- Email: [email protected]
Mitochondrial disease: Beyond etiology unknown
Mitochondrial Disease: Beyond Etiology Unknown Catherine Yetter Read, RN, MS Robin J. Calnan, RN, BS, CPN
Mitochondrial dysfunction is now recognized as a relatively common cause of degenerative disease in children. Mutations in either the mitochondrial or the nuclear genome that cause errors in the synthesis of enzymes essential for energy production and metabolism lead to a wide variety of pediatric problems, including developmental delays, sensorimotor impairment, seizures, diabetes, and organ failure. This article reviews the role of mitochondria in health and illness, discusses the clinical aspects of mitochondrial dysfunction, describes the experiences of three children with mitochondrial disease, and presents nursing strategies for affected families. Copyright r 2000 by W.B. Saunders Company
G
ENETIC CAUSES of mitochondrial dysfunction have recently been implicated in some previously unexplained degenerative conditions in children. Mitochondrial diseases can cause multiple disabilities that present in puzzling, atypical ways. Parents of children with mitochondrial disease must meet the complex physical and psychological needs of their children, often without the benefit of a definitive diagnosis. Nurses play an important role in the health care of the family of a child with a disability, which may be especially challenging in mitochondrial disease. It is essential for nurses to understand the role of mitochondria in health and illness, and to tailor interventions to meet the particular needs of affected families. This article presents the scientific basis for the care of children with mitochondrial disease, describes the experiences of three affected children, and suggests strategies for nursing care.
From the University of Massachusetts, Lowell, MA; and Children’s Hospital, Boston, MA. Support by the Leadership Education in Neurodevelopmental Disabilities (LEND) grant, awarded Institute for Community Inclusion, a University-Affıliated Program of Children’s Hospital, Boston, by Health Resources and Services Administration, U.S. Department of HHS, Maternal and Child Health Bureau (Grant No. MCJ-259150). Address reprint requests to Catherine Yetter Read, RN, MS, 22 University Avenue, Burlington, MA 01803. E-mail: [email protected] Copyright r 2000 by W.B. Saunders Company 0882-5963/00/1504-0006$10.00/0 doi:10.1053/jpdn.2000.8042
232
THE MITOCHONDRION The human body, like any machine, requires a source of energy and a way to convert that energy into work. This is accomplished in the mitochondria, the intracellular organelle where chemical energy from food is harvested through oxidative phosphorylation (OXPHOS) (Wallace, 1999). OXPHOS is an intricate chain of events that involves five multipolypeptide enzyme complexes. This process results in the production of adenosine triphosphate (ATP), the primary source of power for all body processes. Mitochondria also perform other functions, depending on the tissue location, including production of steroid hormones, manufacture of building blocks of DNA, and elimination of ammonia in the liver. Any disruption of mitochondrial function may lead to disease. Tissues that rely heavily on cellular energy production via OXPHOS are typically affected. Many of the mitochondrial disorders found in Table 1 involve alteration of these high-energy systems, including the brain, skeletal muscle, heart, and liver. MITOCHONDRIAL VERSUS NUCLEAR GENOME Disruption of mitochondrial function resulting in mitochondrial disease is caused by inherited or spontaneous mutations in either the mitochondrial or nuclear DNA. Advances in our understanding of mitochondrial genetics have resulted in the rejection of the notion that babies inherit exactly half of their DNA from the mother and half from the father. This principle only holds true for the double helical DNA found in the nucleus. Mitochondrial
Journal of Pediatric Nursing, Vol 15, No 4 (August), 2000
MITOCHONDRIAL DISEASE
233 Table 1. Clinical Synopsis of Mitochondrial Disorders Disease
MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes
MERRF: Myoclonic epilepsy associated with ragged-red fibers
NARP: Neuropathy, ataxia, and retinitis pigmentosa
KSS: Kearns-Sayre syndrome Pearson syndrome LHON: Leber’s hereditary optic neuropathy CPEO: chronic progressive external ophthalmoplegia Leigh syndrome (infantile necrotizing encephalopathy)
Wolfram syndrome
MNGIE: Myoneurogastrointestinal encephalopathy syndrome
Mitochondrial respiratory chain disorders: Named for the missing protein or protein complex, e.g., Complex I, II, III, IV, V, cytochrome oxidase deficiencies. There are over 100 proteins involved in the respiratory chain.
Miscellaneous: Fatty acid oxidation disorders, urea cycle defects, and other ‘‘inborn errors of metabolism’’
Clinical Synopsis
Headaches, seizures, stroke-like episodes, encephalopathy, muscle weakness, episodic vomiting, progressive bilateral sensorineural hearing loss, bilateral cataracts, cortical blindness. Laboratory studies reveal an elevated resting serum lactate, increased with exercise. RRF on muscle biopsy. Myoclonic epilepsy, ataxia, spasticity, muscle weakness, sensorineural hearing loss. Laboratory studies reveal elevations in serum pyruvate or pyruvate and lactate and RRF on muscle biopsy. Developmental delay, seizures, ataxia, sensory neuropathy, retinitis pigmentosa with loss of vision, muscle weakness. No consistent abnormal laboratory findings. Short stature, visual loss owing to paralysis of eye muscles and retinal degeneration, hearing loss, cardiomyopathy, diabetes, kidney failure. Severe anemia and pancreatic and liver dysfunction in children; may progress to KSS in adolescence. Permanent or temporary blindness stemming from damage to the optic nerve. Presents in adulthood. Usually presents in adolescence with eye muscle paralysis, drooping eyelids, muscle weakness, and fatigue. Progressive, unremitting degenerative disorder, usually appearing before the age of 2 years and fatal in less than 1 year. Weakness, hypotonia, tremor, ataxia, abnormal eye movements, blindness, respiratory difficulty, liver disease, hypertrophic cardiomyopathy. Laboratory tests reveal high blood pyruvate and lactate. Optic atrophy, sensorineural hearing loss, autonomic dysfunction, nystagmus, mental retardation, seizures, diabetes mellitus, diabetes insipidus, hydronephrosis, distended bladder, hematologic abnormalities. Diagnostic studies may reveal vasopressin deficiency and widespread atrophic brain changes on MRI. External ophthalmoplegia, malabsorption, intermittent diarrhea, chronic malnutrition, proximal limb weakness, muscle atrophy, polyneuropathy, encephalopathy, neurosensory hearing loss. Diagnostic studies may reveal lactic acidosis after moderate glucose loads, increased excretion of hydroxybutyric and fumaric acids, density of cerebral white matter on MRI, and ragged-red ocular and skeletal myopathy. Most mitochondrial diseases are the result of deficiencies in one or more of these respiratory chain proteins. At the present time, classification of mitochondrial disease is not standardized, and conditions may be named for the syndrome and/or the complex or enzyme deficiency. For example, many cases of Leigh disease are caused by Complex I deficiency, with either nuclear or mitochondrial DNA mutations (Kirby et al., 1999). Many conditions result from aberrant metabolism within the mitochondria; these are not universally classified as mitochondrial diseases. For example, medium-chain acyl CoA dehydrogenase deficiency (MCAD) causes nonketotic hypoglycemia or a Reye’s-like syndrome, and has been associated with sudden infant death syndrome (SIDS) (Burton, 1998).
NOTE. This is a partial listing of disorders that are associated with mitochondrial dysfunction. Most are associated with mutations in mtDNA, although some have been found to result from nuclear DNA mutations or other processes that impair mitochondrial function. There is also overlap among some of these conditions. (Compiled from Online Mendelian Inheritance in Man [OMIM] database, 1999; and Wallace, 1999.)
DNA (mtDNA), a circular molecule, is inherited exclusively from the egg of the mother. This is because mitochondria reside in the cytoplasm, which is stripped from the sperm cell before fertilization. Thus, men inherit their mtDNA from
their mother, but cannot pass it along to their offspring. Pedigree analysis may provide a clue that a particular disorder is the result of a mtDNA mutation, if transmission occurs exclusively from mother to child of either sex (Jorde, Carey, Bam-
234
shad, & White, 1999). Figure 1 depicts this maternal inheritance pattern. Mitochondrial disease is not limited to conditions inherited at birth. Much recent attention has been given to the role of mtDNA mutations in late onset conditions, such as Alzheimer’s disease, cancer, and Parkinsonism. It is well known that mtDNA has a mutation rate that is much higher than that of nuclear DNA, owing to poor mtDNA repair mechanisms and damage from free radicals released during OXPHOS (Jorde et al., 1999). The precise mechanisms of many common degenerative disorders, and perhaps even the aging process, are poorly understood at the present time, but many scientists believe that the explanations relate to mitochondrial dysfunction (Naviaux & Longenecker, 1997). Mitochondrial genome disorders display wide phenotypic variability. Identical twins with the same mtDNA mutation may have vastly different disease presentations, and different mtDNA mutations may produce similar disorders (Wallace, 1999). This unpredictability in the course of mito-
READ AND CALNAN
chondrial diseases can be partially explained by heteroplasmy, wherein a different proportion of mutant to normal (wild-type) mtDNA exists in each cell or tissue. As cells divide, the mutant and wild-type mtDNA are randomly distributed to the daughter cells, so the proportion of mutant to wild-type mtDNA may increase or decrease with each subsequent generation of the cell line. If that proportion increases past a certain threshold, the cellular energy capacity will decline, and symptoms appear. Thus, a twin who originally received a higher proportion of mutant mtDNA, experienced a spontaneous mtDNA mutation, or whose mutation became more abundant over time, may be affected with a mitochondrial disease that the other twin has escaped. Mitochondrial malfunction may also be caused by mutations in the DNA found in the 23 pairs of chromosomes in the cell nucleus. In fact, nuclear DNA encodes most of the proteins necessary for mitochondrial function (Jorde et al., 1999). Thus, the more familiar Mendelian inheritance patterns, such as autosomal recessive or X-linked, are also
Figure 1. Pedigree showing maternal inheritance, which is characteristic of mitochondrial DNA mutations. Note that only affected women can transmit the disease.
