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1.  Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients 
BMC Medical Genetics  2002;3:10.
Background
Fabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement.
Methods
We non-invasively investigated cochlear functions in 22 consecutive hemizygous males (age 19–64 years, mean 39) affected with classic FD. Conventional audiometry, tympanometry, ABR audiometry, otoacoustic emissions were performed in all patients, together with medical history record and physical examination as part of an exhaustive baseline evaluation prior to enzyme replacement therapy.
Results
A total of 12 patients (54.5%) with classic FD were found to have abnormal audition. Five patients had progressive hearing loss and seven patients (32%) experienced sudden deafness. In addition, a hearing loss on high-tone frequencies was found in 7 out of the 10 remaining patients without clinical impairment, despite their young age at time of examination. The incidence of hearing loss appeared significantly increased in FD patients with kidney failure (P < 0.01) or cerebrovascular lesions (P < 0.01), whereas there was no correlation with left ventricular hypertrophy. In addition, tinnitus aurium was also found in six patients (27%).
Conclusion
This is the first evidence of a high incidence of both progressive hearing loss and sudden deafness in a cohort of male patients affected with classic Fabry disease. The exact pathophysiologic mechanism(s) of the cochlear involvement deserves further studies.
doi:10.1186/1471-2350-3-10
PMCID: PMC134464  PMID: 12377100
2.  Fabry disease presenting with sudden hearing loss and otosclerosis: a case report 
Introduction
Fabry disease is an X-linked lysosomal storage disorder resulting in a multiple-system disorder with a wide spectrum of physical signs and symptoms, predominantly affecting the central and peripheral nervous systems, skin, heart, kidneys, and eyes.
Case presentation
We describe the case of a 26-year-old European Caucasian man who had Fabry disease and who presented with episodic sudden unilateral hearing loss and was treated with glucocorticoids, pentoxifylline, hyperbaric oxygen, and fluoride because of concomitant audiometric evidence of otosclerosis. This case demonstrates the partial and transient beneficial effect of standard treatment for sudden hearing loss not related to Fabry disease and analyzes the possible connection between typical Fabry disease inner-ear lesions and otosclerosis. Whereas hearing loss has been described in connection with Fabry disease, otosclerosis-associated hearing loss in Fabry disease has not yet been described.
Conclusions
Although progressive hearing loss in patients with Fabry disease seems to be influenced by replacement therapy, few data concerning treatment of sudden hearing loss are available. The lack of literature concerning the pathogenesis of the otological involvement in Fabry disease makes it impossible to identify a connection between the latter and otosclerosis. Therefore, this report may help to reinforce the importance of a thorough evaluation of hearing in patients with Fabry disease and may be of help with therapeutic decision-making.
doi:10.1186/1752-1947-6-112
PMCID: PMC3342865  PMID: 22507244
3.  Dysregulated Autophagy Contributes to Podocyte Damage in Fabry’s Disease 
PLoS ONE  2013;8(5):e63506.
Fabry’s disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase α-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally α-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3) in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry’s disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry’s disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry’s disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of α-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in α-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry’s disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients.
doi:10.1371/journal.pone.0063506
PMCID: PMC3656911  PMID: 23691056
4.  Inner ear involvement in Anderson-Fabry disease: long-term follow-up during enzyme replacement therapy 
Summary
This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the effects of enzyme replacement therapy with human α-galactosidase A. The study population comprised 20 patients (11 males, 9 females) aged 15-69 years (mean 39.7). Patients underwent a complete clinical and instrumental evaluation before starting and during enzyme replacement therapy. Median follow-up was 51.5 months (range 25-73). Nine patients (45%) complained of hearing symptoms (hearing loss, tinnitus); for six of them the onset and/or progression of the hearing loss were sudden. Vertigo or dizziness was reported by 6 patients (30%). Audiological evaluation showed a sensorineural hearing loss in 18 ears (45%; 10 in male patients, 8 in females). The hearing thresholds for 0.5, 1, 2 and 4 kHz frequencies ranged from 10 to 65 dB HL. Hearing loss was unilateral in 8 cases (40%; 4 in male patients, 4 in females). Also high frequency hearing loss for 4 and 8 kHz was evaluated. No signs of retro-cochlear lesions were observed by means of otoacoustic emissions and auditory brainstem response. Vestibular examinations showed a functional impairment in 7 ears (17.5%, all male patients). During enzyme replacement therapy the auditory function showed some degrees of worsening but no significant changes were observed at statistical analysis. In conclusion involvement of the inner ear is common in men and women with Fabry disease. In this study, a high incidence of cochlear hearing loss was found, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement showed a lower incidence and different pattern, thus suggesting that several patho-physiological mechanisms could play a role in determining inner ear damage in Fabry disease. Results obtained show that enzyme replacement therapy may stabilize hearing function; however, further studies on the physiopathology of the inner ear damage are needed.
