A novel mitochondrial DNA deletion in a patient with Kearns-Sayre syndrome: a late-onset of the fatal cardiac conduction deficit and cardiomyopathy accompanying long-term rGH treatment
© Obara-Moszynska et al.; licensee BioMed Central Ltd. 2013
Received: 20 August 2012
Accepted: 12 February 2013
Published: 20 February 2013
Kearns-Sayre Syndrome (KSS) is a multisystem disorder caused by a dysfunction of the oxidative phosphorylation system within mitochondria. Mitochondrial DNA (mtDNA) rearrangements are a key molecular feature of this disease, which manifest a broad phenotypic spectrum.
Here, we present a boy with KSS whose symptoms included cardiac conduction deficit, cardiomyopathy and growth hormone (GH) deficiency. The patient showed typical symptoms for KSS from early childhood (chronic progressive external ophthalmoplegia, retinopathy, short stature). Long-range PCR analysis disclosed a 7663-base pair heteroplasmic deletion in the mtDNA encompassing nucleotides 6340–14003. At 12 years of age, GH deficiency was recognized and recombinant growth hormone (rGH) therapy was started. At 15 years of age, a complete atrioventicular block was diagnosed and the patient received a pacemaker. During the following 6 months, progressive deterioration of the left ventricle was observed and an echocardiogram showed features of dilated cardiomyopathy. The rGH treatment was then discontinued at a final height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years.
The response to rGH therapy in the patient was very satisfactory. The large mtDNA deletion had no apparent impact on the response to rGH. Cardiac disturbances occurred as part of the syndrome and were not related to rGH therapy; however, the progression of the disease led to death.
KeywordsGrowth hormone treatment Mitochondrial disease Atrio-ventricular block Cardiomyopathy Short stature
Kearns-Sayre Syndrome (KSS) is a rare metabolic disorder which belongs to the group of mitochondrial cytopathies . The diagnosis of KSS is made based on the classic triad of symptoms: onset of the disease before 20 years of age, progressive external ophthalmoplegia (PEO) and pigmentary retinopathy (PR) . KSS is manifested also by other systemic abnormalities: cardiac conduction defects, different neurological abnormalities and several endocrine disorders . Progression of the clinical symptoms in KSS usually lead to death before the age of 30. Spontaneous mitochondrial DNA (mtDNA) rearrangements underlie this disease. A variety of deletions and/or duplications in mtDNA, affecting genes encoding respiratory chain proteins, are found in most cases [4–6]. This leads to defects in energy production by mitochondria and dysfunction of many tissues. This is particularly noticeable in tissues with a high energy demand - like muscles and the brain. The mutated mtDNA coexists with normal molecules (heteroplasmy) and the proportion of mutated to normal mtDNA correlates with the severity of clinical symptoms. There is no effective treatment for KSS and the complicated character of clinical features can impede the establishment of the correct diagnosis .
In this report we present the comprehensive clinical diagnosis of KSS in a young male. The patient was initially hospitalized based on neurological symptoms, followed by a diagnosis of his endocrinopathies. The most serious features of the disease - a cardiac conduction deficit and cardiomyopathy developed some years later. The final diagnosis was made several years after the first symptoms appeared, and was established using molecular biology techniques.
The presented patient is an 18-year-old boy with Kearns-Sayre Syndrome coexisting with GH deficiency, complicated by a cardiac conduction deficit and cardiomyopathy.
At the age of 11, he was admitted to the neurology clinic. An electromyogram (EMG) was performed and revealed a myogenic pattern. A magnetic resonance imaging (MRI) of the head showed hypoplasia of the pituitary gland. Examination of cerebrospinal fluid, auditory evoked potentials of the brainstem and electroencephalogram (EEG) were all normal. Psychological examination identified an IQ at average level. The genetic analysis showed a normal male (46,XY) karyotype.
Due to the clinical picture (CPEO, PR) and EMG examination the diagnosis of Kearns-Sayre Syndrome (KSS) was proposed.
