A case of CD36 deficiency with multiple white matter lesions

Abstract

Background

CD36 deficiency is associated with abnormal fatty acid metabolism, which may increase the risk of developing atherosclerosis. However, there are few reports on a possible link between CD36 deficiency and cerebral white matter lesions.

Case report

We present the case of a 44-year-old woman with heart failure due to CD36 deficiency and multiple white matter lesions. Her comprehensive examination for heart failure, including a single-photon emission computed tomography (SPECT) with ²⁰¹thallium and ¹²³I-β-methyl-p-iodophenyl pentadecanoic acid, revealed a fatty acid metabolism disorder in the myocardium. Flow cytometry confirmed CD36 deficiency, and a subsequent head magnetic resonance imaging (MRI) demonstrated multiple T2-hyperintense lesions in the cerebral white matter. Although the patient had hypertriglyceridemia and a history of smoking, the contribution of CD36 deficiency to the formation of white matter lesions remains unclear.

Conclusion

This case suggests a potential association between CD36 deficiency and cerebral small-vessel disease. Further studies in patient cohorts with CD36 deficiency are warranted to clarify the impact of this condition on cerebral microcirculation.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-026-04945-y.

Background

Cluster of differentiation 36 (CD36) is a type Ⅱ cell-surface scavenger receptor detected in various cells, including cardiomyocytes, hepatocytes, platelets, macrophages, B cells, and T cells. In the central nervous system, vascular endothelial cells, astrocytes, and microglia express CD36 [1]. Its role in cardiomyocytes is crucial as it facilitates the transport of long-chain fatty acids (LCFA) into cells, providing an essential energy source. In patients with CD36 deficiency, reduced fatty acid uptake alters energy metabolism [2], increasing the risk of chronic heart failure.

CD36 deficiency is classified into two types: type I, characterized by the absence of CD36 in all cell types; and type II, in which CD36 deficiency is restricted to platelets. CD36 deficiency is more prevalent in Asian populations (1–7%) and rare in Caucasians. Type I accounts for approximately one-tenth of type II cases [3, 4]. However, reports of patients with CD36 deficiency presenting with cerebral small-vessel disease are limited, and the impact of CD36 deficiency on cerebral microcirculation remains unclear. Here, we report a case of multiple white matter lesions in a patient with CD36 deficiency and discuss the potential underlying biochemical mechanisms.

Case presentation

A 44-year-old woman was referred to the cardiology department of our hospital with bilateral lower leg edema, pleural effusion, and elevated BNP levels, suggesting heart failure. She had a history of bronchial asthma and subclinical hypothyroidism, treated with inhaled corticosteroids and bronchodilators. She smoked 30 cigarettes per day for 20 years, but denied alcohol or illicit drug use. She had no relevant family history. Transthoracic echocardiography revealed a mildly reduced left ventricular ejection fraction of 41%, with decreased wall motion in the ventricular septum, anterior wall, and inferior wall, as well as thinning of the myocardium in the anterior septum and lateral wall. Laboratory investigations showed normal serum levels of angiotensin-converting enzyme and soluble interleukin-2 receptor. A lipid profile demonstrated hypertriglyceridemia (triglycerides, 414 mg/dL), with low-density lipoprotein (LDL) cholesterol of 129 mg/dL and high-density lipoprotein (HDL) cholesterol of 47 mg/dL. There was no evidence of impaired glucose tolerance (HbA1c, 4.9%; fasting glucose, 81 mg/dL) or coagulopathy that could otherwise explain the cerebral small-vessel disease. After the initial evaluation, single-photon emission computed tomography (SPECT) with ²⁰¹thallium (²⁰¹Tl) and ¹²³I-β-methyl-p-iodophenyl pentadecanoic acid (¹²³I-BMIPP) was conducted. The results confirmed the absence of ¹²³I-BMIPP accumulation in the myocardium, indicating a fatty acid metabolism disorder (Fig. 1). Flow cytometry confirmed type I CD36 deficiency, demonstrating the absence of CD36 expression on both monocytes and platelets (Fig. 2).

