Fabry disease, respiratory symptoms, and airway limitation – a systematic review

Abstract

BackgroundFabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A, resulting in accumulation of glycosphingolipids in multiple organs, primarily heart, kidneys, skin, CNS, and lungs.Materials and methodA systematic literature search was performed using the PubMed database, leading to a total number of 154 hits. Due to language restriction, this number was reduced to 135; 53 papers did not concern Fabry disease, 19 were either animal studies or gene therapy studies, and 36 papers did not have lung involvement in Fabry disease as a topic. The remaining 27 articles were relevant for this review.ResultsThe current literature concerning lung manifestations describes various respiratory symptoms such as dyspnoea or shortness of breath, wheezing, and dry cough. These symptoms are often related to cardiac involvement in Fabry disease as respiratory examinations are seldom performed. Pulmonary function tests primarily show obstructive airway limitation, but a few articles also report of patients with restrictive limitation and a mixture of both. No significant association has been found between smoking and the development of symptoms or spirometry abnormalities in patients with Fabry disease. Electron microscopy of lung biopsy and induced sputum show lamellar inclusion bodies (Zebra bodies) in the cytoplasm of cells in the airway wall. X-ray and CT scan have shown patchy ground-glass pulmonary infiltrations, fibrosis, and air trapping. Fibrosis diagnosed by high-resolution CT has not been significantly correlated with lung spirometry.ConclusionConsistent findings have not been shown in the current literature. Pulmonary function tests and registration of symptoms showed various results; however, there is a trend towards obstructive airway limitation in patients with Fabry disease. Further studies are needed to evaluate pathogenesis, progression, and the effects of treatment.

European expert consensus statement on therapeutic goals in Fabry disease

“…Male and female patients with Fabry disease can develop pulmonary manifestations, usually presenting as shortness of breath during exercise, chronic cough, and wheezing, with many patients having obstructive airway limitation [173,174]. It is not clear how much pulmonary involvement may contribute to cause dyspnoea in patients with Fabry disease, as asthma and chronic obstructive pulmonary disease are also prevalent in the general population [174].…”

“…Male and female patients with Fabry disease can develop pulmonary manifestations, usually presenting as shortness of breath during exercise, chronic cough, and wheezing, with many patients having obstructive airway limitation [173,174]. It is not clear how much pulmonary involvement may contribute to cause dyspnoea in patients with Fabry disease, as asthma and chronic obstructive pulmonary disease are also prevalent in the general population [174]. On the other hand, although evidence on the effect of ERT on pulmonary involvement is limited, several case reports and an observational study suggest that symptoms can be improved or at least stabilized by treatment [175][176][177].…”

“…On the other hand, although evidence on the effect of ERT on pulmonary involvement is limited, several case reports and an observational study suggest that symptoms can be improved or at least stabilized by treatment [175][176][177]. The impact of ERT may depend on the extent of lung involvement prior to treatment, as with other organ dysfunction in Fabry disease, and early initiation of ERT should be considered [174].…”

Screening, diagnosis, and management of patients with Fabry disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

“…30 The benefits of early treatment, before irreversible tissue injury occurs, should be balanced against the burden of biweekly infusions in very young individuals. In a recent pediatric randomized controlled trial (RCT), Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all biopsied FD patients with normal GFR and urinary albuminto-creatinine ratio (UACR) < 30 mg/g, 31 suggesting early ERT as well as the role of b2-agonists 86,114 Provide uniform description and categorization of study populations in future reports on the efficacy of therapy, including genotype, phenotype, sex, and age at initiation of therapy Conduct long-term outcome studies of (pediatric) patients who started ERT when asymptomatic or paucisymptomatic Collect histologic evidence of ERT-induced clearance of Gb3 in longlived cells: vascular smooth muscle cells, cardiomyocytes, podocytes Conduct studies on the pathophysiology and treatment of gastrointestinal involvement and lymphedema Develop more sensitive patient-reported outcome measures ERT, enzyme replacement therapy; FD, Fabry disease.…”

“…A mixture of different etiologic mechanisms of obstructive and restrictive pulmonary symptoms has been reported in several small studies and case reports, and a recent systematic review could not identify consistent findings in the literature. 86 A registry study concluded that 23 of 67 patients had airway obstruction similar to chronic obstructive pulmonary disease, and obstructive lung disease has been m e e t i n g r e p o r t reported to be up to 10 times more prevalent in people with FD than in the general population.…”