PMCID: PMC2882147  PMID: 20559478
Inner ear; Sensorineural hearing loss; Fabry disease; Vestibular damage; Enzyme replacement therapy; α-galactosidase A
5.  Fabry disease 
Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.
doi:10.1186/1750-1172-5-30
PMCID: PMC3009617  PMID: 21092187
6.  Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease 
Brain : a journal of neurology  2006;130(Pt 1):143-150.
Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of α-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6–58 years (mean 31 years, SD 13) and 24 females aged 22–72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL95, defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2–67.2)] of the males. Prevalence of HL95 was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL95 was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL95 had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0–30.1 ± versus 0, IQR 0–0], more pronounced cold perception deficit [19.4 ± 5.5 versus 13.5 ± 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 ± 1.2 versus 0.77 ± 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 ± 14.1 versus 10.3 ± 3.28 mg/dl] than those without HL95 (P < 0.001). Of the females, 38% had HL95. There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.
doi:10.1093/brain/awl310
PMCID: PMC1950668  PMID: 17105746
Fabry disease; stroke; hearing impairment; peripheral neuropathy; X-linked disorder
7.  Temporal Intradiploic Dilative Vasculopathy: An Additional Pathogenic Factor for the Hearing Loss in Fabry Disease? 
JIMD Reports  2012;7:7-12.
Fabry disease (FD) is caused by progressive accumulation of neutral glycosphingolipids, including in ganglion neural and vascular endothelial cells, as a result of lysosomal α-galactosidase deficiency. High frequencies progressive sensorineural hearing loss (HL), sudden deafness, tinnitus and dizziness are otological symptoms frequently reported.
A 45-year-old man with FD, on haemodialysis since age 25, complaining of progressive HL, was started on enzyme replacement therapy (ERT) because of cardiac complications. A bilateral sloping sensorineural HL was found at baseline audiological evaluation. Computed tomography of the ears showed enlargement of the intradiploic vascular channels, principally in the petrous bone. The magnetic resonance angiography showed elongation and ectasia of the middle cerebral arteries and the arteries of the Circle of Willis, particularly the internal carotid and the basilar arteries. Follow-up audiological evaluations documented progressive worsening of HL, mainly in the high frequencies range, despite high dose ERT and evidence of cardiac improvement.
The intradiploic vascular abnormalities of the temporal bones reported herein have never been described in association with FD and may have contributed to the pathogenesis of progressive HL, by a ‘stealing’ effect upon the cochlear blood supply (like in cavernous haemangioma of the internal auditory meatus), in addition to the other mechanisms of ischaemic injury to the Organ of Corti described in FD. This clinical observation shows the value of comprehensive neuroimaging investigation of HL in FD and emphasizes the importance of early institution of specific therapy, before the occurrence of irreversible inner ear lesions and hearing damage.
doi:10.1007/8904_2012_132
PMCID: PMC3575050  PMID: 23430488
8.  Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy 
Nephrology Dialysis Transplantation  2009;24(7):2102-2111.
Background. In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized.
Methods. We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement and/or death before the initiation of enzyme replacement therapy.
