Mitochondrial disease in children and adolescents.
Joey is a seven-year-old boy with developmental delay and chronic constipation. His parents have recently noted that he cannot keep up with other children at the neighborhood playground, becoming exhausted after 30 minutes of play, On multiple occasions, Joey has had limited use of his legs after exercise, complains of leg pain, and must be carried home by his parents. He recovers from these episodes after a period of rest. Joey's concerned parents bring him to your primary care office for evaluation.
Historically known as the "powerhouse" of the cell, the mitochondria play a key role in maintaining energy homeostasis for all tissues in the body (McFarland & Turnbull, 2010). In 1959, R. Luft evaluated a woman with severe perspiration, generalized weakness, and an inability to gain weight; a muscle biopsy determined her symptoms were caused by a disorder of her mitochondria (Luft, 1994). Nearly 30 years later, the first mutation of mitochondrial DNA (mtDNA) was identified in an individual with optic neuropathy, giving rise to the understanding that changes in mtDNA alter energy production, in this case, causing ophthalmic disease (Wallace et al., 1988). Since then, the understanding of mitochondrial energy production, mtDNA mutation, and clinical effects on individuals, has exponentially grown. Alterations in mtDNA causing decreased cellular energy production are now understood to cause more than 400 different syndromes. These disorders are collectively known as mitochondrial disease (Jeyakumar, Williamson, Brickman, Krakovitz, & Parikh, 2009).
The primary purpose of mitochondria is to produce adenosine triphosphate (ATP) (Kisler, Whittaker, & McFarland, 2010). Mitochondria convert the caloric supply of macronutrients (carbohydrates, amino acids, fatty acids) to ATP by oxidative phosphorylation (OXPHOS) through a series of reactions, producing essential energy required by all tissues in the human body (Schiff et al., 2011). In mitochondrial disease, one or more of these reactions do not function properly, causing a disruption in cellular energy production. Often, parents or guardians of a child with mitochrondrial disease will use a "car analogy" to describe their child's condition. It is as if their child is a six-cylinder car running on only two cylinders; as long as they are driving on a flat country road, they do fine. But as soon as they start going up a mountain pass and do not have the extra power to get them up the hill, that is when they get into trouble.
Each cell, depending on its metabolic needs, contains hundreds to thousands of mitochondria, each containing two to 10 copies of mtDNA (Jeyakumar et al., 2009). However, mtDNA encode only 13 of the more than 1,000 proteins needed for mitochondrial biosynthesis and function; the rest are encoded in the nucleus by nuclear deoxyribonucleic acid (nDNA) (Jeyakumar et al., 2009). Seventy percent to 75% of mitochondrial disorders are due to mutations in nDNA and are passed to offspring through maternal lineage. The remaining 25% to 30% of cases are due to alterations in mtDNA and generally occur de novo (Kisler et al., 2010).
When a cell contains only identical genotype mtDNA, the cell is said to have homoplasmy. If a cell has more than one mtDNA genotype, that cell is said to have heteroplasmy (Saneto & Sedensky, 2013). The vast spectrum of clinical signs and symptoms of mitochondrial disease is due to the phenomenon of heteroplasmy (Jeyakumar et al., 2009). Each individual person, each mtDNA mutation, and each tissue and organ system has a different percentage threshold for physical symptoms; once that "threshold" is surpassed, causing OXPHOS impairment, the affected individual begins to display symptoms in that particular organ system (McFarland & Turnbull, 2009). On average, more than 70% of the mtDNA must be mutant for symptoms to appear (Sacconi et al., 2008). For example, if a child with mitochondrial disease has a threshold of 70% mutant mtDNA in the skeletal muscles, he or she may be completely asymptomatic at 69% diseased mtDNA. Once the child's mutant mtDNA reaches 71%, he or she has surpassed the threshold and will have mild symptoms, such as muscle fatigue and exercise intolerance. If the child develops even more dysfunctional mtDNA, such as 80% of the skeletal muscle mtDNA, he or she now has mitochondrial dysfunction and will display more debilitating symptoms, such as hypotonia or ataxia.