MITOCHONDRIAL DISEASE
found in families with mitochondrial disease. In addition, spontaneous mutations may occur in either nuclear or mitochondrial DNA. Thus, genetic counseling in mitochondrial disease is particularly challenging. Information about the recurrence risk is not always certain, and it is often impossible to predict disease severity, even after the risk is estimated. Because the study of diseases involving mitochondria is an emerging field, the terminology and classification system may cause confusion. Clinicians may label mitochondrial disease according to a name previously assigned to a syndrome, a general term for the type of disorder, or a biochemical defect. Thus, one child may correctly be said to have Leigh syndrome, mitochondrial encephalomyopathy, or Complex I deficiency. Some investigators adopt a broad definition of mitochondrial disease, and include any disorder that involves mitochondrial dysfunction (Naviaux & Longenecker, 1997). Others restrict the term mitochondrial disease to those conditions caused by mtDNA mutations (Jorde et al., 1999). In reality, there is complex interplay between mtDNA and nuclear DNA, and some conditions may be caused by mutations in either genome. Table 1 summarizes some of the conditions associated with mitochondrial dysfunction, regardless of specific cause. CLINICAL ASPECTS OF MITOCHONDRIAL DYSFUNCTION Mitochondrial disease, once considered rare, is now thought to account for a wide variety of degenerative conditions in both children and adults (Wallace, 1999). In fact, it is likely that there are many children with developmental delays, failure to thrive, seizures and other neurological disorders, or other unexplained health problems who actually have undiagnosed mitochondrial dysfunction. Incidence data are generally unavailable for mitochondrial diseases, but those patients that have been identified are considered to be ‘‘just the tip of the iceberg’’ (Naviaux & Longenecker, 1997, p. 42). Children with mitochondrial disease are typically normal at birth. The signs and symptoms often begin as mild developmental delays or subtle neurological signs not always associated with disease. However, mitochondrial disease should be suspected whenever signs and symptoms involve three or more organ systems, become worse in the presence of acute illness, or present in an atypical fashion. Other clues include muscle weakness, hypotonia, vital sign instability, sensorimotor impairment, feeding problems, and worsening of
235
symptoms when the child is dehydrated. Mitochondrial disease may initially present as a behavior problem, and some children experience sleep disorders owing to excessive daytime fatigue. Diagnosis of mitochondrial disease is particularly challenging owing to the variable and complex presentation and inheritance patterns, and the process may take months or even years. Blood or urine tests may reveal lactic acidosis, low carnitine levels, atypical amino acid profiles, or other abnormalities, but such results may be inconclusive. In many mitochondrial diseases, electron microscopy of a skeletal muscle biopsy stained with Gomori trichrome shows the presence of ragged red fibers (RRF), indicative of abnormal proliferation of mitochondria (Rose, 1998). Deficiencies in particular enzymes involved in OXPHOS may be detected through biochemical assays conducted on muscle biopsies or skin fibroblasts (Clarke, 1992). Nuclear magnetic resonance spectroscopy may show abnormalities of muscle tissue in mitochondrial disease, and this noninvasive test holds promise for faster diagnosis in the future (Griggs & Kaparti, 1999). If there is cardiac involvement, abnormalities may be noted on electrocardiography and echocardiography. Atrophy or calcification of the nervous system may be found with computed tomography (CT) scanning or magnetic resonance imaging (MRI). Cerebrospinal fluid elevations in protein or lactate may be found (Clarke, 1992). Finally, molecular genetic analysis of mitochondrial and nuclear DNA may pinpoint mutations associated with specific mitochondrial diseases. Clearly, the diagnostic evaluation of mitochondrial disease requires specialty care, at a center with access to laboratories that perform the required analyses. Unfortunately, these services are not widely available at the present time. Patients may be required to travel far from home to undergo tests, which may or may not ultimately reveal a specific diagnosis. Some parents prefer to forego muscle biopsies or other invasive tests, and opt for empirical treatment with dietary supplements and vitamins. These inconsistencies in patterns of care contribute to the difficulty in determining accurate estimates of the incidence of mitochondrial disease. There is no known cure for mitochondrial disease, but certain therapies may help alleviate symptoms or slow the disease progression. Small frequent meals and avoidance of fasting may provide significant benefit for some patients, whose metabolic processes are impaired by mitochondrial
236
dysfunction. Some physicians recommend manipulation of fat and carbohydrate intake, although this must be tailored to the needs of the individual patient. Vitamins and supplements that have been found to improve energy levels in some patients include CoQ10 (coenzyme Q10), levo-carnitine (Carnitor, Sigma-tau Pharmaceuticals, Inc., Gaithersburg, MD), thiamine (B1), riboflavin (B2), nicotinamide (B3), vitamin E, vitamin C, lipoic acid, selenium, and beta carotene. Some clinicians have also reported improvement with supplements of calcium, magnesium, phosphorus, vitamin K, succinate, and citrate. It is hypothesized that these substances act by enhancing enzyme function, leading to more efficient energy generation, or serve as antioxidants, which may slow the disease progression (Cohen, 1997). Some children with mitochondrial disease have experienced improvements in stamina and alertness after corticosteroid administration, but this is generally avoided owing to numerous undesirable side effects (Naviaux & Longenecker, 1997). Treatment of mitochondrial disease is best handled through a multidisciplinary approach. Movement, speech, and cognitive disorders should be addressed through early intervention programs with appropriate specialists. Families need guidance to help the child avoid stressors that may exacerbate symptoms, such as cold, heat, infection, lack of sleep, and inadequate intake of food and fluids. Physical and occupational therapists may supervise exercise programs to build muscle strength (Naviaux & Longenecker, 1997). Psychosocial support for the family of a child with mitochondrial disease is an essential aspect of care. There is some evidence that mothers of children with mitochondrial disorders suffer from psychological dysfunction. In one study (Varvogli & Waisbren, 1999), 56% of mothers of children with mitochondrial disease had scores in the pathological range on three or more scales on the Minnesota Multiphasic Personality Inventory (MMPI). The investigators are careful to point out that this result may be attributable to carrier status characteristics or situational anxiety and stress; nevertheless, there is an obvious need for support services for these mothers. As with other chronic illnesses, therapy for mitochondrial disease must be tailored to the needs of the individual patient and family. The following case studies exemplify the diverse and complex needs that result from mitochondrial dysfunction.
READ AND CALNAN
THREE CASES OF MITOCHONDRIAL DISEASE1 A Teenager With Kearns-Sayre Syndrome Mari’s mother sensed from the beginning that there was something wrong with her daughter. She was not growing as fast as her older sisters had, and she was constantly contracting colds and other illnesses that caused her a great deal of distress. The doctors at the health clinic were perplexed, but could offer little but reassurance that baby Mari’s health would improve as she got older. Around the age of three, Mari began to experience visual problems, which were linked to ophthalmoplegia and pigmentary retinopathy. A few years later, fainting spells led to the diagnosis of complete heart block, and Mari had a permanent pacemaker implanted. Her pediatrician detected short stature and thoracic kyphosis, and Mari continued to suffer exaggerated responses to viral illnesses. When she was 10 years old, Mari was referred to the mitochondrial disease clinic at a major medical center. A muscle biopsy showed RRF. The diagnosis of Kearns-Sayre syndrome (KSS) was confirmed by mitochondrial DNA analysis, which revealed a specific mtDNA mutation. This mutation often appears spontaneously, which explains why Mari’s mother and siblings were not affected. Mari’s mother was relieved to learn that there was an explanation for her daughter’s many problems, but now had to face the unpredictable nature of the disease progression. At the time of the diagnosis of KSS, Mari was enjoying school and play activities, despite mild diffuse hypotonia and occasional fatigue. She was started on carnitine, Coenzyme Q, and vitamin C, which sometimes improve symptoms of mitochondrial disease by enhancing transport of nutrients into mitochondria and speeding up the process of OXPHOS. Unfortunately, Mari did not respond to these medications, and her condition continued to worsen. She began to have trouble with her schoolwork, and she felt too weak to participate in gym activities. A hearing evaluation revealed that Mari was suffering from bilateral high frequency sensorineural hearing loss. The clinic nurse met with Mari’s teachers and the school nurse to explain KSS. Mari’s daily schedule was paced to optimize her energy, and she was allowed to take breaks with the nurse when she felt the need. With a new schedule, new hearing aids, and new glasses, Mari showed stable progress in school. 1The
names and details of these cases have been changed to protect confidentiality.