Results. The mean rate of estimated glomerular filtration rate (eGFR) decline for patients was −2.93 for males, and −1.02 ml/min/1.73 m2/year for females. Prevalence and severity of proteinuria, baseline eGFR <60 ml/min/1.73 m2 and hypertension were associated with more rapid loss of eGFR. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events (mainly arrhythmias), strokes and transient ischaemic attacks occurred in 49, 11, 6% of males, and in 35, 8, 4% of females, respectively. The mean age at death for 20 male patients was 49.9 years.
Conclusions. Baseline proteinuria, reduced baseline eGFR, hypertension and male gender were associated with more rapid progression of Fabry nephropathy. The eGFR progression rate may increase with advancing nephropathy, and may differ between subgroups of patients with Fabry disease.
doi:10.1093/ndt/gfp031
PMCID: PMC2698092  PMID: 19218538
albuminuria; arrhythmia; Fabry disease; nephropathy; proteinuria; stroke
9.  Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease 
BMC Neurology  2002;2:4.
Background
Fabry disease is a lysosomal X-linked enzyme deficiency of α-galactosidase A associated with an increased mortality and morbidity due to renal failure, cardiac disease and early onset stroke.
Methods
We examined the functional blood flow response of the brain after visual stimulation (reversing checkerboard pattern), and cerebral vasoreactivity following acetazolamide (15 mg/kg) with [15O]H2O and positron emission tomography (PET) in Fabry disease. Twenty-six hemizygous patients (age range 19–47 years) were enrolled in a randomized double-blind placebo-controlled 6-month trial of enzyme replacement therapy administered by intravenous infusion every two weeks. Regional cerebral blood flow (rCBF) was measured with PET at the beginning and end of the trial.
Results
Fabry patients had a significantly greater increase in rCBF following visual stimulation and acetazolamide challenge compared to controls. Visual reactivity was normal. The time for recovery of the cerebral vasculature following acetazolamide was prolonged in Fabry patients compared to controls. The abnormal rCBF response induced by visual stimulation and acetazolamide decreased significantly following enzyme replacement therapy, as did the prolonged recovery of the cerebral vasculature.
Conclusions
Enzyme replacement therapy reverses the exaggerated cerebrovascular response in Fabry disease.
doi:10.1186/1471-2377-2-4
PMCID: PMC116601  PMID: 12079501
10.  Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease 
PLoS ONE  2014;9(1):e87054.
A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males – females; normal – impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.
doi:10.1371/journal.pone.0087054
PMCID: PMC3903616  PMID: 24475221
11.  Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests 
BMC Neurology  2010;10:38.
Background
Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.
Methods
Forty-eight Fabry patients (15 male, 30 treated with enzyme replacement therapy) and 48 sex- and age-matched controls completed a questionnaire on autonomic symptoms (the Autonomic Symptom Profile). Thirty-six Fabry patients underwent cardiovascular function tests.
Results
The Autonomic Symptom Profile revealed a significantly higher sum score in Fabry patients than in healthy control subjects (22 versus 12), but a relatively low score compared to patients with proven autonomic neuropathy. Fabry patients scored worse than healthy controls in the orthostatic intolerance domain. Scores in the male sexual dysfunction domain were comparable between healthy controls and male Fabry patients. The cardiovascular autonomic function tests revealed only mild abnormalities in seven patients. None of these seven patients showed more than one abnormal test result. Enzyme replacement therapy was not associated with less severe disease, lower ASP scores or less frequent abnormal cardiovascular function test results.
Conclusions
Male sexual function and autonomic control of the cardiovascular system are nearly normal in Fabry patients, which cast doubt on the general accepted assumption that autonomic neuropathy is the main cause of symptoms and signs compatible with autonomic dysfunction in Fabry disease. Possibly, end-organ damage plays a key role in the development of symptoms and signs in Fabry patients. An exceptional kind of autonomic neuropathy is another but less likely explanation.
doi:10.1186/1471-2377-10-38
PMCID: PMC2892441  PMID: 20529242
12.  Qualitative evaluation of the Canadian Fabry Disease Initiative 
Canadian Pharmacists Journal : CPJ  2012;145(3):136-141.e3.