Incidence and Prevalence
Mitochondrial disease is the most frequent of the inherited metabolic disorders; however, epidemiologic studies remain limited (Sanderson, Green, Preece, & Burton, 2006). Sanderson et al. (2006) found a prevalence of mitochondrial disease of roughly one in 5,000 live births, with only 8% of children with mitochondrial disease diagnosed before one year of age, while 28% were diagnosed by age 18 (Sanderson et al., 2006). Due to the variability of the disease presentation, many individuals go undiagnosed well into adulthood, delaying the opportunity for supportive treatment and genetic counseling (Kisler et al., 2010).
The hallmark of mitochondrial disease, and one of the many reasons it is so difficult to diagnose, is that the individual can present "at any age, with a spectrum of symptoms and signs, to several medical specialties" (Kisler et al., 2010, p. 423). Affected individuals can range from those who are completely care-dependent to those who are high functioning, attend school, and participate in developmentally and age-appropriate activities. Although any organ system can be affected, organs with high-energy demand are more likely to display symptoms of mitochondria dysfunction, such as skeletal and cardiac muscle, endocrine organs, and the central nervous system (Haas et al., 2007). Children with mitochondrial disease often present with developmental delay, behavioral problems, fatigability, and a general lack of energy (Koene et al., 2013). Table 1 lists common signs and symptoms by organ system of mitochondrial disease. To provide insight into the phenotypic variability of mitochondrial disease, Table 2 describes a few of the over 400 identified mitochondrial syndromes.
Leigh's syndrome is the most commonly diagnosed mitochondrial disease in children. Infants and young children usually present with developmental delay and regression. Some affected infants have failure to thrive, hypotonia, weakness, and dysphagia, as well as other symptoms of severe disease. Others may not be affected with severe multi-system disease until many years later, despite an identical genotype. This is due to the phenomenon of heteroplasmy previously described (Kisler et al., 2010).
Because the mitochondria can be defective in ATP production in any organ system, the hallmark of mitochondrial disease is multi-organ dysfunction. If three or more systems are impaired without unifying disease, particularly those that require high levels of energy to function, mitochondrial disease should be suspected (Haas et al., 2007). In addition, the clinician should consider mitochondrial disease in children with a history of neurodevelopmental regression following an acute illness (Kisler et al., 2010). A recent article in the The New Yorker by Groopman (2013) profiles two children affected by complex mitochondrial disease. One child, named Gwen, has an especially complicated medical history, including a five-organ transplant. Groopman's (2013) article sheds light on the day-to-day lives of children with mitochondrial disease and the multiple medical specialties required to keep them alive.
A study to determine which clinical manifestations of mitochondrial disease were viewed as most burdensome by parents of children with the condition found that developmental delay and behavioral problems are the most concerning (Koene et al., 2013). Parents of children birth to six-year old rated speech and language problems, muscle weakness, and developmental delay as the most burdensome. The parents of children seven to 12 years old stated behavioral abnormalities, fatigue, lack of energy, developmental delay, and problems with social interactions as the most burdensome symptoms, while parents of children over the age of 13 would most like to change their children's behavioral problems, fatigue, lack of energy, and intellectual problems (Koene et al., 2013). Although the symptoms of mitochondrial disease can be severe and even life-threatening, this study illustrates that the symptoms that affect the child's ability and development have the greatest impact on the child and their family's quality of life.
Even at a resting state, the energy requirements of organs with high metabolic demand, such as the brain and liver, are significant. For mitochondria to produce energy, they must be both well fed and well rested. The most common forms of energy drain for persons with mitochondrial disease include physical exertion, anxiety, depression, hyperactivity, temperature extremes, and infections (O'Keeffe, 2007).
The diagnosis of mitochondrial disease requires the collaboration of several subspecialties and can be laborious and complicated for the child, parents, caregivers, and health care providers. Clinicians have limited evidence-based guidelines on which to base diagnosis (Parikh et al., 2013). Mitochondrial medicine is a subspecialty that is still new, and an international shortage of metabolic specialists contributes to the challenge of diagnosing the disease (Haas et al., 2007). Testing is time-consuming and expensive. A reliable biomarker for the disease does not exist, and muscle biopsies and other highly invasive and costly procedures are often required (Haas et al., 2007).
