Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) Disease via the TYMP Gene

The mitochondrial DNA depletion syndromes (MDSs) form a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen et al. 2010; El-Hattab and Scaglia 2013).

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is an inherited, multi-systemic MDS that manifests with a combination of gastrointestinal, neurological, and ocular symptoms (Garone et al. 2011; Hirano 2016). MNGIE disease is characterized by gastrointestinal dysmotility, peripheral neuropathy, leucoencephalopathy, cachexia, ptosis, and progressive external ophthalmoplegia. Other features may include severe hypokalaemia, infections (due to either aspiration or rupture of diverticuli), short stature, cardiopathy, anaemia, amenorrhea, pigmentary retinopathy, dry mouth/eyes, psoriasis, and coarse bronze skin. In a subset of patients, disease progression can be further complicated by endocrine or exocrine pancreatic insufficiency. In addition to mtDNA depletion, MNGIE is often associated with the accumulation of multiple mtDNA deletions in various tissues over time.

MNGIE symptoms may manifest at any time between infancy to the third decade of life, but average age at onset generally occurs between 15 to 20 years (Garone et al. 2011). Allogeneic haematopoetic stem cell transplantation is a potentially promising enzyme replacement therapy for MNGIE disease, although this treatment requires timely and accurate diagnosis.

MNGIE disease, which is inherited in an autosomal recessive manner, is caused primarily by pathogenic variants in the TYMP gene (Nishino et al. 1999; Nishino et al. 2000; Copeland 2012; Hirano 2016). TYMP has 9 coding exons that encode thymidine phosphorylase, an enzyme involved in the pyrimidine salvage pathway. Defects of this enzyme cause a marked accumulation of deoxythymidine and deoxyuridine, resulting in mitochondrial DNA instability and respiratory chain dysfunction.

Genetic defects in the TYMP gene include pathogenic missense, nonsense, and splicing variants, in addition to numerous small deletions and/or insertions (Human Gene Mutation Database). Only one gross deletion, encompassing the entire TYMP gene and several neighboring genes, has been reported in a patient with MNGIE (Vondráčková et al. 2014). Although much less frequently reported, defects in RRM2B have also been associated with a MNGIE-like phenotype (Shaibani et al. 2009).

In one large cohort study, compound heterozygous or homozygous pathogenic variants in TYMP were identified in 92 out of 102 unrelated individuals (~ 90%) with clinical presentations suggestive of MNGIE disease (Garone et al. 2011).

Only one gross deletion, encompassing the entire TYMP gene and several neighboring genes, has been reported in a patient with MNGIE (Vondrácková et al. 2014). Although we can not precisely estimate clinical sensitivity at this time, large deletions or insertions in TYMP appear to be a rare cause of MNGIE.

This test provides full coverage of all coding exons of the TYMP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).