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The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer‐reviewed publications and case‐reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha‐galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3) and sphingosine‐globotriaosylceramide (lyso‐Gb3) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non‐elevated lysoGb3/Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels. [ABSTRACT FROM AUTHOR]

Background Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. Methods This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. Results In all, 52 patients with consecutive mGFR values (n  = 841) over median 7 years (range 1–13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of −0.8 ± 0.2 with an annual slope of −0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin–creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. Conclusions ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data. [ABSTRACT FROM AUTHOR]

Background: Germline mutations in the succinate dehydrogenase complex genes SDHB, SDHC, and SDHD predispose to pheochromocytomas and paragangliomas. Here, we examine the SDHB, SDHC, and SDHD mutation spectrum in the Danish population by screening of 143 Danish pheochromocytoma and paraganglioma patients. Methods: Mutational screening was performed by Sanger sequencing or next-generation sequencing. The frequencies of variants of unknown clinical significance, e.g. intronic, missense, and synonymous variants, were determined using the Exome Aggregation Consortium database, while the significance of missense mutations was predicted by in silico and loss of heterozygosity analysis when possible. Results: We report 18 germline variants; nine in SDHB, six in SDHC, and three in SDHD. Of these 18 variants, eight are novel. We classify 12 variants as likely pathogenic/pathogenic, one as likely benign, and five as variants of unknown clinical significance. Conclusions: Identifying and classifying SDHB, SDHC, and SDHD variants present in the Danish population will augment the growing knowledge on variants in these genes and may support future clinical risk assessments. [ABSTRACT FROM AUTHOR]

Background/Aims: Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-α (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals. Methods: A 10.5-year-old male was diagnosed with PPNAD; the patient's mother also had iPPNAD. A 13-year-old sibling and 7 other relatives (mean age 58.2, range 29.1-80.2 years) were referred for PRKAR1A mutation analysis. Results: DNA analysis of the index case and parent revealed a novel germline heterozygous PRKAR1A mutation at the +1 position of the acceptor site of intron 3 [c.349 G>T]. The same heterozygous splice site mutation was present in the sibling with no PPNAD or CNC manifestations and 2 other individuals aged 54.9 and 57.1 years who had subclinical Cushing's syndrome but no features of CNC. Conclusion: We conclude that c.349 G>T, a novel splice site germline PRKAR1A defect, has low penetrance resulting in incomplete clinical expression in this kindred. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. Methods Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. Results The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. Conclusion Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE — Severe hypoglycemia is a major problem for patients with type 1 diabetes and their relatives. The aim of this study was to compare patients' and relatives' assessments of rates of severe hypoglycemia and state of awareness and to explore the influence on involvement and concern of relatives. RESEARCH DESIGN AND METHODS — A cross-sectional paired questionnaire survey on hypoglycemia and the state of awareness was used in our study comprising 284 unselected adult patients with type 1 diabetes and their closest cohabitant. The cohabitant questionnaires also addressed involvement and concern. RESULTS — The agreement between assessments of rates of severe hypoglycemia and state of awareness made by patients and cohabitants was weak (κ 0.404 and 0.442, respectively; P < 0.001). Cohabitants recalled more episodes of severe hypoglycemia than patients (2.7 vs. 1.6 episodes/patient-year; P < 0.001). Degree of involvement was positively related to the rate of severe hypoglycemia (P = 0.002) and negatively related to the state of awareness (P = 0.007) but not to level of HbA[sub 1c], duration of diabetes, or presence of late complications, except for peripheral neuropathy (P = 0.01). CONCLUSIONS — Cohabitants of patients with type 1 diabetes recall significantly more episodes of severe hypoglycemia than the patients. The rate of severe hypoglycemia and state of hypoglycemic awareness are the principal determinants of degree of cohabitants' involvement in their partners' disease. [ABSTRACT FROM AUTHOR]