Symptoms Of Fabry Disease Research Articles

Hearing loss in patients with Fabry disease

Fabry disease is an X-linked lysosomal storage disease involving deficient activity of alpha-galactosidase A, which leads initially to pain, and later to renal insufficiency, cardiomyopathy and stroke. Until now few details are available on hearing impairment in patients with Fabry disease, and especially few relating to female patients. We examined 43 female and 29 male patients. In this study we looked into the question of whether and to what extent patients of both genders are affected by hearing impairment. Hearing loss is characteristic being more severe at high frequencies frequencies. Overall, 22 female and 15 male patients were found to have suffered a hearing loss. Patients with severe symptoms of Fabry disease usually demonstrate more prominent hearing losses. Both men and women with Fabry disease are affected by hearing impairment. It seems that the hearing loss is less marked in female than in male patients. Children with Fabry disease complain of tinnitus more frequently than other children and quite early in the course of the disease.

Proteomics of specific treatment-related alterations in Fabry disease: A strategy to identify biological abnormalities

Fabry disease is inherited as an X-linked disorder secondary to deficiency of alpha-galactosidase A, resulting in abnormal metabolism of substances containing alpha-d-galactosyl moieties. As a consequence, a multisystem disorder develops, culminating in strokes, progressive renal, and cardiac dysfunction. Signs and symptoms of Fabry disease become manifest in childhood, but diagnosis is often delayed. Thirteen children with Fabry disease (age range, 6.5-17 years) were studied as part of a 6-month open-label study of enzyme replacement therapy (ERT) with agalsidase alfa. Paired serum samples were drawn at the start of the study and after 6 months of ERT. Global protein changes in paired samples were compared by using differential stable isotope labeling of peptide lysine residues with O-methylisourea and subsequent nanoHPLC-tandem MS. Statistically significant decreases were observed for five proteins following ERT: alpha(2)-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-alpha-2 C chain, and alpha-2-antiplasmin. The presence of low levels of alpha-2-antiplasmin and plasminogen was confirmed by alternate means in 34 consecutive patients, including four of five ERT-naïve subjects. Decreased alpha-2-antiplasmin was associated with a parallel increase in circulating VEGF. Soluble VEGF receptor-2 was significantly elevated in plasma of patients compared with pediatric controls and decreased with ERT. These results suggest previously unknown abnormalities of fibrinolysis and angiogenesis factors in Fabry disease. We demonstrated the feasibility of identifying treatment-specific alterations in a small number of subjects that point to previously unsuspected disease-related biological abnormalities.

Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life

PurposeTo determine if there is significant symptomatology in women with heterozygous α-galactosidase mutations. MethodsData from medical records of the 44 heterozygous females followed at Cedars-Sinai Medical Center were compiled and analyzed for symptoms of Fabry disease. Quality of life data were also analyzed. ResultsSeventy-six percent were referred due to an affected male relative; 76% reported acroparesthesias as their first symptom. A mean of 15.7 years elapsed from onset of first symptoms to the diagnosis. Quality of life, measured by the SF-36 survey, was globally reduced. Pain affected mood and enjoyment of life. Central/peripheral nervous, cardiopulmonary, and renal system manifestations of Fabry disease were present far above that predicted for random X-inactivation of the normal allele. Fatigue, present in 59%, was associated with reduced maximum oxygen consumption (P = 0.049); exercise intolerance, present in 83%, was associated with reduced maximal heart rate during exercise testing (P = 0.0089). Women diagnosed via family history experienced more angina (P = 0.035), decreased vibration sense (P = 0.026), and had a worse percentage predicted FEF25–75 (P = 0.037) compared to women diagnosed because of symptoms. ConclusionsThis study indicates that the asymptomatic female carrier of Fabry disease is the exception, not the rule: heterozygotes suffer from significant multisystemic disease and reduced quality of life and must be monitored and treated accordingly.