The primary care provider, who cares for a child with suspected or possible mitochondrial disease, should begin their assessment with a thorough history and physical examination. This should include a detailed family history, age of symptom onset, and an evaluation for at least three organ systems of dysfunction without underlying known cause (Wong, Scaglia, Graham, & Craigen, 2010). The Mitochondrial Medicine Society (www.mitosoc.org) is a helpful resource to guide the clinician through the diagnostic and referral process.
Disease Management and Treatment
Having been identified only in the last two decades, the understanding of and treatments for mitochondrial disease are still in their infancy. Treatment is focused on conserving energy, assuring frequent intake of nutrients, and maintaining health.
Every child with mitochondrial disease has his or her own baseline energy balance between conserving energy (rest), using energy (activities), and feeding their body's energy needs with foods and fluids (O'Keeffe, 2007). Deviation from their baseline energy expenditure due to physical (increased activity, infection) or emotional (difficulty in school, anger, depression) stress requires the child to balance this energy expenditure with increased rest, nutrition, and fluids. This might come in the form of a daytime nap, an extra snack, or in more severe cases, intravenous fluids and hospitalization.
People affected with mitochondrial disease often need extra sleep, both at night and during the day. Pacing activities is incredibly important and helps buffer the energy drain felt by persons with mitochondrial disease (O'Keeffe, 2007). Some children can only tolerate a three-hour school day, while others must be home-schooled because the standard school environment is not conducive to energy conservation.
Although research examining dietary therapy is limited, most metabolic specialists believe the number and quality of calories a child with mitochondrial disease consumes each day affects mitochondrial health. Nutritious meals, snacks, and frequent hydration provide cells with the nutrients needed to make energy. Like many aspects of mitochondrial disease, nutritional needs are individualized depending on the mtDNA mutation (Parikh et al., 2009). Periods of prolonged fasting should be avoided because the clinical manifestations of mitochondrial disease are worsened during times of catabolic stress (Parikh et al., 2013). Depending on the severity of the baseline clinical presentation, some infants and children with mitochondrial disease may need supplemental enteral or intravenous nutrition and evaluation by a registered dietician who specializes in metabolic disease (Parikh et al., 2013). For most affected children, having access to fluids like water or juice as well as nutritious snacks throughout the day keep the mitochondria "well fed" and allow the child to maintain the physical and mental energy needed for school and other daily activities.
Current pharmacological treatments primarily consist of vitamins and dietary supplementation prescribed with the intention of increasing respiratory chain substrate availability. Carnitine, niacin, and thiamine, for example, facilitate the transfer of fatty acids, therefore increasing the availability of metabolites from the citric acid cycle (Pfeffer et al., 2013). Metabolic specialists will often prescribe a "mitochondrial cocktail" of thiamine, vitamin C, vitamin E, and alphalipoic acid, all of which have antioxidant properties (Parikh et al., 2009). Coenzyme Q10 (CoQlO) is endogenously synthesized in the mitochondria and is an essential component of the mitochondrial electron transport chain; thus, it is commonly prescribed by metabolic specialists (Parikh et al, 2009). Additional supplementation includes riboflavin, 1-creatine, 1-arginine, and 1-carnitine. Although these vitamins and minerals are widely used among metabolic specialists and are the mainstay of medical treatment, the evidence for their use is relatively limited (Parikh et al., 2013).
Certain medications should be avoided in individuals with mitochondrial disease (see Table 3). These medicines are toxic to mitochondria and can further impair their function (Parikh et al., 2009).
The primary care provider should consult with the metabolic specialist regarding surveillance laboratory assessment and screening. Electrolytes, transaminase, hemoglobin A1C, thyroid function, urinalysis, CoQ10 levels, and a lipid panel are usually run every six months to two years. An ophthalmology and audiometry screening are regularly performed, even in asymptomatic children, to identify early changes in these systems. Periodic educational testing should be done to screen for change in cognitive ability or educational support needs. Due to the high risk of cardiac complications, most metabolic specialists obtain electrocardiograms and echocardiograms every couple of years or if symptoms present (Parikh et al., 2013).
