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RRM2B-Related Mitochondrial Disease

, MD, MRCP and , PhD.

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Estimated reading time: 20 minutes

Summary

Clinical characteristics.

RRM2B-related mitochondrial disease can be grouped by disease pathogenesis, phenotype, and mode of inheritance into two major types: mitochondrial DNA (mtDNA) depletion and multiple mtDNA deletions.

  • Mitochondrial DNA depletion usually manifests as severe multisystem disease (encephalomyopathy with proximal renal tubulopathy) and is often fatal in early life. Inheritance is autosomal recessive.
  • Multiple mtDNA deletions cause tissue-specific cytochrome c oxidase (COX) deficiency. Inheritance can be either autosomal recessive (with progressive external ophthalmoplegia [PEO] and multisystem involvement manifesting during early childhood/adulthood) or autosomal dominant (with less severe, often tissue-specific manifestations [e.g., chronic PEO] developing in later adulthood).

Other rarer phenotypes are Kearns-Sayre syndrome (KSS) and mitochondrial neurogastrointestinal encephalopathy (MNGIE).

Diagnosis/testing.

The presence of biallelic RRM2B pathogenic variants confirms the diagnosis of an autosomal recessive RRM2B-related mitochondrial disease. The presence of a heterozygous RRM2B pathogenic variant confirms the diagnosis of an autosomal dominant RRM2B-related mitochondrial disease in those suspected of having a late-onset disorder of mtDNA maintenance.

Management.

Treatment of manifestations: No cures and few effective treatments exist for any form of mitochondrial disease, including this one. Treatment, which focuses on symptomatic management and supportive care, is best provided by a multidisciplinary team. Management issues for those with systemic involvement may include: nutritional support (gastrointestinal involvement), care by a pediatric nephrologist (renal tubulopathy), care by a pediatric pulmonologist (impaired respiratory function), physical therapy (to maintain strength and mobility and to prevent contractures), care by a pediatric neurologist (seizures), and care by hearing loss specialists (to determine the best habilitation options for sensorineural hearing loss). Management issues for those with PEO may include: ptosis surgery for cosmetic effect and/or symptomatic relief; ECG to screen for significant cardiac conduction defects. For both clinical presentations: aggressive management of fever and infection.

Surveillance: No clinical guidelines specific to RRM2B-related mitochondrial disease are available; however, for those with systemic involvement the following should be considered: regular evaluation of: neurodevelopment, speech, and language; presence/severity of encephalopathy and/or seizures/subclinical status epilepticus; renal function; nutritional status, growth, and body mass index (BMI); and pulmonary function. For those with PEO the following biannual evaluations should be considered: neurologic status; occupational and physical therapy assessments; CBC, electrolytes, liver function (albumin, coagulation factors), liver enzymes (AST, ALT, GGT), blood glucose, and HBA1C; and nutritional status, weight, and body mass index (BMI).

Agents/circumstances to avoid: Specifically: Valproic acid (theoretic risk of precipitating/exacerbating organ failure due to mitochondrial toxicity); metformin (theoretic risk of exacerbating metabolic acidosis); prolonged use of linezolid (reported association with optic and peripheral neuropathy and lactic acidosis due to mitochondrial toxicity); and zidovudine (reported risk of inducing mitochondrial disease by interfering with mtDNA replication). In general: dehydration and prolonged fasting to prevent clinical deterioration.

Evaluation of relatives at risk: If the pathogenic variant(s) have been identified in an affected family member, it is appropriate to clarify the genetic status of at-risk relatives so that those who harbor the pathogenic variant(s) can (1) undergo timely routine surveillance for disease complications and (2) avoid possible precipitating factors.

Genetic counseling.

RRM2B-related mitochondrial disease can be inherited in either an autosomal recessive (AR) or an autosomal dominant (AD) manner.

  • AR inheritance. The parents of an affected child are obligate heterozygotes (carriers) and are asymptomatic. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • AD inheritance. Most affected individuals likely have an affected parent; the proportion caused by de novo pathogenic variants is unknown. The offspring of an affected individual has a 50% chance of inheriting the pathogenic variant and, thus, being symptomatic.

If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible.

