Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria

Mechtler, Thomas P.; Stary, Susanne; Metz, Thomas F.; Jesús, Víctor R. De; Greber‐Platzer, Susanne; Pollak, Arnold; Herkner, Kurt; Streubel, Berthold; Kasper, David C.

doi:10.1016/s0140-6736(11)61266-x

Cited by 266 publications

(176 citation statements)

References 41 publications

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“…The prevalence of the p.Ala143Thr mutation in our highrisk populations (0.33 %, Table 3) is almost 20 times higher than in a European newborn population (0.017 %, Mechtler et al 2012). Low a-aGAL A activity could be one cofactor contributing to endothelial stress, provoking stroke, renal failure, or other signs, and symptoms classically associated with FD.…”

Section: Discussionmentioning

confidence: 70%

“…On the other hand, as FD remains the subject of screening studies in high-risk populations including patients with renal failure and/or stroke, there is a danger of misdiagnosis as a result of selection bias, especially as the p.Ala143Thr mutation was not only detected in screening studies in Belgium (Terryn et al 2008;De Schoenmakere et al 2008;) but also in newborn screenings in Italy (Spada et al 2006), Taiwan (Lin et al 2009) Austria (Mechtler et al 2012), and in other screening studies .…”

Section: Discussionmentioning

confidence: 99%

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Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

et al. 2012

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Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

et al. 2012

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“…Bekri et al 2005;Spada et al 2006;Brouns et al 2007;Lin et al 2009;Wallin et al 2011;Dubuc et al 2012;Mechtler et al 2012). These screening studies have revealed a high number of individuals with variants in the GLA gene (Kobayashi et al 2012;Terryn et al 2013;van der Tol et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

et al. 2014

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Introduction: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the a-galactosidase A (GLA) gene may be unclear. This uncertainty often leads to considerable distress and inappropriate counselling and treatment. We developed a clinical approach for these individuals with an uncertain diagnosis of FD.Materials and Methods: A document was presented to an FD expert panel with background information based on

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“…26 Measuring GAA activity in DBS using MS/MS is a fast and cost-effective way of diagnosing PD and allows multiplexing with additional lysosomal storage disorders for high throughput screening of newborn infants or at risk individuals. 10,25,27,28 The challenges of this approach are the higher initial investment cost for instrumentation and the longer overall analytical time from sample receipt to report of 48 hours compared with less than 24 hours for fluorometric assays. 24,26 The MS/MS method has so far to the best of our knowledge only be validated for enzyme analysis in DBS, but not in other biological matrices.…”

Section: 23mentioning

confidence: 99%

“…8 PD is a pan-ethnic disease with an estimated frequency of 1:40,000, although recent reports from newborn screening studies suggest that PD may be more frequent. 1,8,10,11 The advent of recombinant human enzyme replacement therapy (ERT) has improved quality of life and reduced morbidity and mortality in the majority of patients with both infantile-onset PD 11,12 and later-onset PD. 13 Recombinant human GAA (rhGAA) is harvested from Chinese hamster ovary (CHO) cells and exerts its activity after proteolytic cleavage in the lysosomes.…”

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confidence: 99%

The Diagnostic Path to Pompe Disease

Bodamer¹,

Hung²

2014

European Neurological Review

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Pompe disease (PD) is a lysosomal disease that primarily affects skeletal and smooth muscles due to a deficiency of acid alpha glucosidase.The resulting clinical phenotype reflects a continuum ranging from severe infantile to later onset forms of PD. Early diagnosis is essential to prevent long-term complications and/or disease progression through initiation of enzyme-replacement therapy. The diagnostic path to PD starts with the ascertainment of medical and family history as well as an in-depth clinical and neurological evaluation. The involvement of proximal muscle groups including hip and thigh muscles as well as the diaphragm is characteristic for later onset PD.Once PD is considered creatine kinase (CK) should be measured, realising that levels may be within normal limits in end stage disease.Ultimately, diagnostic confirmation is readily achieved by enzyme analysis in dried blood spots and/or leukocytes followed by molecular analysis. Muscle biopsy is not sensitive enough for diagnostic testing of PD but may be an important diagnostic test for the differential diagnosis of myopathies. Future diagnostic approaches include whole exome and genome sequencing, which may contribute to our understanding of genotype-phenotype correlation and phenotype prediction. KeywordsPompe disease, alpha glucosidase, glycogen storage disease II, diagnosis, laboratory testing, dried blood spot Disclosure: Olaf A Bodamer is a member of Genzyme speaker's bureau and has also received research funding. Christina Y Hung has no conflicts of interest to declare.

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Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria

Cited by 266 publications

References 41 publications

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

Uncertain Diagnosis of Fabry Disease in Patients with Neuropathic Pain, Angiokeratoma or Cornea Verticillata: Consensus on the Approach to Diagnosis and Follow-Up

The Diagnostic Path to Pompe Disease

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