Clinical characteristics: Four phenotypes comprise the RRM2B mitochondrial DNA maintenance defects (RRM2B-MDMDs):

1. RRM2B encephalomyopathic MDMD, the most severe phenotype, usually manifesting shortly after birth as hypotonia, poor feeding, and faltering growth requiring hospitalization. Subsequent assessments are likely to reveal multisystem involvement including sensorineural hearing loss, renal tubulopathy, and respiratory failure.

2. Autosomal dominant progressive external ophthalmoplegia (adPEO), typically adult onset; other manifestations can include ptosis, bulbar dysfunction, fatigue, and muscle weakness.

3. RRM2B autosomal recessive progressive external ophthalmoplegia (arPEO), a typically childhood-onset predominantly myopathic phenotype of PEO, ptosis, proximal muscle weakness, and bulbar dysfunction

4. RRM2B mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like, characterized by progressive ptosis, ophthalmoplegia, gastrointestinal dysmotility, cachexia, and peripheral neuropathy.

To date, 78 individuals from 52 families with a molecularly confirmed RRM2B-MDMD have been reported.

Diagnosis/testing: The diagnosis of an RRM2B-MDMD is established in a proband with suggestive findings and either biallelic RRM2B pathogenic variants or a heterozygous RRM2B pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: To date, there are no known cures and few effective treatments for any forms of mitochondrial disease, including the RRM2B-MDMDs. Treatment modalities focusing on symptomatic management and supportive care are best implemented by a multidisciplinary team.

Surveillance: Because most infants and young children with the encephalomyopathic phenotype are severely affected and are hospitalized for prolonged periods, monitoring typically occurs regularly by senior clinical specialists. Individuals with the other phenotypes warrant routine monitoring based on their clinical findings, rate of disease progression, and response to interventions.

Agents/circumstances to avoid: Valproic acid should be used only in exceptional circumstances. Use of prescription drugs should always take into consideration the specific needs of and potential risks for the affected individual.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk relatives of an affected family member so that those with the RRM2B pathogenic variant(s) can undergo timely routine surveillance for disease complications and avoid possible precipitating factors.

Genetic counseling: With the exception of autosomal dominant progressive external ophthalmoplegia, RRM2B mitochondrial DNA maintenance defects – RRM2B encephalomyopathic MDMD, RRM2B MNGIE-like, and RRM2B-arPEO – are inherited in an autosomal recessive manner.

1. Autosomal recessive inheritance. If both parents are known to be heterozygous for an RRM2B pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic RRM2B pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial RRM2B pathogenic variants.

2. Autosomal dominant inheritance. If a parent of the proband is affected and/or is known to have the RRM2B pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.

Once the RRM2B pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for RRM2B-MDMD are possible.