GeneReview Scope

RRM2B-Related Mitochondrial Disease: Included Phenotypes 1
  • Mitochondrial DNA depletion syndrome (encephalomyopathic form with renal tubulopathy)
  • Mitochondrial neurogastrointestinal encephalopathy
  • Chronic progressive external ophthalmoplegia with multiple mtDNA deletions
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

RRM2B-related mitochondrial disease can, for the most part, be characterized by disease pathogenesis, phenotype, and mode of inheritance:

RRM2B-related mitochondrial disease should be suspected in the following

  • Children with:
    • Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency
    • Gastrointestinal disturbance manifesting as dysmotility
    • Proximal renal tubulopathy with nephrocalcinosis
    • CNS findings including seizures, developmental delay, microcephaly, and hearing loss
    • Lactic acidosis
    • Skeletal muscle tissue showing severe mtDNA depletion and mitochondrial respiratory chain defects
  • Adults with:
    • Progressive external ophthalmoplegia (PEO)
    • Ptosis of variable severity
    • Proximal muscle weakness and/or fatigue
    • Bulbar dysfunction
    • Absent or minimal CNS findings, including ataxia, cognitive dysfunction, and mood disturbance
    • Sensorineural hearing loss (SNHL)
    • Sensory axonal peripheral neuropathy
    • Gastrointestinal problems, including irritable bowel syndrome-like symptoms and low body mass index (BMI)
    • Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
  • Individuals with Kearns-Sayre syndrome when inheritance appears to follow a Mendelian pattern and/or examination of muscle tissue reveals evidence of multiple mtDNA deletions.
  • Individuals with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease when plasma thymidine concentration is <3 µmol/L, plasma deoxyuridine concentration <5 µmol/L, thymidine phosphorylase enzyme activity in leukocytes is >10% of the control mean, and molecular genetic testing does not identify biallelic pathogenic variants in TYMP (the gene encoding thymidine phosphorylase).

One strategy for establishing the molecular diagnosis of RRM2B-related mitochondrial disease in a proband is to perform a skeletal muscle biopsy to evaluate for characteristic histopathologic changes that are only apparent in muscle tissue: cytochrome c oxidase (COX)-deficient fibers and subsarcolemmal mitochondrial accumulation (classic "ragged-red" fibers).

If the muscle tissue shows evidence of mitochondrial disease, perform (in skeletal muscle) the following:

  • Quantitative studies of mtDNA copy number for evidence of mtDNA depletion (typically <30% of age- and tissue-matched control samples)
  • Qualitative studies for evidence of clonally expanded multiple mtDNA deletions (deletion/duplication analysis, Table 1)

If a skeletal muscle biopsy cannot be obtained, perform (on DNA extracted from leukocytes) sequence analysis of the entire RRM2B coding region, including intron/exon boundaries (Table 1).

A different strategy for establishing the molecular diagnosis of RRM2B-related mitochondrial disease in a proband is the use of a multigene panel comprising a number of genes known to disturb mtDNA maintenance (see Differential Diagnosis for a discussion of some of these disorders).

Table 1.

Molecular Genetic Testing Used in RRM2B-Related Mitochondrial Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
RRM2BSequence analysis 2>95% 3
Deletion/duplication analysis 4Unknown 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Because of the difficulty of detecting small deletions by conventional sequencing strategies, pathogenic variant frequency is reported to be <100%.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long RRM2B -range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No RRM2B deletions have been reported to date.

Clinical Characteristics

Clinical Description

Pathogenic variants in RRM2B are associated predominantly with either:

  • Mitochondrial DNA depletion syndrome (encephalomyopathic form with renal tubulopathy), which usually presents as a childhood-onset severe multisystem disease;
    OR
  • Chronic progressive external ophthalmoplegia with multiple mtDNA deletions, which is usually adult-onset, milder, and often tissue-specific.

However, other phenotypes include Kearns-Sayre syndrome and mitochondrial neurogastrointestinal encephalopathy (MNGIE).

RRM2B-related mitochondrial diseases are emerging as an important cause of both pediatric and adult-onset mitochondrial disease. To date, 73 individuals from 42 families with molecularly confirmed RRM2B-related mitochondrial disease have been reported [Bourdon et al 2007, Bornstein et al 2008, Acham-Roschitz et al 2009, Kollberg et al 2009, Shaibani et al 2009, Spinazzola et al 2009, Tyynismaa et al 2009, Fratter et al 2011, Takata et al 2011, Pitceathly et al 2011, Pitceathly et al 2012].

