RRM2B-Related Mitochondrial Disorders via the RRM2B 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 and Isohanni 2010; El-Hattab and Scaglia 2013).

The RRM2B-related encephalomyopathic form of MDS is an early-onset disorder, manifesting at either the neonatal or infantile stage with multi-organ involvement (Bourdon et al. 2007; El-Hattab and Scaglia 2013; Gorman and Taylor 2014). Clinical features typically include hypotonia, lactic acidosis, respiratory insufficiency, renal tubulopathy, sensorineural hearing loss, psychomotor delay, microcephaly, and rapid progression to early childhood mortality. The encephalomyopathic form of MDS, which can also be caused by defects in SUCLA2 or SUCLG1, represents the most severe end of the RRM2B-related phenotypic spectrum (El-Hattab and Scaglia 2013).

Defects in RRM2B have also been reported in at least one patient with a mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like phenotype with mtDNA depletion (Shaibani et al. 2009). In this patient, the MNGIE-like phenotype presented as a progressive neurodegenerative disorder characterized by ophthalmoplegia, ptosis, cachexia, gastrointestinal dysmotility, peripheral neuropathy, and leukoencephalopathy. In contrast with classic MNGIE, which is caused by defects in the TYMP gene, patients with RRM2B-related disease have normal levels of plasma thymidine (Shaibani et al. 2009; El-Hattab and Scaglia 2013). RRM2B defects can also cause mtDNA deletion disorders, such as the autosomal dominant (ad) and recessive (ar) forms of progressive external ophthalmoplegia (PEO) (Gorman and Taylor 2014; Fratter et al. 2011). Patients with arPEO develop disease during childhood with multi-organ presentations. adPEO typically occurs in adulthood with milder phenotypes. In addition to myopathy, the clinical features of RRM2B-related PEO may include ptosis, bulbar dysfunction, ataxia, sensorineural hearing loss, and/or gastrointestinal disturbance (Pitceathly et al. 2012).

Finally, Kearns-Sayre syndrome (KSS) with mtDNA deletion has been reported in at least one patient (Pitceathly et al. 2011). KSS is a multi-system disorder characterized by PEO, pigmentary retinopathy, sensorineural hearing loss, increased cerebral spinal fluid protein, and onset prior to 20 years of age (Gorman and Taylor 2014). Additionally, patients with KSS may present with cardiomyopathy.

RRM2B has 9 exons that encode the p53-inducible small subunit (p53R2) of ribonucleotide reductase, which is essential for mitochondrial DNA synthesis. The RRM2B-related mtDNA depletion syndromes, including the encephalomyopathic form of MDS and MNGIE, are inherited as autosomal recessive disorders (Bourdon et al. 2007; Shaibani et al. 2009). RRM2B-related mtDNA deletion syndromes, such as PEO and KSS, can be inherited in either an autosomal dominant or recessive pattern (Fratter et al. 2011; Gorman and Taylor, 2014). Pathogenic variants are located across the RRM2B gene and include missense, nonsense, and splicing variants in addition to small deletions and insertions (Human Gene Mutation Database). Defects in the RRM2B gene are the third most frequent cause of multiple mtDNA deletions in adults, following defects in POLG andC10orf2 (Fratter et al. 2011; Pitceathly et al. 2012).

In a cohort of patients with mtDNA deletions, 13% of cases carried either heterozygous or compound heterozygous pathogenic variants in the RRM2B gene (Pitceathly et al. 2012). Defects in the RRM2B gene are the third most frequent cause of multiple mtDNA deletions in adults, following defects in POLG andC10orf2 (Fratter et al. 2011; Pitceathly et al. 2012).

No gross deletions or insertions have been reported in the RRM2B gene to date (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the RRM2B 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).