Alpha-fucosidosis is a very rare AR lysosomal storage condition with a male-to-female ratio of approximately 1.75:1. It is linked to a mutation in the L-fucosidase 1 gene (FUCA1), which causes an extreme deficiency of the lysosomal enzyme alpha-L-fucosidase [1]. Since alpha-L-fucosidase is involved in the cleavage of fucosyl residues from whole glycoconjugates, a deficiency or absence of the enzyme in fucosidosis disorder can impair lysosomal degradation of fucose-containing glycoproteins and glycolipids, resulting in deposition of these substances in various body tissues with a myriad of symptoms [2]. Fucosidosis is divided into two sub-types based on the age of onset and life expectancy: type I which starts at 6 months of age and progresses rapidly, resulting in neurological deterioration and death during the first decade of life; and type II which begins between 12 and 24 months of age and progresses more slowly, resulting in longer survival until the second decade. However, there is no specific clinical distinction between type I and type II. Moreover, among members of the same family, there is a wide range of variation in clinical presentation [3]. Our case is more likely to be type II fucosidosis, based on the age of presentation. Less than 120 cases of fucosidosis have been identified to date, with many cases occurring in Italians and Mexican Indians in New Mexico and Colorado [2]. To our knowledge, this is the second report of fucosidosis in Egyptian patients. The first case was a 2-year-old boy who had neither coarse facial features nor cutaneous angiokeratoma at the time of diagnosis [4].
Severe global developmental delay (95%), muscle stiffness (87%), coarse facies (79%), recurrent respiratory infections (78%), visceromegaly (44%), seizures (38%), and abnormal bone development (58%) are among the extracutaneous manifestations of alpha-Fucosidosis, while the mucocutaneous features include tortuous conjunctival vessels (53%), angiokeratoma corporis diffusum (ACD) (52%), widespread telangiectasias, acrocyanosis, purple transversal distal nail bands, increased palmo‐plantar vascularity, dry thin skin, and sweating abnormalities (hyper‐ or hypo‐hidrosis) [1, 5]. Several reported patients with fucosidosis were found to have no cutaneous symptoms [3]. With age, the risk of developing ACD and the severity of the condition increase. Patients can present with telangiectasia at first, then develop angiokeratomas later [1]. The accumulation of pathologic material inside the cytoplasm of endothelial cells, which could trigger their apoptosis, with continuous reactive regeneration, leading to the emergence of newly developed ectatic capillaries, is thought to be the cause of ACD in various metabolic diseases, including fucosidosis [3]. ACD is more common in patients that have lived longer. Besides fucosidosis, ACD has also been reported in Fabry disease (FD), sialidosis, α-mannosidosis, β-mannosidosis, aspartylglucosaminuria, galactosialidosis [6].
Due to glycolipid accumulation, prominent gray matter atrophy, prominent white matter demyelination, dysostosis multiplex, kyphosis or scoliosis, widening of long bones diaphysis, and thickening of the skull are all seen on radiologic tests [2]. Recurrent pulmonary infections and neurological decline are the most common causes of death [7].
In our patient, the majority of her systems were involved. The genetic testing is the definitive way to diagnose fucosidosis, however, the radiologic findings, together with clinical signs and symptoms, can be helpful. There is currently no accepted treatment for fucosidosis, and the disorder is treated predominantly by supportive and symptomatic therapy, including muscle relaxants, physical therapy and massage for spasticity, feeding therapy, antacids and pureed food for the feeding problems and gastroesophageal reflux [8]. Enzyme replacement therapy and hematopoietic cell transplantation are still in the early stages of development [9].
Lysosomal storage diseases (LSDs) are among the disorders associated with an exceptionally high risk of serious COVID-19 infection [10]. The immune system function is impaired in several LSDs. Gaucher disease (GD), mucopolysaccharidosis (MPS VII), and -mannosidosis are LSDs that tend to suppress the immune system. Antigen presentation and processing, secretion of perforins by cytotoxic-T lymphocytes, and release of pro-inflammatory mediators by mast cells are all immune system functions in which the lysosome plays a key role [11].