Hyperhidrosis: a new and often early symptom in Fabry disease. International experience and data from the Fabry Outcome Survey

Hypohidrosis is a classic feature of Fabry disease; in contrast, hyperhidrosis has only been rarely described. The aim of the study is to characterise the baseline descriptive data on hyperhidrosis (frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy) in hemizygous male and heterozygous female patients with Fabry disease. We describe case histories of five patients with Fabry disease and hyperhidrosis seen at three different centres. We have also analysed a cohort of 21 paediatric patients in the UK and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three female, two male) with hyperhidrosis were originally identified, although each had additional symptoms related to Fabry disease. The age at onset of hyperhidrosis was less than 18 years in four cases. In the cohort of 21 paediatric patients (12 female, nine male), one female had hyperhidrosis; the age at onset of this symptom was 11 years. In the FOS cohort, 66 of 714 patients with Fabry disease had hyperhidrosis (44 of 369 females, 11.9%; 22 of 345 males, 6.4%). The female predominance was observed in seven of nine countries from which data were analysed. Hyperhidrosis is an increasingly recognised feature of the Fabry disease phenotype. It is more prevalent in females than in males and often appears in childhood or adolescence. The efficacy of enzyme replacement therapy on this recently recognised symptom should be assessed.

Hearing loss in Fabry disease: data from the Fabry Outcome Survey

Hearing loss is a common symptom in Fabry disease, but neither its natural course nor its aetiology has been defined precisely. The aim of this study was to provide a detailed epidemiological description of hearing impairment in patients in the Fabry Outcome Survey (FOS), which is the largest available database of Fabry patients. Questionnaires were completed by 566 Fabry patients, of whom 316 reported ear-related symptoms. Pure-tone audiograms from 86 patients, performed before starting enzyme replacement therapy, were analysed and compared with age- and sex-specific normal values (International Organization for Standardization, ISO 7029). When compared to an age-matched population (ISO 7029), 74% of patients had a threshold elevated above the 95th centile in at least one tested frequency. All frequencies were affected to a similar degree. However, only 14 patients (16%) were clinically affected by hearing impairment according to the age-independent World Health Organization (WHO) classification (mean threshold at 0.5, 1 and 2 kHz worse than 25 dB). Hearing loss was sensorineural in 63 patients (73%) of whom 7 patients (8%) had also a conductive component. One patient had a purely conductive hearing loss. Episodes of sudden hearing loss seemed to occur more frequently than in the general population. Men were affected earlier and more severely than women. Hearing in Fabry disease is significantly worse than in an age-matched general population but leads to clinically relevant hearing impairment in only 16% of cases. It resembles accelerated presbycusis with an additional Fabry-specific strial-type hearing loss.

The Mainz Severity Score Index (MSSI): development and validation of a system for scoring the signs and symptoms of Fabry disease

Fabry disease is a rare lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme alpha-galactosidase A. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. This paper describes the development of the Mainz Severity Score Index (MSSI), a scoring system for patients with Fabry disease. The MSSI score has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy.

The Mainz Severity Score Index (MSSI): development and validation of a system for scoring the signs and symptoms of Fabry disease

AbstractFabry disease is a rare lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α‐galactosidase A. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life‐threatening manifestations affecting multiple organ systems in the body. This paper describes the development of the Mainz Severity Score Index (MSSI), a scoring system for patients with Fabry disease. Conclusion: The MSSI score has been proven to be representative in patients with ‘classic’ Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy.

Does enzyme replacement therapy improve symptoms of Fabry disease in patients undergoing dialysis?

Does enzyme replacement therapy improve symptoms of Fabry disease in patients undergoing dialysis?

