified in up to 15% of AHC cases, thus TANGO2 may be an important gene to consider in the differential of AHC.10 Dystonia, however, has not previously been a well-described phenotype in the TANGO2 spectrum. The dystonic features demonstrated in this case are most consistent with multifocal combined dystonia and suggest that TANGO2 mutations should be included in the genetic causes of dystonia. We would like to acknowledge The Parkinson's Foundation, the Dystonia Medical Research Foundation, and the Barbara Padgett Dein Professorship for fellowship and scientific support. Special thanks to the patient and her family for their time and support. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Genomic Analysis: A. Collection of Data/Pedigree, B. Analysis and interpretation, C. Figure preparation; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. J.F.: 1A, 1B, 1C, 2C, 3A, 3B M.B.: 1A, 1B, 1C, 2C, 3A, 3B S.Y.C.: 1B, 1C, 3B A.W.S.: 3B A.E.K.: 1B, 1C, 3B J.J.: 2A, 2B, 2C P.H.A.: 2A, 2B, 2C I.A.M.: 1A, 1B, 1C, 3B Ethical guidelines were followed in the absence of an IRB, with informed consent obtained from both the patient and her mother. Written informed patient consent was obtained from the patient's mother for the writing of this case report. 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. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. AEK reports disclosures from Abbvie, unrelated to this work. IA reports disclosures from Abbvie, Boston Scientific, Eli Lilly, Neuroderm, Revance, Robert Rose Publishers, Medscape, Efficient CME, and Cleveland Clinic, unrelated to this work." @default.
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• W4200540129 title "<scp><i>TANGO2</i></scp> Mutation: A Genetic Cause of Multifocal Combined Dystonia" @default.
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• W4200540129 doi "https://doi.org/10.1002/mdc3.13400" @default.
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