The Cardiovascular Profile Score in Patients with Non-immune Hydrops Fetalis and Cardiac Anomalies - a Pilot Study.

The purpose of this paper is to explore whether the cardiovascular profile score (CVPS) correlates with fetal outcome in patients with non-immune hydrops fetalis (NIHF) and cardiac anomalies. In this retrospective study, we included fetuses with NIHF and the suspicion of a cardiac anomaly in prenatal ultrasound. The CVPS was calculated using information obtained by fetal echocardiographic examination. Feto-neonatal mortality (FNM) was defined as intrauterine fetal demise or death in the first 6 months of life. We reviewed 98 patients, who were referred to the Department of Obstetrics and Gynecology of the Johannes Gutenberg University in Mainz with the diagnosis of NIHF between January 2007 and March 2021. By eighteen of them, the suspicion of a cardiac anomaly was raised. After exclusion of six pregnancies (one termination of pregnancy and five because of incomplete data), 12 cases were left for analysis. Mean gestational age at which the CVPS was calculated was 29 + 2 weeks. Two fetuses died in utero. Of the remaining ten hydropic fetuses, three newborns died in the neonatal period, and seven survived after a 6-month surveillance period. Median CVPS of all fetuses was 6 points. Surviving fetuses showed statistically significantly higher CVPS values (median 8 points) than fetuses with FNM (median 5 points, p value = 0.009). Our results point towards a positive association between CVPS and fetal outcome in fetuses with NIHF and cardiac anomalies. The CVPS appears to be a useful marker in the assessment of heart failure in utero.

A single center experience in 90 cases with nonimmune hydrops fetalis: diagnostic categories ‒ mostly aneuploidy and still often idiopathic.

OBJECTIVES: The prognosis of nonimmune hydrops fetalis (NIHF) is still poor with a high mortality and morbidity rate despite progress in perinatal care. This study was designed to investigate etiology and outcome of NIHF. METHODS: A retrospective review of 90 NIHF cases from 2007 to 2019 was conducted at University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Demographics, genetic results, prenatal and postnatal outcomes including one year survival as well as autopsy data were extracted. Etiology of hydrops was classified using 13 previously established categories. In 4 patients observed between 2016 and 2019, we used a next-generation-sequencing (NGS) panel for genetic evaluation. RESULTS: Ninety NIHF cases were identified, with a median gestational age (GA) at diagnosis of 14 weeks. There were 25 live-born infants with a median GA of 34 weeks at birth, 15 patients survived to one year. There was aneuploidy in more than one third of the cases. All 90 cases were subclassified into etiologic categories with chromosomal 35, idiopathic 15, syndromic 11, cardiovascular 9, inborn errors of metabolism 6, lymphatic dysplasia 3, thoracic 3, infections 3, gastrointestinal 3 and hematologic 2. The NGS panel was used in 4 cases and 4 diagnoses were made. CONCLUSIONS: In 90 cases with NIHF we identified an aneuploidy in more than one third of the cases. Improved techniques, such as possibly specific genetic analysis, could reduce the high rate of unexplained cases of NIHF.

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 32 weeks of gestation. Multiple births and Caesarean sections were reported more frequent in the NIHF group. NIHF was associated with poor outcome with 14.6% stillbirths and in 26.5% early neonatal death. Overall, 58.7% of live-born children with NIHF were alive at 12 months compared with 99.7% of controls. The most common causes of death were cardiovascular diseases and thoracic abnormalities. CONCLUSION: NIHF at birth is associated with obstetric complications and poor prognosis for the neonate related to underlying disease. The low incidence of NIHF observed in this study may reflect well-developed antenatal care.

Rapid detection by hydrops panel of Noonan syndrome with PTPN11 mutation (p.Thr73Ile) and persistent thrombocytopenia.

BACKGROUND: Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 + 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. METHODS: DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. RESULTS: The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). CONCLUSION: The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia.

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

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 contractures, hyperechogenic amniotic fluid and polyhydramnion. After birth, palliative treatment was provided and she died on her first day of life. Sequence analysis of the ABCA12 gene identified two novel mutations, c.1857delA (predicting p.Lys619) in exon 15 and c.5653-5655delTAT (predicting p.1885delTyr) in exon 37, each in heterozygous state. The c.5653-5655delTAT mutation is not truncating, but the deleted tyrosine at position 1885 is perfectly conserved among vertebrates and molecular studies evaluated the mutation as probably disease causing and damaging.

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.