Background: In late 2005, the federal and provincial governments responded to an increasing demand from physicians and their patients with Fabry disease for access to enzyme replacement therapy (ERT). This response took the form of a nationwide clinical research study, the Canadian Fabry Disease Initiative (CFDI). Patients who enrolled as participants in this longitudinal study received 1 of 2 ERT treatments. The present study used a qualitative evaluative approach to describe the perspectives of various key stakeholders regarding the CFDI and its potential as a model for providing access to expensive drugs for rare diseases.
Methods: The CFDI was evaluated from the perspectives of 4 groups of key informants: patients, CFDI investigators, policy-makers and pharmaceutical manufacturers. The qualitative methods strategy used for the study involved semistructured interviews, a holistic-inductive design and content analysis.
Results: Eighteen participants were interviewed. The study revealed that stakeholders held the following perceptions about the CFDI. The CFDI was created as a response to a drug reimbursement problem in Canada. Through specialist physicians, the CFDI has provided ERT to patients with Fabry disease across the country. The CFDI established a national database for collecting and monitoring the incidence of Fabry disease and information about ERT. The CFDI represented a collaborative effort among the various stakeholders (federal, provincial, pharmaceutical), but no stakeholder group thought that the CFDI was the correct response to the need for access to ERT. Finally, the CFDI can and should be redesigned, through modification of either its governing structure or its outcome goals.
Discussion: The CFDI was a prototype for sharing the costs of expensive therapies for rare diseases. It has provided ERT to many patients with Fabry disease for several years. However, it was poorly designed to meet its outcome goals and has been unable to provide therapy to all individuals with the disease. Therefore, many stakeholders saw this initiative as an inappropriate solution.
Conclusions: The CFDI has not met the expectations of key informant groups and some modifications may be necessary. A registry study might better accomplish the CFDI's original goals of providing access to treatment, gathering data and monitoring patients' progress.
doi:10.3821/145.3.cpj136
PMCID: PMC3567523  PMID: 23509529
13.  The meaning of modern audiological tests in relation to noise-induced deafness: a review 
Wilmot, T. J. (1972).Brit. J. industr. Med.,29, 125-133. The meaning of modern audiological tests in relation to noise-induced deafness: a review. If noise-induced deafness becomes a prescribed disease, it is inevitable that a very large number of workers with hearing difficulties will be discovered and will pose serious problems for both industrial medical officers and otologists working in the National Health Service.
The two main problems are detection of deafness and a decision whether the hearing loss is attributable to noise damage. This paper is concerned largely with the second problem, and outlines in general terms the procedures likely to be required.
After a short discussion of the initial screening procedure the paper concentrates upon those who fail to pass the requisite standard, and describes how modern hearing tests help to differentiate between various types of hearing loss. The traditional belief that conductive deafness and sensorineural deafness are easily differentiated holds true only in classical examples. In practice, in many cases, there are often mixed elements of both. In these individuals the acoustic impedance meter may give important objective evidence on the functions of the Eustachian tube, the tympanic membrane and ossicular chain, and the small but important intratympanic muscles.
Even a pure sensorineural deafness may be present without being caused by noise, and the uses of speech tests and tests for `recruitment' are invaluable in the differential diagnosis of this type of hearing loss.
Whereas noise-induced deafness is usually bilateral, unilateral deafness can be caused or aggravated by noise, and our problems are increased in these cases as efficient `masking' of the good ear is essential before we can obtain any true information about the impaired hearing ear.
One of the other problems is malingering. This may be deliberate, or a person with good hearing may believe it to be impaired; both varieties are now usually known as non-organic hearing loss. Usually the simplest differentiating factor is the ability of someone with non-organic hearing loss to hear the spoken word much more easily than pure tones, and this sign should always make one suspicious of this type of disorder.
Modern auditory analysis should enable the otologist who is equipped with suitable apparatus to diagnose with some precision the site and extent of most auditory disorders and to evaluate the proportion of noise-induced hearing loss in each individual affected.