MITOCHONDRIAL DISEASE
When Mari missed her next clinic appointment, the clinic nurse called her home. Mari’s mother said that they just wanted to stay away from the hospital for awhile. They were tired of the long trip to their specialty clinic, as they had recently visited the cardiologist, the eye doctor, the hearing clinic, and the pediatrician. However, a few weeks later, Mari showed up in the mitochondrial clinic because she was experiencing difficulty walking and severe fatigue. Laboratory studies revealed hypoparathyroidism and lactic acidosis. Endocrinology was added to her list of specialty clinics, and a trial of dichloroacetate (DCA) was begun to combat lactic acidosis. Lactate, a byproduct of cellular metabolism that often builds up in mitochondrial disease, is thought to have harmful effects on the nervous system. Unfortunately, Mari suffered peripheral neuropathy from the DCA, so it had to be discontinued. Over the next few years, Mari’s condition progressed. She had to be hospitalized when she contracted strep throat to treat dehydration and metabolic acidosis. She developed diabetes, and she and her mother learned to give insulin injections and perform blood sugar checks twice a day. A CT scan showed white matter changes consistent with worsening mitochondrial disease. Now, at age 13, Mari uses a cane to walk, but continues to attend school, where she benefits from physical, occupational, and speech therapy. Her family lovingly cares for her, and faithfully brings her to her numerous appointments. They feel helpless, but pray that her condition will stabilize and that new treatments will be developed for KSS in the near future. A 5-Year-Old With Leigh Syndrome Concern for Annie’s health began before she was born, when intrauterine growth retardation (IUGR) was diagnosed via ultrasound. Her mother was mildly concerned, but her first child had also been on the small side and was now perfectly healthy. She experienced an uneventful labor and delivery at 38 weeks gestation, and Annie’s Apgar scores were 7 at 1 minute and 9 at 5 minutes. Everyone was pleased that Annie had arrived safely, even though she weighed slightly more than 5 pounds. Annie needed extra attention in the newborn nursery owing to feeding difficulties. She was discharged at the age 5 days, but continued to have a weak suck and to fall asleep during feedings. Her pediatrician noted a heart murmur, and an echocardiogram revealed small atrial and ventricular septal
237
defects. The cardiologist found no evidence of congestive heart failure that would explain Annie’s feeding difficulties and failure to thrive, and assured her parents that small septal defects usually close spontaneously. A gastroenterology work-up was negative, but Annie’s growth and development was clearly way behind schedule. At the age of 9 months, Annie became very hypotonic, and she made her first trip to the neurologist. The diagnostic tests were conclusive: Annie had a mitochondrial disease. Her cerebrospinal fluid and blood showed markedly elevated lactate levels, and an MRI showed abnormal white matter in her basal ganglia. A muscle biopsy showed changes consistent with a deficiency in Complex I of the respiratory chain. Nuclear DNA analysis later revealed a mutation associated with Leigh syndrome. Annie’s parents finally had an explanation for her problems, but with it came the sad news that her condition was going to deteriorate. In addition, they learned that Leigh syndrome is inherited. Although not definite, it appeared that Annie’s Leigh syndrome was transmitted in an autosomal recessive fashion. If so, both parents must be carriers, and there is a 25% chance that subsequent children will be affected. Annie’s parents were frustrated with the fact that the prognosis, though poor, is extremely unpredictable. Her mother told the clinic nurse that she thought she was going crazy, because she was constantly worrying about Annie’s every move. It was almost impossible to know what was significant and what was not. Annie had a gastrostomy tube at this point, so feedings and medications were easier to administer, but there were other worries now. Was that movement a seizure? Was Annie falling more than usual, or was she just tired? Should her sister be allowed to invite friends over and add to the risk that Annie would catch a virus that she could not handle? Annie’s mother came to rely on the support offered by visiting nurses. She appreciated the time they spent just listening, and their objective assessments of signs and symptoms. When Annie’s mother correctly suspected nighttime apnea, the nurses intervened to get a monitor. They helped her through the maze of paperwork required to get the health maintenance organization (HMO) to pay for Coenzyme Q and vitamin C. Although these substances may be the only hope for boosting energy in mitochondrial disease, many third-party payers regard them as optional dietary supplements because they are available in health food stores.
238
Now, at age 5, Annie is a beautiful little girl with a progressive degenerative disease. She has developed autonomic dysfunction resulting in periods of hypotension, bradycardia, and apnea. She is still able to eat certain foods in addition to her nighttime gastrostomy tube feedings, but she chokes frequently. She has a noticeable tremor, and wears a helmet because of her frequent falls, hypotonia, and seizures. Her eyesight is failing, and her intellectual development is slow. An individualized education plan that provides physical, occupational, and speech therapies at school, along with the support of the school nurse, has enabled Annie to begin kindergarten. At the present time, Annie’s parents lives revolve around her care, but they are thankful for each day they have with her. A Young Adult With Suspected Wolfram Syndrome Allen is a proud young man who, like most 22-year-olds, is trying to make it on his own. Despite a lifetime of medical and developmental problems, and strained relations with his parents, he has managed to get his own apartment and get by on his monthly disability checks. Allen’s history is unclear because it is limited to what he recalls or can be found in his thick medical record. He knows that his mother is an insulin-dependent diabetic who suffered several miscarriages, and her sister is mentally retarded. Allen’s father and his side of the family are healthy. It appears that Allen was a healthy baby until he was diagnosed with insulindependent diabetes mellitus (IDDM) at the age of 2. For many years, poor diabetic control was blamed for Allen’s many problems, including generalized tonic-clonic seizures, poor eyesight, developmental delays, and learning disabilities. But when an ophthalmology examination revealed optic nerve hypoplasia instead of diabetic retinopathy, suspicions were raised about the true nature of Allen’s condition. He was referred to the mitochondrial clinic, where the search began for an underlying genetic cause for his multiple problems. A careful history and physical examination generated additional information consistent with a diagnosis of mitochondrial disease. Allen admitted to tiring very easily and having difficulty tolerating extremes of temperature, especially very hot weather. A cardiac work-up revealed mild cardiomyopathy with left ventricular hypertrophy, although Allen denied any symptoms related to heart problems. Autonomic testing indicated that Allen had early vagal neuropathy with a resting tachycardia. A skeletal muscle biopsy confirmed mitochondrial
READ AND CALNAN
pathology. A tentative diagnosis of Wolfram syndrome was made, even though the clinical picture differed somewhat from other patients. Wolfram syndrome can result from mutations in either the nuclear or mitochondrial genome (OMIM, 1999), but Allen’s DNA analysis indicated that his disease was caused by a mitochondrial DNA deletion. As a man, Allen is not at risk for transmitting the disease to his children because this is an example of mitochondrial inheritance. With this definitive diagnosis, Allen’s care could now be centralized in the mitochondrial clinic, where the initial challenge was to establish trusting relationships between Allen and the staff. It was important to Allen that he be treated as an adult, and he refused to involve his parents in his care. However, his frequent emergency admissions for the treatment of hypoglycemia indicated that he needed more careful supervision. His complex multisystemic needs exemplify the nursing care challenges of mitochondrial disease. Because of his learning disabilities, Allen had trouble budgeting his limited income and feeding himself a balanced diabetic diet. Visiting nurses helped him to organize his kitchen and structure his routine to maintain better control of his blood sugar. Grocery store gift certificates were obtained that the nurses could give to Allen when he ran out of money for food at the end of the month. Daily doses of Coenzyme Q improved Allen’s energy level, and his vision improved with a new eyeglass prescription. Allen’s diabetes and seizure disorder stabilized. Allen has benefited from the knowledge that there is an underlying cause for his problems. He no longer suffers from the guilt imposed by practitioners who blamed him for problems thought to be related to poor glucose control. He makes frequent visits to the clinic, where a unified health team helps him to cope with his situation and feel better about himself. He understands that his prognosis is uncertain, but strives for quality of life through maintenance of healthy habits. NURSING STRATEGIES IN MITOCHONDRIAL DISEASE Nurses who care for children with mitochondrial diseases are part of the expanding field of genetic nursing, a holistic practice that includes assessment, planning, implementing, and evaluating the physical and psychosocial needs of patients and families with genetic concerns (American Nurses Association, 1998). McCloskey and Bulechek (1996) define genetic counseling as a nursing
MITOCHONDRIAL DISEASE
intervention that uses ‘‘an interactive helping process focusing on the prevention of a genetic disorder or the ability to cope with a family member who has a genetic disorder’’ (p. 300). Because of the extreme variability in all aspects of mitochondrial disease, nurses must tailor interventions to meet the expressed needs of the child and family, given their particular situation. Nursing care consists of four interacting elements of the client-professional relationship (Cox, 1982): provision of information, affective support, decisional control, and professional-technical competencies. Provision of Information Information forms the basis of parents’ coping strategies, but there may be several barriers to knowledge development in mitochondrial disease. Most children develop signs and symptoms very gradually, and it often takes months or years to establish a diagnosis. Even when a definitive diagnosis is made, there is often no way to predict the course of the disease in any particular child. Nurses and other providers are still learning about this new class of diseases, and the scientific explanations, when known, can be complicated. Health care professionals serve as the most common source of information for parents, at least initially. Later, parents may turn to reference books, journals, and information available on the Internet. (See Table 2 for a list of resources related to mitochondrial disease.) Nurses often find themselves helping parents interpret information acquired from other places. Although the internet is a Table 2. Resources Related to Mitochondrial Disease United Mitochondrial Disease Foundation
P.O. Box 1151, Monroeville, PA 15146-1151; phone (412) 793-8077; http://www. umdf.org National Institutes of Health Federal Building, Room 618, (NIH) Office of Rare Diseases 7550 Wisconsin Avenue, Bethesda, MD 20892-9120; phone (301) 402-4336; http://rarediseases.info. nih.gov/ord March of Dimes Birth Defect 1275 Mamaronek Ave., White Foundation—Resource Center Plains, NY 10605; phone (888) 663-4637; http://www. modimes.org Mitochondrial and metabolic Sigma-tau Pharmaceuticals, Inc., disorders: A parent’s guide. 800 S. Frederick Avenue, Suite 300, Gaithersburg, MD 20877. Also appeared as a three-part educational series in Exceptional Parent magazine, June, July, and August 1997.
