Fatigue as hallmark of Fabry disease: role of bioenergetic alterations 2024 Gambardella et al

Andy · Feb 9, 2024

Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The “metabolic hypothesis” to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged.

In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.

Open access, https://www.frontiersin.org/articles/10.3389/fcvm.2024.1341590/full

Hutan · Feb 9, 2024

The molecular pathogenesis of FD encompasses several pathologic mechanisms involving mitochondrial dysfunction, lysosomal dysfunction, GB3 accumulation, endothelial dysfunction, and autophagy abnormalities (3, 4). Today, more than 1,000 GLA gene variants have been identified in the chromosomal region Xq22.1, including splicing alterations, deletions, translocations, complex gene rearrangement, and point missense variants (5, 6), but an exact genotype-phenotype correlation in FD cannot be established.
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The signs and symptoms of FD are heterogeneous with high variability among patients (7). Males carrying the defective gene will develop the pathology with often severe clinical manifestations while females, once thought to be just asymptomatic carriers, could develop the disease with mild to severe signs (8). The complete loss of enzyme function is usually associated with the “classic” phenotype with severe symptoms appearing in childhood while the residual enzyme activity may lead to a slow progression of the disease (the “late-onset” phenotype) with milder symptoms occurring in adults. Pain, and gastrointestinal (9) ocular, ear, or skeletal manifestations are the earliest symptoms of Fabry disease, which are not always immediately associated with FD. If left untreated, this multisystemic disease is progressive with cardiac and renal involvements as severe complications (10–12). FD may also manifest with mild nonspecific symptoms frequently affecting the musculoskeletal system (13).
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Genetic screening is the key to diagnosis - but how many people presenting with vague symptoms get offered that?

The disease presents a variable expression of symptoms, which are also gender and age-dependent, therefore, their association with FD is very difficult. To identify Fabry patients and avoid delay or lack of diagnosis, it is essential to consider all potential conditions that could generate “clinical suspicion” and trigger the diagnostic process as soon as possible.
The FD diagnosis is mainly based on the genetic screening of GLA gene mutations and activity, especially for women as enzymatic levels of the female heterozygote could not associate with the pathologic manifestations. Such diagnosis is then confirmed by the analysis of urine Gb3 and plasma lyso-Gb3 levels.
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Hutan · Feb 9, 2024

It sounds as though there are some treatments.

Nice recognition of the debilitation caused by fatigue

Fatigue represents the most bothersome symptom for most pathological conditions, including Fabry disease.
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Today, several reports suggest that the reduced tolerance to physical activity in patients with FD is not a secondary effect of diastolic heart failure, but a self-standing clinical phenotype that occurs independently from chronic renal or cardiac dysfunction (17–19). The involvement of the skeletal muscle leads to muscular cramps in the early phase and muscular pain, fatigability, and asthenia, in the advanced phases of the disease which involve walking and motor performance (19). The resulting chronic fatigue has a significant impact on quality of life, affecting patients' daily activities. This mainly concerns children's participation in after-school activities, and alterations of concentration and memory at work, with resulting negative impacts also on psychosocial attitudes.
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CPET

The few recent findings suggest that Fabry patients have impaired cardiopulmonary exercise capacity and failed to reach maximum heart rate both before and after ERT [enzymatic replacement therapy] treatment (21). This suggests that alterations in the exercise performance of Fabry patients cannot be improved by ERT.
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However, several Fabry patients without organ complications still suffer from muscle fatigue (17) suggesting that the motor system is primarily affected and muscle fatigue is an independent symptom in FD.
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Hutan · Feb 9, 2024

Muscular work must be supported by a high supply of ATP energy. Indeed, skeletal muscle is the district with the highest energetic demand, and as such, it is the main determinant of the whole body's metabolic rate. In particular, skeletal muscle can vary its metabolism to a greater extent than any other tissue through high metabolic flexibility, shifting its reliance between anaerobic glycolysis with lactate production, and aerobic oxidation of pyruvate or lipid (41, 42). Disruptions of metabolic flexibility of skeletal muscle are associated with several pathological conditions characterized by exercise intolerance and fatigue (42, 43). Growing evidence supports significant metabolic alterations of skeletal muscle in Fabry disease. We have recently shown a muscle fibers switch in a mouse model of Fabry Disease resulting in a higher abundance of Type II/glycolytic fibers. Accordingly, we recorded high glycolytic rate and lactate overproduction, in line with reduced exercise tolerance and fatigability in Fabry mice and patients
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The mechanism of this metabolic remodeling involves miR-17-mediated HIF-1 upregulation, which in turn induces the high expression of the key enzymes of lactacid metabolism.
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Specifically, we have shown a metabolic remodeling in Fabry patients characterized by reduced levels of acetyl-carnitine, fatty acids, and diacyl glycerol, alongside triglycerides accumulation, confirming the altered mitochondrial oxidation of lipids. A similar metabolic profile has been described for metabolic myopathies, a group of genetic myopathies characterized by an increased rate of anaerobic glycolysis, exercise intolerance, blood lactate accumulation, and reduction of circulating Acylcarnitine
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I have to stop, but this looks interesting, if only as a differential diagnosis. These researchers might be interested in collaborating with the DecodeME team to see if many people with an ME/CFS diagnosis have indications of problematic gene variants in that Xq22.1 region? @Andy, @Simon

Andy · Feb 9, 2024

Hutan said: ↑

I have to stop, but this looks interesting, if only as a differential diagnosis. These researchers might be interested in collaborating with the DecodeME team to see if many people with an ME/CFS diagnosis have indications of problematic gene variants in that Xq22.1 region? @Andy, @Simon
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The genetic analysis covers the GLA gene so we will be able to see if the problematic variants are represented in the DecodeME cohort.

Snow Leopard · Dec 14, 2024

I wonder more about the neuropathy being associated with fatigue in Fabry disease.

It is associated with SFN including autonomic dysfunction and altered heat sensation, with lipid accumulation affecting the functioning of those nerves.
https://www.sciencedirect.com/science/article/abs/pii/S1096719212001114
https://onlinelibrary.wiley.com/doi/abs/10.1002/mus.10236

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Fatigue as hallmark of Fabry disease: role of bioenergetic alterations 2024 Gambardella et al

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Fatigue as hallmark of Fabry disease: role of bioenergetic alterations 2024 Gambardella et al

Andy Retired committee member

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