In fucosidosis patients, recurrent infections of the sinus cavities, ears, and airway are thought to be caused by a local deficiency in mucus clearance rather than a systemic immune defect. The fact that recurrent infections in such patients are restricted to areas of mucus-secreting ciliated epithelia, with no evidence of a rise in the prevalence of extrapulmonary infections, supports this hypothesis. Alterations in the mucus cross-linking and viscoelasticity are caused by changes in enzymatic cleavage of sugars combined with incomplete assembly of mucus glycoprotein as well as failure of glycoprotein secretion in fucosidosis. The abnormally watery, low-elasticity mucus will be difficult to remove from the airway, contributing to chronic pulmonary infection [12]. Recurrent respiratory infections are one of the most common symptoms in patients with fucosidosis, with a prevalence of 78%. Skeletal deformities of the chest wall can be an additional risk factor for COVID-19 complications due to pulmonary and cardiac power limitation and insufficient airway ventilation. Hepatosplenomegaly can reduce lung volume and hasten respiratory decline in these patients, resulting in a fatal COVID-19 infection [10]. Regarding the present case, we suspected that her extreme hepatosplenomegaly and scoliosis contributed to her severe COVID-19 infection and death.
COVID-19 had a major effect on LSD patients in Italy, with 49 percent of patients undergoing enzyme replacement therapy in hospitals experiencing delays compared to just 6% of those treated at home, with fear of infection (62.9%) and reorganization of infusion centers (37%) being the key reasons for missed infusions. COVID-19 was not present in any of the 102 people interviewed [13]. Since LSD patients often suffer from a multisystem disorder, the study found them to be at a high risk of developing serious complications if infected with SARS-CoV-2 [13]. In a separate study from Italy, people with LSDs reported higher levels of anxiety and psychological fear, particularly, they have rare diseases that are susceptible to complications if they contract COVID-19, but there was no statistically significant difference when compared to controls [14]. Just one patient with FD had laboratory-verified COVID-19 among the approximately 400 confirmed MPS, GD, and FD patients in Morocco. He had no signs of SARS-CoV-2 infection and was kept in isolation at home for 14 days [10]. The accumulation of glycosphingolipid in FD, which modifies and shapes the biology of gut bacteria and may have a prophylactic effect against SARS-CoV-2 disease, may be the reason for asymptomatic infection in this patient despite his critical condition [15]. In a cohort study of around 550 symptomatic cases of GD from Israel and Australia (median age 46 (18–94) years), only one woman, who was pregnant in her third trimester and was 24 years old, had a reported COVID-19 infection. She had a moderate clinical course that was only handled by a 14-day quarantine [16].
Recent studies have come up with some very plausible explanations for the low incidence of LSD patients infected with COVID-19. Balout et al. hypothesized that the intracellular biochemical abnormalities of LSDs, in general, and Niemann–Pick disease type C (NPC) in particular, could establish a "unfavorable" host cell environment for SARS-CoV-2 entry, trafficking, and fusion. The suggested mechanism could be, first and foremost, altered plasma membrane and lipid raft composition in NPC, which could influence the trafficking of ACE2, the primary host cell membrane receptor responsible for viral entry. Other reasons include decreased cathepsin L activity in NPC, a key protease needed for successful SARS-CoV-2 fusion, and a high level of oxysterols in NPC, which have potent antiviral properties. The authors hypothesized that LSDs may be a successful therapeutic axis for COVID-19 in the future [17]. When exposed to COVID-19 infection, Zimran et al. hypothesized that the accumulated glycosphingolipids in patients with GD might induce immune tolerance rather than inflammation, resulting in a defensive line against infection [16]. Furthermore, LSDs with accumulating metabolites can induce new immune activation involving Natural Killer cells and other immune cells, such as B cells, resulting in different immune responses [18].