239
rich source of information and networking for parents, they often need assistance to understand terminology or determine what is applicable to their child’s condition. In some cases, nurses must provide printed material for parents who do not have access to these resources. An important responsibility of a nurse with expertise in mitochondrial disease is to educate other professionals. Mari and Annie, described earlier, both benefited from the mitochondrial clinic nurse’s visits with school personnel. Their extreme fatigue related to mitochondrial dysfunction could be managed effectively with moderate limitations of physical activity. In Allen’s case, the visiting nurses needed to be educated about the relationship of diabetes to mitochondrial pathology, so that they could better understand the complexity of his disease. It is also necessary to educate third-party payers about the special needs of children with mitochondrial disease to obtain reimbursement for medications, monitors, or home care. Parents often ask nurses for information about whether or not treatments are working. This is often difficult to determine. Although certain treatments produce an immediate beneficial effect, others may take months. In some cases, the treatment effect may never be noticeable, yet it may delay or stop the progression of the disease (Cohen, 1997). Other parents, like Annie’s, turn to nurses for help deciding whether signs and symptoms signify disease progression or require medical treatment. Parents of children with genetically transmitted diseases are especially concerned about recurrence risk in future pregnancies. Such information is particularly difficult to estimate in mitochondrial disease. Prenatal diagnosis for mitochondrial disease is limited at the present time, and is hindered by the inability to predict accurately the clinical severity expected, even if a specific mutation is present in fetal tissue. Many parents of severely affected children simply choose not to risk another pregnancy (Read, 2000). Affective Support Affective support refers to the interpretation of and therapeutic response to an individual’s emotional needs. It is comprised of components considered central to the nurse-patient relationship, such as active listening, verbal reassurance, therapeutic touch, empathy, advocacy, and nonverbal communication. Parent emotional responses to having a child with a disability vary tremendously over time, and may include shock, disbelief, guilt, denial, and an overwhelming sense of loss. Relatives and
240
friends may be unable to provide needed support if they are having difficulty accepting the diagnosis, blame one of the parents, or just feel uncomfortable because they do not know what to say (Trachtenberg & Batshaw, 1997). For parents of children with mitochondrial disease, the nurse may become a primary provider of affective support. Mitochondrial disease is a challenge to practitioners, and parents have expressed frustrations about lack of caring (Nishio, 1997). In the early phase, before the actual diagnosis, failure to acknowledge concerns about subtle delays or problems implies that the professional believes that the parent is imagining things. Later, when the diagnosis is known and the child’s condition deteriorates, professionals may distance themselves from a parent who is perceived as demanding. The parent is constantly trying to reconcile the need for assistance from health care providers with the feeling that others cannot give the same quality of care. The nurse must continually reassess the family’s coping skills and strategies, and tailor counseling and interventions appropriately. For some families, spirituality is a primary source of strength; for others, networking with other families facing similar conditions provides the greatest comfort. Decisional Control A parent’s need or desire for control in decisions related to their child’s health is impacted by several things, including the age of the child, the nature of the disease, previous experiences, psychosocial factors, and involvement of significant others. Health care providers should offer the parent maximal decisional control, after careful assessment of individual strengths and limitations. The overall approach to the family should be one of empowerment (Trachtenberg & Batshaw, 1997). The parents of a newborn with significant but undiagnosed health problems may be very comfortable relinquishing decisional control to health professionals because they feel helpless, uninformed, and overwhelmed by their new responsibilities. On the other end of the spectrum, the parents of an older child may have spent years educating themselves about their child’s mitochondrial diagnosis. They are often well equipped to share decisions with the health team, and are certainly more capable of making decisions about their child than others in the community. Parents of children with mitochondrial disease are accustomed to dealing with professionals who
READ AND CALNAN
lack knowledge about their child’s specific condition, especially outside of the mitochondrial disease specialty center. Providers must be sensitive to the knowledge level of the parent, and acknowledge their own inadequacies. Information is more readily available than ever, thanks to the internet. Professionals must be able to access these resources, evaluate the quality of the information, and discuss the implications with the parent. Shared decision making between the parent and professional leads to a balance between parent empowerment and provider support. Professional-Technical Competencies Parents of children with mitochondrial disease, like all parents of sick or disabled children, need health professionals who are capable of providing state-of-the-art therapy. Care of these patients is a relatively new concern, and their needs are met in various ways at the present time. The diagnosis of mitochondrial disease is often made after the child has been referred to a major medical center. Mitochondrial disease specialists may be found in metabolism or neurology departments of children’s hospitals, or in other specialty clinics. Many children are cared for by primary care pediatricians or specialists with expertise in the system affected, such as endocrinology, ophthalmology, or cardiology. Parents often must travel far from home to obtain care for the child, sometimes for extended periods of time. At the clinic visited by the children described in the case studies, the approach to care involves a centralized multidisciplinary team of physicians, nurses, nutritionists, psychologists, social workers, and therapists. The nurse plays a major role in the coordination of services, and guides families through what is initially perceived as an overwhelming maze. Parents often need help from the specialty clinic to obtain insurance approval for home care visits from nurses of health aides. The unpredictability of many mitochondrial diseases means that parents often have questions, and sometimes they need support and encouragement. Frequent telephone and e-mail communication with parents is an important part of nursing care. Finding competent care at a medical center is not the parents’ only concern. They must also find help in the community. The child’s special needs may severely impact many aspects of the parent’s lives, especially work and leisure time activities. They are often unable to find a daycare provider or babysitter who is able to administer medications or
MITOCHONDRIAL DISEASE
241
other treatments, or handle the child’s developmental delays. Frequently, families rely on family members to help with care, or, as in Annie’s case, establish strong ties with visiting nurses. In summary, scientists, clinicians, and parents are all in the learning phase with regard to mitochondrial disease. Although there may be some relief
associated with knowing the specific cause of a degenerative disease, it is only the first step. There remains much work to be performed to establish effective treatments. In the meantime, families affected by genetically transmitted disease can be well served through the holistic approach that is provided by nurses.
REFERENCES American Nurses Association. (1998). Statement on the scope and standards of genetics clinical practice. Washington, DC: author. Burton, B. (1998). Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics, 102(6), E69. Clarke, L. (1992). Mitochondrial disorders in pediatrics. Pediatric Clinics of North America, 39(2), 319-335. Cohen, B. (1997). Mitochondrial cytopathies. Disorders of oxidative phosphorylation and beta oxidation primer: Diagnosis and principles of management [on-line]. Available: http:// www.imdn.org/mitowhat.htm [1999, October 12]. Cox, C. (1982). An interaction model of client health behavior: Theoretical prescription for nursing. Advances in Nursing Science, 5, 41-56. Griggs, R., & Karpati, G. (1999). Muscle pain, fatigue, and mitochondriopathies. New England Journal of Medicine, 341(14), 1077-1078. Jorde, L., Carey, J., Bamshad, M., & White, R. (1999). Medical genetics (2nd ed.). St. Louis: Mosby. Kirby, D., Crawford, M., Cleary, M., Dahl, H., Dennett, X., & Thorburn, D. (1999). Respiratory chain complex I deficiency: An underdiagnosed energy generation disorder. Neurology, 52, 1255-1264.
McCloskey, J., & Bulechek, G. (1996). Nursing interventions classification (2nd ed.). St. Louis: Mosby. Naviaux, R.K., & Longenecker, A. (1997). The spectrum of mitochondrial disease. Exceptional Parent, 27, 40-43. Nishio, K. (1997). A family affected by mitochondrial encephalomyopathy: A nursing protocol. Clinical Nurse Specialist, 11(5), 195-202. Online Mendelian Inheritance in Man (OMIM). Available: http://www.ncbi.nlm.nih.gov/omim/ [September 17, 1999]. Read, C.Y. (2000). [Survey of parents of metabolic patients in New England]. Unpublished raw data. Rose, M. (1998). Mitochondrial myopathies. Archives of Neurology, 55, 17-24. Trachtenberg, S.W., & Batshaw, M. (1997). Caring and coping: The family of the child with disabilities. M. Batshaw (Ed.), Children with Disabilities (4th ed., pp. 743-756). Baltimore: Brookes Publishing Co. Varvogli, L., & Waisbren, S.E. (1999). Personality profiles of mothers of children with mitochondrial disorders. Journal of Inherited Metabolic Disease, 22, 615-622. Wallace, D. (1999). Mitochondrial diseases in man and mouse. Science, 283, 1482-1488.
