Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes ...have been described "Classic" and "late onset" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations.
In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.
N215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as lyso-Gb3*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001).
These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.
Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules or by inborn errors of metabolism impairing liver glucose production. We ...studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and in one case in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.
Fabry disease is an X-linked inherited condition due to the absence or reduction of α-galactosidase activity in lysosomes, that results in accumulation of globotriaosylceramide (Gb3) and related ...neutral glycosphingolipids. Manifestations of Fabry disease include serious and progressive impairment of renal and cardiac function. In addition, patients experience pain, gastrointestinal disturbance, transient ischaemic attacks and strokes. Additional effects on the skin, eyes, ears, lungs and bones are often seen. The first symptoms of classic Fabry disease usually appear in childhood. Despite being X-linked, females can suffer the same severity of symptoms as males, and life expectancy is reduced in both females and males. Enzyme replacement therapy (ERT) can stabilize the progression of the disease. The rarity of the classic form of Fabry disease, however, means that there is a need to improve the knowledge and understanding that the majority of physicians have concerning Fabry disease, in order to avoid misdiagnosis and/or delayed diagnosis. This review aims to raise awareness of the signs and symptoms of Fabry disease; to provide a general diagnostic algorithm and to give an overview of the effects of ERT and concomitant treatments. We highlight a need to develop comprehensive international guidelines to optimize ERT and adjunctive therapy in patients with Fabry disease, including females and children.
The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported.
Median length ...of follow up was 10 years 3 months (range = 1 y 2 m to 18 years 6 month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (n = 16) = 15.13 years (range = 9.53 to 20.58 y), and untreated (n = 17) = 11.43 y (0.5 to 19.13 y) p = .0005). Early introduction of ERT improved respiratory outcome at 16 years, the median FVC (% predicted) of those in whom ERT initiated <8 years = 69% (range = 34–86%) and 48% (25–108) (p = .045) in those started >8 years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8 years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.
Summary
Background Fabry disease (also known as Anderson–Fabry disease) is a rare, X‐linked lysosomal storage disorder that is characterized by accumulation of globotriaosylceramide throughout a ...range of tissues in the body.
Objectives To ascertain the prevalence and nature of cutaneous manifestations in patients with Fabry disease and to relate these to the severity of systemic manifestations of the disease.
Methods We have documented the dermatological features of this disease with reference to data from 714 patients (345 males, 369 females) registered on the Fabry Outcome Survey (FOS), a multicentre European database.
Results We confirm that the commonest disease manifestation is angiokeratoma. Overall, 78% of males and 50% of females had one or more dermatological abnormality, the commonest being angiokeratoma (66% males, 36% females), hypohidrosis (53% males, 28% females), telangiectasia (23% males, 9% females) and lymphoedema (16% males, 6% females). We demonstrate for the first time that the presence of cutaneous vascular lesions correlates with the severity of the systemic manifestations of the disease (pain, renal failure, cardiac disease, premature cerebrovascular disease) as assessed by a severity scoring system. Although the condition is X linked, there is a surprisingly high prevalence of abnormalities in females.
Conclusions The FOS database is a useful epidemiological tool in establishing the variety and relevance of cutaneous manifestations in Fabry disease. The present study confirms that the presence of dermatological manifestations appears to be a marker of greater severity of systemic disease, which emphasizes the importance of the dermatological assessment of these patients.
Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the ...lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented.
Summary
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease ...have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years;
p
= 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years;
p
α 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.
Fabry disease is an X linked lysosomal disorder associated with severe multiorgan failure and premature death. This study aims to determine the prevalence of ophthalmic manifestations in children ...with the condition and investigate the correlation with genotype and systemic disease severity.
The records of 26 children from 18 pedigrees with Fabry disease undergoing regular ophthalmic and systemic examination were reviewed. All pedigrees underwent GLA gene sequencing to determine genotype. Correlations between ocular and systemic phenotype and genotype were investigated.
Corneal verticillata occurred in 50% of the children in this study (95% CI, 29% to 79%). Children with ophthalmic manifestations were more likely to have loss-of-function GLA mutations (p=0.003). Retinal vascular tortuosity was seen in seven children (27%), all of whom had systemic symptoms suggestive of autonomic neuropathy, such as diarrhoea and syncope. These symptoms seemed less prevalent in children without retinal vascular changes, although this did not reach statistical significance (p=0.134).
Ophthalmic manifestations of Fabry disease are common even in young children with loss-of-function GLA gene mutations. Although the limited sample size possibly prevented statistical significance, systemic symptoms of autonomic neuropathy often coexist with retinal vascular changes and may share the same pathogenesis.
Background Fabry disease is a rare X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells ...throughout the body leads to major organ failure and premature death. The Fabry Outcome Survey (FOS) is a European outcomes database which was established to collect data on the natural history of this little‐known disease and to monitor the long‐term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. This paper presents the first analysis of the FOS database on the effects of ERT on renal function, heart size, pain and quality of life.
Design The effects of 1 and 2 years of ERT with agalsidase alfa on renal function (assessed by estimated glomerular filtration rate), heart size (assessed by echocardiography), pain (assessed by the Brief Pain Inventory) and quality of life (assessed by the European Quality of Life Questionnaire EQ‐5D) were analyzed in a cohort of 545 patients, 314 of whom were receiving treatment (188 for at least 12 months and 92 for at least 24 months; mean duration of treatment, 17 months; maximum duration, 56 months).
Results Treatment with agalsidase alfa stabilized renal function in patients with a mild or moderate deterioration in renal function at baseline, reduced left ventricular size in patients who had an enlarged heart at baseline, and improved pain scores and quality of life. These improvements were similar in hemizygous men and heterozygous women with Fabry disease.
Conclusions Enzyme replacement therapy with agalsidase alfa leads to significant clinical benefits in patients with Fabry disease, and treatment is likely to alter the natural history of this disorder.
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