Febrile Illness and Infections
In children with mitochondrial disease, the increased metabolic demands associated with acute or febrile illness can have dangerous consequences, such as dehydration, decreased gut motility, fasting intolerance, hypoglycemia, and lactic acidosis. The effects of the catabolic state can worsen the clinical manifestations of mitochondrial disease (Parikh et al., 2013). An emergency plan of care, similar to a plan of care developed for a child with asthma or diabetes, should be developed
The primary care provider should determine the source of the fever, assess hydration status, assess for worsening of their "typical" symptoms, and assess for gut motility and bladder function. Fever should be managed with ibuprofen, and any source of infection should be aggressively treated. The primary care provider should pay special attention to the child's ability to consistently eat or at least drink fluids to meet their increased requirements due to fever and/or vomiting and diarrhea. Examples of emergency protocols for the care of children with mitochondrial disease and acute infection are available at mitoaction.org.
The child should be encouraged to consume extra calories, either from food or fluid, and small frequent feedings may be better tolerated than boluses or large meals. When there is a history of fasting intolerance, hypoglycemia, or secondary fatty acid oxidation dysfunction, the child should be encouraged to take in foods or fluids high in carbohydrate and low in fat on a regular basis. A child with a history of gut dysmotility should consume foods or fluids high in carbohydrates and low in fat because fat can slow gastric emptying. If the child cannot tolerate this regimen, is vomiting, or refuses fluids, intravenous fluids are required (Mitoaction.org, 2013). If the primary care provider determines the child is unstable at home, the child should be referred to the emergency department (ED). In the ED, electrolytes, blood gases, lactate levels, and liver functions should be monitored (Mitoaction.org, 2013). Copies of the emergency protocol developed with the metabolic specialist should be easily accessible and kept on file at the primary care office, the child's school, and at the child's home, and brought to every visit to the emergency department so timely and appropriate care is provided.
Role of the Primary Care Provider
The primary care provider is vital to ensuring routine health maintenance is provided and coordination occurs between all health professionals involved in the child's care. Timely immunizations, including the yearly influenza vaccine, are critical to illness prevention. Early diagnosis and management of acute illness in the primary care office can prevent further progression of symptoms associated with mitochondrial disease and the need for inpatient hospitalizations. Developmental, vision, and hearing screening by the primary care provider enables early identification of changes and timely referral and intervention.
The primary care provider may need to assist parents in working with the school system to plan a schedule that supports the child's need for rest and nutrition by identifying appropriate goals for the child's Individualize Education Program and 504 accommodations, and educating school personnel regarding their child's condition. Some children may need time set aside during the day to rest, while others may need special permission to have easy access to snacks and fluids. Specific guidelines for physical activities, such as physical education classes, should be clearly defined for the school. These guidelines and emergency plans should be created in collaboration with the metabolic specialist and should be readily available for parents, health care providers, and their school.
Families with an infant, child, or adolescent who is diagnosed with mitochondrial disease often feel alone and isolated due to the lack of public awareness and understanding of these disorders. The primary care provider should be sensitive to this fact and provide support as necessary. Organizations such as United Mitochondrial Disease Foundation (www.umdf.org) and Mito Action (www.mitoaction.org) are important resources that should be suggested to families and individuals who are faced with this life-altering diagnosis. Living Well with Mitochondrial Disease: A Handbook for Patients, Parents, and Families, by Cristy Balcells, MSN, RN, (Balcells, 2012), a mother of a child with mitochondrial disease, is an excellent resource for families to better understand the cause of the disorder, treatment approaches, and practical advice on how to manage symptoms and achieve the best quality of life possible.
The primary care provider must be suspicious of mitochondrial disease when evaluating a child with dysfunction of three or more organ systems without unifying illness. Recognition of symptom clusters and referral to a specialist is the first of many steps to diagnosis. Management varies significantly from child to child and is determined by the child's level of heteroplasmy and "threshold" for clinical symptoms. Monitoring for energy expenditure is critical, and children with mitochondrial disease need extra rest, nutritional supplements, and careful management and treatment during episodes of acute illness. Finally, the primary care provider must understand that families of children with mitochondrial disease may need extra support and assistance as they navigate this consuming and life-altering condition.
