Objective:

A 70 year male who has a Complex phenotype with at chronic history of persistent autonomic dysfunction compatible with pure autonomic failure. He subsequently revealed to have chronic hyposmia and REM sleep behaviour which was followed by subsequent development of clinical Parkinsonism and abnormal DAT. He was noted with bilateral nonfatigable ptosis and  early external ophthalmoplegia and reported a insidious onset of gradually reduced visual acuity and abnormal/delayed visual evoked responses bilaterally suggestive of optic neuropathy. During his follow up he was diagnosed with a left PCA territory infarct. Due to the multidomain neurological symptomatology and after extensive investigations, mitochondrial genetic testing has identified a pathogenic mutation in TWNK confirming a diagnosis of autosomal dominant TWNK-related mitochondrial disease. The natural history of TWNK related mitochondrial disorders
is that it is invariably fatal and most commonly present during childhood as a life shortening and terminal illness.

Background:

70 year male with a history is compatible with pure autonomic failure
(PAF) and  has features suggestive of a synucleinopathy. However, he seems to have
developed other features in terms of Parkinsonism and an ophthalmoplegia.

Design/Methods:

n/a

Results:

 Complex case of persistent dysautonomia found to have heterozygous pathogenic variant detected for a TWNK c.1092C>G

Conclusions:

Mutations in TWNK gene is related to multiple conditions including Ataxia neuropathy spectrum, Infantile-onset spinocerebellar ataxia, Perrault syndrome, Progressive external ophthalmoplegia, mtDNA depletion hepatocerebral form. TWNK associated syndromes have a much broader phenotype as originally published. This is the first report about TWNK mutation presenting as a persistent autonomic failure hence possessing unique challenge before a complex phenotype could be unified into a single entity. In the future, it will be necessary to continue to identify such new patients, and follow-up the existing patients to better characterize the phenotype and be able to provide the best possible care by understanding the disease.