Fig. 1.

¹²³I-BMIPP/²⁰¹TlCl dual-isotope myocardial scintigraphy. A Thallium-201 uptake was preserved in three myocardial segments (RCA, LAD, and LCX areas). B Iodine-123 BMIPP uptake was absent throughout the myocardium. C A diffuse mismatch pattern between ¹²³I-BMIPP and ²⁰¹TlCl, indicative of globally impaired fatty acid metabolism and consistent with underlying CD36 deficiency. LAD: Left anterior descending artery, LCX: Left circumflex artery, RCA: Right coronary artery

Fig. 2.

Flow cytometry analysis of CD36 expression in monocytes and platelets. Upper panels: Monocytes were gated by forward and side scatter (FSC/SSC) and identified as CD14⁺/CD64⁺ cells (red). These monocytes showed a complete absence of CD36 expression. Lower panels: Platelets were gated as CD41a⁺/CD61⁺ cells (green), which also lacked CD36 expression. The absence of CD36 on both CD14⁺/CD64⁺ monocytes and CD41a⁺/CD61⁺ platelets confirms type I CD36 deficiency

Neurological examination revealed no focal neurological deficits, including parkinsonism; however, bilateral postural and action tremor of the upper extremities without functional impairment was observed, prompting brain magnetic resonance imaging (MRI). Brain MRI revealed multiple T2-weighted hyperintense lesions in the deep white matter bilaterally, corresponding to Grade 2 on the Fazekas scale (Fig. 3). No atrophy was observed in the brainstem or cerebellum, which could be associated with tremor. Time-of-flight magnetic resonance angiography (TOF-MRA) revealed no intracranial arterial stenosis, and unenhanced CT from the head to the chest demonstrated no significant atherosclerotic calcifications in the aorta, cerebral arteries, or carotid arteries.

Fig. 3.

Fluid-attenuated inversion recovery and TOF-MRA image of the brain. Left: Fluid‑attenuated inversion recovery (FLAIR); right: Time‑of‑flight magnetic resonance angiography (TOF‑MRA) images acquired on a 1.5‑tesla non‑contrast MRI. White matter lesions corresponding to Grade 2, according to the Fazekas scale, were observed in both hemispheres, and no intracranial arterial stenosis was demonstrated on TOF-MRA. The white matter lesions were predominantly located in the deep white matter of both cerebral hemispheres, with mild periventricular involvement. No lesions that might be responsible for the tremor were observed in the cerebellum or brainstem. The Fazekas grading was assessed by board-certified neurologists

Discussion and conclusions

CD36 is a membrane glycoprotein expressed on the surface of various cells, including macrophages, monocytes, and vascular endothelial cells. It is also present in astrocytes and microglia within the central nervous system. CD36 facilitates the intracellular transport of LCFA and plays diverse roles in physiological processes, including the regulation of apoptosis and promotion of angiogenesis. Patients with CD36 deficiency are susceptible to myocardial damage and altered energy metabolism due to reduced fatty acid uptake [2, 5], resulting in an increased risk of heart failure.

In this case, ²⁰¹Tl and ¹²³I-BMIPP scintigraphy, performed to investigate the decreased myocardial wall motion, led to the diagnosis. BMIPP, a fatty acid analog, is taken up by the LCFA membrane transport system; therefore, the absence of myocardial BMIPP accumulation despite normal thallium uptake is a characteristic of CD36 deficiency. Reduced LCFA uptake deprives cardiomyocytes of essential energy sources, leading to hypertrophic or dilated cardiomyopathy [2, 4].

