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Mitochondrial DNA Maintenance Defects Overview

, MD, FAAP, FACMG, , MD, PhD, FACMG, , PhD, FACMG, and , MD, FAAP, FACMG.

Author Information

Initial Posting: .

Estimated reading time: 14 minutes

Summary

This overview focuses on the clinical features and molecular genetics of mitochondrial DNA (mtDNA) maintenance defects.

The goals of this overview are the following.

Goal 1.

Describe the pathomechanism of mtDNA maintenance defects.

Goal 2.

Review the genetic causes of mtDNA maintenance defects.

Goal 3.

Describe the clinical characteristics of mtDNA maintenance defects.

Goal 4.

Provide clinical and laboratory evaluation strategies to facilitate the diagnosis of a mtDNA maintenance defect and to establish a genetic cause in a proband (when possible).

Goal 5.

Inform genetic counseling for mtDNA maintenance defects.

Goal 6.

Summarize current management recommendations for individuals with mtDNA maintenance defects.

1. Mitochondrial DNA Maintenance Defects

The maintenance of mtDNA is essential to the functioning of the mitochondria and, thus, to meeting the energy needs of all cells. The maintenance of mtDNA requires proteins essential for mtDNA synthesis, for maintenance of the mitochondrial nucleotide pool, and for mediating mitochondrial fusion [El-Hattab et al 2017].

Mitochondrial DNA is synthesized continuously and is not regulated by the cell cycle. The enzymes that synthesize mtDNA require a balanced supply of intramitochondrial nucleotides. These are supplied through mitochondrial nucleotide salvage pathways and the import of nucleotides from the cytosol via specific transporters. To function properly in mtDNA synthesis the quantities of these enzymes need to be perfectly balanced, a phenomenon achieved – in part – by the exchange of content between mitochondria through the process of mitochondrial fission and fusion.

The proteins known to be required for mtDNA synthesis are encoded by nuclear genes (i.e., genes found in the nucleus of cells). When pathogenic variants disrupt the function of any one of the proteins encoded by these genes, mtDNA synthesis is impaired, resulting in either quantitative defects in mtDNA (mtDNA depletion) or qualitative defects in mtDNA (multiple mtDNA deletions). These defects in mtDNA maintenance result in energy deficiency within cells. Cellular energy production insufficient to meet the needs of a given organ results in organ dysfunction (see Figure 1).

Figure 1.

Figure 1.

A diagram showing the proteins that are involved in mtDNA maintenance and known to be associated with mtDNA maintenance defects Enzymes of the mitochondrial nucleotide salvage pathway. Thymidine kinase 2 (TK2; encoded by TK2) and deoxyguanosine kinase (more...)

When first identified, defects in mtDNA maintenance were viewed as two clinically distinct groups of disorders:

  • Mitochondrial DNA depletion syndromes that typically present during infancy and are characterized by severe disease manifestations and shortened life expectancy; and
  • Multiple mtDNA deletion syndromes that typically present in adulthood and are characterized by milder disease manifestations including progressive external ophthalmoplegia (CPEO) and myopathy.

However, with the current understanding that both mtDNA depletion and multiple mtDNA deletions result from failure of proper mtDNA maintenance, it has become evident that these two groups of disorders represent the ends of a phenotypic continuum. The term "mtDNA maintenance defects" is used to represent the broad disease spectrum that encompasses both presentations as well as those that are intermediate.

2. Causes of mtDNA Maintenance Defects

To date, pathogenic variants in 20 nuclear genes are known to be associated with mtDNA maintenance defects. These genes and their primary presenting features are organized in Table 1 by the category of defect: mtDNA synthesis, mitochondrial nucleotide salvage pathway, cytosolic nucleotide metabolism, mitochondrial nucleotide import, and mitochondrial fusion.

Note: Disorders of mtDNA are not the subject of this overview (see Mitochondrial Disorders Overview).

Table 1.

