Dilated cardiomyopathy revealing Refsum disease: a case report

Abstract

Background

Refsum disease is a rare autosomal recessive hereditary disorder of lipid metabolism that results in the accumulation of phytanic acid. This syndrome is characterized with a range of classic symptoms including ataxia, peripheral neuropathy, amyotrophy, retinopathy, ichthyosis, and hearing loss. Later in life, individuals with Refsum disease may present cardiac manifestations, such as arrhythmias or conduction defects (first-degree atrioventricular block and bundle branch block) and hypertrophic or dilated cardiomyopathy, leading to heart failure and sudden death. To the best of our knowledge, this is the first case revealed by cardiac manifestations described in literature.

Case presentation: We report the case of 38-year-old white Moroccan male who was admitted in our department for an acute decompensated heart failure episode. Transthoracic echocardiography found a dilated cardiomyopathy with a reduced ejection fraction at 15%. Further evaluation showed different features of Refsum disease. High plasma level of phytanic acid confirmed the diagnosis. Cardiac manifestations are frequent in the late course of the adult Refsum disease and include, cardiomyopathy, electrical abnormalities, and sudden cardiac death. Moreover, arrhythmias remain one of the main causes of death in these patients.

Conclusion

Refsum’s disease is an autosomal recessive disorder. It presents as retinitis pigmentosa with anosmia, deafness ataxia, and cardiac defects. Current interventions for individuals with Refsum disease consist of dietary phytanic acid restriction and lipid apheresis to control symptoms and enhance quality of life.

Introduction

Refsum disease is a rare autosomal recessive hereditary disorder of lipid metabolism that results in the accumulation of phytanic acid. Refsum disease is divided into two subtypes classic/adult Refsum disease (CRD) and infantile Refsum disease (IRD) based on differences in the affected enzymes, accumulated metabolites, genetics, symptoms, and treatment. The majority (over 90%) of patients with CRD have a deficiency in the phytanoyl-CoA hydroxylase enzyme, encoded by the PHYH gene. Mutations in the PHYH gene result in an inactive enzyme, leading to an imbalance in downstream pathways and the accumulation of phytanic acid [1].

This syndrome is characterized with a range of classic symptoms including ataxia, peripheral neuropathy, amyotrophy, retinopathy, ichthyosis, and hearing loss. Later in life, individuals with Refsum disease may present cardiac manifestations, such as arrhythmias or conduction defects (for example, first-degree atrioventricular block or bundle branch block), and hypertrophic or dilated cardiomyopathy, leading to heart failure and sudden death [2].

CRD leads to the progressive degeneration of myelinated nerve fibers and disruption of the heart’s electrical conduction pathways, resulting in symptoms such as nerve damage, arrhythmias, impaired vision, and hearing loss. Arrhythmias are a common cause of death in patients with CRD. Survival is typically limited to the fourth or fifth decade of life [2, 3].

We report the case of a 38-year-old man who was admitted to the cardiology department with symptoms of acute heart failure. Upon complete evaluation, he was diagnosed with Refsum disease. To the best of our knowledge, this is the first described case of Refsum disease being revealed through cardiac manifestation.

Case presentation

We present the case of a 38-year-old white Moroccan male with no cardiovascular risk factors and a prior history of unexplored bilateral cecity, who presented to the emergency department with chronic edema of the limbs and progressive shortness of breath.

The initial evaluation found a hemodynamically stable patient with a normal blood pressure 105/76 mmHg, a pulse rate at 45 beats per minute, and oxygen saturation at 93% on ambient air. Physical examination showed an external jugular vein distension, extensive legs edema, and ascites. Cardiopulmonary auscultation was notable for a 4/6 holosystolic murmur at the mitral focus with symmetrical bilateral diffuse crackles. The ophthalmological assessment found a visual acuity reduced to light perception.

An electrocardiogram showed sinus bradycardia with a heart rate of 45 beats per minute and complete right bundle branch block (Fig. 1). Chest radiography was notable for cardiomegaly and perihilar congestion. The B-type natriuretic peptide level was 1230 pg/ml (for a normal range under 300 pg/ml), the creatinine level was 9.6 mg/l (for a normal range between 6 and 12.5 mg/l), the albumin level was slightly low at 36 g/l (for a normal range higher than 39 g/l), and there was a high sensitivity troponin at 294 ng/l (for a normal range under 35 ng/l). Other laboratory test results were normal particularly ferritin, TSH, and electrolyte levels.

Fig. 1

Electrocardiogram showing sinus bradycardia with right bundle brunch block

Transthoracic echocardiography (TTE) showed a dilated left ventricle (end diastolic basal diameter of 60 mm) with a severely reduced ejection fraction at 15% (Simpson biplane), mild mitral regurgitation, and an apical thrombus measuring 19 mm × 18 mm. The right ventricle was severely dilated (end diastolic basal diameter of 51 mm), with systolic dysfunction (Tricuspid Annular Plane Systolic Excursion (TAPSE) of 12 mm and Right Ventricle S' wave on tissue doppler (S’VD) of 5 cm/s) and severe tricuspid regurgitation. The inferior vena cava (IVC) was plethoric with a maximal diameter of 37 mm (Fig. 2 and supplementary video).