PMCID: PMC1009389  PMID: 4553812
14.  Development of a Highly Sensitive Immuno-PCR Assay for the Measurement of α-Galactosidase A Protein Levels in Serum and Plasma 
PLoS ONE  2013;8(11):e78588.
Fabry disease is an X-linked genetic disorder caused by defects in the α-galactosidase A (GLA) gene, and heterogeneous mutations lead to quantitative and/or qualitative defects in GLA protein in male patients with Fabry disease. Random X-chromosomal inactivation modifies the clinical and biochemical features of female patients with Fabry disease. Functional polymorphisms have been frequently reported in recent times, and these increase the difficulty of understanding the pathogenetic basis of the disease. To date, GLA protein level has been measured using an enzyme-linked immunosorbent assay (ELISA). However, ELISA is not highly sensitive due to the high background noise. In this paper, we introduce a novel application of the immuno-polymerase chain reaction (PCR) method (termed Multiple Simultaneous Tag [MUSTag]) for measurement of the GLA protein level in blood samples. We compared the sensitivities of the MUSTag method with plates or magnetic beads with those of ELISA for recombinant human GLA and found that the apparent maximal sensitivity was higher for the former than for the latter. We then measured the GLA concentrations in serum and plasma from male patients with classic Fabry disease (Male Fabry), females with Fabry disease (Female Fabry), male subjects harboring the functional polymorphism p.E66Q (E66Q), and control (Control) subjects. Our results revealed that compared to the MUSTag plate and ELISA, the MUSTag beads assay afforded a clearer estimation of the GLA protein levels in the serum and plasma with minimal or no background noise, although all the methods could differentiate between the Male Fabry, E66Q, and Control groups. The Female Fabry group showed characteristic heterogeneity, which was consistent with the X-linked inheritance. This novel method is expected to be useful for the sensitive determination of GLA level in blood and elucidation of the pathogenetic basis of Fabry disease.
doi:10.1371/journal.pone.0078588
PMCID: PMC3827252  PMID: 24236025
15.  X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria 
PLoS Medicine  2007;4(3):e66.
Background
Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection.
Methods and Findings
We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies.
Conclusions
The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait.
In two populations in rural Mali, West Africa, G6PD A- deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria.
Editors' Summary
Background.
“Favism” is a condition that results from a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD), and this disorder is thought to be the commonest enzyme-deficiency disease worldwide. The disease is named favism after the Italian word for broad beans (fava), which cause a classic reaction when eaten by people with G6PD deficiency. The G6PD enzyme is particularly important in red blood cells, where it protects against damage that can be caused by certain drugs or other stresses. There are a number of normal variants of G6PD, with G6PD A and G6PD B being common in Africa. However, abnormal mutations in the gene can lead to anemia as a result of the red blood cells breaking down in response to certain drugs or types of food, or in other situations. G6PD deficiency is not spread evenly around the world; it is particularly common in Africa and the Mediterranean, and up to 20%–25% of people in certain African regions can have the condition. Although there can be serious clinical outcomes from G6PD deficiency that result from the red blood cells being broken down, G6PD deficiency may protect against malaria.
Why Was This Study Done?
The researchers here wanted to find out whether, in regions where virtually all children get malaria during early childhood, a mutation in G6PD A (written as G6PD A−) that leads to G6PD deficiency protects children from having their malaria episodes worsen into severe, life-threatening disease. They also wanted to look at whether the degree of protection from G6PD A− deficiency differed between boys and girls. The reason for looking at this had to do with the genetics of G6PD deficiency. The gene coding for G6PD is carried on the X chromosome, of which males have only one copy, whereas females have two. Therefore, males will be G6PD deficient when they inherit only one mutant gene, but females need to inherit two abnormal genes (or have the normal gene turned off, which happens by a process known as X-inactivation in a proportion of female cells).
What Did the Researchers Do and Find?