Mitochondrial dysfunction is now recognized as a relatively common cause of degenerative disease in children. Mutations in either the mitochondrial or the nuclear genome that cause errors in the synthesis of enzymes essential for energy production and metabolism lead to a wide variety of pediatric problems, including developmental delays, sensorimotor impairment, seizures, diabetes, and organ failure. This article reviews the role of mitochondria in health and illness, discusses the clinical aspects of mitochondrial dysfunction, describes the experiences of three children with mitochondrial disease, and presents nursing strategies for affected families. Copyright r 2000 by W.B. Saunders Company
G
ENETIC CAUSES of mitochondrial dysfunction have recently been implicated in some previously unexplained degenerative conditions in children. Mitochondrial diseases can cause multiple disabilities that present in puzzling, atypical ways. Parents of children with mitochondrial disease must meet the complex physical and psychological needs of their children, often without the benefit of a definitive diagnosis. Nurses play an important role in the health care of the family of a child with a disability, which may be especially challenging in mitochondrial disease. It is essential for nurses to understand the role of mitochondria in health and illness, and to tailor interventions to meet the particular needs of affected families. This article presents the scientific basis for the care of children with mitochondrial disease, describes the experiences of three affected children, and suggests strategies for nursing care.
From the University of Massachusetts, Lowell, MA; and Children’s Hospital, Boston, MA. Support by the Leadership Education in Neurodevelopmental Disabilities (LEND) grant, awarded Institute for Community Inclusion, a University-Affıliated Program of Children’s Hospital, Boston, by Health Resources and Services Administration, U.S. Department of HHS, Maternal and Child Health Bureau (Grant No. MCJ-259150). Address reprint requests to Catherine Yetter Read, RN, MS, 22 University Avenue, Burlington, MA 01803. E-mail: [email protected] Copyright r 2000 by W.B. Saunders Company 0882-5963/00/1504-0006$10.00/0 doi:10.1053/jpdn.2000.8042
232
THE MITOCHONDRION The human body, like any machine, requires a source of energy and a way to convert that energy into work. This is accomplished in the mitochondria, the intracellular organelle where chemical energy from food is harvested through oxidative phosphorylation (OXPHOS) (Wallace, 1999). OXPHOS is an intricate chain of events that involves five multipolypeptide enzyme complexes. This process results in the production of adenosine triphosphate (ATP), the primary source of power for all body processes. Mitochondria also perform other functions, depending on the tissue location, including production of steroid hormones, manufacture of building blocks of DNA, and elimination of ammonia in the liver. Any disruption of mitochondrial function may lead to disease. Tissues that rely heavily on cellular energy production via OXPHOS are typically affected. Many of the mitochondrial disorders found in Table 1 involve alteration of these high-energy systems, including the brain, skeletal muscle, heart, and liver. MITOCHONDRIAL VERSUS NUCLEAR GENOME Disruption of mitochondrial function resulting in mitochondrial disease is caused by inherited or spontaneous mutations in either the mitochondrial or nuclear DNA. Advances in our understanding of mitochondrial genetics have resulted in the rejection of the notion that babies inherit exactly half of their DNA from the mother and half from the father. This principle only holds true for the double helical DNA found in the nucleus. Mitochondrial
Journal of Pediatric Nursing, Vol 15, No 4 (August), 2000
MITOCHONDRIAL DISEASE
233 Table 1. Clinical Synopsis of Mitochondrial Disorders Disease
MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes
MERRF: Myoclonic epilepsy associated with ragged-red fibers
NARP: Neuropathy, ataxia, and retinitis pigmentosa
KSS: Kearns-Sayre syndrome Pearson syndrome LHON: Leber’s hereditary optic neuropathy CPEO: chronic progressive external ophthalmoplegia Leigh syndrome (infantile necrotizing encephalopathy)
Wolfram syndrome
MNGIE: Myoneurogastrointestinal encephalopathy syndrome
Mitochondrial respiratory chain disorders: Named for the missing protein or protein complex, e.g., Complex I, II, III, IV, V, cytochrome oxidase deficiencies. There are over 100 proteins involved in the respiratory chain.
Miscellaneous: Fatty acid oxidation disorders, urea cycle defects, and other ‘‘inborn errors of metabolism’’
Clinical Synopsis
Headaches, seizures, stroke-like episodes, encephalopathy, muscle weakness, episodic vomiting, progressive bilateral sensorineural hearing loss, bilateral cataracts, cortical blindness. Laboratory studies reveal an elevated resting serum lactate, increased with exercise. RRF on muscle biopsy. Myoclonic epilepsy, ataxia, spasticity, muscle weakness, sensorineural hearing loss. Laboratory studies reveal elevations in serum pyruvate or pyruvate and lactate and RRF on muscle biopsy. Developmental delay, seizures, ataxia, sensory neuropathy, retinitis pigmentosa with loss of vision, muscle weakness. No consistent abnormal laboratory findings. Short stature, visual loss owing to paralysis of eye muscles and retinal degeneration, hearing loss, cardiomyopathy, diabetes, kidney failure. Severe anemia and pancreatic and liver dysfunction in children; may progress to KSS in adolescence. Permanent or temporary blindness stemming from damage to the optic nerve. Presents in adulthood. Usually presents in adolescence with eye muscle paralysis, drooping eyelids, muscle weakness, and fatigue. Progressive, unremitting degenerative disorder, usually appearing before the age of 2 years and fatal in less than 1 year. Weakness, hypotonia, tremor, ataxia, abnormal eye movements, blindness, respiratory difficulty, liver disease, hypertrophic cardiomyopathy. Laboratory tests reveal high blood pyruvate and lactate. Optic atrophy, sensorineural hearing loss, autonomic dysfunction, nystagmus, mental retardation, seizures, diabetes mellitus, diabetes insipidus, hydronephrosis, distended bladder, hematologic abnormalities. Diagnostic studies may reveal vasopressin deficiency and widespread atrophic brain changes on MRI. External ophthalmoplegia, malabsorption, intermittent diarrhea, chronic malnutrition, proximal limb weakness, muscle atrophy, polyneuropathy, encephalopathy, neurosensory hearing loss. Diagnostic studies may reveal lactic acidosis after moderate glucose loads, increased excretion of hydroxybutyric and fumaric acids, density of cerebral white matter on MRI, and ragged-red ocular and skeletal myopathy. Most mitochondrial diseases are the result of deficiencies in one or more of these respiratory chain proteins. At the present time, classification of mitochondrial disease is not standardized, and conditions may be named for the syndrome and/or the complex or enzyme deficiency. For example, many cases of Leigh disease are caused by Complex I deficiency, with either nuclear or mitochondrial DNA mutations (Kirby et al., 1999). Many conditions result from aberrant metabolism within the mitochondria; these are not universally classified as mitochondrial diseases. For example, medium-chain acyl CoA dehydrogenase deficiency (MCAD) causes nonketotic hypoglycemia or a Reye’s-like syndrome, and has been associated with sudden infant death syndrome (SIDS) (Burton, 1998).
NOTE. This is a partial listing of disorders that are associated with mitochondrial dysfunction. Most are associated with mutations in mtDNA, although some have been found to result from nuclear DNA mutations or other processes that impair mitochondrial function. There is also overlap among some of these conditions. (Compiled from Online Mendelian Inheritance in Man [OMIM] database, 1999; and Wallace, 1999.)
DNA (mtDNA), a circular molecule, is inherited exclusively from the egg of the mother. This is because mitochondria reside in the cytoplasm, which is stripped from the sperm cell before fertilization. Thus, men inherit their mtDNA from
their mother, but cannot pass it along to their offspring. Pedigree analysis may provide a clue that a particular disorder is the result of a mtDNA mutation, if transmission occurs exclusively from mother to child of either sex (Jorde, Carey, Bam-
234
shad, & White, 1999). Figure 1 depicts this maternal inheritance pattern. Mitochondrial disease is not limited to conditions inherited at birth. Much recent attention has been given to the role of mtDNA mutations in late onset conditions, such as Alzheimer’s disease, cancer, and Parkinsonism. It is well known that mtDNA has a mutation rate that is much higher than that of nuclear DNA, owing to poor mtDNA repair mechanisms and damage from free radicals released during OXPHOS (Jorde et al., 1999). The precise mechanisms of many common degenerative disorders, and perhaps even the aging process, are poorly understood at the present time, but many scientists believe that the explanations relate to mitochondrial dysfunction (Naviaux & Longenecker, 1997). Mitochondrial genome disorders display wide phenotypic variability. Identical twins with the same mtDNA mutation may have vastly different disease presentations, and different mtDNA mutations may produce similar disorders (Wallace, 1999). This unpredictability in the course of mito-
READ AND CALNAN
chondrial diseases can be partially explained by heteroplasmy, wherein a different proportion of mutant to normal (wild-type) mtDNA exists in each cell or tissue. As cells divide, the mutant and wild-type mtDNA are randomly distributed to the daughter cells, so the proportion of mutant to wild-type mtDNA may increase or decrease with each subsequent generation of the cell line. If that proportion increases past a certain threshold, the cellular energy capacity will decline, and symptoms appear. Thus, a twin who originally received a higher proportion of mutant mtDNA, experienced a spontaneous mtDNA mutation, or whose mutation became more abundant over time, may be affected with a mitochondrial disease that the other twin has escaped. Mitochondrial malfunction may also be caused by mutations in the DNA found in the 23 pairs of chromosomes in the cell nucleus. In fact, nuclear DNA encodes most of the proteins necessary for mitochondrial function (Jorde et al., 1999). Thus, the more familiar Mendelian inheritance patterns, such as autosomal recessive or X-linked, are also
Figure 1. Pedigree showing maternal inheritance, which is characteristic of mitochondrial DNA mutations. Note that only affected women can transmit the disease.