Categories of mtDNA Maintenance Defects: Genes and Primary Presenting Features

Category
of Defect
GenePrimary Presenting Features
Encephalo-
hepatopathy
Encephalo-
myopathy
Encephalo-
neuropathy
Neurogastro-
intestinal
Encephalopathy
MyopathyOphthal-
moplegia
Optic
Atrophy
Neuropathy
Mitochondrial
DNA
synthesis
POLGXXXXXX
POLG2X
TWNKXXX
TFAMX
RNASEH1X
MGME1X
DNA2X
Mitochondrial
nucleotide
salvage
pathway
TK2XX
DGUOKXX
SUCLA2X
SUCLG1X
ABATX
Cytosolic
nucleotide
metabolism
TYMPX
RRM2BXXX
Mitochondrial
nucleotide
import
SLC25A4XX
AGKX
MPV17X
Mitochondrial
fusion
OPA1XXX
MFN2XX
FBXL4X

3. Clinical Characteristics of mtDNA Maintenance Defects

Mitochondrial DNA maintenance defects are characterized by mtDNA depletion and/or multiple mtDNA deletions in mitochondria of cells of affected organs. The organs/tissues affected most often are the brain, liver, skeletal muscle, peripheral nerves, and gastrointestinal tract. Depending on the organ(s) predominantly affected, these disorders can be classified into groups associated mainly with encephalohepatopathy (see Table 2a), encephalomyopathy (Table 2b), encephaloneuropathy (Table 2c), neurogastrointestinal encephalopathy (Table 2d), myopathy (Table 2e), ophthalmoplegia (Table 2f), optic atrophy (Table 2g), or neuropathy (Table 2h).

Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy

Mitochondrial DNA maintenance defects manifesting as encephalohepatopathy (hepatocerebral) are typically associated with mtDNA depletion and generally present in neonates or infants with neurologic manifestations (including developmental delay and epilepsy), and with liver dysfunction and failure. Other common manifestations include growth failure, lactic acidosis, and hypoglycemia.

Table 2a.

Mitochondrial DNA Maintenance Defects Presenting with Encephalohepatopathy

GeneDisorder/PhenotypeMOImtDNA
Maintenance
Defect
Usual Age
of Onset
Common Manifestations
in Addition to Liver
Dysfunction/Failure
DGUOKDeoxyguanosine kinase deficiencyARDepletionNeonatal
  • DD
  • Hypotonia
  • Nystagmus
  • Lactic acidosis
MPV17Hepatocerebral mtDNA depletion syndromeARDepletionNeonatal
or infancy
  • DD
  • Hypotonia
  • Failure to thrive
  • Hearing impairment
  • Lactic acidosis
POLGAlpers-Huttenlocher syndromeARDepletionEarly
childhood
  • DD
  • Psychomotor regression
  • Epilepsy
  • Hearing impairment
TFAMEncephalohepatopathy (OMIM 617156)ARDepletionNeonatal
  • IUGR
  • Hypoglycemia
TWNKEncephalohepatopathy (OMIM 271245)ARDepletionNeonatal
or infancy
  • DD
  • Hypotonia
  • Lactic acidosis

AR = autosomal recessive; DD = developmental delay; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mtDNA = mitochondrial DNA

Mitochondrial DNA Maintenance Defects Presenting with Encephalomyopathy

The majority of encephalomyopathic mtDNA maintenance defects are associated with mtDNA depletion and are early-onset diseases with an infantile presentation. The two disorders, however, that are usually associated with multiple mtDNA deletions rather than depletion are adult-onset diseases: POLG-related myoclonic epilepsy-myopathy-sensory ataxia and RNASEH1-related encephalomyopathy.

Table 2b.

