Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

TLDR

Twinkle is a mitochondrial helicase whose mutations cause autosomal dominant progressive external ophthalmoplegia and recessive infantile onset spinocerebellar ataxia, while Alpers–Huttenlocher syndrome is linked to polymerase gamma, another mtDNA replicative enzyme. The study reports a novel phenotype of early‑onset encephalopathy with liver involvement in siblings carrying compound heterozygous Twinkle mutations. Affected individuals presented with hypotonia, athetosis, sensory neuropathy, ataxia, hearing loss, ophthalmoplegia, intractable epilepsy, and elevated serum transaminases. Recessive Twinkle mutations caused tissue‑specific mtDNA depletion, with marked depletion in liver but only mild loss in muscle, producing an Alpers‑like encephalopathy with liver dysfunction.

Abstract

Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA). We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement. The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases. The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected. Alpers–Huttenlocher syndrome has previously been associated with mutations of polymerase gamma, a replicative polymerase of mtDNA. We show here that recessive mutations of the close functional partner of the polymerase, the Twinkle helicase, can also manifest as early encephalopathy with liver involvement, a phenotype reminiscent of Alpers syndrome, and are a new genetic cause underlying tissue-specific mtDNA depletion.