The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families. If you are interested in author guidelines and/or assistance, contact Patricia L. Jackson Allen at firstname.lastname@example.org
Balcells, C. (2012). Living well with mitochondrial disease: A handbook for patients, parents, and families. Bethesda, MD: Woodbine House, Inc.
Groopman, J. (2013). Lives less ordinary: Chronically ill children are living longer than ever. How should we care for them? The New Yorker, 89, 34-39.
Haas, R., Parikh, S., Falk, M., Saneto, R., Wolf, N., Darin, N., & Cohen, B. (2007). Mitochondrial disease: A practical approach for primary care physicians. Pediatrics, 120, 1326-1333.
Jeyakumar, A., Williamson, M.E., Brickman, T.M., Krakovitz, P., & Parikh, S. (2009). Otolaryngologic manifestations of mitochondrial cytopathies. American Journal of Otolaryngology--Head and Neck Medicine and Surgery, 30, 162-165.
Kisler, J., Whittaker, R., & McFarland, R. (2010). Mitochondrial diseases in childhood: A clinical approach to investigation and management. Developmental Medicine and Child Neurology, 52, 422-433.
Koene, S., Wortmann, S., deVries, M., Jonckheere, A., Morava, E., de Groot, I., & Smeitink, J. (2013). Developing outcome measures for pediatric mitochondrial disorders: Which complaints and limitations are most burdensome to patients and their parents? Mitochondrion, 13, 15-24.
Luft, R. (1994). The development of mitochondrial medicine. Proceedings of the National Academy of Sciences of the United States of America, 91, 8731-8738. Retrieved from http://www. pnas.org/content/91/19/8731
Mitoaction.org. (2013). Protocol for fever or when infection suspected. Retrieved from http://www.mitoaction.org/files/protocol-fever-andinfection.pdf
O'Keeffe, G., (2007). Understanding the energy budget. Retrieved from http://www.mitoaction.org/energy-mito-man
McFarland, R., & Turnbull, D.M. (2009). Batteries not included: Diagnosis and management of mitochondrial disease. Journal of Internal Medicine, 265, 210-228.
Parikh, S., Goldstein, A., Koenig, M.K., Scaglia, F., Enns, G.M., Saneto, R., ... Wolfe, L.A. (2013). Practice patterns of mitochondrial disease physicians in North America. Part 2: Treatment, care and management. Mitochondrion, 13, 681-687.
Parikh, S., Saneto, R., Falk, M.J., Anselm, I., Cohen, B.H., & Haas, R. (2009). A modern approach to the treatment of mitochondrial disease. Current Treatment Options in Neurology, 11, 414-430.
Pfeffer, G., Horvath, R., Klopstock, T., Mootha, V.K., Suomalainen, A., Koene, S., ... Chinnery, P.F. (2013). New treatments for mitochondrial disease--No time to drop our standards. Nature Reviews Neurology, 9, 474-481.
Sacconi, S., Salvaiati, L., Nishigaki, Y., Walker, W.F., Hernandez-Rosa, E., Trevisson, E., ... Davidson, M.M. (2008). A functionally dominant mitochondrial DNA mutation. Human Molecular Genetics, 17, 1814-1820.
Sanderson, S., Green, A., Preece, M.A., & Burton, H. (2006). The incidence of inherited metabolic disorders in the West Midlands, UK. Archives of Disease in Childhood, 91, 896-899.
Saneto, R.P., & Sedensky, M.M. (2013). Mitochondrial disease in childhood: MtDNA encoded. Neurotherapeutics, 10, 199-211. Retrieved from http://link.springer.eom/article/10.1007/s13311012-0167-0
Schiff, M., Benit, R, Coulibaly, A., Loublier, S., El-Khoury, R., & Rustin, P. (2011). Mitochondrial response to controlled nutrition in health and disease. Nutrition Reviews, 69, 65-75.
Wallace, D., Singh, G., Lott, M., Hodge, J., Schurr, T., Lezza, A., ... Nikoskelainen, E. (1988). Mitochondrial DNA associated with Leber's hereditary optic neuropathy. Science, 242, 1427-1430.