Mitochondrial DNA Maintenance Defects Presenting with Encephalomyopathy

GeneDisorderMOImtDNA
Maintenance
Defect
Usual Age
of Onset
Common Manifestations in
Addition to Muscle Weakness
ABATEncephalomyopathy w/elevated GABA (OMIM 613163)ARDepletionInfancy
  • DD
  • Hypotonia
  • Epilepsy
  • ↑ GABA in plasma, urine, & CSF
FBXL4Encephalomyopathic mtDNA depletion syndromeARDepletionNeonatal
or infancy
  • DD
  • Hypotonia
  • Epilepsy
  • Hearing impairment
  • Lactic acidosis
OPA1Encephalomyopathy
(OMIM 616896)
ARDepletionInfancy
  • DD
  • HCM
  • Optic atrophy
POLGMyoclonic epilepsy-myopathy-sensory ataxia ARMultiple deletionsEarly
adulthood
  • Epilepsy
  • Ataxia
RNASEH1Encephalomyopathy
(OMIM 616479)
ARDepletion & multiple deletionsEarly
adulthood
  • Ophthalmoplegia
  • Ptosis
  • Ataxia
RRM2BEncephalomyopathy w/renal tubulopathyARDepletionNeonatal
or infancy
  • DD
  • Hypotonia
  • GI dysmotility
  • Renal tubulopathy
SUCLA2Mitochondrial DNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduriaARDepletionInfancy
or early
childhood
  • DD
  • Hypotonia
  • Dystonia
  • Hearing impairment
  • ↑ methylmalonic acid
SUCLG1Mitochondrial DNA depletion syndrome, encephalomyopathic form w/methylmalonic aciduriaARDepletionNeonatal
or infancy
  • DD
  • Hypotonia
  • Hearing impairment
  • ↑ methylmalonic acid

AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance; mtDNA = mitochondrial DNA

Mitochondrial DNA Maintenance Defects Presenting with Encephaloneuropathy

Mitochondrial DNA maintenance defects exhibiting encephaloneuropathy can be associated with mtDNA depletion or multiple mtDNA deletions, and are characterized by manifestations related to the central and peripheral nervous systems.

Table 2c.

Mitochondrial DNA Maintenance Defects Presenting with Encephaloneuropathy

GeneDisorderMOImtDNA Maintenance
Defect
Usual Age
of Onset
Common Manifestations in
Addition to Peripheral
Neuropathy and Ataxia
OPA1Behr syndrome
(OMIM 210000)
ARNAInfancy or
early childhood
  • Vision impairment
  • Optic nerve pallor
POLGAtaxia neuropathy spectrum disordersARMultiple deletionsEarly adulthoodEpilepsy
TWNKInfantile-onset spinocerebellar ataxiaARDepletion2nd year of life
  • Hypotonia
  • Hearing impairment

AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA

Mitochondrial DNA Maintenance Defects Presenting with Neurogastrointestinal Encephalopathy

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by a variable age of onset (generally in the 2nd decade) and progressive gastrointestinal dysmotility, peripheral neuropathy, and leukoencephalopathy. The gastrointestinal manifestations of the disease may mimic anorexia nervosa. MNGIE is most commonly caused by biallelic pathogenic variants in TYMP, the gene encoding thymidine phosphorylase; however, biallelic pathogenic variants in POLG or RRM2B also cause this disorder.

Table 2d.

Mitochondrial DNA Maintenance Defects Presenting with Neurogastrointestinal Encephalopathy

GeneDisorderMOImtDNA Maintenance
Defect
Usual Age of OnsetCommon Manifestations
TYMPMNGIE type 1ARDepletion & multiple deletionsAdolescence
or early adulthood
  • Gastrointestinal dysmotility
  • Cachexia
  • Peripheral neuropathy
  • Ophthalmoplegia
  • Muscle weakness
  • Leukoencephalopathy 1
POLGMNGIE type 4BARDepletion & multiple deletionsInfancy or childhood
RRM2BMNGIE type 8BARDepletionEarly adulthood

AR = autosomal recessive ; MOI = mode of inheritance; mtDNA = mitochondrial DNA

1.

Note: Leukoencephalopathy is not present in POLG-related neurogastrointestinal encephalopathy.

Mitochondrial DNA Maintenance Defects Presenting with Myopathy

Myopathic mtDNA maintenance defects include a group of diseases that vary in their age of onset. Skeletal muscles are the main system involved in all of them. Cardiomyopathy can occur in some of these disorders.

Table 2e.