This study was carried out in two regions of Mali, West Africa, where malaria affects virtually all children under the age of 5 years. The children recruited at each study site came from two distinct cultural groups, the Dogon people of Bandiagara and the Malinké people of Kangaba and Kela. The researchers studied children coming to the medical clinics in each area with either uncomplicated malaria (i.e., mild symptoms) or severe malaria. All patients were treated normally according to the standard practices for this region. Blood samples were collected from each child in order to see how many malaria parasites were in the blood, as well as to analyze each patient's DNA to work out whether they had a mutant form of the G6PD*A gene that causes the G6PD A− form of deficiency.
Overall, 3,197 children were recruited into the study, 2,765 of whom had uncomplicated malaria and 432 had severe malaria. In both ethnic groups, children with severe malaria were much less likely to have the mutant form of the G6PD*A gene than children with uncomplicated malaria, showing that the gene mutation protected children from having their malaria progress to severe malaria. The researchers then looked at whether the protection given by the mutant forms of G6PD affected boys and girls differently. The researchers found that protection against severe malaria occurred in boys but not girls who had inherited one mutant G6PD*A− gene.
What Do These Findings Mean?
These data show that the mutation in G6PD*A that leads to the G6PD A− deficiency gives children substantial protection against severe malaria, but this protection seems to be the case for boys and not girls who have only one mutant copy of the gene. There seems to be around a two-thirds drop in risk of severe malaria in boys with G6PD deficiency as compared to normal boys. At present the reason for this difference in protection is not clear, because it is not known how malaria parasites are affected by red blood cells that lack G6PD activity.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040066.
Medline Plus has an article on glucose-6-phosphate dehydrogenase deficiency
Wikipedia has an entry on glucose-6-phosphate dehydrogenase deficiency (Wikipedia is a free internet encyclopedia that anyone can edit)
Information on malaria is available from the US Centers for Disease Control
doi:10.1371/journal.pmed.0040066
PMCID: PMC1820604  PMID: 17355169
16.  Natural history of Fabry disease in females in the Fabry Outcome Survey 
Journal of Medical Genetics  2005;43(4):347-352.
Background
Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of α‐galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females.
Aims
This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients.
Methods
Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement.
Results
The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL.
Conclusions
Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.
doi:10.1136/jmg.2005.036327
PMCID: PMC2563231  PMID: 16227523
Fabry disease; Fabry Outcome Survey; heterozygotes
17.  Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies 
PLoS Genetics  2012;8(9):e1002898.
Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.
Author Summary
The domestic dog offers a unique opportunity to study complex disorders similar to those seen in humans, but within the context of the much simpler genetic backgrounds of pure breeds, which represent closed populations. We performed a whole-genome search for genetic risk factors of adult-onset deafness in the Border Collie, a breed of herding dog that relies on acute hearing to perceive and respond to commands while working. Adult-onset deafness in Border Collies typically begins in early adulthood and is similar to age-related hearing loss in humans. This earlier onset has particular impact on the utility of working Border Collies and the livelihoods of their owners, and it appears to have a genetic cause. We identified three genetic variants that were strongly associated with adult-onset deafness in a sample of 405 Border Collies. These variants are located in two genes that have previously been linked to deafness, one involved in ear development and another that appears to mitigate tissue damage in the ear. These results provide new insight regarding genetic risk factors for age-related hearing loss in both dogs and humans.
doi:10.1371/journal.pgen.1002898
PMCID: PMC3441646  PMID: 23028339
18.  Mandarin Chinese speech recognition by pediatric cochlear implant users 
Objectives
Because of difficulties associated with pediatric speech testing, most pediatric cochlear implant (CI) speech studies necessarily involve basic and simple perceptual tasks. There are relatively few studies regarding Mandarin-speaking pediatric CI users' perception of more difficult speech materials (e.g., words and sentences produced by multiple talkers). Difficult speech materials and tests necessarily require older pediatric CI users, who may have different etiologies of hearing loss, duration of deafness, CI experience. The present study investigated how pediatric CI patient demographics influence speech recognition performance with relatively difficult test materials and methods.