Wong, L., Scaglia, F., Graham, B., & Craigen, W. (2010). Current molecular diagnostic algorithm for mitochondrial disorders. Molecular Genetics and Metabolism, 100, 111-117.
Alexis Dassler, MSN, RN, is an FNP Candidate, Yale University, School of Nursing, New Haven, CT.
Patricia Jackson Allen, MS, RN, PNP-BC, FAAN, is a Professor and Specialty Coordinator, Pediatric Nurse Practitioner Program, Yale University School of Nursing, New Haven, CT.
Table 1. Common Affected Systems and Signs of Mitochondrial Disease Neurologic Encephalopathy, seizures, developmental disability, cognitive disability migraines, stroke-like events, ataxia, spasticity dystonia, progressive sensorineural hearing impairment Cardiovascular Cardiomyopathy conduction defects, arrhythmias Opthalmologic Opthalmoplegia, ptosis, optic atrophy, retinitis pigmentosa Musculoskeletal Fatigability, exercise intolerance, hypotonia Gastrointestinal Recurrent vomiting, constipation, pseudo-obstructions, dysphagia Endocrine Short stature, diabetes mellitus, exocrine pancreatic failure, thyroid dysregulation Note: Adapted from Kisler, Whittaker, & McFarland, 2010. Table 2. Clinical Phenotype of Mitochondrial Syndromes Syndrome Age of Onset Clinical Features Barth syndrome Infancy or early Cardiomyopathy skeletal childhood myopathy, growth failure, hypotonia, neutropenia Kearn-Sayers Later childhood Progressive opthlamoplegia, syndrome pigmentary retinopathy cerebellar ataxia, increased cerebrospinal fluid protein, cardiac conduction defects Leigh syndrome Infancy or early Neurodevelopmental childhood regression associated with acute encephalopathic illness, dystonia, hypotonia, ataxia, nystagmus, optic atrophy, dysphagia, central respiratory dysfunction Mitochondrial Child or adult Stroke-like events, encephalopathy with seizures, diabetes lactic acidosis and mellitus, cardiomyopathy, stroke-like episodes sensorineural hearing (MELAS) impairment, pigmentary retinopathy, cerebellar ataxia Maternally inherited Infancy or early Sub-acute or acute Leigh syndrome childhood encephalopathy, lactic (MILS) acidosis, seizures, neurodevelopmental regression, cerebellar and brainstem dysfunction Neurogenic weakness Late childhood Peripheral neuropathy, with ataxia and or adult ataxia, pigmentary retinitis pigmentosa retinopathy (NARP) Pearson syndrome Early childhood Pancytopenia, pancreatic failure, renal-tubular defects. Survivors develop Kearn-Sayers syndrome Note: Adapted from Kisler, Whittaker, & McFarland, 2010. Table 3. Medications with Reported Mitochondrial Toxicity Medication Symptoms Mechanism Acetaminophen Hepatopathy Oxidative stress Aminoglycoside Hearing loss, Impaired mtDNA translation antibiotics cardiac toxicity, renal toxicity Aminoglycoside Hearing loss, Impaired mtDNA translation and platinum cardiac chemotherapeutics toxicity, renal toxicity Aspirin Reye syndrome Inhibition and uncoupling of OXPHOS Antiretrovirals Peripheral Impairment of mtDNA neuropathy, replication causing mtDNA liver depletion; carnitine dysfunction, deficiency, lactic acidosis, myopathy lipodystrophy Beta-blockers Reduced Oxidative stress exercise intolerance Metformin Lactic acidosis Inhibition of OXPHOS, enhanced glycolysis Valproic acid Hepatopathy; Inhibition of fatty acid infrequently oxidation, the citric acid direct cycle, and OXPHOS; carnitine encephalopathy depletion; complex IV inhibition Note: Adapted from Parikh et al., 2009.
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|Title Annotation:||Primary Care Approaches|
|Author:||Dassler, Alexis; Allen, Patricia Jackson|
|Article Type:||Clinical report|
|Date:||May 1, 2014|
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