Mitochondrial DNA depletion syndrome (encephalomyopathic form with renal tubulopathy), the most severe form of the disease, is a multisystem disorder associated with severe mtDNA depletion; it has been reported in 15 individuals [Bourdon et al 2007, Bornstein et al 2008, Acham-Roschitz et al 2009, Kollberg et al 2009, Spinazzola et al 2009]. Onset typically occurs in the first six months of life; affected children succumb in early childhood.

Disease characteristics include myopathy manifest as muscle hypotonia (in all 15 affected individuals), weakness associated with respiratory insufficiency (in 10), lactic acidosis (13), failure to thrive and gastrointestinal dysmotility (9), and proximal renal tubulopathy with nephrocalcinosis (9) [Bourdon et al 2007, Bornstein et al 2008].

Central nervous system (CNS) features can include seizures (5 affected individuals), sensorineural hearing loss of varying severity (3), microcephaly (2), cerebral atrophy (1), and generalized central hypomyelination (1).

Chronic progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. In 31 adults with chronic PEO and multiple mtDNA deletions in muscle in whom mutation of all other genes known to cause this phenotype (i.e., POLG, POLG2, SLC25A4, and TWNK) had been excluded, Pitceathly et al [2012], identified an autosomal dominant RRM2B-related disorder in 24 individuals and an autosomal recessive RRM2B- related disorder in seven.

Ptosis and PEO were universal. Extra-ocular neurologic complications were common in adults with genetically confirmed RRM2B-related mitochondrial disease. Also prominent were myopathy (followed by bulbar dysfunction) and fatigue. Sensorineural hearing loss of varying severity and gastrointestinal dysmotility (including irritable bowel syndrome-like symptoms and low body mass index) were also common. Endocrinopathies including diabetes mellitus, hypothyroidism, hypoparathyroidism, and hypogonadism were important additional clinical features.

  • Autosomal dominant inheritance
  • Autosomal recessive inheritance
    • In children with compound heterozygous RRM2B pathogenic variants, disease onset was at a mean age of seven years. The predominantly myopathic phenotype of PEO, ptosis, proximal muscle weakness, and bulbar dysfunction was more severe than the multisystem disorder observed in individuals with a heterozygous RRM2B pathogenic variant [Pitceathly et al 2012].
    • Additionally, a homozygous missense pathogenic variant in RRM2B has been described in a 43-year-old man who presented at age 16 years with progressive hearing loss followed by the insidious onset of PEO, muscle weakness, retinopathy, and a major depressive disorder, findings that further extend the phenotype [Takata et al 2011].

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) has been reported in a woman age 42 years with RRM2B biallelic missense pathogenic variants and mtDNA depletion in clinically relevant tissues [Shaibani et al 2009]. For more information about this phenotype, see MNGIE.

Kearns-Sayre syndrome (KSS). RRM2B pathogenic variants have been identified in one individual with onset before age 20 years of PEO-plus / Kearns-Sayre syndrome (PEO, pigmentary retinopathy, sensorineural hearing loss, and increased CSF protein), which is similar to single mtDNA deletion disorders [Pitceathly et al 2011].

Genotype-Phenotype Correlations

Genotype-phenotype correlations cannot be clearly defined in RRM2B-related mitochondrial disease. RRM2B pathogenic variants have been associated with both simplex (i.e., a single occurrence in a family) and familial mitochondrial disease characterized by either autosomal recessive mtDNA depletion syndrome (which is associated with a quantitative loss of mtDNA copies) or autosomal recessive and autosomal dominant pathogenic variants (which cause the accumulation of multiple mtDNA deletions in post-mitotic tissues).

The same RRM2B pathogenic variants are associated with varied phenotypic severity depending on whether they are biallelic or heterozygous.

Mitochondrial DNA depletion is commonly seen in children with clinically severe biallelic pathogenic variants in genes encoding proteins essential to mtDNA maintenance [Bourdon et al 2007, Bornstein et al 2008, Acham-Roschitz et al 2009, Kollberg et al 2009, Shaibani et al 2009, Spinazzola et al 2009]; however, it has also been observed in one adult with biallelic RRM2B pathogenic variants [Shaibani et al 2009, Takata et al 2011]. Thus, RRM2B-related mtDNA depletion can potentially cause a relatively mild clinical phenotype.