Mitochondrial DNA Maintenance Defects Presenting with Myopathy

GeneDisorderMOImtDNA
Maintenance
Defect
Usual Age
of Onset
Common Clinical Manifestations
in Addition to Muscle Weakness
AGKSengers syndrome
(OMIM 212350)
ARDepletionNeonatal period
  • Hypotonia
  • Hypertrophic cardiomyopathy
  • Cataracts
DGUOKMyopathyARMultiple deletionsEarly or mid-
adulthood
  • Ptosis
  • Ophthalmoplegia
DNA2Myopathy
(OMIM 615156)
ADMultiple deletionsChildhood or
early adulthood
  • Ptosis
  • Ophthalmoplegia
MGME1Myopathy
(OMIM 615084)
ARDepletion & multiple deletionsChildhood or
early adulthood
  • Ptosis
  • Ophthalmoplegia
POLG2Myopathy
(OMIM 610131)
ADMultiple deletionsInfancy to
adulthood
  • Ptosis
  • Ophthalmoplegia
SLC25A4Cardiomyopathy
(OMIM 615418)
ARMultiple deletionsChildhood
  • Exercise intolerance / easy fatigability
  • Hypertrophic cardiomyopathy
Cardiomyopathy
(OMIM 617184)
ADDepletionBirth
  • Hypotonia
  • Hypertrophic cardiomyopathy
TK2Mitochondrial DNA depletion syndromeARDepletionInfancy or
childhood
  • Hypotonia
  • Loss of acquired motor skills

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA

Mitochondrial DNA Maintenance Defects Presenting with Ophthalmoplegia

Mitochondrial DNA maintenance defects that cause ophthalmoplegia are associated with multiple DNA deletions and are characterized by progressive weakness of the extraocular eye muscles resulting in ptosis (drooping of the eyelids) and ophthalmoplegia (paralysis of the extraocular muscles causing limitation in horizontal and vertical eye movements).

Although these are typically diseases of adulthood, earlier onset can be seen in the recessively inherited diseases. Although ophthalmoplegia and ptosis are consistent, and are the main manifestations in these diseases, a more generalized myopathy (sometimes mild) can be observed in some affected individuals.

Table 2f.

Mitochondrial DNA Maintenance Defects Presenting with Ophthalmoplegia

GeneDisorderMOImtDNA
Maintenance
Defect
Usual Age
of Onset
Common Clinical Manifestations
in Addition to Ptosis and Ophthalmoplegia
POLGProgressive external ophthalmoplegiaARMultiple deletionsAdolescence
or young
adulthood
Easy fatigability / exercise intolerance
ADMultiple deletionsAdulthoodEasy fatigability / exercise intolerance
RRM2BChronic progressive external ophthalmoplegiaARMultiple deletionsChildhood
  • Muscle weakness
  • Bulbar dysfunction
ADMultiple deletionsAdulthood
  • Ataxia
  • Muscle weakness
  • Bulbar dysfunction
SLC25A4Progressive external ophthalmoplegia
(OMIM 609283)
ADMultiple deletionsAdulthoodEasy fatigability / exercise intolerance
TK2Progressive external ophthalmoplegia
(OMIM 617069)
ARMultiple deletionsAdulthoodMuscle weakness
TWNKProgressive external ophthalmoplegia
(OMIM 609286)
ADMultiple deletionsEarly
adulthood
Easy fatigability / exercise intolerance

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mtDNA = mitochondrial DNA

Mitochondrial DNA Maintenance Defects Presenting with Optic Atrophy

Table 2g.

Mitochondrial DNA Maintenance Defects Presenting with Optic Atrophy

GeneDisorderMOImtDNA Maintenance
Defect
Usual Age
of Onset
Common Clinical Manifestations
OPA1Optic atrophy type 1ADMultiple deletionsChildhoodVision impairment
MFN2Optic atrophyADMultiple deletionsEarly childhood
  • Vision impairment
  • Optic nerve pallor
  • Peripheral neuropathy
  • Muscle weakness

Mitochondrial DNA Maintenance Defects Presenting with Neuropathy

Table 2h.