Fig. 2

Transthoracic echocardiography (A dilated left ventricle in the parasternal long axis view and B apical thrombus and severe reduced ejection fraction in the two cavity view)

A detailed history revealed that since his early twenties, the patient had troubles walking, hearing loss, and anosmia and that his cecity started with altered night vision, but he had never been assessed or evaluated by an ophthalmologist prior to this presentation. The neurological examinations showed bilateral legs amyotrophy with bilateral ataxia. A fundoscopic examination was performed to explore his cecity and revealed retinitis pigmentosa (Fig. 3). The patient’s clinical image associating a dilated cardiomyopathy with the specific neurological signs was strongly suggestive of Refsum's disease. We conducted an assay of plasma phytonic acid concentrations, which revealed a remarkably elevated level of 324 μmol/l, which confirmed the Refsum disease. Initially, the patient was put on intravenous furosemide, which provided subsequent relief from his heart failure symptoms. Following that, he received treatment with oral furosemide [40 mg twice per day (b.i.d)], Angiotensin converting enzyme (ACE) inhibitors (ramipril 2.5 mg b.i.d), spironolactone (25 mg Once daily (o.d)), and an SGLT2 inhibitor (empagliflozine 10 mg o.d.). Beta-blockers were not administered due to sinus bradycardia. Additionally, the patient received vitamin K antagonists for the left ventricular thrombus.

Fig. 3

Fundoscopic examination showing bilateral retinitis pigmentosa

In terms of the specific treatment for Refsum disease, the patient was counseled to adhere to a dietary restriction regimen designed to eliminate phytol-containing foods, with a daily phytanic acid intake below 10 mg. This involved avoiding the consumption of meat or fats from ruminating animals (such as lamb and beef) and baked goods containing animal fats, as well as dairy products such as butter and cheese.

The patient recovered and his condition became stabilized with NYHA class 2 symptoms of chronic heart failure; therefore, he was discharged on medical treatment for heart failure, vitamin K antagonists (VKA), and a low phytanic acid regimen.

Discussion

Refsum’s disease is a rare hereditary autosomal recessive disorder of lipid metabolism caused by a defective α-oxydation of phytonic acid. The defective enzyme is phytanoyl-coenzyme A hydroxylase. The deficit can be isolated, which gives rise to classic Refsum disease (CRD)—the most common form of Refsum disease or associated with other enzyme deficit and causing infantile Refsum’s disease [2, 3]. To this date, two genes have been identified to be responsible for adult refsum’s disease, which are the PAHX gene in 1997 and PEX7 in 2003 [4, 5]. Mutations in these genes cause ineffective phytanoyl coenzyme A, which in turn causes defective α-oxidation of phytonic acid; this results in an accumulation of phytanic acid, with subsequent elevation of concentration in the plasma and target tissues including neurons and myocardial cells [6]. The mechanism of phytanic acid toxicity remains unclear.

The onset of symptoms of CRD is usually early—in late childhood or adolescence—but may manifest later in life. The most common finding is retinitis pigmentosa, which is present in all of the patients with Refsum disease. Typically, night blindness is the mode of entry of visual impairment and manifests years earlier [7]. Other neurological findings include: anosmia, auditory nerve involvement causing hearing loss, and ataxia, with relatively late onset, indicating the advanced stage of the disease in our patient [8, 9].

Cardiac manifestations are frequent in the late course of the disease and include cardiomyopathy, electrical abnormalities, and sudden cardiac death. The most common forms of electrical abnormalities reported in literature include a first-degree AV block and a bundle branch block [10].

On plasma analysis, an isolated and highly raised phytanic acid level > 200 µmol/l is highly suggestive of adult Refsum disease, and genetic testing will research biallelic pathogenic variants in the PAHX or PEX7 gene. If molecular genetic testing is unavailable or the results are not diagnostic, specialized biochemical testing can be used to establish the diagnosis [11]. In our case, the patient had most of the typical clinical findings of Refsum’s disease, along with a highly elevated level of phytanic acid. Hence, the diagnosis was made without the genetic testing.

Treatment is based mainly on phytanic acid restricted diet, with a goal of reducing daily dietary intake of phytanic acid to less than 10 mg a day, without reducing calories intake. Plasmapheresis, or low-density lipoprotein low-density lipoprotein (LDL) apheresis, can be used in case of very high levels of phytonic acid that require rapid reduction of its plasma levels [12]. For arrythmias management, amiodarone should not be used because of the risk of hyperthyroidism, which would increase catabolism and, hence, phytanic acid release from tissues.

The course of the disease is often marked by recurrent hospitalizations, progressive deterioration in health and quality of life, incapacitating pain, and limitation of physical activity. Li et al. [13] demonstrated in their work that around 32% of patients with CRD were hospitalized more than once, 53.8% had recurrent disabling pain, and only 20.7% were not limited in terms of physical activity, while 82.8% of patients included in the study suffering from depression at different levels.

As a result, without therapy Refsum illness will certainly be gradually worsening its symptoms, particularly retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. This progression can result in total loss of vision, ataxia, muscle pain or wasting, and arrhythmias that may lead to sudden death [14, 15]. Disease progression can be slowed with treatment, which may involve a low phytanate diet and lipid apheresis techniques. Treatment can help stabilize the condition, lower the level of phytanic acid, and reduce symptoms, which. in turn. improves quality of life drastically. Currently, new and more advanced therapies are under investigation, such as enzyme replacement therapy and gene therapy [14, 16, 17].

Conclusion

Refsum’s disease is an autosomal recessive disorder in which the α-oxidation of phytanic acid is impaired, probably due to mutations in phytanoyl-CoA hydroxylase (PAHX) and/or PEX7. It presents as retinitis pigmentosa with anosmia, deafness ataxia, and cardiac defects. The diagnosis is suspected on the basis of elevated plasma phytanic acid levels and confirmed by genetic testing. Current interventions for individuals with Refsum disease consist of dietary phytanic acid restriction and lipid apheresis to control symptoms and enhance quality of life. This research has led to advanced therapeutics such as enzyme replacement and gene therapy.