Paroxysmal vertigo as the presenting symptom of Fabry disease

A 50-year-old woman presented with a 10-year-history of paroxysmal attacks of severe rotational vertigo lasting seconds without hearing loss or tinnitus, occurring approximately once monthly. MRI revealed megadolichobasilar artery and white-matter lesions (figure, A). Figure. (A) T2-weighted axial MRI shows asymmetric, widespread, hyperintense white-matter lesions. (B, C) Three-dimensional-CISS …

The Relationship of Vascular Glycolipid Storage to Clinical Manifestations of Fabry Disease

Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (Gb3), in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb3 levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (>150 g protein/24-h urine) in 23 of 38 (61%), low estimated glomerular filtration rate (<90 mL/min per 1.73 m) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible.

Psychiatrische und neuropsychologische Auffälligkeiten bei Patienten mit Morbus Fabry: Literaturübersicht

Fabry Disease (FD) is an X-linked lysosomal storage disorder (prevalence about 1 : 100 000) caused by a genetic defect associated with a lack of alpha-galactosidase A (alpha-GAL) enzyme activity. As a consequence, neutral glycosphingolipides can not be cleaved and metabolized, and accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. The most prominent symptoms comprise pain attacks and acroparesthesia, angiokeratoma, corneal opacity, renal and cardiac dysfunction, hypo- and anhidrosis, gastrointestinal symptoms, and cerebrovascular dysfunction with vertigo, headache, and cerebral ischemia. Characteristic symptoms of FD can occur in male and female patients with the same prevalence, while females with FD seem to be less severely affected. The course of untreated illness is progressive with considerable interindividual variability. Since 2001 two enzyme replacement therapies are approved which can possibly stop the disease progress and alleviate symptoms. The very few reports and clinical observations have shown that a very high proportion of FD patients develop neuropsychiatric symptoms. However, accurate data are lacking. Although the pathophysiologic mechanisms are quite unknown, it is surmised that sphingolipid deposits in the endothelium of small cerebral vessels lead to regional cerebral ischemia accompanied by neuropsychiatric symptoms and deficits. Furthermore, patients with FD are chronically distressed by pain attacks and additional somatic and psychological impairment. Frequently, pain attacks are triggered by psychosocial stress. The high interindividual variability can, thus, also be interpreted on the basis of existing stress and coping models. The present paper will review the presently available psychiatric and neuropsychological findings in FD and will discuss difficulties associated with classification and differential diagnosis of psychiatric disorders occurring in patients with FD.

302 Hearing Abnormalities in Children with Fabry Disease: Data from FOS - the Fabry Outcome Survey

Background: Fabry disease is an X-linked glycosphingolipid storage disorder due to a deficiency of the enzyme alpha-galactosidase A. Accumulation of substrate results in a progressive and life-threatening multisystemic disease. Early clinical manifestations include pain and gastrointestinal symptoms. Sensorineural hearing loss and vertigo are well-recognized features of the disorder, occurring in approximately 50% of adults with Fabry disease. We have investigated the audiological symptoms of Fabry disease in children using pure-tone and impedance audiometry. Methods: Symptom history was obtained using a standardized questionnaire from FOS − the Fabry Outcome Survey. Hearing was measured using pure-tone audiometry of both air (250–8000 Hz) and bone (500–4000 Hz) conduction thresholds, with masking as appropriate. Impedance audiometry was performed to exclude effusions. Results: Symptom questionnaires were completed by 46 boys and 52 girls, with a median age of 12 (range, 1–18) and 14 (range, 2–18) years, respectively. A total of 15% of both boys and girls complained of dizziness. Tinnitus was reported in 22% of boys and 35% of girls. Generally, the children with hearing loss were found to have different degrees of impairment in each ear. Air conduction thresholds in the ear with the most significant hearing loss were abnormal (> 20 dB) in 20–40% of boys and 10–25% of girls. Approximately 79% of children with ear-related symptoms also complained of neurological pain and gastrointestinal signs and symptoms. Conclusions: Audiological symptoms, especially tinnitus, and abnormal hearing thresholds are not uncommon in children with Fabry Disease. A large proportion of children with audiological symptoms also suffered from pain and gastrointestinal manifestations. A cluster of acroparaesthesiae, gastrointestinal manifestations and hearing abnormalities are therefore suggestive of Fabry disease.