Mitochondrial DNA Maintenance Defects Presenting with Neuropathy

GeneDisorderMOImtDNA Maintenance DefectUsual Age of OnsetCommon Clinical Manifestations
MFN2Charcot-Marie-Tooth neuropathy type 2aADNAChildhood or early adulthoodPeripheral neuropathy

AD = autosomal dominant; MOI = mode of inheritance; mtDNA = mitochondrial DNA; NA= not available

4. Evaluation Strategies to Diagnose mtDNA Maintenance Defects and to Establish a Genetic Cause in a Proband

Establishing a specific genetic cause of a mtDNA maintenance defect can aid in discussion of prognosis (which is beyond the scope of this GeneReview) and in genetic counseling. See Genetic Counseling.

Establishing the specific genetic cause of a mtDNA maintenance defect usually requires a medical history, physical and neurologic examination, laboratory testing including routine studies and specialized biochemical genetic studies, imaging studies such as brain MRI, echocardiogram, abdominal ultrasound examination, family history, and genomic/genetic testing.

Clinical and Laboratory Findings

The diagnosis of a mtDNA maintenance defect is suspected based on the involved organs, age of onset, and results of commonly available laboratory tests (e.g., presence of lactic acidemia or methylmalonic aciduria).

Biopsies of affected tissues typically show mtDNA depletion and/or multiple mtDNA deletions as well as decreased activity of multiple electron transport complexes (ETC). However, because tissue biopsies are often invasive procedures, molecular genetic testing of leukocyte DNA is typically performed first to determine if the diagnosis of a mtDNA maintenance defect can be established. When molecular genetic test results are equivocal or fail to confirm the diagnosis of a mtDNA maintenance defect, tissue samples can be obtained to assay for mtDNA depletion and/or multiple mtDNA deletions and to assess ETC activity.

Family History

A three-generation family history should be obtained, with attention to relatives with signs and symptoms that could be related to a mtDNA maintenance defect and documentation of relevant findings through direct physical examination, or review of medical records, including results of molecular genetic testing.

Molecular Genetic Testing

Approaches include gene-targeted testing (multigene panel or single-gene testing) or comprehensive genomic testing (exome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing may not. Options for testing include the following:

  • Serial single-gene testing can be considered if clinical findings and/or family history indicate that mutation of a particular gene is most likely (see Tables 2a-2h). Sequence analysis of the gene of interest can detect small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected by sequence analysis, therefore, deletion/duplication analysis should also be performed to detect intragenic deletions or duplications.
  • A multigene panel that includes some or all of the mtDNA maintenance genes (Table 1) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may not include all the genes discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) can be considered. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. Genetic Counseling

Mode of Inheritance

Mitochondrial DNA maintenance defects can be inherited in an autosomal recessive or autosomal dominant 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 mtDNA maintenance defect-related pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Offspring of an individual with a mtDNA maintenance defect are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a mtDNA maintenance defect-related pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with a mtDNA maintenance defect have an affected parent.
  • Some individuals diagnosed with a mtDNA maintenance defect have the disorder as the result of a de novo pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported to date.
  • The family history of some individuals diagnosed with a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history is not definitive unless appropriate clinical evaluation and/or molecular genetic testing has been performed for the parents of the proband.

Sibs of a proband

Offspring of a proband. Each child of an individual with a mtDNA maintenance defect has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the mtDNA maintenance defect-related pathogenic variant, his or her family members may be at risk.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

6. Management of Individuals with mtDNA Maintenance Defects

Most mtDNA maintenance defects affect multiple organs; therefore, affected individuals need comprehensive evaluations to assess the degree of involvement of different organs. Management should also involve a multidisciplinary team to provide clinical care for these multiorgan diseases.

Assessment of Disease Extent

For individuals with chronic disease, Table 3 summarizes evaluations that are recommended if they have not already been completed:

Table 3.