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 or postnatal is suggested. Transient forms of NIHF and/or ascites in association with MPS IVA, MPS VII and NPC are described for the first time in this publication. CONCLUSIONS: LSD should be considered in transient hydrops. Enzymatic studies in chorionic villous sample or amniotic cultured cells, once the most common conditions associated with fetal ascites or hydrops have been ruled out, are important. This paper emphasizes the fact that LSD is significantly higher than the estimated 1% in previous studies, which is important for genetic counseling as there is a high risk of recurrence and the availability of enzyme replacement therapy for an increasing number of LSD.

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

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. After an item analysis to explore how items performed and combined into domains, a battery of psychometric analyses was performed to assess the measurement properties of this new instrument. RESULTS: Eighty-seven children (ages 4-18 years) completed the questionnaire. Twenty-three items in three subscales of the questionnaire emerged: pain associated with heat or exertion, pain associated with cold, and abdominal pain and fatigue symptoms. Internal consistency reliability for all three subscales was good (Cronbach alpha ≥ 0.84). Reliability was equally high for all age groups (4-7, 8-12, and 13-18). Test-retest reliability was high for all three subscales (intraclass correlation coefficient ≥ 0.74). Construct validity was demonstrated by moderate correlation with brief pain inventory (BPI), KINDL, and EQ-5D. Known group validity showed all subscales were able to discriminate between Fabry disease severity groups as classified by above or below median of the FOS MSSI (Mainz Severity Score Index) grade. The heat or exertion subscale was responsive to change in symptoms between responders and non-responders as defined by change in EQ-5D index scores between the first and second visit. CONCLUSIONS: Preliminary results indicate that the measurement properties of FPHPQ are valid and reliable for assessing patient-reported symptoms of FD. The questionnaire could be a useful tool for clinicians to understand the progression of disease and monitor treatment effects. FPHPQ will be further validated and refined as the FOS registry is continuously adding more patients.

Paraoxonase (PON1) gene polymorphisms in Fabry disease: correlation with renal disease.

BACKGROUND: Fabry disease is associated with cardiomyopathy, early-onset stroke, and progressive renal failure, and other features. No markers predict multisystemic disease progression. The hypothesis of the current study is to assess a clinically relevant marker for Fabry disease using polymorphic genotyping of a marker that has been shown to be involved in interrelated cardiac, vascular, and renal abnormalities in patients not affected by Fabry disease. The paraoxonase (PON1) polymorphisms, Leu55Met and Gln192Arg, modulate intima-medial artery thickening, prognosis of cardiovascular stroke, and renal failure in other diseases. METHODS: PON1 polymorphisms were ascertained. The Mainz Severity Score Index (MSSI) for Fabry disease was calculated. Local Institutional Review Board approval was received. RESULTS: 104 patients (58 female) and 46 controls (23 female) were evaluated. There was a significant difference (p = 0.04) in PON55LL (42.3%) among patients as compared to controls (21.7%) but none in PON192 genotypes. PON55 variant (MM) was correlated with severe MSSI renal sub-scores (p < 0.001) also when age-adjusted but not with cardiac, neurological, or general sub-scores. PON55LL genotype, correlated with higher PON1 activity, had lowest α-galactosidase-A activity (n = 45). CONCLUSION: There was no combined effect of PON55-PON192 polymorphisms. PON55LL was more common among patients. PON55MM genotype was correlated with non-mild renal sub-scores. However, sample size needs to be enlarged.

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

PURPOSE: 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. METHODS: 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. RESULTS: The Mainz Severity Score Index, a measure of total disease burden, was significantly reduced after 12 months (P < 0.01) of treatment and continuously improved over 4 years. Brief Pain Inventory "pain at its worst" score was reduced from 4.6 +/- 2.9 at baseline to 3.3 +/- 2.9 after 12 months (P = 0.001) and remained reduced through 4 years. Mean left-ventricular mass decreased from 89.4 +/- 29.3(2.7) g/m at baseline to 66.5 +/- 29.3(2.7) g/m after 12 months (P < 0.001) and remained reduced through 4 years. Average kidney function (estimated glomerular filtration rate and proteinuria) remained constant during the study. No safety issues were identified. CONCLUSIONS: Long-term agalsidase alfa is effective and was well tolerated in women with Fabry disease.

Onset and progression of the Anderson-Fabry disease related cardiomyopathy.

BACKGROUND: Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS: We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS: In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION: AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Cardiac manifestations of Anderson-Fabry disease in children and adolescents.

