Kearns–Sayre syndrome presenting with progressive external ophthalmoplegia and third-degree atrioventricular block diagnostic challenge in resource-limited settings: a case report

Abstract

Background

Kearns–Sayre syndrome is a rare autosomal recessive mitochondrial disorder characterized by progressive external ophthalmoplegia and pigmentary retinopathy. Onset typically occurs before the age of 20 years and is attributed to mutations within mitochondrial DNA affecting proteins critical for the oxidative phosphorylation pathway. Since these mitochondrial disorders usually present with an isolated manifestation such as complete heart block, a meticulous search for other organ-specific manifestations is necessary for an early diagnosis. Reporting such cases facilitates recognition of common clinical presentations, enabling earlier diagnosis, earlier interventions, and genetic counseling.

Case presentation

A 29-year-old right-handed Ethiopian male patient presented with progressive exercise intolerance for 10 years. He had had bilateral ptosis since childhood and experienced gait difficulty with intermittent balance problems, particularly at night. In 2018, he was diagnosed with a third-degree atrioventricular block with a resting electrocardiogram, and a permanent pacemaker was placed. Despite marked improvement in shortness of breath following pacemaker placement, the patient’s progressive ptosis and gait ataxia prompted further workup, ultimately leading to the diagnosis of Kearns–Sayre syndrome. This case highlights the importance of comprehensive assessment in patients presenting with isolated organ manifestations, as exemplified by the delayed diagnosis of Kearns–Sayre syndrome following the initial recognition of a complete heart block.

Conclusion

Given the early-onset nature of Kearns–Sayre syndrome, it should be considered as a differential diagnosis in young individuals presenting with complete heart block. A thorough evaluation for additional organ involvement is crucial in such cases, as early intervention and genetic counseling significantly impact patient outcomes.

Introduction

Third-degree (complete) atrioventricular block, necessitating permanent pacemaker implantation, is common in the geriatric population. However, a thorough evaluation of underlying etiologies is crucial in younger patients [1]. This case report describes a young individual diagnosed with Kearns–Sayre syndrome (KSS) presenting with third-degree atrioventricular (AV) block. This finding emphasizes the importance of considering KSS and other secondary causes in the differential diagnosis of young patients with complete heart block.

Kearns–Sayre syndrome (KSS) is a rare and severe mitochondrial disease (MD) characterized by a triad of progressive external ophthalmoplegia (PEO), pigmentary retinal degeneration, and early onset (before the age of 20 years). There is also a high prevalence of cardiac involvement. This distinguishes KSS from other MDs, where cardiac complications are less frequent. Furthermore, cardiac dysfunction significantly impacts prognosis in KSS patients [2, 3]. KSS can manifest with additional systemic complications beyond the core triad. These may include deafness, cerebellar ataxia, and pigmentary retinopathy. Notably, pigmentary retinopathy is a hallmark feature of KSS, although its severity can vary considerably. Ranging from subtle pigmentary changes to extensive pigment atrophy, the retinal degeneration in KSS can mimic retinitis pigmentosa [4, 5]. KSS management focuses on close monitoring for the development of ophthalmologic complications [5].

If these arise, surgical intervention may be considered on a case-by-case basis [5]. Additionally, current guidelines recommend permanent pacemaker implantation for patients with neuromuscular diseases experiencing atrioventricular block, including KSS [6].

Case presentation

A 29-year-old right-handed Ethiopian male patient presented with a 10-year history of exercise intolerance that worsened with mild-to-moderate exertion. In addition, he reported bilateral ptosis (drooping eyelids) since childhood. He also had difficulty ambulating, with intermittent loss of balance, especially at night. A permanent pacemaker was inserted in 2018 after he was diagnosed with third-degree AV block with an electrocardiogram (ECG) (Fig. 1). Pacemaker implantation resulted in substantial improvement in exercise tolerance. However, the patient subsequently developed new neurological symptoms, including dysarthria (slurred speech) and intermittent attention deficits, particularly during listening tasks. Moreover, he reported a decline in hearing ability. Family history was negative for similar presentations. Physical examination revealed general muscle wasting and bilateral symmetrical ptosis. Limitation of ocular movements in all quadrants was found on examination of cranial nerves 3, 4, and 6. On examinations of cranial nerve 8, he could not hear finger rubbing sounds from 2 cm, but there was no lateralization on Rhine and Webber tests. The muscle bulk was comparable in all four extremities, and power and tone were normal. However, dysmetria on the finger-to-nose test was noted. He was also unable to perform tandem gait. He was referred to the otolaryngology department for audiometry evaluation and was found to have mild bilateral sensorineural hearing loss.

