Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease

Fabry disease (FD) is an X-chromosomal disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. We performed mutation screening on a cohort of 121 patients including 84 male and 37 female index cases and identified a total of 90 different mutations, 34 of which are reported for the first time here. Both point mutations (74.4%) and 'short length' rearrangements (25.6%) were found, including missense (54.4%), nonsense (14.4%), and splice site point mutations (5.6%), deletions (17.8%) or insertions/duplications (5.6%) of a few nucleotides, and complex rearrangements including larger deletions (2.2%). GLA mutations were identified in 82 (97.6%) of the 84…

743 Lysosomal Storage Disorders in Non-Immunological Hydrops Fetalis - More Common than Assumed?

Background Although non immunological hydrops fetalis (NIHF) is a very rare disorder, the disturbance accounts for a disproportionate share (3%) of overall mortality in the perinatal period. Lysosomal storage disorders (LSD) are only exceptionally considered to be the cause of NIHF. The reported incidence is about 1%. On the other hand, in about 18% of all cases, NIHF is classified as idiopathic. Patients and methods We report four cases of transient NIHF due to LSD and reviewed the literature for LSD associated with NIHF. Results At present, 12 different LSD are described to be associated with NIHF. The majority of reported patients already had a family history of NIHF, which had not been …

Identification of novel mutations in the ABCA12 gene, c.1857delA and c.5653–5655delTAT, causing harlequin ichthyosis

Abstract Harlequin ichthyosis (HI) is a severe autosomal recessive developmental disorder of the skin that is frequently but not always fatal in the first few days of life. In HI, mutations in both ABCA12 gene alleles must have a severe impact on protein function and most mutations are truncating. The presence of at least one nontruncating mutation (predicting a residual protein function) usually causes a less severe congenital ichthyosis (lamellar ichthyosis or congenital ichthyosiform erythroderma). Here we report on a girl with severe HI diagnosed by prenatal ultrasound at 33 5/7 week gestation. Ultrasound findings included ectropion, eclabium, deformed nose, hands and feet, joint contra…

Cardiac manifestations of Anderson-Fabry disease in heterozygous females.

AbstractObjectivesWe sought to define the prevalence of cardiac involvement in female patients with Anderson–Fabry disease (AFD).BackgroundAnderson–Fabry disease is a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb3), the major substrate of the deficient α-galactosidase A enzyme, accumulates progressively in vulnerable cells, including the cardiovascular system. It has been believed that heterozygous females have less cardiac involvement than hemizygous males with AFD.MethodsWe performed two-dimensional echocardiographic examinations of female patients heterozygous for AFD.ResultsSince 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to 70.8 y…

Morbus Fabry, Glomerulonephritis mit Halbmondbildung und granulomat�se interstitielle Nephritis

Eine 26-jahrige Patientin wurde unter der Diagnose "Fieber unbekannter Ursache" und Nierenversagen aufgenommen. Mittels Nierenbiopsie, einschlieslich histologischer, immunhistochemischer und elektronenmikroskopischer Verfahren wurden neben einem Morbus Fabry, eine extrakapillar-proliferative Glomerulonephritis (mit Halbmondbildung) und granulomatose interstitielle Nephritis diagnostiziert. Der Bruder der Patientin hatte vor Jahren eine Nierenbiopsie mit der Diagnose einer metabolischen Storung. Die Nachbeurteilung dieser Nierenbiopsie zeigte auch hier Nierenveranderungen im Rahmen eines Morbus Fabry, wobei assoziiert eine tubulointerstitielle Nephritis vorlag. Nach unserer Kenntnis ist dies…

Enzyme replacement therapy with agalsidase alfa in children with Fabry disease.

Aim: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease. Methods: Safety and efficacy of ERT with agalsidase alfa, 0.2 mg/kg infused over 40 minutes every 2 weeks for 23 weeks, were studied in a multicentre open-label trial in nine boys and four girls. Median age at the start of the study was 11.0 years (range 3.5–18 years). Results: Fifty-four adverse events were reported in 11 patients. No serious adverse events related to ERT were reported. Twelve of the 54 adverse events were considered possibly or probably related to ERT. Infusion reactions (8 mild, 3 moderate) occurred in four boys, in seven infusions. One boy developed IgG antibodies, although he…

Cumulative incidence rates of the mucopolysaccharidoses in Germany

In order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100,000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100,000 births (1.3 cases per 100,000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in…

Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ)

Abstract Introduction Common symptoms for children with Anderson-Fabry Disease (FD) such as acroparaesthesia and gastrointestinal manifestations can only be objectively assessed in patients using a valid instrument. To date, no such instrument exists. Methods A preliminary 40-item measure of symptoms and experience with FD, the Fabry-specific Paediatric Health and Pain Questionnaire (FPHPQ) was developed, but lacked a formal assessment of its measurement properties. The FPHPQ was used in the Fabry Outcome Survey (FOS), a registry for all patients with a confirmed diagnosis of FD who are receiving agalsidase alfa, or are treatment naïve and who are managed by physicians participating in FOS.…

Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.