Method
In this study, open-set recognition of multi-talker (two males and two females) Mandarin Chinese disyllables and sentences were measured in 37 Mandarin-speaking pediatric CI users. Subjects were grouped according to etiology of deafness and previous acoustic hearing experience. Group 1 subjects were all congenitally deafened with little-to-no acoustic hearing experience. Group 2 subjects were not congenitally deafened and had substantial acoustic hearing experience prior to implantation. Multiple linear regression analyses were performed within each group using subject demographics such as age at implantation and age at testing.
Results
Pediatric CI performance was generally quite good. For Group 1, mean performance was 82.3% correct for disyllables and 82.8% correct for sentences. For Group 2, mean performance was 76.6% correct for disyllables and 84.4% correct for sentences. For Group 1, multiple linear regression analyses showed that age at implantation predicted disyllable recognition, and that age at implantation and age at testing predicted sentence recognition. For Group 2, neither age at implantation nor age at testing predicted disyllable or sentence recognition. Performance was significantly better with the female than with the male talkers.
Conclusions
Consistent with previous studies' findings, early implantation provided a significant advantage for profoundly deaf children. Performance for both groups was generally quite good for the relatively difficult materials and tasks, suggesting that open-set word and sentence recognition may be useful in evaluating speech performance with older pediatric CI users. Differences in disyllable recognition between Groups 1 and 2 may reflect differences in adaptation to electric stimulation. The Group 1 subjects developed speech patterns exclusively via electric stimulation, while the Group 2 subjects adapted to electric stimulation relative to previous acoustic patterns.
doi:10.1016/j.ijporl.2011.03.009
PMCID: PMC3095677  PMID: 21489643
cochlear implant; children; speech; Mandarin Chinese; pediatric
19.  Heritability and complex segregation analysis of deafness in Jack Russell Terriers 
Background
The association between patterns of pigmentation and deafness in the dog has a long-documented history, with reports dating back over one hundred years. Long suspected of having a genetic basis, the search for loci with a pronounced influence in the expression of hearing loss in the dog has yet to be successful. No studies in the dog to date have found a possible influence of a specific colour locus associated with deafness. The present study is intended to evaluate the heritability of deafness in the Jack Russell Terrier (JRT), characterize the mode of inheritance, and evaluate the existence of a sex, coat colour, or coat texture influence on the expression of sensorineural deafness.
Results
The estimation of heritability of deafness in the JRT was 0.22 when deafness was considered a binary (normal/deaf) trait and 0.31 when deafness was considered a three-category (normal/unilateral/bilateral deafness). The influence of coat colour in the incidence of JRT deafness was statistically significant, indicating that dogs with more white are more likely to be deaf. The influence of sex or coat texture was not statistically significant in the incidence of JRT deafness. Complex segregation analysis revealed a model of a single locus with a large effect on the binary measure of hearing loss is not supported.
Conclusion
This is the first attempt, to our knowledge, to characterize a genetic component responsible for deafness in the JRT. The heritability of deafness in the JRT was found to be 0.22 and 0.31 considering deafness to be a two-category or three-category trait, respectively. There appears to be an influence of coat colour on the expression of deafness. In an attempt to characterize the mode of inheritance of deafness in the JRT, a model of a single locus with a large effect on hearing loss is not supported with this data. Further study is needed to determine if a single locus may be influencing deafness in the JRT. While the absence of a clear mode of inheritance complicates genetic dissection of deafness in the JRT, the assembling of this pedigree provides a tool for eventually defining the genetic bases of this disorder.
doi:10.1186/1746-6148-3-31
PMCID: PMC2194672  PMID: 17999773
20.  Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications 
Journal of Internal Medicine  2013;274(4):331-341.
Objective
The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.
Methods
A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.
Results
During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.
Conclusion
Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.
doi:10.1111/joim.12077
PMCID: PMC4282332  PMID: 23586858
dialysis; Fabry disease; prognosis; stroke; sudden cardiac death; α-galactosidase A
21.  Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN) 
Nephrology Dialysis Transplantation  2009;25(7):2168-2177.
Background. In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function.
Methods. An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported.
Results. We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 μmol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m2 and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1–2 chronic kidney disease with minimal proteinuria.
