Twinkle-associated mitochondrial DNA depletion

Salma Remtulla, Cam-Tu Emilie Nguyen, Chitra Prasad, Craig Campbell.  Twinkle-Associated Mitochondrial DNA Depletion.  Pediatric Neurology.  In press.

Abstract

Background

Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy.

Methods

We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed.

Results

Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years.

Conclusions

In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered.

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From the article:

Mitochondrial depletion syndromes (MDS) are comprised of autosomal recessive disorders caused by mutations in nuclear genes encoding for key enzymes involved in mitochondrial DNA (mtDNA) replication and/or maintenance. These mutations result in decreased mtDNA copy number, leading to impaired energy production in various tissues.

The C10orf2 gene, also called PEO1 or Twinkle, encodes the mtDNA replicative Twinkle helicase—important for mtDNA replication. Dominant mutations in the Twinkle gene can cause multiple mtDNA deletions and result in chronic progressive external ophthalmoplegia or mitochondrial myopathy. Recessive Twinkle mutations cause mtDNA depletion. 

MDS are phenotypically heterogeneous and manifest clinically as early onset encephalopathy, hepatoencephalopathy, encephalomyopathy, infantile onset spinocerebellar ataxia, or Perrault syndrome.  The hepatocerebral form of MDS is associated with mutations in Twinkle, POLG1, DGUOK , and MPV. MDS associated with POLG1 is known as Alpers-Huttenlocher (Alpers) syndrome…

Chromosomal microarray was performed initially with normal results. Subsequently, a comprehensive next generation sequencing panel of 183 genes associated with muscular dystrophy and myopathy revealed two heterozygous novel variants in the C10orf2 gene. The first variant, c.853C>T, was reportedly the type expected to be pathogenic and results in change of an arginine residue to a stop codon at amino acid position 285 (p.Arg285Ter), predicted to cause premature truncation of the protein. The second variant, c1592+4A>G is an intronic splice site variant, resulting in change from an adenine to a guanine residue located at c.1592+4 and was predicted to alter the exon 3 donor site with potential to alter splicing. The data were insufficient for definitive classification and the variant classified as of unknown significance. Sanger sequencing confirmed the results. Parental testing revealed the p.R285* variant was paternally and the c.1592+4A>G variant maternally inherited.