Abstract
Friedreich ataxia is a neurodegenerative disease characterized by gait abnormalities, cardiomyopathy, and diabetes. Congestive heart failure was recently reported as the most frequent cause of Friedreich ataxia mortality. Cardiac dysfunction is suspected to result from a frataxin deficiency that leads to oxidative damage in cardiac tissues and possible metabolic syndrome characteristics. In this report, we describe 2 patient cases whose cardiac function worsened dramatically in the presence of underlying endocrinopathies. We report on one Friedreich ataxia teenager with previously undiagnosed diabetes that resulted in diabetic ketoacidosis and rapid progression to severe left ventricular dysfunction. We also describe a Friedreich ataxia teenager whose underlying Graves disease led to rapid worsening of known cardiomyopathy. Cardiac management and treatment for the endocrinopathies returned cardiac function to baseline. We conclude that screening for and awareness of underlying endocrinopathies in Friedreich ataxia may provide novel therapeutic targets for preventing Friedreich ataxia–associated cardiac dysfunction.
Friedreich ataxia is an autosomal recessive, progressive, neurodegenerative disorder that typically affects young adults, resulting in speech, balance, and gait difficulties. In 97% of patients, the disease is caused by a homozygous expansion of a guanine-adenine-adenine trinucleotide repeat on chromosome 9q13, causing a reduction in frataxin, a mitochondrial protein. 1,2 Approximately 10% of Friedreich ataxia patients develop diabetes mellitus, and at least 20% of patients have carbohydrate intolerance. 2 –4 Cardiac dysfunction affects almost all Friedreich ataxia patients to some degree, leading to shortened life expectancy. 5 –7 One clinical and electrocardiographic study of 115 Friedreich ataxia patients found that 90% of patients had an abnormal electrocardiogram. 5 Another retrospective study found that cardiac dysfunction due to congestive heart failure and arrhythmias was the most frequent cause of death in Friedreich ataxia patients. 8
In this report, we discuss 2 Friedreich ataxia patients whose cardiac function decompensated in the setting of endocrinopathies. We first describe the effects of previously undiagnosed diabetes in a teenager with Friedreich ataxia that resulted in diabetic ketoacidosis, atrial fibrillation, and severe left ventricular dysfunction. Aggressive cardiac medical management and insulin treatment reversed the patient’s cardiac ejection fraction back to his baseline measurements. The second patient is a teenager with Friedreich ataxia whose undiagnosed Graves disease resulted in significant worsening of his cardiomyopathy. Treatment for hyperthyroidism normalized the patient’s echocardiograms and electrocardiograms.
Case 1
The first patient is an 18-year-old man who developed imbalance and gait dysfunction at age 12 years and was subsequently diagnosed with Friedreich ataxia (guanine-adenine-adenine repeats of 1180 and 987). The patient had been asymptomatic for cardiac disease until age 18 years. At age 16 years, his echocardiogram showed an interventricular septal thickness of 10 mm (normal indexed by body surface area <6.9 mm/m2; <10.5 mm) and a cardiac ejection fraction of 55% (normal 50%-70%), and a repeat echocardiogram 1 year later showed an increase in septal thickness to 13.4 mm with an unchanged ejection fraction. Electrocardiograms performed at these times also showed only nonspecific T-wave inversions. The patient developed an episode of paroxysmal atrial fibrillation shortly after his 18th birthday, and he was placed on atenolol 25 mg daily with good rate control. Routine yearly laboratories were normal, including fasting blood glucose levels, thyroid function tests, metabolic panels, and complete blood counts.
The patient presented to an academic movement disorders center for a routine visit in March 2010, at age 18 years. His body surface area at that time was 1.5 mm/m2. He reported increasing difficulty with performing fine motor tasks, but denied any cardiac symptoms, polydipsia, or polyuria. His physical examination was unremarkable. A fasting blood glucose taken soon after this visit was 98 mg/dL. An echocardiogram performed at this time showed trace mitral regurgitation, interventricular septal thickness of 13.4 mm, and left ventricular posterior wall measurement of 12.7 mm (normal indexed by body surface area <6.2 mm/m2; <9.3 mm), with mild to moderate left ventricular hypertrophy and mild left ventricular dilation. The ejection fraction was 55%.