Natural history of the cerebrovascular complications of Fabry disease

Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of alpha-galactosidase A, which results in progressive accumulation of globotriaosylceramide in a range of cells and tissues. Neurological symptoms of Fabry disease, including peripheral neuropathy and cerebrovascular events, are among the most significant clinical aspects. In this paper we present the natural history and mechanisms involved in the cerebrovascular complications of Fabry disease using data reported in FOS-- the Fabry Outcome Survey--and other registries and clinical studies. We discuss ways in which these manifestations can be modified by intervention, including both general measures for cerebrovascular disease and enzyme replacement therapy. Data from FOS have provided important insights into the natural history of the cerebrovascular complications of Fabry disease. Furthermore, the database has demonstrated that significant renal or cardiac disease often co-exists with cerebrovascular disease, and may predispose patients with Fabry disease to neurological disability and stroke.

Recurrence of Fabry disease as a result of paternal germline mosaicism for α-galactosidase a gene mutation

We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.

38-Year-Old Man With Priapism and a History of Paranoid Schizophrenia

38-Year-Old Man With Priapism and a History of Paranoid Schizophrenia

Relief of gastrointestinal symptoms under enzyme replacement therapy [corrected] in patients with Fabry disease.

Gastrointestinal symptoms, including diarrhoea and abdominal pain, are one of the earliest and most frequently reported signs of Fabry disease, a rare X-linked lipid storage disorder. As the disease progresses, renal, cardiac and cerebrovascular complications develop, resulting in more serious symptoms and early mortality. The present study evaluated the effects of enzyme replacement therapy (ERT) with agalsidase alfa on the gastrointestinal symptoms of Fabry disease. Following 6 months of treatment, both the severity ( p < 0.02) and frequency ( p < 0.02) of abdominal pain decreased. For those patients who had received agalsidase alfa for more than 6 months, the observed improvement was generally maintained. This is the first study indicating a significant beneficial effect of ERT on gastrointestinal symptoms in a group of patients treated for Fabry disease.

Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey

Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. In response to the recent introduction of enzyme replacement therapy, the Fabry Outcome Survey (FOS) was established to pool data from European clinics on the natural history of this little-known disease and to monitor the long-term efficacy and safety of treatment. This paper presents the first analysis of the FOS database and provides essential baseline data against which the effects of enzyme replacement can be measured. Baseline data from a cohort of 366 patients from 11 European countries were analysed in terms of demography and clinical manifestations of Fabry disease. Misdiagnosis of Fabry disease is common, and the mean delay from onset of symptoms to correct diagnosis was 13.7 and 16.3 years in males and females, respectively. Although previously thought to have serious manifestations only in hemizygous men, the FOS database has confirmed that females heterozygous for Fabry disease are similarly affected. Furthermore, signs and symptoms of Fabry disease may be present from early childhood. With the advent of enzyme replacement therapy, it is important that general practitioners and physicians in a range of specialties recognize the signs and symptoms of Fabry disease so that effective treatment can be given. Baseline data from FOS demonstrate that enzyme replacement therapy should not be restricted to hemizygous men, but should be considered for both heterozygous females and children.

Clinical benefit in Fabry patients given enzyme replacement therapy--a case series.