Penetrance

The clinical manifestations of RRM2B-related disorders are similar in males and females.

Prevalence

The prevalence of RRM2B-related mitochondrial disorders is unknown.

Pathogenic variants in RRM2B are now increasingly recognized as an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mtDNA deletions in adults, following pathogenic variants in POLG (encoding pol γ) and TWNK (encoding the Twinkle helicase) [Pitceathly et al 2012].

Differential Diagnosis

The first reported human diseases attributed to mutation of RRM2B were associated with a quantitative loss of mtDNA copies – the so-called mtDNA depletion syndromes. To date, mutation of the following nine nuclear genes has been associated with mtDNA depletion syndromes: DGUOK, MPV17, TWNK, POLG, SUCLA2, SUCLG1, TK2, TYMP, and RRM2B. Clinical characteristics (and the associated gene) can be summarized as [Suomalainen & Isohanni 2010]:

See Mitochondrial DNA depletion syndrome: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Comparison of RRM2B-related mitochondrial disorders with other mtDNA depletion and mtDNA deletion syndromes

In children. Hypotonia, lactic acidosis, and proximal renal tubulopathy in association with mitochondrial respiratory chain defects and severe mtDNA depletion in skeletal muscle should prompt testing of RRM2B before other nuclear-encoded genes (in which muscle weakness is the predominant clinical feature). In children with biallelic RRM2B pathogenic variants gastrointestinal disturbance is often severe, but CNS involvement is less common than in other syndromic mitochondrial disorders [Fratter et al 2011, Pitceathly et al 2012].

In adults. Progressive external ophthalmoplegia (PEO), ptosis, and proximal muscle weakness are the predominant clinical characteristics seen with mutation of POLG and TWNK (encoding twinkle), the two most common causes of multiple mtDNA deletions. In contrast, bulbar dysfunction, sensorineural hearing loss, and gastrointestinal problems (including irritable bowel syndrome-like symptoms and low body mass index) appear to occur more often in adults with mutation of RRM2B than mutation of POLG or TWNK. Thus, in adults the presence of PEO, multiple mtDNA deletions in skeletal muscle, bulbar dysfunction, sensorineural hearing loss, and gastrointestinal problems in the absence of overt CNS features supports testing of RRM2B before POLG and TWNK.

Kearns-Sayre syndrome (KSS). RRM2B testing should be considered when the pattern of inheritance appears to be Mendelian and/or evidence of multiple mtDNA deletions is observed on muscle biopsy.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE). RRM2B testing should be considered in individuals with MNGIE if deoxyuridine and thymidine levels in both blood and urine are negative, thymidine phosphorylase activity is normal in white cells and platelets, and molecular genetic testing does not identify causative pathogenic variants in TYMP.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with RRM2B-related mitochondrial disease, the following evaluations are recommended:

  • Comprehensive clinical examination and neurology consultation that includes measures of functional neurologic status
  • Formal developmental evaluation (particularly in a child with the encephalomyopathic form with renal tubulopathy)
  • Formal assessment of vision and hearing
  • Brain MRI and electroencephalogram (EEG) in individuals with encephalopathy and/or seizures. Note: these may be normal with certain RRM2B-related mitochondrial disease phenotypes.
  • Nutritional assessment
  • Speech and language assessment
  • Physical therapy assessment
  • Occupational therapy assessment
  • Pulmonary function testing
  • For those with Kearns-Sayre syndrome, cardiac evaluation to include electrocardiogram (ECG) and/or echocardiogram
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Detailed evaluations are outlined in Wellcome Trust Centre for Mitochondrial Research Clinical Guidelines.

To date, there are no known cures and few effective treatments for any forms of mitochondrial disease, including RRM2B-related mitochondrial disease. Treatment modalities currently focus on symptomatic management and supportive care, and are best implemented by a multidisciplinary team.

