Diagnostic Criteria

Suggestive Findings

RRM2B mitochondrial DNA maintenance defects should be suspected in individuals with suggestive findings of the two and considered in those with suggestive findings of the two ; the diagnosis should be informed by family history. Note: While muscle biopsy is not required to consider this diagnosis, muscle biopsy findings – in the event that one was obtained for other reasons – may include cytochrome c oxidase (COX)-deficient fibers and subsarcolemmal mitochondrial accumulation (classic "ragged-red" fibers).

Common Phenotypes

RRM2B encephalomyopathic mitochondrial DNA maintenance defect (MDMD) should be suspected in children with combinations of the following clinical and laboratory findings and family history:

• Clinical findings

Source: GeneReviews — "RRM2B Mitochondrial DNA Maintenance Defects"

Differential Diagnosis

To date, pathogenic variants in 20 nuclear genes are known to be associated with mtDNA maintenance defects (see Mitochondrial DNA Maintenance Defects Overview). These genes and their primary presenting features are organized in by the category of the defect: mtDNA synthesis, mitochondrial nucleotide salvage pathway, cytosolic nucleotide metabolism, mitochondrial nucleotide import, and mitochondrial fusion. Note: As is apparent in , mitochondrial disease phenotypes are associated with significant locus heterogeneity (i.e., multiple genes can be associated with the same clinical features). For this reason, single-gene testing is rarely useful; use of multigene panels that target all nuclear genes known to be associated with mitochondrial disorders is recommended to establish a molecular diagnosis of mitochondrial disease. Table 5. Categories of mtDNA Maintenance Defects: Genes and Primary Presenting Features

Management Guidelines

No clinical guidelines specific to RRM2B mitochondrial DNA maintenance defects (RRM2B-MDMD) are available; however, detailed evaluations are outlined in the Wellcome Centre for Mitochondrial Research Clinical Guidelines. The management of the two common phenotypes, RRM2B-MDMD encephalomyopathic form and RRM2B autosomal dominant progressive external ophthalmoplegia (adPEO), is discussed below. For management of the two rare phenotypes, mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like disease and Kearns-Sayre syndrome-like, see Mitochondrial DNA Maintenance Defects Overview and Mitochondrial DNA Deletion Syndromes, respectively. Evaluations Following Initial Diagnosis RRM2B-MDMD, Encephalomyopathic Form To establish the extent of disease and needs in an individual diagnosed with RRM2B-MDMD encephalomyopathic form, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 6. Recommended Evaluations Following Initial Diagnosis of RRM2B-MDMD, Encephalomyopathic Form

Source: GeneReviews — "RRM2B Mitochondrial DNA Maintenance Defects"

Surveillance Guidelines

RRM2B-MDMD, Encephalomyopathic Form Because most infants and young children with the encephalomyopathic form are severely affected and are hospitalized for prolonged periods from the onset of disease manifestations, they should be reviewed regularly by senior clinical specialists if they are hospitalized. The recommendations regarding frequency in pertain to outpatient surveillance only. Table 10. Recommended Surveillance of RRM2B-MDMD, Encephalomyopathic Form

Source: GeneReviews — "RRM2B Mitochondrial DNA Maintenance Defects"