Fabry disease is a rare lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A and subsequent pathological accumulation of glycosphingolipids throughout the body. Traditionally, Fabry disease was managed symptomatically, but the introduction of enzyme replacement therapies (ERTs) (agalsidase beta (Fabrazyme); agalsidase alfa (Replagal)) has transformed treatment of this disorder. Clinical studies of both compounds have demonstrated clearance of glycosphingolipds from key tissues. To explore whether substrate clearance translates into clinical benefit, a retrospective survey of 17 patients (mean age 34.7 years) treated with agalsidase beta (1 mg/kg every 2 weeks) was undertaken, using an eight-item retrospective questionnaire developed specifically to assess the effect of ERT on the symptoms of Fabry disease. Pain severity, heat tolerance, physical activity, fatigue and psychological status were scored using a 10-point visual analogue scale (e.g. for pain severity: 1=none, 10=strong). Answers to all other questions were quantitative. Changes in mean scores were 4.69 to 2.25 (p =0.012) for pain severity; 4.38 to 2.21 (p =0.019) for number of pain crises per month; 8.69 to 2.98 (p =0.097) for duration of pain crises in hours; 2.76 to 5.76 (p =0.002) for heat tolerance; 3.28 to 2.51 (p =0.058) for bowel movements per day; 2.47 to 4.47 (p =0.007) for frequency of physical activity; 5.53 to 3.71 (p =0.046) for fatigue, and 5.82 to 8.12 (p =0.005) for psychological status. All patients improved in at least one aspect, although the degree of improvement across patients and aspects varied widely; reasons for this remain unclear. Despite the inherent bias involved in retrospective questionnaires, we believe that the findings are encouraging. A prospective version of the questionnaire is currently under validation.

The Molecular Defect Leading to Fabry Disease: Structure of Human α-Galactosidase

Fabry disease is an X-linked lysosomal storage disease afflicting 1 in 40,000 males with chronic pain, vascular degeneration, cardiac impairment, and other symptoms. Deficiency in the lysosomal enzyme α-galactosidase (α-GAL) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms. Here, we present the structure of the human α-GAL glycoprotein determined by X-ray crystallography. The structure is a homodimer with each monomer containing a (β/α) 8 domain with the active site and an antiparallel β domain. N-linked carbohydrate appears at six sites in the glycoprotein dimer, revealing the basis for lysosomal transport via the mannose-6-phosphate receptor. To understand how the enzyme cleaves galactose from glycoproteins and glycolipids, we also determined the structure of the complex of α-GAL with its catalytic product. The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues (D170 and D231), which act as a nucleophile and an acid/base, respectively. As a point mutation in α-GAL can lead to Fabry disease, we have catalogued and plotted the locations of 245 missense and nonsense mutations in the three-dimensional structure. The structure of human α-GAL brings Fabry disease into the realm of molecular diseases, where insights into the structural basis of the disease phenotypes might help guide the clinical treatment of patients.

Auditory and vestibular findings in Fabry disease: a study of hemizygous males and heterozygous females.

This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the early effects of enzyme replacement therapy with human alpha-galactosidase A. Fourteen patients (10 males, 4 females) aged 14-57 years were studied. Each patient underwent a clinical (history of otological and vestibular aspects, otoscopy) and instrumental (pure tone and speech audiometry, impedance, auditory brainstem response and oto-acoustic emission recordings, vestibular caloric tests, electronystagmography during acceleratory stimulation, dynamic posturography) evaluation before starting enzyme replacement therapy. Fifty per cent of patients complained of hearing symptoms (hearing loss, tinnitus, ear fullness). Subjective hearing loss was present in six cases and in three cases it was the first reported symptom of Fabry disease. In six of the seven cases the onset and/or progression of hearing symptoms were sudden. Vertigo or dizziness was reported by four patients and in two cases was associated with hearing symptoms. Audiological evaluation showed sensorineural hearing loss in eight patients (5 males, 3 females). Hearing loss was unilateral in six cases and bilateral in the remaining two cases. The hearing loss (HL) ranged from 30 to 80 dB HL (mean, 43 dB HL) and the lesion was always cochlear. Vestibular examination showed abnormalities in four patients (bilateral weak/abolished response in three cases, side prevalence in one case), which were not related to either the audiological results or the history of vertigo/dizziness. Involvement of the inner ear is common in men and women with Fabry disease. We found a high incidence of cochlear hearing loss, 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 had a lower incidence and showed a different pattern, thus suggesting that several pathophysiological mechanisms could play a role in determining inner ear damage in Fabry disease. Our preliminary results show that enzyme replacement therapy may stabilize hearing function; however, further follow-up is required.