General management guidelines for those with systemic involvement:

  • Nutritional support (e.g., nasogastric tube, gastrostomy) as needed for significant gastrointestinal involvement
  • Early referral to a pediatric renal specialist for those with proximal renal tubulopathy
  • Early referral to a pediatric pulmonologist for children with evidence of reduced respiratory function. Management may include consideration of tracheostomy and artificial ventilation.
  • Physical therapy to maintain muscle strength and mobility and to prevent contractures
  • Referral to a pediatric neurologist for seizure management. Of note, seizures may be refractory to treatment.
  • Referral to hearing loss specialists to determine the best habilitation options for sensorineural hearing loss (see Hereditary Hearing Loss and Deafness for discussion of management issues)

General management guidelines for those with progressive external ophthalmoplegia (PEO):

  • Ptosis surgery for cosmesis and/or symptomatic relief in those with good residual orbicularis oculi muscle strength
  • ECG in all individuals with PEO to screen for significant cardiac conduction defects which may warrant placement of a pacemaker, particularly in those with the Kearns-Sayre syndrome phenotype

General management guidelines for both those with systemic involvement and those with PEO:

  • Aggressive management of fever and infection

Surveillance

No clinical guidelines specific to RRM2B-related mitochondrial disease are available; however, detailed evaluations are outlined in Wellcome Trust Centre for Mitochondrial Research Clinical Guidelines.

The following evaluations should be considered:

RRM2B-related mitochondrial DNA depletion syndrome (encephalo-myopathic form with renal tubulopathy)

  • Regular assessments of neurodevelopment, speech, and language
  • Regular evaluations by a pediatric neurologist to evaluate for the presence and/or severity of encephalopathy, with consideration of EEG and video EEG monitoring to determine presence of seizures and/or subclinical status epilepticus
  • Regular evaluation by a pediatric renal specialist, including assessment of renal function (electrolytes in blood and urine and urine analysis)
  • Routine assessment of nutritional status, growth, and body mass index (BMI)
  • Regular pulmonary function testing including monitoring of blood gases for early detection of respiratory compromise

RRM2B-related mitochondrial DNA depletion syndrome and mitochondrial neurogastrointestinal encephalopathy

  • Biannual:
    • Comprehensive neurology consultation and clinical examination to include measures of functional neurologic status
    • Occupational therapy and physical therapy assessments
    • CBC, electrolytes, liver function (albumin, coagulation factors), liver enzymes (AST, ALT, GGT), blood glucose, and HBA1C
  • Annual pulmonary function testing including assessment of blood gases to monitor for early respiratory compromise
  • Routine assessment of nutritional status, weight gain, and BMI, including regular review with speech and language therapist with consideration of gastrostomy as needed for nutritional support
  • Imaging and diagnostic procedures including EEG, ECG, and brain MRI as indicated by clinical findings and rate of disease progression

RRM2B-related multiple mtDNA deletions with external ophthalmoplegia

Care will be directed by clinical findings. The following general evaluations are recommended:

  • Biannual:
    • Comprehensive neurology consultation and clinical examination to include measures of functional neurologic status
    • Occupational therapy and physical therapy assessments
    • CBC, electrolytes, liver function (albumin, coagulation factors), liver enzymes (AST, ALT, GGT), blood glucose, and HBA1C
  • Annual pulmonary function testing including assessment of blood gases to monitor for early respiratory compromise
  • Routine assessment of nutritional status, weight gain and BMI, biannually
  • Imaging and diagnostic procedures to include EEG, ECG, and MRI brain- as indicated by clinical findings and rate of disease progression
  • ECG advised biannually (KSS phenotype)

Agents/Circumstances to Avoid

Avoid the following:

  • Valproic acid (commonly used for seizures and known to interfere with beta-oxidation) because it is considered to be a mitochondrial toxin with a theoretic risk of precipitating/exacerbating organ failure
  • Metformin (used to treat diabetes mellitus) because of the theoretic risk of exacerbating metabolic acidosis
  • Prolonged use of linezolid (an antibiotic used to treat S. aureus infections) because of the reported association with optic and peripheral neuropathy and lactic acidosis due to mitochondrial toxicity
  • Zidovudine (an antiretroviral nucleoside analog reverse transcriptase used to treat HIV) because of the reported risk of inducing mitochondrial disease by interfering with mtDNA replication
  • Dehydration and prolonged fasting, which can lead to clinical deterioration

Evaluation of Relatives at Risk

If the pathogenic variant(s) have been identified in an affected family member, it is appropriate to clarify the genetic status of at-risk relatives so that those who harbor the pathogenic variant(s) can (1) undergo timely routine surveillance for disease complications and (2) avoid possible precipitating factors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

RRM2B-related mitochondrial DNA depletion syndrome (encephalomyopathic form with renal tubulopathy) and RRM2B-related mitochondrial neurogastrointestinal encephalopathy are inherited in an autosomal recessive manner.