Selected parameters during rGH therapy
Bone age [G&P] [years]
Height velocity [cm/year]
Predicted adult height based on Bayley-Pinneau method [cm]
rGH Dose [mg/kg/24 h]
the beginning of rGH therapy
after 6 months of rGH therapy
after 12 months of rGH therapy
after 2 years of rGH therapy
after 3 years of rGH therapy
after 4 years of rGH therapy
after 5 years of rGH therapy
Discontinuation of treatment
The onset of puberty was spontaneous and initiated at 12 years and 3 months of age.
Levels of hormones and other biochemical parameters in blood samples ( abnormal values are given in bold )
max GH (after clonidine) (ng/ml)
max GH (after insulin) (ng/ml)
Total protein (g/dl)
Further analysis revealed hyposecretion of insulin and an elevated blood glucose in oral glucose tolerance test (OGTT), glutamic acid decarboxylase (GAD), anti-insulin (IAA) and insulinoma antigen 2 (IA2) antibodies were all tested and were negative. Long acting insulin therapy was started and rGH dose was reduced. The glucose concentration then normalized. Insulin-like growth factor 1 (IGF-1) levels during rGH administration were within the normal range, however, usually higher than the mean expected for age and sex. Levels of hormones and other biochemical parameters in blood samples are shown in Table 2.
During the next 6 months, a progressive deterioration of the left ventricle was observed. In the performed echocardiogram, features of dilated cardiomyopathy were revealed. The picture of the heart suggested left ventricle noncompaction (LVNC), which is a congenital genetic developmental defect of heart muscle. At that time the boy had an implanted cardioverter – defibrillator with resynchronising stimulation. The prognosis was at that time also uncertain.
At the age of 17, the rGH therapy was discontinued due to a deceleration of height velocity - with a final obtained height of 163 cm. Unfortunately, due to multi-organ insufficiency and inflammation, the patient died at the age of 18 years.
Quantitative analysis of the heteroplasmy level was performed by Real-Time PCR technique. 20 ng of total DNA was analyzed using QuantiTect SYBR Green PCR Kit (Qiagen) on a Mastercycler ep realplex machine (Eppendorf) and four specially designed primer sets. All reactions were done in triplicate. Melting curve analysis was added at the end of all reactions. Relative expression ratios of mtDNA levels were calculated using the ΔCT method. As a control of the total mtDNA level, we analyzed the DNA of five healthy individuals, using the same primers as for the patient. Amplification results were presented as a relative expression towards the expression level of a housekeeping, nuclear gene - GAPDH. The results of this analysis revealed that the total level of mtDNA in the patient’s blood was comparable to the normal mtDNA level in the first, older DNA sample, but significantly higher (2.6×) in the second sample.
Next, we tested the heteroplasmy level, analyzing in separate reactions only normal, non-deleted mtDNA molecules, or only molecules with the deletion. A comparison of the results of these two reactions revealed that mtDNA molecules with the deletion comprise about 3% of the total mtDNA pool in the patient’s blood.
This observation, with changing total mtDNA, fits well with the standard pattern of genetic rearrangements during the course of mitochondrial cytopathies. It was demonstrated that in patients with single deletions at high heteroplasmy levels the amount of mitochondria within the cells was nearly doubled . Therefore, even considerably reduced levels of enzyme activity can be compensated for by increased amounts of mitochondria. In another investigation, an approximately nine-fold amplification of mtDNA in muscle was detected . Other reports also indicate a synchronous increase in the levels of deleted and normal mtDNA in the course of KSS .
The low percentage of the deleted form of mtDNA compared to total mtDNA was not surprising, because the level of mutated mtDNA in blood is usually very low and sometimes undetectable . The observed level of mutated mtDNA in blood lymphocytes does not correlate with the severity of observed clinical symptoms of the disease. It is also likely that the level of mutated mtDNA in other tissues was much higher, but that was impossible for us to test because we lacked a muscle biopsy specimen for analysis.
The boy had the classic triad, plus the cardiac conduction defect. The dominant disturbances at the beginning of disease manifestation were ophthalmologic, then endocrinologic. With the development of the disease, the cardiac complications became very severe, subsequently leading to a life-threatening state.