Recommended Evaluations Following Initial Diagnosis in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease

System/
Concern
EvaluationComment
EyesOphthalmologic evaluation (see POLG-Related Disorders)To assess for optic atrophy, ptosis, ophthalmoplegia, & nystagmus
ENT/MouthHearing evaluation (see POLG-Related Disorders)
Cardiovascular
  • Echocardiogram
  • Electrocardiogram
For individuals w/myopathy
Respiratory
  • Venous blood gases
  • Pulse oximetry & pulmonary function tests
  • Polysomnography
To identify respiratory insufficiency in individuals w/myopathy
Gastrointestinal
  • Liver function test (transaminases, albumin, coagulation profile)
  • Liver ultrasound
For individuals w/hepatopathy
For MNGIE disease (see Mitochondrial Neurogastrointestinal Encephalopathy Disease):
  • Consultation w/gastroenterologist
  • Depending on manifestations: abdominal films, abdominal CT, upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, antroduodenal manometry
To evaluate for gastrointestinal dysmotility
Feeding
  • Swallowing assessment
  • Nutritional evaluation
In individuals w/feeding difficulty & growth failure 1
Renal
  • Urinalysis
  • Urine amino acids, calcium, phosphate, & protein
To evaluate for tubulopathy
Neurologic
  • Comprehensive neurologic examination
  • Brain MRI & MRS
  • Nerve conduction studies & electromyography (if neuropathy is suspected)
  • Electroencephalography (if seizures are suspected)
For individuals w/neurologic manifestations
MusculoskeletalReferral to rehabilitation specialistEvaluate gait, weakness, safety, activities of daily living
Genetics & metabolic
  • Consultation w/clinical geneticist &/or genetic counselor
  • Lactate level to evaluate for lactic acidosis
  • Glucose level to evaluate for hypoglycemia

Treatment of Manifestations

Currently there is no clinical therapy to treat the primary defect in affected individuals. Management, which is primarily supportive, is outlined in Table 4. Some specific considerations:

  • As exogenous thymidine phosphorylase can improve outcome in MNGIE resulting from thymidine phosphorylase deficiency, experimental therapy for MNGIE includes both bone marrow and liver transplantation.
  • Nucleoside therapy has been considered in TK2 deficiency.
  • Affected individuals may be at increased risk for acidosis and hypoglycemia during illness and surgery and protocols to prevent prolonged fasting should be provided.
  • Certain medications and anesthetic agents should be avoided; see Mitochondrial Disorders Overview.

Table 4.

Treatment of Manifestations in a Proband with a mtDNA Maintenance Defect Resulting in Chronic Disease

Manifestation/
Concern
Treatment
PtosisPtosis blepharoplasty
Sensorineural hearing lossHearing aids & cochlear implantation (see POLG-Related Disorders, RRM2B-Related Mitochondrial Disease, Hereditary Hearing Loss and Deafness Overview)
Cardiomyopathy, hypertrophic or dilated
  • Referral to cardiologist
  • Standard treatment
Respiratory insufficiency
  • Referral to pulmonologist &/or sleep medicine physician
  • Aggressive antibiotic treatment of chest infections
  • Chest physiotherapy
  • Artificial ventilation including assisted nasal ventilation (CPAP or BiPAP) or intubation w/use of tracheostomy & ventilator (see TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form)
Liver failure
  • Referral to hepatologist
  • Reduction in dietary protein
  • Correction of coagulopathy
  • Frequent or continuous feeding to prevent hypoglycemia
  • Consideration of liver transplant
Gastrointestinal dysmotility
Failure to thrive &
feeding difficulties
  • Nutritional support
  • Gastrostomy tube placement
Renal tubulopathy
  • Referral to nephrologist
  • Correction of acidosis & other metabolic derangements
Neuropathy
  • Referral to neurologist
  • Amitriptyline, nortriptyline, & gabapentin
Seizures
  • Referral to neurologist
  • Standard AEDs (Refractory epilepsy may require high doses &/or use of multiple AEDs.)
Hypoglycemia
  • Frequent feeding & avoidance of fasting
  • Uncooked cornstarch

AEDs = antiepileptic drugs

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.

Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.

In the US:

  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility.
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that it is safe for the individual to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.

References

Literature Cited

  • El-Hattab AW, Craigen WJ, Scaglia F. Mitochondrial DNA maintenance defects. Biochim Biophys Acta Mol Basis Dis. 2017;1863:1539–55. [PubMed: 28215579]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]

Chapter Notes

Revision History

  • 8 March 2018 (bp) Review posted live
  • 13 October 2017 (aeh) Original submission
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