RRM2B-related chronic progressive external ophthalmoplegia with multiple mtDNA deletions can be inherited in either an autosomal dominant or autosomal recessive manner.

Autosomal Recessive Inheritance

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Individuals with RRM2B-related mitochondrial DNA depletion syndrome, (encephalomyopathic form with renal tubulopathy) are not known to reproduce.
  • The offspring of individuals with less severe manifestations of RRM2B-related disorders are obligate heterozygotes for an RRM2B pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Individuals diagnosed with autosomal dominant RRM2B-related chronic progressive external ophthalmoplegia with multiple mtDNA deletions likely have an affected parent; the proportion resulting from de novo pathogenic variants is unknown.
  • Recommendations for the evaluation of parents of a proband in whom mutation apparently occurred de novo include determining the genetic status of the proband's parents.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • At conception, if a parent of the proband is affected and/or has an RRM2B pathogenic variant, each sib has a 50% chance of inheriting the pathogenic variant.

Offspring of a proband. The offspring of individuals with an autosomal dominant RRM2B-related disorder have a 50% chance of inheriting the RRM2B pathogenic variant.

Other family members. The risk to other family members of a proband depends on the status of the proband's parents.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the RRM2B pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for RRM2B-related mitochondrial disease are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Mito Foundation (formerly the Australian Mitochondrial Disease Foundation)
    21 Mary Street
    Suite 3
    Surry Hills New South Wales 2010
    Australia
    Phone: 61-1-300-977-180
    Fax: 61-2-9999-3474
    Email: info@mito.org.au
  • The Charlie Gard Foundation
    United Kingdom
    Email: hello@thecharliegardfoundation.org
  • The Lily Foundation
    31 Warren Park
    Surrey CR6 9LD
    United Kingdom
    Phone: 07947 257247
    Fax: 01883 623799
    Email: liz@thelilyfoundation.org.uk
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Mitochondrial Disease Registry and Tissue Bank
    Massachusetts General Hospital
    185 Cambridge Street
    Simches Research Building 5-238
    Boston MA 02114
    Phone: 617-726-5718
    Fax: 617-724-9620
    Email: nslate@partners.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

RRM2B-Related Mitochondrial Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for RRM2B-Related Mitochondrial Disease (View All in OMIM)

604712RIBONUCLEOTIDE REDUCTASE, M2 B; RRM2B
612075MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY); MTDPS8A
613077PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5; PEOA5

Gene structure. RRM2B, a nuclear-encoded mitochondrial maintenance gene, comprises nine coding exons. Alternate splicing results in multiple transcript variants (see Table A). The longest known transcript variant (NM_015713.4 ) encodes a 351-amino acid protein (molecular weight 37 kd). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, 73 individuals from 42 families have been reported to harbor:

The majority of reported RRM2B pathogenic variants are missense variants. Spliced transcript variants have also been described [Spinazzola et al 2009].

Identification of truncating pathogenic variants in exon 9 in unrelated individuals with familial autosomal dominant PEO has shown that the mutated mRNA escapes nonsense mediated decay and results in a truncated protein that has been postulated to cause a dominant-negative or gain-of-function effect on the heterotetrameric structure of the RNR enzyme, identifying exon 9 as a mutation hot spot [Tyynismaa et al 2009, Fratter et al 2011].

Table 2.