Notably, myocardial and cerebral energy metabolism differ substantially. While cardiac metabolism predominantly relies on fatty acid oxidation, the brain primarily uses glucose as its energy source under normal conditions. Therefore, the direct metabolic consequences of CD36 deficiency in cardiomyocytes may not translate directly into cerebral energy metabolism. Although reports on the effects of CD36 deficiency on the central nervous system are limited, brain MRI in this case revealed extensive white matter lesions exceeding age-related expectations. A large population‑based study of 5,000 healthy adults undergoing brain check‑ups in Japan reported that among 2,668 individuals younger than 50 years (mean age 40.8 years), deep white matter hyperintensities of Grade 2 were observed in 1.3% of the cohort [6]. According to this cohort study, the presence of white matter lesions in this patient is considered comparatively rare among individuals of the same age.

On cerebral perfusion SPECT images, the patient showed relative perfusion reduction in the bilateral frontal lobes compared with an age-matched normal database (Supplementary Data). Considering the patient’s heart failure, an acetazolamide challenge to evaluate cerebrovascular reserve was not performed because of the potential risks. Consequently, although resting hypoperfusion was confirmed, it remains uncertain whether vasodilatory reserve is preserved.

Several mechanisms have been proposed to contribute to the pathogenesis of cerebral microangiopathy in CD36 deficiency, including lipid metabolism abnormalities, impaired endothelial apoptosis, and altered angiogenesis. Vascular endothelial cells normally take up oxidized low-density lipoprotein (Ox-LDL) via CD36. CD36 deficiency may reduce Ox-LDL uptake and increase circulating Ox-LDL levels [7]. Ox-LDL promotes macrophage foam cell formation in the vascular intima, thereby contributing to atherosclerosis [8]. In angiogenesis, endothelial CD36 binds to thrombospondin-1 (TSP-1) and induces apoptosis, eliminating vulnerable cells [9]. Conversely, CD36 deficiency impairs this apoptotic pathway, leading to excessive angiogenesis and possible retention of maladaptive cells. However, these mechanisms are largely extrapolated from experimental and non-cerebral vascular studies, and their direct relevance to human cerebral small-vessel disease remains uncertain.

In this case, serum LDL cholesterol levels were within the normal range, whereas triglyceride levels were elevated. There were no major atherosclerotic risk factors such as diabetes, hypertension, or alcohol consumption. However, the patient had a significant history of smoking 30 cigarettes per day for 20 years. Associations between smoking and progression of white matter hyperintensities (WMH), as well as a dose‑dependent relationship with increasing pack‑years, have been reported [10]. Therefore, in this case, smoking history cannot be excluded as a contributing factor to the development of white matter lesions. To accurately assess the extent to which CD36 deficiency influences the formation of white matter lesions, it will be essential to collect head MRI data from patients with CD36 deficiency.

In conclusion, we report a case of type I CD36 deficiency associated with multiple white matter lesions. Smoking history and elevated triglyceride levels should be considered as potential contributing factors in this patient. This observation generates a hypothesis that CD36 deficiency may be associated with the development of white matter lesions through impairment of the cerebral microvasculature. Further studies in cohorts of CD36-deficient patients are necessary to clarify the effects of the deficiency on cerebral microcirculation and its role in microangiopathy.

Abbreviations

¹²³I-BMIPP

¹²³I-β-methyl-p-iodophenyl pentadecanoic acid

²⁰¹Tl

²⁰¹thallium

CD36

cluster of differentiation 36

LCFA

Long-chain fatty acids

MRI

Magnetic resonance imaging

Ox-LDL

Oxidized low-density lipoprotein

SPECT

Single-photon emission computed tomography

TSP-1

Thrombospondin-1

Authors’ contributions

Study concept and design: Y. K., H. Y., Y. I., J. S., C. T., M. I., and J. N.; Data collection and interpretation: H.Y., Y. Y., T. A., and H. M.; Manuscript drafting: Y. K., Y. I.

Funding

This study did not receive any specific funding from public, commercial, or nonprofit organizations.

Data availability

All data generated or analyzed during this study are included in this published article and supplementary information files.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The patient has provided written informed consent for the publication of this paper.

Competing interests

The authors declare no competing interests.