Rrm2b-Related Mitochondrial Disease

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.

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
  • The first individuals reported were from two large, unrelated families with autosomal dominant PEO caused by a heterozygous nonsense pathogenic variant in exon 9 (c.979C >T) predicting p.Arg327Ter) that resulted in truncation of the translated p53R2 (see Molecular Genetics, Normal gene product) protein [Tyynismaa et al 2009]. In these families the earliest onset was in the third decade (average age 46 years). The cardinal features were PEO and ptosis as well as ataxia, cognitive dysfunction, exercise intolerance, sensorineural hearing loss, mood disturbance, and peripheral neuropathy.
  • More recently, heterozygous RRM2B pathogenic variants have been shown to be frequent in familial PEO with muscle-restricted multiple mtDNA deletions [Fratter et al 2011, Pitceathly et al 2012]. The phenotype is a milder myopathy with proximal muscle weakness, bulbar dysfunction, and fatigue. Mean age of disease onset is 46 years.
• 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].

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.