MITOCHONDRIAL DISEASE
found in families with mitochondrial disease. In addition, spontaneous mutations may occur in either nuclear or mitochondrial DNA. Thus, genetic counseling in mitochondrial disease is particularly challenging. Information about the recurrence risk is not always certain, and it is often impossible to predict disease severity, even after the risk is estimated. Because the study of diseases involving mitochondria is an emerging field, the terminology and classification system may cause confusion. Clinicians may label mitochondrial disease according to a name previously assigned to a syndrome, a general term for the type of disorder, or a biochemical defect. Thus, one child may correctly be said to have Leigh syndrome, mitochondrial encephalomyopathy, or Complex I deficiency. Some investigators adopt a broad definition of mitochondrial disease, and include any disorder that involves mitochondrial dysfunction (Naviaux & Longenecker, 1997). Others restrict the term mitochondrial disease to those conditions caused by mtDNA mutations (Jorde et al., 1999). In reality, there is complex interplay between mtDNA and nuclear DNA, and some conditions may be caused by mutations in either genome. Table 1 summarizes some of the conditions associated with mitochondrial dysfunction, regardless of specific cause. CLINICAL ASPECTS OF MITOCHONDRIAL DYSFUNCTION Mitochondrial disease, once considered rare, is now thought to account for a wide variety of degenerative conditions in both children and adults (Wallace, 1999). In fact, it is likely that there are many children with developmental delays, failure to thrive, seizures and other neurological disorders, or other unexplained health problems who actually have undiagnosed mitochondrial dysfunction. Incidence data are generally unavailable for mitochondrial diseases, but those patients that have been identified are considered to be ‘‘just the tip of the iceberg’’ (Naviaux & Longenecker, 1997, p. 42). Children with mitochondrial disease are typically normal at birth. The signs and symptoms often begin as mild developmental delays or subtle neurological signs not always associated with disease. However, mitochondrial disease should be suspected whenever signs and symptoms involve three or more organ systems, become worse in the presence of acute illness, or present in an atypical fashion. Other clues include muscle weakness, hypotonia, vital sign instability, sensorimotor impairment, feeding problems, and worsening of
235
symptoms when the child is dehydrated. Mitochondrial disease may initially present as a behavior problem, and some children experience sleep disorders owing to excessive daytime fatigue. Diagnosis of mitochondrial disease is particularly challenging owing to the variable and complex presentation and inheritance patterns, and the process may take months or even years. Blood or urine tests may reveal lactic acidosis, low carnitine levels, atypical amino acid profiles, or other abnormalities, but such results may be inconclusive. In many mitochondrial diseases, electron microscopy of a skeletal muscle biopsy stained with Gomori trichrome shows the presence of ragged red fibers (RRF), indicative of abnormal proliferation of mitochondria (Rose, 1998). Deficiencies in particular enzymes involved in OXPHOS may be detected through biochemical assays conducted on muscle biopsies or skin fibroblasts (Clarke, 1992). Nuclear magnetic resonance spectroscopy may show abnormalities of muscle tissue in mitochondrial disease, and this noninvasive test holds promise for faster diagnosis in the future (Griggs & Kaparti, 1999). If there is cardiac involvement, abnormalities may be noted on electrocardiography and echocardiography. Atrophy or calcification of the nervous system may be found with computed tomography (CT) scanning or magnetic resonance imaging (MRI). Cerebrospinal fluid elevations in protein or lactate may be found (Clarke, 1992). Finally, molecular genetic analysis of mitochondrial and nuclear DNA may pinpoint mutations associated with specific mitochondrial diseases. Clearly, the diagnostic evaluation of mitochondrial disease requires specialty care, at a center with access to laboratories that perform the required analyses. Unfortunately, these services are not widely available at the present time. Patients may be required to travel far from home to undergo tests, which may or may not ultimately reveal a specific diagnosis. Some parents prefer to forego muscle biopsies or other invasive tests, and opt for empirical treatment with dietary supplements and vitamins. These inconsistencies in patterns of care contribute to the difficulty in determining accurate estimates of the incidence of mitochondrial disease. There is no known cure for mitochondrial disease, but certain therapies may help alleviate symptoms or slow the disease progression. Small frequent meals and avoidance of fasting may provide significant benefit for some patients, whose metabolic processes are impaired by mitochondrial
236
dysfunction. Some physicians recommend manipulation of fat and carbohydrate intake, although this must be tailored to the needs of the individual patient. Vitamins and supplements that have been found to improve energy levels in some patients include CoQ10 (coenzyme Q10), levo-carnitine (Carnitor, Sigma-tau Pharmaceuticals, Inc., Gaithersburg, MD), thiamine (B1), riboflavin (B2), nicotinamide (B3), vitamin E, vitamin C, lipoic acid, selenium, and beta carotene. Some clinicians have also reported improvement with supplements of calcium, magnesium, phosphorus, vitamin K, succinate, and citrate. It is hypothesized that these substances act by enhancing enzyme function, leading to more efficient energy generation, or serve as antioxidants, which may slow the disease progression (Cohen, 1997). Some children with mitochondrial disease have experienced improvements in stamina and alertness after corticosteroid administration, but this is generally avoided owing to numerous undesirable side effects (Naviaux & Longenecker, 1997). Treatment of mitochondrial disease is best handled through a multidisciplinary approach. Movement, speech, and cognitive disorders should be addressed through early intervention programs with appropriate specialists. Families need guidance to help the child avoid stressors that may exacerbate symptoms, such as cold, heat, infection, lack of sleep, and inadequate intake of food and fluids. Physical and occupational therapists may supervise exercise programs to build muscle strength (Naviaux & Longenecker, 1997). Psychosocial support for the family of a child with mitochondrial disease is an essential aspect of care. There is some evidence that mothers of children with mitochondrial disorders suffer from psychological dysfunction. In one study (Varvogli & Waisbren, 1999), 56% of mothers of children with mitochondrial disease had scores in the pathological range on three or more scales on the Minnesota Multiphasic Personality Inventory (MMPI). The investigators are careful to point out that this result may be attributable to carrier status characteristics or situational anxiety and stress; nevertheless, there is an obvious need for support services for these mothers. As with other chronic illnesses, therapy for mitochondrial disease must be tailored to the needs of the individual patient and family. The following case studies exemplify the diverse and complex needs that result from mitochondrial dysfunction.
READ AND CALNAN
THREE CASES OF MITOCHONDRIAL DISEASE1 A Teenager With Kearns-Sayre Syndrome Mari’s mother sensed from the beginning that there was something wrong with her daughter. She was not growing as fast as her older sisters had, and she was constantly contracting colds and other illnesses that caused her a great deal of distress. The doctors at the health clinic were perplexed, but could offer little but reassurance that baby Mari’s health would improve as she got older. Around the age of three, Mari began to experience visual problems, which were linked to ophthalmoplegia and pigmentary retinopathy. A few years later, fainting spells led to the diagnosis of complete heart block, and Mari had a permanent pacemaker implanted. Her pediatrician detected short stature and thoracic kyphosis, and Mari continued to suffer exaggerated responses to viral illnesses. When she was 10 years old, Mari was referred to the mitochondrial disease clinic at a major medical center. A muscle biopsy showed RRF. The diagnosis of Kearns-Sayre syndrome (KSS) was confirmed by mitochondrial DNA analysis, which revealed a specific mtDNA mutation. This mutation often appears spontaneously, which explains why Mari’s mother and siblings were not affected. Mari’s mother was relieved to learn that there was an explanation for her daughter’s many problems, but now had to face the unpredictable nature of the disease progression. At the time of the diagnosis of KSS, Mari was enjoying school and play activities, despite mild diffuse hypotonia and occasional fatigue. She was started on carnitine, Coenzyme Q, and vitamin C, which sometimes improve symptoms of mitochondrial disease by enhancing transport of nutrients into mitochondria and speeding up the process of OXPHOS. Unfortunately, Mari did not respond to these medications, and her condition continued to worsen. She began to have trouble with her schoolwork, and she felt too weak to participate in gym activities. A hearing evaluation revealed that Mari was suffering from bilateral high frequency sensorineural hearing loss. The clinic nurse met with Mari’s teachers and the school nurse to explain KSS. Mari’s daily schedule was paced to optimize her energy, and she was allowed to take breaks with the nurse when she felt the need. With a new schedule, new hearing aids, and new glasses, Mari showed stable progress in school. 1The
names and details of these cases have been changed to protect confidentiality.