Most cases of KSS (like the presented patient) and other mitochondrial cytopathies are first diagnosed as various endocrine disorders and the diagnosis of KSS is later established after several years [10, 11].
Endocrinologic pathologies in the presented patient were as follows: GH deficiency, hypothyroidism and impaired endocrine function of the pancreas. At the beginning of rGH treatment the prognosis concerning the therapy response was uncertain. The improvement of height velocity during rGH therapy was very satisfactory, and exceptional if compared to other children treated with KSS in our clinic. After glucose metabolism became impaired and the dose of rGH was reduced, the patient still accelerated on his growth chart. This means that the growth signal was transduced properly, despite the main disease. The large mtDNA deletion and resultant metabolic defects had no impact on treatment response to rGH.
The cardiac manifestations of KSS are the most important aspects of the disease for determining the prognosis . Manifestations of cardiac disease occur in 57% of patients with Kearns-Sayre Syndrome, including syncopal attacks, heart failure and cardiac arrest . Patients with KSS typically develop cardiac conduction defects that progress to complete heart block and then manifest clinically as heart failure, syncope or sudden death. Cases described in the literature show the progressive course of life-threatening conduction abnormalities in KSS . Patients who do not have conduction disturbances should be closely monitored for the development of conduction defects. In all patients with mtDNA mutations, not just KSS patients, mortality among those with no cardiac disease is 26% vs. 71% in patients with cardiomyopathy . Pacemakers are recommended for all patients with neuromuscular diseases (including KSS) who have developed atrioventricular (AV) block, however, prophylactic pacemaker placement prior to the development of third-degree or advanced second-degree AV block is discussed with patients and families as well . Based on the International Society of Heart and Lung Transplantation database, 6 patients who received heart transplantation between 1990 and 2003 had a diagnosis of myopathy due to a mitochondrial pathology .
The question is whether rGH treatment could have an impact on the cardiological complications in the patient. GH, both in excess and in deficient states can be associated with increased cardiovascular disturbances. Exposure to high GH levels causes the hypertrophy of cardiac myocyte . Patients with GH oversecretion develop acromegalic cardiomyopathy, biventricular hypertrophy and eventual heart failure . Dysrhythmias are also observed in acromegaly. Most common are ventricular arhythmias, like premature ventricular beats, ventricular bigeminy and ventricular tachycardia . In GH deficiency an increased risk of ischemic heart disease is described . GH deficiency results in a change in body composition, bone mineral density, an altered lipid profile, and decreased muscle mass. Therefore the proper balance within the GH and IGF-1 axis is necessary for maintaining normal cardiac function.
The presented patient had growth hormone deficiency and was treated with substitution doses of rGH. The IGF-1 concentration during rGH administration was within the normal range throughout the entire period of treatment. Therefore, the proper homeostasis of GH and IGF-1 axis was maintained. There is no evidence that rGH could have had a negative impact on cardiac function in this boy. It is rather to be suspected that treatment with rGH could even have a beneficial influence on the heart. There are some studies that show a positive influence of rGH on myocardium, also in dilated cardiomyopathy. GH can improve left ventricle structure and cardiac output, leading to a better hemodynamic profile of the heart [22, 23].
The presented case shows the classical clinical characteristics of Kearns-Sayre Syndrome. The urgent and rapid manifestation of severe cardiac dysfunction emphasizes the necessity of careful cardiological follow-up in KSS. The response to rGH in KSS is somewhat unpredictable, similarly to cardiac dysfunction, and there is no proof that rGH treatment contributes to the onset of the conduction block.
Written informed consent was obtained from the mother of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.
Recombinant growth hormone
Progressive external ophthalmoplegia
Chronic progressive external ophthalmoplegia
Magnetic resonance imaging
Oral glucose tolerance test
Glutamic acid decarboxylase
Insulinoma antigen 2
Insulin-like growth factor 1
Polymerase chain reaction
*Sections of this work were presented during the Joint Meeting of European Society for Paediatric Endocrinology and The Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES), 44th Annual ESPE Meeting in Lyon (September 2005) and 50th Annual ESPE Meeting in Glasgow (September 2011).
This work was supported by a grant from MNiSzW (2 P05A 070 30).
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