Background Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. Aim Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). Methods Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 4…

Disease manifestations and X inactivation in heterozygous females with Fabry disease

Aim: Fabry disease is an X-linked lysosomal storage disorder characterized by an accumulation of neutral glycosphingolipids in multiple organ systems caused by α-galactosidase A deficiency due to mutations in the GLA gene. The majority of heterozygous females show the characteristic signs and symptoms of the disease, and some of them are severely affected. The current hypothesis for the occurrence of disease manifestations in females is skewed X inactivation favouring the mutant GLA allele. Method: We analyzed the patterns of X inactivation in the leukocytes of 28 biochemically and genetically characterized symptomatic Fabry disease heterozygotes and their correlation with clinical and bioc…

207 Diagnosis of Anderson-Fabry Disease in Childhood. What Should We Focus on?

Background: Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder which also affects female carriers and has an early onset of symptoms in childhood in both genders. Signs and symptoms are frequently misunderstood and often diagnosis is made approximately 10–20 years after their onset. This has been clearly demonstrated by Fabry outcome survey (FOS) a European database on the natural history of FD and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). Methods: Demographic data on 82 children (40 boys and 42 girls) below 18 years of age, with a median age at FOS entry of 12.9 (0.7–17.9) were analysed Results: Most frequently reported symptoms (60–80%) …

Measuring patient experiences in fabry disease: validation of the Fabry Outcome Survey (FOS) paediatric health and pain questionnaire

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 a…

Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF) - more common than assumed? Report of four cases with transient NIHF and a review of the literature

Abstract Background Lysosomal storage disorders (LSD) are a rare cause of non immunological hydrops fetalis (NIHF) and congenital ascites. The reported incidence is about 1%. The incidence of idiopathic NIHF is estimated to be about 18%. Patients and methods We report four cases with transient hydrops fetalis resulting from LSD and performed a literature review on LSD with NIHF and congenital ascites in combination. Results At present, 12 different LSDs are described to be associated with NIHF or congenital ascites. Most patients had a family history of NIHF, where the preceding sibling had not been examined. A diagnostic approach to the fetus with NIHF due to suspected LSD either in utero …

The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents.

Fabry disease (FD) is a debilitating progressive multisystem X-linked lysosomal storage disorder. It was generally believed that the disease affects only adult males. Through systematic pedigree analysis, we identified 35 paediatric FD patients (age 1 to 21 years, mean 12.6 years) in 25 families. Predominant signs in this cohort were: acroparesthesia, hypohidrosis, and cornea verticillata. Neurological and psychological changes, such as tinnitus, recurrent vertigo, headache, diminished level of activity, fatigue, and depression were often observed. Angiokeratoma and gastrointestinal symptoms were frequent. Some patients also showed cardiac abnormalities. Six children and adolescents (three …

Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study.

Summary: Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency of α-galactosidase A. Affected patients experience debilitating neuropathic pain and have premature mortality due to renal failure, cardiovascular disease or cerebrovascular complications. The disease may be X-linked dominant, since most females heterozygous for Fabry disease are affected clinically. We evaluated the safety, efficacy and pharmacokinetics of agalsidase alfa (Replagal) administered intravenously to female patients with Fabry disease in an open-label, single-centre study. Fifteen severely affected patients received agalsidase alfa at 0.2 mg/kg every other week for up to 55 weeks. Ag…

PND44 Validation of the Fabry Outcome Survey (FOS) Paediatric Health and Pain Questionnaire

Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.

Anderson-Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal alpha-galactosidase A. Clinical manifestations of Anderson-Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson-Fabry disease. This rev…

The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy

Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system--the Mainz Severity Score Index (MSSI)--to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained fro…

Non‐immune hydrops fetalis was rare in Sweden during 1997‐2015, but cases were associated with complications and poor prognosis

Aim: The study was designed to document the incidence of non-immune hydrops fetalis (NIHF) at birth and characterise associated outcomes and obstetric complications. Methods: Data on more than 1.9 million births were extracted from the Swedish Birth Register for 1997-2015. Pregnancies not affected by NIHF served as controls. National registers on mortality and hospitalisations provided follow-up information. Results: There were 309 cases of NIHF at birth corresponding to an incidence of 1.6 per 10 000, lower than in previous studies. NIHF was more frequent in mothers aged ≥35 years and with a history of stillbirth. Preterm delivery occurred in 77.7% in the NIHF group, including 31.7% before…

Mucopolysaccharidosis Type VII (Sly disease) survivors

treatment. Onset of neurological symptoms at age 8 and in adolescence. Pair 4: L.M. died at age 5 months due to liver failure. P.M. (7 years): earlyinfantile form, despite treatment start at age 2 progressive neurological deterioration. Pair 5: R.K.: late-infantile form, untreated, died at age 9 due to progressive neurological involvement. M.K.: late infantileform, start of treatment at age 5, died at age 13 due to epileptic encephalopathy. These cases reveal that disease onset and progression in siblings with NPC vary, and that miglustat can slow disease progression.

A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease

Although Fabry disease is X linked and considered to affect primarily male hemizygotes, female heterozygotes may experience all the signs and symptoms of this metabolic disorder. This prospective, single-center, open-label, clinical trial was performed to evaluate the long-term response of female patients with Fabry disease to enzyme replacement therapy.Symptomatic women (average age = 47 years) enrolled in this 4-year study were treated with agalsidase alfa (Replagal, Shire HGT, Inc.) at a dose of 0.2 mg/kg, every other week for 4 years (N = 36). Clinical and biochemical assessments were conducted at 12-month intervals.The Mainz Severity Score Index, a measure of total disease burden, was …