MITOCHONDRIAL DISEASE
When Mari missed her next clinic appointment, the clinic nurse called her home. Mari’s mother said that they just wanted to stay away from the hospital for awhile. They were tired of the long trip to their specialty clinic, as they had recently visited the cardiologist, the eye doctor, the hearing clinic, and the pediatrician. However, a few weeks later, Mari showed up in the mitochondrial clinic because she was experiencing difficulty walking and severe fatigue. Laboratory studies revealed hypoparathyroidism and lactic acidosis. Endocrinology was added to her list of specialty clinics, and a trial of dichloroacetate (DCA) was begun to combat lactic acidosis. Lactate, a byproduct of cellular metabolism that often builds up in mitochondrial disease, is thought to have harmful effects on the nervous system. Unfortunately, Mari suffered peripheral neuropathy from the DCA, so it had to be discontinued. Over the next few years, Mari’s condition progressed. She had to be hospitalized when she contracted strep throat to treat dehydration and metabolic acidosis. She developed diabetes, and she and her mother learned to give insulin injections and perform blood sugar checks twice a day. A CT scan showed white matter changes consistent with worsening mitochondrial disease. Now, at age 13, Mari uses a cane to walk, but continues to attend school, where she benefits from physical, occupational, and speech therapy. Her family lovingly cares for her, and faithfully brings her to her numerous appointments. They feel helpless, but pray that her condition will stabilize and that new treatments will be developed for KSS in the near future. A 5-Year-Old With Leigh Syndrome Concern for Annie’s health began before she was born, when intrauterine growth retardation (IUGR) was diagnosed via ultrasound. Her mother was mildly concerned, but her first child had also been on the small side and was now perfectly healthy. She experienced an uneventful labor and delivery at 38 weeks gestation, and Annie’s Apgar scores were 7 at 1 minute and 9 at 5 minutes. Everyone was pleased that Annie had arrived safely, even though she weighed slightly more than 5 pounds. Annie needed extra attention in the newborn nursery owing to feeding difficulties. She was discharged at the age 5 days, but continued to have a weak suck and to fall asleep during feedings. Her pediatrician noted a heart murmur, and an echocardiogram revealed small atrial and ventricular septal
237
defects. The cardiologist found no evidence of congestive heart failure that would explain Annie’s feeding difficulties and failure to thrive, and assured her parents that small septal defects usually close spontaneously. A gastroenterology work-up was negative, but Annie’s growth and development was clearly way behind schedule. At the age of 9 months, Annie became very hypotonic, and she made her first trip to the neurologist. The diagnostic tests were conclusive: Annie had a mitochondrial disease. Her cerebrospinal fluid and blood showed markedly elevated lactate levels, and an MRI showed abnormal white matter in her basal ganglia. A muscle biopsy showed changes consistent with a deficiency in Complex I of the respiratory chain. Nuclear DNA analysis later revealed a mutation associated with Leigh syndrome. Annie’s parents finally had an explanation for her problems, but with it came the sad news that her condition was going to deteriorate. In addition, they learned that Leigh syndrome is inherited. Although not definite, it appeared that Annie’s Leigh syndrome was transmitted in an autosomal recessive fashion. If so, both parents must be carriers, and there is a 25% chance that subsequent children will be affected. Annie’s parents were frustrated with the fact that the prognosis, though poor, is extremely unpredictable. Her mother told the clinic nurse that she thought she was going crazy, because she was constantly worrying about Annie’s every move. It was almost impossible to know what was significant and what was not. Annie had a gastrostomy tube at this point, so feedings and medications were easier to administer, but there were other worries now. Was that movement a seizure? Was Annie falling more than usual, or was she just tired? Should her sister be allowed to invite friends over and add to the risk that Annie would catch a virus that she could not handle? Annie’s mother came to rely on the support offered by visiting nurses. She appreciated the time they spent just listening, and their objective assessments of signs and symptoms. When Annie’s mother correctly suspected nighttime apnea, the nurses intervened to get a monitor. They helped her through the maze of paperwork required to get the health maintenance organization (HMO) to pay for Coenzyme Q and vitamin C. Although these substances may be the only hope for boosting energy in mitochondrial disease, many third-party payers regard them as optional dietary supplements because they are available in health food stores.
238
Now, at age 5, Annie is a beautiful little girl with a progressive degenerative disease. She has developed autonomic dysfunction resulting in periods of hypotension, bradycardia, and apnea. She is still able to eat certain foods in addition to her nighttime gastrostomy tube feedings, but she chokes frequently. She has a noticeable tremor, and wears a helmet because of her frequent falls, hypotonia, and seizures. Her eyesight is failing, and her intellectual development is slow. An individualized education plan that provides physical, occupational, and speech therapies at school, along with the support of the school nurse, has enabled Annie to begin kindergarten. At the present time, Annie’s parents lives revolve around her care, but they are thankful for each day they have with her. A Young Adult With Suspected Wolfram Syndrome Allen is a proud young man who, like most 22-year-olds, is trying to make it on his own. Despite a lifetime of medical and developmental problems, and strained relations with his parents, he has managed to get his own apartment and get by on his monthly disability checks. Allen’s history is unclear because it is limited to what he recalls or can be found in his thick medical record. He knows that his mother is an insulin-dependent diabetic who suffered several miscarriages, and her sister is mentally retarded. Allen’s father and his side of the family are healthy. It appears that Allen was a healthy baby until he was diagnosed with insulindependent diabetes mellitus (IDDM) at the age of 2. For many years, poor diabetic control was blamed for Allen’s many problems, including generalized tonic-clonic seizures, poor eyesight, developmental delays, and learning disabilities. But when an ophthalmology examination revealed optic nerve hypoplasia instead of diabetic retinopathy, suspicions were raised about the true nature of Allen’s condition. He was referred to the mitochondrial clinic, where the search began for an underlying genetic cause for his multiple problems. A careful history and physical examination generated additional information consistent with a diagnosis of mitochondrial disease. Allen admitted to tiring very easily and having difficulty tolerating extremes of temperature, especially very hot weather. A cardiac work-up revealed mild cardiomyopathy with left ventricular hypertrophy, although Allen denied any symptoms related to heart problems. Autonomic testing indicated that Allen had early vagal neuropathy with a resting tachycardia. A skeletal muscle biopsy confirmed mitochondrial
READ AND CALNAN
pathology. A tentative diagnosis of Wolfram syndrome was made, even though the clinical picture differed somewhat from other patients. Wolfram syndrome can result from mutations in either the nuclear or mitochondrial genome (OMIM, 1999), but Allen’s DNA analysis indicated that his disease was caused by a mitochondrial DNA deletion. As a man, Allen is not at risk for transmitting the disease to his children because this is an example of mitochondrial inheritance. With this definitive diagnosis, Allen’s care could now be centralized in the mitochondrial clinic, where the initial challenge was to establish trusting relationships between Allen and the staff. It was important to Allen that he be treated as an adult, and he refused to involve his parents in his care. However, his frequent emergency admissions for the treatment of hypoglycemia indicated that he needed more careful supervision. His complex multisystemic needs exemplify the nursing care challenges of mitochondrial disease. Because of his learning disabilities, Allen had trouble budgeting his limited income and feeding himself a balanced diabetic diet. Visiting nurses helped him to organize his kitchen and structure his routine to maintain better control of his blood sugar. Grocery store gift certificates were obtained that the nurses could give to Allen when he ran out of money for food at the end of the month. Daily doses of Coenzyme Q improved Allen’s energy level, and his vision improved with a new eyeglass prescription. Allen’s diabetes and seizure disorder stabilized. Allen has benefited from the knowledge that there is an underlying cause for his problems. He no longer suffers from the guilt imposed by practitioners who blamed him for problems thought to be related to poor glucose control. He makes frequent visits to the clinic, where a unified health team helps him to cope with his situation and feel better about himself. He understands that his prognosis is uncertain, but strives for quality of life through maintenance of healthy habits. NURSING STRATEGIES IN MITOCHONDRIAL DISEASE Nurses who care for children with mitochondrial diseases are part of the expanding field of genetic nursing, a holistic practice that includes assessment, planning, implementing, and evaluating the physical and psychosocial needs of patients and families with genetic concerns (American Nurses Association, 1998). McCloskey and Bulechek (1996) define genetic counseling as a nursing
MITOCHONDRIAL DISEASE
intervention that uses ‘‘an interactive helping process focusing on the prevention of a genetic disorder or the ability to cope with a family member who has a genetic disorder’’ (p. 300). Because of the extreme variability in all aspects of mitochondrial disease, nurses must tailor interventions to meet the expressed needs of the child and family, given their particular situation. Nursing care consists of four interacting elements of the client-professional relationship (Cox, 1982): provision of information, affective support, decisional control, and professional-technical competencies. Provision of Information Information forms the basis of parents’ coping strategies, but there may be several barriers to knowledge development in mitochondrial disease. Most children develop signs and symptoms very gradually, and it often takes months or years to establish a diagnosis. Even when a definitive diagnosis is made, there is often no way to predict the course of the disease in any particular child. Nurses and other providers are still learning about this new class of diseases, and the scientific explanations, when known, can be complicated. Health care professionals serve as the most common source of information for parents, at least initially. Later, parents may turn to reference books, journals, and information available on the Internet. (See Table 2 for a list of resources related to mitochondrial disease.) Nurses often find themselves helping parents interpret information acquired from other places. Although the internet is a Table 2. Resources Related to Mitochondrial Disease United Mitochondrial Disease Foundation
P.O. Box 1151, Monroeville, PA 15146-1151; phone (412) 793-8077; http://www. umdf.org National Institutes of Health Federal Building, Room 618, (NIH) Office of Rare Diseases 7550 Wisconsin Avenue, Bethesda, MD 20892-9120; phone (301) 402-4336; http://rarediseases.info. nih.gov/ord March of Dimes Birth Defect 1275 Mamaronek Ave., White Foundation—Resource Center Plains, NY 10605; phone (888) 663-4637; http://www. modimes.org Mitochondrial and metabolic Sigma-tau Pharmaceuticals, Inc., disorders: A parent’s guide. 800 S. Frederick Avenue, Suite 300, Gaithersburg, MD 20877. Also appeared as a three-part educational series in Exceptional Parent magazine, June, July, and August 1997.