In August 2010, the patient developed mild upper respiratory symptoms for 3 to 4 days. He gradually became lethargic and listless throughout the week and was brought to the emergency room where his pulse was 162 and his respiratory rate was 23. He had bilateral rales, and his chest radiograph showed bilateral pleural effusions. He had a blood glucose level of 600 mg/dL and severe ketoacidosis, with an arterial CO2 of 23.5. An electrocardiogram showed atrial fibrillation, and an echocardiogram revealed a left ventricular ejection fraction of 20% to 25%, with moderate concentric left ventricular hypertrophy and severe global hypokinesis.
The patient was transported to a cardiac intensive care unit, where he was treated with continuous intravenous insulin, Cardizem, digoxin, metoprolol, and antibiotics, including Rocephin, and Levaquin, 500 mg intravenous daily. Blood cultures were negative. Serum glucose levels, white blood cell count, arterial blood gas, and chest radiograph gradually reverted to normal. His heart rate also returned to baseline within 24 hours, and his ejection fraction improved. He became alert and talkative. The patient was discharged home after 10 days, and remains on daily insulin, digoxin, and metoprolol.
One month after hospitalization, a repeat echocardiogram demonstrated a cardiac ejection fraction of 57%; his pulse was normal. He was asymptomatic for respiratory or cardiac disease. Blood glucose levels range from 120 to 250 mg/dL on daily insulin.
Case 2
A 16-year-old individual was diagnosed with Friedreich ataxia in 2005 at the age of 10 years (guanine-adenine-adenine repeat lengths of 857 and 1041). After being noted to have an abnormal gait at age 6 years, he developed hypertrophic cardiomyopathy and severe scoliosis. An echocardiogram in March 2008 showed a shortening fraction of approximately 36% (normal 20%-44%), and stable left ventricular hypertrophy. In August 2008 (age 13 years), he began to experience rapid weight loss and weakness, and in October 2008 and November 2008 was admitted to the hospital for 2 episodes of emesis, hypovolemia, and altered mental status. An echocardiogram between these episodes showed a shortening fraction of 34.4%. After being treated with rehydration each time, he returned to baseline.
In February 2009, he developed mild tachycardia, chorea, and additional weight loss. He was admitted to the hospital 1 week later after also developing emesis, hypotension, tachypnea, and multisystem organ failure. He was diagnosed with Graves disease March 5, 2009: thyroid-stimulating hormone 0.007 (normal 0.5-3.8 μIU/mL), free T4 5.1 (normal 1.1-2.1), thyroxine 15.3 (normal 4.7-9.9), thyroid-stimulating hormone receptor antibody 5.2 (normal <1.5). An echocardiogram from this time showed a shortening fraction of 15.7%, at one point dropping to below 10%. He also had moderate to severely decreased global systolic functioning, abnormal wall motion, and resultant congestive heart failure. Plasma troponin I levels were as high as 13 (normal <0.4). He was treated with ionotropic agents and afterload reduction, and became dependent on a ventilator and a G tube. He was started on methimazole. Two months later, a follow-up echocardiogram revealed a shortening fraction of 39.3%. Present echocardiograms and electrocardiograms show a full return to normal with the exception of a prolonged QTc.
