Roberta Ricci

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

Background  Fabry disease is a rare X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. 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.

Early Detection of Fabry Cardiomyopathy by Tissue Doppler Imaging

Background—Fabry cardiomyopathy is diagnosed by detection of left ventricular hypertrophy (LVH) in patients with &agr;-Galactosidase A deficiency. Conventional noninvasive tools are unable to provide a preclinical diagnosis allowing prompt institution of enzymatic therapy. Methods and Results—We studied three groups of patients: 10 patients with causal mutations for Fabry disease and LVH, 10 mutation-positive patients without LV, and 10 healthy relatives without causal mutations and no LVH. All patients with LVH and 6 patients with Fabry disease without LVH with complex repetitive ventricular arrhythmias underwent biventricular endomyocardial biopsy to assess cardiac involvement. In all patients 2-dimensional echocardiography with tissue Doppler analysis in the pulsed Doppler mode was performed: systolic (Sa), early diastolic (Ea), and late diastolic (Aa) velocities were measured, and the Ea/Aa ratio and the dimensionless parameter E/Ea were computed at both corners of the mitral annulus. Histology and electron microscopy studies showed glycosphingolipid deposits in all cases. All mutation-positive patients had significant reduction of Sa, Ea, and Aa velocities at both corners of the mitral annulus compared with normal control subjects. Ea/Aa ratio was significantly lower and E/Ea ratio significantly higher in mutation-positive patients than in control subjects. Patients with LVH showed significantly lower contraction and relaxation tissue Doppler velocities, lower Ea/Aa ratio, and higher E/Ea ratio in comparison with mutation-positive patients with no LVH. Conclusions—Fabry cardiomyopathy is characterized by reduced myocardial contraction and relaxation tissue Doppler velocities, detectable even before development of LVH. Tissue Doppler imaging can provide a preclinical diagnosis of Fabry cardiomyopathy, allowing early institution of enzyme replacement therapy.

Fabry disease: overall effects of agalsidase alfa treatment

Background  Fabry disease is a rare X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A. Progressive accumulation of the substrate globotriaosylceramide in cells throughout the body leads to major organ failure and premature death. The Fabry Outcome Survey (FOS) is a European outcomes database which was established to collect data on the natural history of this little‐known disease and to monitor the long‐term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. This paper presents the first analysis of the FOS database on the effects of ERT on renal function, heart size, pain and quality of life.

Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey).

Background: Fabry disease is an X linked lysosomal storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A. This leads to accumulation of globotriaosylceramide in nearly all tissues, including the blood vessels, kidney, myocardium, and nervous system. Symptoms often begin in childhood and include acroparaesthesia, with burning or tingling pain that spreads from the extremities to more proximal sites. Aims: This study set out to evaluate pain and its influence on quality of life in patients with Fabry disease receiving enzyme replacement therapy (ERT) with agalsidase alfa. Methods: Data were obtained from the Fabry Outcome Survey. Pain was measured using the Brief Pain Inventory (BPI), and health-related quality of life (HRQoL) was documented with the European Quality of Life Questionnaire (EQ-5D). Results: The mean (SD) score for “pain at its worst” on the BPI prior to ERT was 5.1 (2.7). One year after commencement of ERT, this had improved by 0.5, and improved by a further 0.6 after 2 years (p<0.05). Similar statistically significant improvements were seen for “pain on average” and “pain now” after 2 years of ERT. The mean HRQoL utility score prior to ERT was 0.66 (0.32). After 12 months of treatment with agalsidase alfa, this had improved to 0.74 (0.26; p<0.05); this improvement was maintained after 2 years. Conclusions: ERT with agalsidase alfa significantly reduces pain and improves quality of life in patients with Fabry disease.

Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy--a retrospective analysis from the Fabry Outcome Survey.

BackgroundFabry disease is a multisystemic life-threatening lysosomal storage disorder caused by deficiency of α-galactosidase A. Symptoms of the disease may occur in different organs including kidney, heart, and the nervous system. ObjectivesTo evaluate the nature and prevalence of pain in a large cohort of patients with Fabry disease and to assess the effect of enzyme replacement therapy (ERT) with agalsidase alfa. MethodsRetrospective analysis of the data of 752 patients with Fabry disease (393 females, 353 males) enrolled in the Fabry Outcome Survey, a multicentre database. ResultsThe prevalence of pain in male patients was 81.4% (females 65.3%). Mean age at onset of pain was 14.8±1.0 year in males (females 19.8±1.4 y). Pain was most frequently reported in the hands (males 76%, females 60%) and feet (males 73%, females 52%), but often affected the whole body. Interference of pain with daily life was higher in females than in males, and was observed predominantly for general activities, mood, and normal work. Fifty-eight percent of the patients were on ERT with agalsidase alfa. At 24 and 36 months after commencement of ERT, pain severity classification shifted towards lower severity (P<0.05). Moreover, after 36 months, “average pain” and “pain now” were significantly reduced (P<0.05). ConclusionsPain is one of the most prevalent symptoms in Fabry disease with onset early in childhood. ERT with agalsidase alfa significantly reduces pain in this debilitating disorder.

Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia

Background/Objectives: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF), 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations.

Functional assessment of Aδ and C fibers in patients with Fabry's disease

The pathophysiology of neuropathic pain in Fabrys disease (FD) is still largely unknown. Seven FD patients were studied by laser evoked potentials (LEPs) to assess the function of the Aδ and C fibers. Laser pulses were delivered on the skin of the hand and perioral region at painful intensity to record LEPs related to Aδ‐fiber inputs and at nonpainful intensity to obtain LEPs related to C‐fiber inputs. When the perioral region was stimulated, a vertex positive component was recorded with a mean latency of 260.3 ms and 376 ms after Aδ‐ and C‐fiber stimulation, respectively. The mean Aδ‐LEP amplitude was significantly lower in FD patients (N1/P1 mean values were 2.8 μV and 4.5 μV after hand and face stimulation, respectively, compared to 4 μV and 8.9 μV for controls; N2/P2 mean values were 8.2 μV and 11.1 μV after hand and face stimulation, respectively, and 16.7 μV and 22.3 μV in controls). Unlike the healthy subjects, 6 FD patients, suffering from neuropathic pain, showed a late positive potential related to C‐fiber function (mean latency, 377.1 ms) also after facial stimulation at painful intensity, suggesting a relative overflow of C‐fiber input, which may be relevant in the pathophysiology of pain in this disease. Muscle Nerve, 2004

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data

Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS ‐ the Fabry Outcome Survey ‐ suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate.

Spina bifida and folate-related genes: A study of gene- gene interactions

Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk.Methods: Case-control study, comparing 203 children with spina bifida to 583 controls.Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02–2.38). For the 844ins68 allele of cystathionine-β-synthase alone, the odds ratio was 0.83 (95% CI, 0.39–1.64). For the joint genotype, the odds ratio was 3.69 (95% CI, 1.04–13.50).Conclusions: Interactions between common alleles of folate genes might contribute to the risk for spina bifida.

Two novel mutations in the gene for human α-mannosidase that cause α-mannosidosis

Summary: Mutation analysis performed on two Italian patients with α-mannosidosis allowed the identification of two new mutations, IVS20−2A>G and 322–323insA. The patients were both homozygous for these mutations. The first mutation causes skipping of exon 21, whereas the second causes a frameshift introducing a stop codon at position 160 of the amino acid sequence.