Fig. 1

Electrocardiogram showing third-degree atrioventricular block

Laboratory evaluations were within normal reference ranges, including a complete blood count (CBC), renal function tests (RFTs), serum electrolytes, and metabolic panels. Specifically, the CBC revealed white blood cells at 6500/μL, hemoglobin at 16.5 g/dL, and platelets at 193,000/μL. Fasting blood sugar was 95 mg/dL, and TSH level was 2.35 ng/dL (Table 1).

Table 1 Laboratory results of the patient

Electrophysiological studies yielded normal results, including electromyography (EMG) and nerve conduction studies (NCS).

Treatment and outcomes

The patient underwent permanent pacemaker placement, resulting in a marked improvement in exertional dyspnea. A multidisciplinary team currently follows him, including the cardiology, neurology, and ophthalmology departments.

Discussion

Kearns–Sayre syndrome (KSS), a rare mitochondrial disease (MD), primarily arises from mitochondrial DNA (mtDNA) rearrangements. The most common pathogenic mtDNA alteration involves a 4.9 kb deletion encompassing nucleotide positions 8470–13,446 [7]. This deletion eliminates several essential functional genes, including MT-ATP8, MT-ATP6, MT-CO3, MT-ND3, MT-ND4L, MT-ND4, and MT-ND5 [2, 8]. Mitochondrial DNA (mtDNA) deletions in KSS are predominantly de novo mutations, arising spontaneously in the oocyte or during early embryonic development. Consequently, most KSS cases are sporadic, with only an estimated 4% showing maternal inheritance of the mtDNA abnormality [9]. The clinical diagnosis of KSS is dependent on a core triad of features: onset before the age of 20 years, progressive external ophthalmoplegia (PEO), and pigmentary retinopathy. In addition, the presence of at least one of the following supporting criteria strengthens the diagnosis: cardiac conduction defects, cerebellar ataxia, or elevated cerebrospinal fluid (CSF) protein levels exceeding 100 mg/dL [10]. The heterogeneous clinical manifestations and severity spectrum observed in KSS patients likely stem from the variable proportion of mtDNA deletions and their distribution across different tissues [11]. The diagnosis of KSS in this case was established on the basis of clinical criteria; owing to limitations in resource availability, genetic testing for mtDNA rearrangements was not pursued. Cardiac complications are a significant prognostic factor in KSS, encompassing a spectrum of presentations. These primarily manifest as cardiac conduction abnormalities and cardiomyopathy [2]. Supporting the significance of cardiac involvement, cardiac conduction abnormalities are a frequent finding in KSS, affecting approximately 84% of patients according to diagnostic criteria [12]. ECG findings in KSS are most characterized by combined intraventricular and atrioventricular (AV) conduction delays [13]. This patient initially presented with shortness of breath, and his ECG showed third-degree AV block. Among patients with cardiac involvement in KSS, cardiomyopathy is a frequent clinical manifestation, either as hypertrophic cardiomyopathy or dilated cardiomyopathy [2]. Heart failure represents the primary cause of mortality in this patient population [14]. Echocardiography was normal in our patient. Although our patient has no endocrine dysfunction, KSS can also manifest with a spectrum of endocrine abnormalities, including short stature, delayed pubertal development, diabetes mellitus, and hypothyroidism [5].

Conclusion

Given the early-onset nature of Kearns–Sayre syndrome (KSS), it should be included in the differential diagnosis for young patients presenting with cardiac conduction abnormalities. This is particularly important when accompanied by supporting neurological or endocrine manifestations. For patients with KSS and high-degree atrioventricular block, permanent pacemaker implantation is a well-established intervention to improve cardiac function and prognosis. A thorough evaluation for additional organ involvement is crucial in such cases, as early intervention and genetic counseling significantly impact patient outcomes. Moreover, close ophthalmologic monitoring is crucial to identify progressive external ophthalmoplegia (PEO) promptly. In some cases, surgical interventions may be considered to address PEO and potentially improve vision.