AIM: Fabry disease (Fabry) is a rare X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The progressive accumulation of the major substrate, globotriaosylceramide, leads to renal dysfunction and hypertrophic cardiomyopathy, which are reported to become apparent in the third decade. This study was performed to determine if signs of cardiac manifestations of Fabry are seen in younger Fabry patients. METHODS: Twenty children and adolescents of 75th percentile of that in healthy controls. After a mean 26-month follow-up, 12 out of 14 patients (85.7%) showed a mean increase of 7.5+/-3.2 g/m(2.7) in LVM/h(2.7). Heart rate variability (HRV) analyses revealed that male, but not female, Fabry patients had significantly reduced HRV, reflecting a reduction in parasympathetic stimulation of the heart (p<0.05). CONCLUSION: Cardiac involvement in children with Fabry is frequent and may progress even at young age.

Genetic polymorphisms of vitamin D receptor (VDR) in Fabry disease.

Fabry disease, an X-linked inborn error of metabolism, is characterized by multi-organ involvement including cardiac signs of left ventricular hypertrophy and abnormal intima-medial (IMT) thickening of arteries, progressive renal failure, neurological involvement, and more. The vitamin D receptor (VDR) and an enzyme producing vitamin D3 result in an autocrine loop with direct effects on blood vessels. The purpose of this study is to assess VDR polymorphisms (BsmI, FokI, ApaI, and TaqI) relative to clinically important disease parameters using a disease-specific severity score (MSSI) and haplotype analysis. There were statistically significant differences between females (43% of 74 patients) and males in MSSI total scores, and in general and neurologic sub-scores. There appears to be a protective effect of the TaqI tt genotype so that there were significantly lower scores in clinical categories between those with the tt genotype versus those with the TT genotype. Multivariate models of haplotypes with MSSI scores reveal that T-A-f-B and t-a-F-b haplotypes of the VDR gene polymorphisms are significantly associated with variation in the Fabry phenotype. Despite the limitations of using the MSSI score as a clinical correlate, these results are provocative and further studies in larger cohorts with more males are recommended.

Enzyme replacement in Fabry disease: pharmacokinetics and pharmacodynamics of agalsidase alpha in children and adolescents.

This multicenter, open-label study evaluated pharmacokinetics, pharmacodynamics, and safety of agalsidase alpha in pediatric compared with adult patients with Fabry disease. The pharmacokinetic parameters of pediatric patients (19 boys, 5 girls, 6-18 years old; mean age, 11.8 years) were compared to those of adult male and female patients who participated in other clinical studies. All patients received agalsidase alpha at a dose of 0.2 mg/kg infused over 40 minutes every other week. Agalsidase alpha exhibited a biphasic serum elimination profile with a maximum serum concentration at the end of the 40-minute infusion; <1% of the maximum concentration was detected 8 hours after dosing. In children, serum clearance was 2.0 to 9.4 mL/min/kg and tended to decrease with increasing age. The average clearance in children, 3.7 +/- 1.5 mL/min/kg (mean +/- SD), was significantly greater than that measured in 33 adults (2.3 +/- 0.7 mL/min/kg, P < .0001). Mean terminal elimination half-life of agalsidase alpha was prolonged in week 25 compared with baseline (150 vs 66 minutes) in 8 of 19 male children. The magnitude of the reduction of plasma globotriaosylceremide was similar in all age groups and was independent of area under the curve and other pharmacokinetic parameters. Except for clearance in younger patients, agalsidase alpha appears to have comparable pharmacokinetic and pharmacodynamic profiles in pediatric and adult Fabry patients of both genders.

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

CONTEXT: Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES: Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS: We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5-18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS: Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS: Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

IgA nephropathy in two adolescent sisters heterozygous for Fabry disease.

We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant glomerulonephritis. Light microscopy of kidney biopsy was characteristic of IgA nephropathy (IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas electron microscopy showed changes typical of Fabry disease (multiple osmiophilic inclusions in the subendothelial and mesangial areas). These two cases and similar reports in the literature suggest that IgA nephropathy in FD is not merely coincidental.