Selected RRM2B Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.48G>A(Glu16Glu) 2NM_015713​.4
NP_056528​.2
c.121C>Tp.Arg41Trp
c.122G>Ap.Arg41Gln
c.122G>Cp.Arg41Pro
c.190T>Cp.Trp64Arg
c.208G>Ap.Asp70Asn
c.253_255delGAGp.Glu85del
c.322-2A>C
(IVS3-2A>C)
c.322-2A>G
(IVS3-2A>G)
c.328C>Tp.Arg110Cys
c.329G>Ap.Arg110His
c.97C>Tp.Pro33Ser
c.362G>Ap.Arg121His
c.368T>Cp.Phe123Ser
c.391G>Ap.Glu131Lys
c.431C>Tp.Thr144Ile
c.556A>Gp.Arg186Gly
c.580G>Ap.Glu194Lys
c.581A>Gp.Glu194Gly
c.583G>Ap.Gly195Arg
c.584delGp.Gly195GlufsTer14
c.606T>Ap.Phe202Leu
c.632G>Ap.Arg211Lys
c.686G>Tp.Gly229Val
c.671T>Gp.Ile224Ser
c.707G>Tp.Cys236Phe
c.817G>Ap.Gly273Ser
c.846G>Cp.Met282Ile
c.850C>Tp.Gln284Ter
c.920delAp.Asn307IlefsTer11
c.949T>Gp.Leu317Val
c.950delTp.Leu317Ter
c.952G>Tp.Glu318Ter
c.965dupAp.Asn322LysfsTer4
c.979C>Tp.Arg327Ter
c.1046C>Gp.Ala349Gly

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Evidence to support pathogenicity includes aberrant splicing, partial intron retention, and premature termination of translation – predicting absence of any functional protein from this allele [Pitceathly et al 2011].

Normal gene product. RRM2B encodes ribonucleoside-diphosphate reductase subunit M2 B, the p53-inducible small subunit (p53R2) of ribonucleotide reductase (RNR), a heterotetrameric enzyme that catalyzes de novo syntheses of dNTPs by direct reduction of ribonucleoside diphosphates to their corresponding deoxyribonucleoside diphosphates. This process supplements the dNTPs produced by the mitochondrial dNTP salvage pathway that is essential for mtDNA synthesis (and in which defects cause many of the mtDNA depletion syndromes [Rahman & Poulton 2009]. Transcription of RRM2B is tightly regulated by the tumor suppressor protein p53.

Abnormal gene product. RRM2B pathogenic variants result in disruption of mtDNA maintenance (replication and repair), leading to qualitative (accumulation of multiple mtDNA deletions) and/or quantitative (depletion of mtDNA copy number) downstream mitochondrial genomic effects.

Adult-onset chronic progressive external ophthalmoplegia (CPEO)/multiple mtDNA deletion disorders are associated with autosomal recessive and autosomal dominant RRM2B pathogenic variants. To further understand the functional consequence of adult-onset CPEO/multiple mtDNA deletion disorders associated with both autosomal recessive and autosomal dominant RRM2B pathogenic variants, Pitceathly et al [2011] mapped the positions of the mutated amino acids on the tertiary p53R2 structure [Smith et al 2009]. Many of the missense pathogenic variants identified appear likely to affect the iron-binding properties of p53R2, and hence impair the catalytic capability of the functional heterotetramer (two p53R2 subunits and two R1 subunits). Gly195, Phe202, and Ile224 are located around the iron-binding pocket. The effect of p.Phe202Leu may be orchestrated through subtle hydrophobic contacts; the effect of amino acids Gly195 and Ile224 is less subtle. Because p.Gly195Arg and p.Ile224Ser are positioned adjacent to amino acids that contribute to the iron coordination environment, substitutions at these two locations influence their amino acid neighbors and alter the coordination of the iron atom(s).

Previous molecular modeling indicated that p.Arg41Gln prevents formation of a salt bridge which is important in the conformational changes that control iron binding [Smith et al 2009, Pitceathly et al 2011]. The variant p.Arg41Trp is also predicted to prevent formation of this salt bridge. Arg211 forms a salt bridge to Glu85, which is thought to be important in stabilizing the di-iron form [Smith et al 2009, Pitceathly et al 2011] and, therefore, p.Arg211Lys may also destabilize the di-iron subunit.

Thr144, Arg186, Thr218, and Gly273 are all located at the end of – or, in the case of Gly273, between – α-helices and appear to stabilize the orientation of the helices. Mutation of these four amino acids may reduce protein folding efficiency and is associated with autosomal recessive disease [Pitceathly et al 2012].

The effect of the p.Asp70Asn pathogenic variant cannot readily be predicted, as Asp70 lies in a poorly understood region of the protein between two helices.

