- Spada M, Burlina A, Donati MA, Gasperini S, Pession A. Therapeutic approach to pediatric patients with classic Fabry disease: towards a new paradigm. JIM 2024; 1 (3): e593. DOI: 10.61012_20248_593
Fabry disease in paediatric patients
Pediatric FD poses a complex clinical challenge, with early symptoms, progressive multiorgan involvement, and diagnostic delays. Early diagnosis and intervention are key.
What is Fabry disease?
Anderson-Fabry disease or more simply Fabry disease is named after the British doctor William Anderson and the German doctor Johann Fabry, who first and independently described the disease in 1898.
It’s a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, which encodes the enzyme alpha-galactosidase A (α-Gal A). This enzyme deficiency results in the accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, lyso-Gb3, within various tissues, leading to progressive cellular damage and a wide spectrum of clinical manifestations. Traditionally considered an adult-onset disease, it is now recognized that Fabry disease begins its pathological course early in life, often during childhood, with symptoms that can significantly affect the quality of life.
Fabry disease follows an X-linked inheritance pattern, as the GLA gene responsible for the condition is located on the X chromosome. Males are typically more severely affected because the presence of a pathogenic variant leads to complete enzyme deficiency. In contrast, females, with two X chromosomes, may exhibit variable clinical manifestations due to random X-chromosome inactivation, also known as lyonization. This process can result in a mosaic expression of the disease, where some cells express the normal allele while others express the mutated version. Over 800 different mutations in the GLA gene have been identified, contributing to the heterogeneity in disease presentation and severity.
Clinical manifestations
The clinical spectrum of Fabry disease in pediatric patients is varied and often leads to a delay in diagnosis. Early signs include neuropathic pain characterized by burning sensations in the extremities, particularly during febrile illness or after physical exertion. Another common symptom is hypohidrosis or anhidrosis, resulting in heat intolerance and exercise limitations. Gastrointestinal complaints, such as abdominal pain, diarrhea, and constipation, are frequently reported and may mimic more common pediatric gastrointestinal disorders, leading to misdiagnosis.
Skin manifestations, such as angiokeratomas, may appear as small, dark red or black papules located mainly in the “bathing trunk” area, although they may be overlooked in the early stages. Ocular findings such as verticillate cornea, identifiable by slit-lamp examination, are asymptomatic but serve as important diagnostic clues. Cardiac involvement, including left ventricular hypertrophy and arrhythmias, along with early signs of renal failure, such as proteinuria, can develop insidiously during childhood, underscoring the need for vigilant monitoring.
Diagnosis
Early diagnosis of Fabry disease requires a high index of suspicion, especially in children with a family history or suggestive clinical features. Enzyme activity assays are critical, especially in males, where markedly reduced α-Gal A activity is diagnostic. In females, due to X chromosome inactivation, enzyme levels may be within normal ranges, necessitating genetic testing for definitive diagnosis. Molecular analysis to identify pathogenic variants in the GLA gene confirms the diagnosis and facilitates familial screening.
Therapeutic approach
Since its introduction in 2001, enzyme replacement therapy (ERT) has been the cornerstone of Fabry disease management. ERT aims to reduce Gb3 accumulation, relieve symptoms, and prevent or delay organ damage. The two main recombinant forms, agalsidase alpha and agalsidase beta, differ slightly in structure and dosing regimens, but both are effective.
Migalastat, an oral pharmacological chaperone, offers an alternative for patients with susceptible GLA mutations, including those older than 12 years. This therapy stabilizes the mutant enzyme, improving its residual activity. Although not universally applicable, migalastat represents a significant advance in personalized treatment strategies.
Supportive care remains an integral part of comprehensive management (management of neuropathic pain, cardiovascular complications, renal protection, psychological support).
Pre-Emptive treatment: a new paradigm
Emerging evidence underscores the benefits of early intervention, even before overt symptoms occur. A landmark study comparing treated and untreated males with classic Fabry disease showed that early initiation of ERT significantly reduces the incidence of renal and cardiac complications. This finding challenges the traditional approach of waiting for clinical signs of organ involvement and supports a paradigm shift toward preventive therapy.
The concept of preventive treatment is gaining ground, reflecting the shift from reactive to proactive disease management. In contrast to preventive treatment, which aims to avert the onset of the disease, preventive therapy targets the first pathological changes before clinical symptoms occur. This approach is based on the knowledge that the pathology of Fabry disease begins long before symptoms become apparent, with detectable Gb3 accumulation in fetal tissues and progressing silently through infancy.
The E-TREAT study group, under the auspices of SIMMESN (Italian Society for the Study of Hereditary Metabolic Diseases and Neonatal Screening), is at the forefront of this change, advocating for early therapeutic intervention based on robust clinical evidence and biomarkers. Their work highlights the potential of early ERT not only to slow disease progression but also to improve survival and quality of life in pediatric patients. The adoption of preventive treatment protocols represents a step forward in the management of Fabry disease, underscoring the importance of early detection and early intervention.
Advances in diagnostic techniques, along with a deeper understanding of the disease, have paved the way for more effective management strategies. The shift to early and preventive treatment represents a paradigm shift, offering new hope for improved outcomes and quality of life.
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