239
rich source of information and networking for parents, they often need assistance to understand terminology or determine what is applicable to their child’s condition. In some cases, nurses must provide printed material for parents who do not have access to these resources. An important responsibility of a nurse with expertise in mitochondrial disease is to educate other professionals. Mari and Annie, described earlier, both benefited from the mitochondrial clinic nurse’s visits with school personnel. Their extreme fatigue related to mitochondrial dysfunction could be managed effectively with moderate limitations of physical activity. In Allen’s case, the visiting nurses needed to be educated about the relationship of diabetes to mitochondrial pathology, so that they could better understand the complexity of his disease. It is also necessary to educate third-party payers about the special needs of children with mitochondrial disease to obtain reimbursement for medications, monitors, or home care. Parents often ask nurses for information about whether or not treatments are working. This is often difficult to determine. Although certain treatments produce an immediate beneficial effect, others may take months. In some cases, the treatment effect may never be noticeable, yet it may delay or stop the progression of the disease (Cohen, 1997). Other parents, like Annie’s, turn to nurses for help deciding whether signs and symptoms signify disease progression or require medical treatment. Parents of children with genetically transmitted diseases are especially concerned about recurrence risk in future pregnancies. Such information is particularly difficult to estimate in mitochondrial disease. Prenatal diagnosis for mitochondrial disease is limited at the present time, and is hindered by the inability to predict accurately the clinical severity expected, even if a specific mutation is present in fetal tissue. Many parents of severely affected children simply choose not to risk another pregnancy (Read, 2000). Affective Support Affective support refers to the interpretation of and therapeutic response to an individual’s emotional needs. It is comprised of components considered central to the nurse-patient relationship, such as active listening, verbal reassurance, therapeutic touch, empathy, advocacy, and nonverbal communication. Parent emotional responses to having a child with a disability vary tremendously over time, and may include shock, disbelief, guilt, denial, and an overwhelming sense of loss. Relatives and
240
friends may be unable to provide needed support if they are having difficulty accepting the diagnosis, blame one of the parents, or just feel uncomfortable because they do not know what to say (Trachtenberg & Batshaw, 1997). For parents of children with mitochondrial disease, the nurse may become a primary provider of affective support. Mitochondrial disease is a challenge to practitioners, and parents have expressed frustrations about lack of caring (Nishio, 1997). In the early phase, before the actual diagnosis, failure to acknowledge concerns about subtle delays or problems implies that the professional believes that the parent is imagining things. Later, when the diagnosis is known and the child’s condition deteriorates, professionals may distance themselves from a parent who is perceived as demanding. The parent is constantly trying to reconcile the need for assistance from health care providers with the feeling that others cannot give the same quality of care. The nurse must continually reassess the family’s coping skills and strategies, and tailor counseling and interventions appropriately. For some families, spirituality is a primary source of strength; for others, networking with other families facing similar conditions provides the greatest comfort. Decisional Control A parent’s need or desire for control in decisions related to their child’s health is impacted by several things, including the age of the child, the nature of the disease, previous experiences, psychosocial factors, and involvement of significant others. Health care providers should offer the parent maximal decisional control, after careful assessment of individual strengths and limitations. The overall approach to the family should be one of empowerment (Trachtenberg & Batshaw, 1997). The parents of a newborn with significant but undiagnosed health problems may be very comfortable relinquishing decisional control to health professionals because they feel helpless, uninformed, and overwhelmed by their new responsibilities. On the other end of the spectrum, the parents of an older child may have spent years educating themselves about their child’s mitochondrial diagnosis. They are often well equipped to share decisions with the health team, and are certainly more capable of making decisions about their child than others in the community. Parents of children with mitochondrial disease are accustomed to dealing with professionals who
READ AND CALNAN
lack knowledge about their child’s specific condition, especially outside of the mitochondrial disease specialty center. Providers must be sensitive to the knowledge level of the parent, and acknowledge their own inadequacies. Information is more readily available than ever, thanks to the internet. Professionals must be able to access these resources, evaluate the quality of the information, and discuss the implications with the parent. Shared decision making between the parent and professional leads to a balance between parent empowerment and provider support. Professional-Technical Competencies Parents of children with mitochondrial disease, like all parents of sick or disabled children, need health professionals who are capable of providing state-of-the-art therapy. Care of these patients is a relatively new concern, and their needs are met in various ways at the present time. The diagnosis of mitochondrial disease is often made after the child has been referred to a major medical center. Mitochondrial disease specialists may be found in metabolism or neurology departments of children’s hospitals, or in other specialty clinics. Many children are cared for by primary care pediatricians or specialists with expertise in the system affected, such as endocrinology, ophthalmology, or cardiology. Parents often must travel far from home to obtain care for the child, sometimes for extended periods of time. At the clinic visited by the children described in the case studies, the approach to care involves a centralized multidisciplinary team of physicians, nurses, nutritionists, psychologists, social workers, and therapists. The nurse plays a major role in the coordination of services, and guides families through what is initially perceived as an overwhelming maze. Parents often need help from the specialty clinic to obtain insurance approval for home care visits from nurses of health aides. The unpredictability of many mitochondrial diseases means that parents often have questions, and sometimes they need support and encouragement. Frequent telephone and e-mail communication with parents is an important part of nursing care. Finding competent care at a medical center is not the parents’ only concern. They must also find help in the community. The child’s special needs may severely impact many aspects of the parent’s lives, especially work and leisure time activities. They are often unable to find a daycare provider or babysitter who is able to administer medications or
MITOCHONDRIAL DISEASE
241
other treatments, or handle the child’s developmental delays. Frequently, families rely on family members to help with care, or, as in Annie’s case, establish strong ties with visiting nurses. In summary, scientists, clinicians, and parents are all in the learning phase with regard to mitochondrial disease. Although there may be some relief
associated with knowing the specific cause of a degenerative disease, it is only the first step. There remains much work to be performed to establish effective treatments. In the meantime, families affected by genetically transmitted disease can be well served through the holistic approach that is provided by nurses.
REFERENCES American Nurses Association. (1998). Statement on the scope and standards of genetics clinical practice. Washington, DC: author. Burton, B. (1998). Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics, 102(6), E69. Clarke, L. (1992). Mitochondrial disorders in pediatrics. Pediatric Clinics of North America, 39(2), 319-335. Cohen, B. (1997). Mitochondrial cytopathies. Disorders of oxidative phosphorylation and beta oxidation primer: Diagnosis and principles of management [on-line]. Available: http:// www.imdn.org/mitowhat.htm [1999, October 12]. Cox, C. (1982). An interaction model of client health behavior: Theoretical prescription for nursing. Advances in Nursing Science, 5, 41-56. Griggs, R., & Karpati, G. (1999). Muscle pain, fatigue, and mitochondriopathies. New England Journal of Medicine, 341(14), 1077-1078. Jorde, L., Carey, J., Bamshad, M., & White, R. (1999). Medical genetics (2nd ed.). St. Louis: Mosby. Kirby, D., Crawford, M., Cleary, M., Dahl, H., Dennett, X., & Thorburn, D. (1999). Respiratory chain complex I deficiency: An underdiagnosed energy generation disorder. Neurology, 52, 1255-1264.
McCloskey, J., & Bulechek, G. (1996). Nursing interventions classification (2nd ed.). St. Louis: Mosby. Naviaux, R.K., & Longenecker, A. (1997). The spectrum of mitochondrial disease. Exceptional Parent, 27, 40-43. Nishio, K. (1997). A family affected by mitochondrial encephalomyopathy: A nursing protocol. Clinical Nurse Specialist, 11(5), 195-202. Online Mendelian Inheritance in Man (OMIM). Available: http://www.ncbi.nlm.nih.gov/omim/ [September 17, 1999]. Read, C.Y. (2000). [Survey of parents of metabolic patients in New England]. Unpublished raw data. Rose, M. (1998). Mitochondrial myopathies. Archives of Neurology, 55, 17-24. Trachtenberg, S.W., & Batshaw, M. (1997). Caring and coping: The family of the child with disabilities. M. Batshaw (Ed.), Children with Disabilities (4th ed., pp. 743-756). Baltimore: Brookes Publishing Co. Varvogli, L., & Waisbren, S.E. (1999). Personality profiles of mothers of children with mitochondrial disorders. Journal of Inherited Metabolic Disease, 22, 615-622. Wallace, D. (1999). Mitochondrial diseases in man and mouse. Science, 283, 1482-1488.