MtDNA depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders characterized by low mtDNA levels in specific tissues. Mitochondrial diseases are often relentlessly progressive with high morbidity and mortality. Clinical diversity and genetic heterogeneity of mitochondrial diseases make diagnosis difficult.

Attempts have been made to create diagnostic algorithms considering clinical history and examination, biochemical parameters, neuroimaging and neurophysiology, and suspected mode of inheritance for determination of clinical phenotype to allow targeted testing for specific genes.Hence, we suggest that expansion of the phenotype may potentially support clinically guided gene testing. Eighteen entries for mtDNA depletion syndromes are listed in OMIM.

MDS can be divided into four clinical presentations: hepatocerebral, myopathic, encephalomyopathic and neurogastrointestinal.

These syndromes are due to defects in mtDNA maintenance caused by mutations in nuclear genes involved in nucleotide synthesis or mtDNA replication. TWNK codes the motor protein TWINKLE that acts as a helicase at the replication fork. Dominant mutations in this gene are known to cause progressive external ophthalmoplegia. TWNK mutations (dominant/recessive) are now being reported as the genetic basis for infantile onset sensory ataxia with or without epilepsy, as well as sensory ataxia associated with dysarthria, and hepatocerebral forms of mtDNA depletion disorders in infancy and adulthood3 and Perrault syndrome. We report on two siblings from non-consanguineous parents of Armenian origin with early onset symptoms of severe encephalopathy, hypotonia, facial dyskinetic movements, abnormal visual behavior, severe failure to thrive, and abnormal renal and hepatic function.

Download and read the full case study here:

Expanding phenotype of mitochondrial depletion syndrome in association with TWNK mutations