The variant p.Ala349Gly could not be modeled because the crystal structure does not include the C-terminal portion of the protein. However, Ala349 is located within a conserved heptapeptide (amino acids 345-351) required for interaction with the R1 subunit [Tyynismaa et al 2009], and loss of this heptapeptide has been proposed as the pathologic basis of the exon 9 truncating pathogenic variants [Tyynismaa et al 2009].

References

Literature Cited

  • Acham-Roschitz B, Plecko B, Lindbichler F, Bittner R, Mache CJ, Sperl W, Mayr JA. A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. Mol Genet Metab. 2009;98:300–4. [PubMed: 19616983]
  • Bornstein B, Area E, Flanigan KM, Ganesh J, Jayakar P, Swoboda KJ, Coku J, Naini A, Shanske S, Tanji K, Hirano M, DiMauro S. Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscul Disord. 2008;18:453–9. [PMC free article: PMC3891825] [PubMed: 18504129]
  • Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chrétien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rötig A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007;39:776–80. [PubMed: 17486094]
  • Fratter C, Raman P, Alston CL, Blakely EL, Craig K, Smith C, Evans J, Seller A, Czermin B, Hanna MG, Poulton J, Brierley C, Staunton TG, Turnpenny PD, Schaefer AM, Chinnery PF, Horvath R, Turnbull DM, Gorman GS, Taylor RW. RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. Neurology. 2011;76:2032–4. [PMC free article: PMC3109879] [PubMed: 21646632]
  • Kollberg G, Darin N, Benan K, Moslemi AR, Lindal S, Tulinius M, Oldfors A, Holme E. A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscul Disord. 2009;19:147–50. [PubMed: 19138848]
  • Pitceathly RD, Fassone E, Taanman JW, Sadowski M, Fratter C, Mudanohwo EE, Woodward CE, Sweeney MG, Holton JL, Hanna MG, Rahman S. Kearns-Sayre syndrome caused by defective R1/p53R2 assembly. J Med Genet. 2011;48:610–7. [PubMed: 21378381]
  • Pitceathly RD, Smith C, Fratter C, Alston CL, He L, Craig K, Blakely EL, Evans JC, Taylor J, Shabbir Z, Deschauer M, Pohl U, Roberts ME, Jackson MC, Halfpenny CA, Turnpenny PD, Lunt PW, Hanna MG, Schaefer AM, McFarland R, Horvath R, Chinnery PF, Turnbull DM, Poulton J, Taylor RW, Gorman GS. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain. 2012;135:3392–403. [PMC free article: PMC3501970] [PubMed: 23107649]
  • Rahman S, Poulton J. Diagnosis of mitochondrial DNA depletion syndromes. Arch Dis Child. 2009;94:3–5. [PubMed: 19103785]
  • Shaibani A, Shchelochkov OA, Zhang S, Katsonis P, Lichtarge O, Wong LJ, Shinawi M. Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Arch Neurol. 2009;66:1028–32. [PMC free article: PMC2747647] [PubMed: 19667227]
  • Smith P, Zhou B, Ho N, Yuan YC, Su L, Tsai SC, Yen Y. 2.6 A X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase . Biochemistry. 2009;48:11134–41. [PMC free article: PMC2844085] [PubMed: 19728742]
  • Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, Giordano I, Meznaric-Petrusa M, Baruffini E, Ferrero I, Zeviani M. Clinical and molecular features of mitochondrial DNA depletion syndromes. J Inherit Metab Dis. 2009;32:143–58. [PubMed: 19125351]
  • Suomalainen A, Isohanni P. Mitochondrial DNA depletion syndromes--many genes, common mechanisms. Neuromuscul Disord. 2010;20:429–37. [PubMed: 20444604]
  • Takata A, Kato M, Nakamura M, Yoshikawa T, Kanba S, Sano A, Kato T. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol. 2011;12:R92. [PMC free article: PMC3308055] [PubMed: 21951382]
  • Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet. 2009;85:290–5. [PMC free article: PMC2725268] [PubMed: 19664747]

Chapter Notes

Author Notes

Wellcome Trust Centre for Mitochondrial Research

Institute for Ageing and Health
Newcastle University
Medical School
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Newcastle upon Tyne
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Fax:0191 222 5685

Revision History

  • 17 April 2014 (me) Review posted live
  • 31 May 2013 (gg) Original submission
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