Discussion
In the 2 Friedreich ataxia patients described above, cardiac function worsened dramatically in the presence of underlying endocrinopathies, but then quickly improved with appropriate management of both the cardiac and endocrine abnormalities. The first patient, despite routine fasting blood glucose levels drawn throughout his life, most likely developed acute diabetic ketoacidosis in association with a viral illness, which in turn triggered left ventricular systolic dysfunction and atrial fibrillation. The second patient developed significant worsening in the presence of known cardiomyopathy following a worsening of undiagnosed Graves disease. The cases illustrate the extreme degree to which cardiac function can decompensate in Friedreich ataxia in the setting of underlying endocrinopathies. Graves disease and diabetes have coexisted in another reported patient with Friedreich ataxia. In that patient, combined treatment of diabetes and hyperthyroidism was initiated and prevented any worsening of underlying cardiomyopathy. 9
Hypertrophic cardiomyopathy is commonly associated with Friedreich ataxia and is reportedly seen in more than 60% of Friedreich ataxia subjects. Additional cardiac manifestations of Friedreich ataxia include arrhythmia and dilated cardiomyopathy (ejection fraction <40%). 8,10 Cardiac dysfunction remains the most frequent cause of death in Friedreich ataxia patients, with dilated cardiomyopathy and arrhythmias most commonly associated with mortality in Friedreich ataxia. Correlations between guanine-adenine-adenine repeat length and severity of cardiomyopathy in Friedreich ataxia have been inconsistent, most likely because of the limited sensitivity of echocardiography and small patient cohort size in these studies. 8,11,12
The development of cardiac symptoms in Friedreich ataxia is suspected to be the result of decreased frataxin levels, possibly leading to increased sensitivity to oxidative stress in cardiac tissues as a result of mitochondrial dysfunction. Although the exact progression of cardiac dysfunction in Friedreich ataxia remains unclear, Raman et al identified abnormal myocardial perfusion reserve and fibrosis as early manifestations in Friedreich ataxia–associated cardiomyopathy. These characteristics were also evident before significant hypertrophy and cardiac failure in a cohort of 26 patients. Additionally, myocardial perfusion reserve in these patients was associated with significant lipid abnormalities, leading to the assumption that metabolic syndrome characteristics induced by frataxin deficiency arise from beta-cell death, decreased insulin levels, and skeletal muscle lipogenesis, thus promoting cardiac abnormalities. 13
The rapid progression of cardiac symptoms in other endocrinopathy-associated disorders has been noted in case studies. These disorders, like Friedreich ataxia, can exhibit mitochondrial dysfunction, leading to oxidative stress in cardiac and muscle tissue, which presumably promotes cardiac abnormalities and associated endocrinopathies. 14 –16 In a case report of a 54-year-old patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and associated mitochondrial diabetes, the patient developed hypertrophic cardiomyopathy that rapidly progressed to dilated left ventricular hypertrophy. 14 A 45-year-old woman with maternally inherited diabetes and deafness was reported to experience rapid progression of cardiac dysfunction, in which left ventricular hypertrophy transitioned to hypokinetic cardiomyopathy over a 10-month period, leading to congestive heart failure. 15 A study of 44 patients with lipodystrophy concluded that hypertrophic cardiomyopathy is commonly associated with this disease, and that this cardiac symptom may be due to severe insulin resistance associated with lipodystrophy or a proposed “lipotoxic cardiomyopathy” that results from an accumulation of triglycerides in cardiac tissue. 16
Although the incidence of diabetes mellitus and carbohydrate intolerance in Friedreich ataxia has been estimated as 10% to 20%, Graves disease is not known to be associated with Friedreich ataxia. 2 –4,9 Review of the literature reveals only the single case report mentioned earlier, in which a Friedreich ataxia patient presented with both diabetes and hyperthyroidism, and whose underlying cardiomyopathy was controlled on treatment of both endocrinopathies. 9 Whether endocrinopathy is the sole pathologic cause for the reversible cardiac dysfunction in the 2 cases we report on remains uncertain; however, they demonstrate the importance of screening for and awareness of underlying endocrinopathies in Friedreich ataxia patients, because metabolic and endocrine dysfunction have been described as triggers of rapid progression of cardiac dysfunction in a number of metabolic disorders. Further investigation of endocrinopathies in Friedreich ataxia may provide novel therapeutic targets for preventing severe Friedreich ataxia–associated cardiomyopathy.
Footnotes
Acknowledgments
The authors thank the University of South Florida Ataxia Research Center, Tampa, Florida, and the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
Author Contributions
MS drafted parts of the manuscript and provided critical review. AR drafted parts of the manuscript. LS and DRL drafted parts of the manuscript, analyzed data of the subjects, and provided critical review. TAZ analyzed data of the subjects and provided critical review.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Participation of authors and production of this manuscript was supported by a grant from the Friedreich’s Ataxia Research Alliance for an ongoing natural history study in Friedreich ataxia.
Ethical Approval
Data on patients was collected as part of an ongoing natural history study of Friedreich ataxia, and approved by the Children’s Hospital of Philadelphia and University of South Florida College of Medicine Institutional Review Boards. Both subjects in this report provided written informed consent for inclusion in the study.