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 alpha-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 biochemical disease expression. RESULTS: X inactivation patterns in symptomatic females who are heterozygous for Fabry disease did not differ from those of female controls of the same age (p = 0.669). Thirteen (46%) of the 28 females with Fabry disease showed random X inactivation, ten (36%) moderate skewing, and five (18%) highly skewed X inactivation. Segregation analysis was performed in the families of six females who had highly or moderately skewed X inactivation. In four of these females, skewing favoured the wild-type GLA allele and in the other two skewing favoured the mutant allele. Patterns of X inactivation or the extent of skewing were not related to the severity of clinical manifestations or to residual enzyme activity. CONCLUSION: In this study we provide evidence that heterozygous females with Fabry disease show random X inactivation. Our data do not support the hypothesis that the occurrence and severity of disease manifestations in the majority of Fabry heterozygotes are related to skewed X inactivation.

Pattern of microstructural brain tissue alterations in Fabry disease: a diffusion-tensor imaging study.

Fabry disease (FD) is a lysosomal storage disorder that is associated with marked cerebrovascular disease. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. To quantify brain structural changes in clinically affected male and female patients with FD we performed a prospective Diffusion-Tensor Imaging (DTI) study in 27 adult Fabry patients (13m, 14f) and 21 age-matched controls (12 m, 9f). Global Mean Diffusivity (MD) was increased in FD (P = 0.003) whereas global Fractional Anisotropy (FA) did not differ significantly between FD and controls. Even FD patients without significant WMLs (9m, 9f) showed increased global MD (P = 0.004). Regions of interest with significant MD elevations were located in the frontal, parietal and temporal white matter. No differences of thalamic and hippocampal DTI measurements could be detected between FD and controls. DTI parameters did not differ between male and female patients. The data provide the first evidence of a pattern of marked structural brain tissue alterations in adult FD male and female patients even without WMLs. DTI seems to be an appropriate diagnostic tool to quantify brain tissue integrity in FD. Moreover, this method could be favorable for longitudinal assessment of brain structure alterations in FD, and for monitoring the cerebral effects of enzyme replacement therapy.

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, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. RESULTS: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2-5 y later in girls than in boys. There was an approximately 3-y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. CONCLUSION: Although the life-threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.

An association study of inflammatory cytokine gene polymorphisms in Fabry disease.

BACKGROUND: Fabry disease is an X-linked disorder associated with early-onset stroke, cardiomyopathy, and progression to end-stage renal failure. Correlations between inflammatory cytokines have been shown in other lysosomal storage diseases. The aim of the study was to evaluate functional gene polymorphisms of key pro- and anti-inflammatory cytokines and to correlate them to a clinical score to assess the potential role of inflammation in Fabry disease. DESIGN: Genotyping for IL-10[819C/T; -592C/A]; IL-1beta[+3954 C/T; -511C/T]; IL-1alpha[-889C/T]; and TNF-alpha[-308G/A] was performed in 76 patients and correlated with MSSI sub-scores and with enzyme (alpha-galactosidase A) levels. Fifty, normal, age- and sex-matched volunteers were also genotyped. RESULTS: Of 76 patients, 31 (41%) were males and 45 (59%) were females. There was no correlation between enzyme levels and any cytokine levels. Statistically significant differences were found in prevalence of TNF-alpha [-308G/A] genotypes: 84% GG in patients versus 63% GG in controls (p = 0.038) and for IL-1alpha [-889C/T] genotypes: 94% CC in patients versus 21% CC in controls (p < 0.001). Statistically significant differences were found in the ratio between the two polymorphisms of IL-10 (p < 0.0001), between the two polymorphisms of IL-1beta (p = 0.001); between IL-1alpha [-889C/T] and IL-1beta [3954C/T] (p = 0.002); and between IL-10[-592C/T] and IL-1beta [3954C/T] (p = 0.041). Correlations between TNF-alpha [-308G/A] and both kidney and neurological MSSI sub-scores (both: p = 0.06) and between IL-10[-819C/T] and the MSSI neurological score (p = 0.03) were noted. The majority of patients with Fabry disease have therefore a profile of low TNF-alpha (increased frequency of GG genotype of the TNF-alpha[-308] polymorphism), high IL-10 production (preponderance of the C allele of the wild type or heterozygous state for the polymorphisms of IL-10 [819; -592], but simultaneously increased production of the pro-inflammatory cytokines IL-1beta and IL-1alpha usually associated with a preponderance of the C allele of the wild type or heterozygous state for the polymorphisms of IL-1beta [3954; -511] and of IL-1 alpha[-889]. CONCLUSIONS: We speculate that sequence variations of important inflammatory genes of the interleukin inflammatory family are associated with differential effects in Fabry disease, and with increased sample size, haplotype blocks might be constructed.