Conclusions. The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.
doi:10.1093/ndt/gfp528
PMCID: PMC2902894  PMID: 19833663
chronic kidney disease; Fabry disease; pathology; sclerosis; scoring
22.  Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease 
PLoS ONE  2012;7(5):e33743.
Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose.
doi:10.1371/journal.pone.0033743
PMCID: PMC3344819  PMID: 22574107
23.  Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes. 
Molecular Medicine  2002;8(6):306-312.
BACKGROUND: Fabry disease (OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism resulting from mutations in the alpha-galactosidase A (alpha-Gal A) gene. The disease is phenotypically heterogeneous with classic and variant phenotypes. To assess the molecular heterogeneity, define genotype/phenotype correlations, and for precise carrier identification, the nature of the molecular lesions in the alpha-Gal A gene was determined in 40 unrelated families with Fabry disease. MATERIALS AND METHODS: Genomic DNA was isolated from affected males or obligate carrier females and the entire alpha-Gal A coding region and flanking sequences were amplified by PCR and analyzed by automated sequencing. Haplotype analyses were performed with polymorphisms within and flanking the alpha-Gal A gene. RESULTS: Twenty new mutations were identified (G43R, R49G, M72I, G138E, W236X, L243F, W245X, S247C, D266E, W287C, S297C, N355K, E358G, P409S, g1237del15, g10274insG, g10679insG, g10702delA, g11018insA, g11185-delT), each in a single family. In the remaining 20 Fabry families, 18 previously reported mutations were detected (R49P, D92N, C94Y, R112C [two families], F113S, W162X, G183D, R220X, R227X, R227Q, Q250X, R301X, R301Q, G328R, R342Q, E358K, P409A, g10208delAA [two families]). Haplotype analyses indicated that the families with the R112C or g10208delAA mutations were not related. The proband with the D266E lesion had a severe classic phenotype, having developed renal failure at 15 years. In contrast, the patient with the S247C mutation had a variant phenotype, lacking the classic manifestations and having mild renal involvement at 64 years. CONCLUSIONS: These results further define the heterogeneity of alpha-Gal A mutations causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis in these families, and provide additional genotype/phenotype correlations in this lysosomal storage disease.
PMCID: PMC2039995  PMID: 12428061
24.  Potential role of vitamin D deficiency on Fabry cardiomyopathy 
Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42 % males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.
doi:10.1007/s10545-013-9653-8
PMCID: PMC3976508  PMID: 24141790
25.  Ocular manifestations of Fabry's disease: data from the Fabry Outcome Survey 
Background
Fabry's disease is an X‐linked lysosomal storage disorder characterised by deficient activity of the enzyme α‐galactosidase A.
Aim
To study eye abnormalities in patients with Fabry's disease in the Fabry Outcome Survey (FOS).
Methods
This is the largest study of ocular manifestations in patients with Fabry's disease. In all, 173 of the 688 patients enrolled in FOS underwent a detailed ophthalmic examination, with a special focus on abnormalities of the cornea, lens, conjunctival and retinal vessels.
Results
Cornea verticillata was reported in 76.9% of females and 73.1% of males; vessel tortuosity was observed in 21.9% of females and in 48.7% of males. Fabry cataract was recorded in 9.8% of females and in 23.1% of males. Cornea verticillata was therefore the most frequently reported ophthalmic abnormality in Fabry's disease in both hemizygotic males and heterozygotic females. Tortuous conjunctival and retinal vessels and Fabry cataract were more frequently found in males than in females. Vessel tortuosity was more frequently observed in patients with a higher severity score and greater impairment of renal and cardiac function, suggesting that it may be associated with a more severe disease. The youngest patient with ocular changes was 3 years old. The prevalence of tortuous vessels in males increased with age.
Conclusion
The presence of cornea verticillata is a useful aid in the diagnosis of Fabry's disease, as it is often present at the time of diagnosis. Vessel tortuosity may have some predictive value for systemic involvement.
doi:10.1136/bjo.2006.100602
PMCID: PMC1857640  PMID: 16973664

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