Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5

Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport

Mosaicism of the UDP-Galactose Transporter SLC35A2 Causes a Congenital Disorder of Glycosylation

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management

P. W. is supported by the Clinical Research Fund, University Hospitals Leuven, Leuven, Belgium. This work is partially funded by the grant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute of Neurological Diseases and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Rare Disorders Consortium Research Network (RDCRN) (E. M., K. R., C. F., H. F., C. L., and A. E.)Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.preprintpublishe

Moonlighting Newborn Screening Markers: The Incidental Discovery of a Second-Tier Test for Pompe Disease

Purpose: To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease. Methods: The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases. Results: The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41–13.26; 99%ile of neonatal controls: 1.10). Verification was by analysis of 39 blinded specimens that included 10 controls, 24 samples with a definitive classification (16 Pompe, 8 false positives), and 5 with genotypes of uncertain significance. The CLIR tool showed 100% concordance of classification for the 24 known cases. Of the remaining five cases, three p.V222M homozygotes, a benign variant, were classified by CLIR as false positives; two with genotypes of unknown significance, one likely informative, were categorized as Pompe disease. Conclusion: The CLIR tool inclusive of the new ratio could have prevented at least 12 of 13 (92%) false-positive outcomes

Precision Newborn Screening for Lysosomal Disorders

Purpose: The implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues. Methods: The Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition software (Collaborative Laboratory Integrated Reports), which is freely available to newborn screening programs for selection of cases for which a biochemical second-tier test is needed. Results: Of five presumptive positive cases, one was affected with infantile Krabbe disease, two with Pompe disease, and one with MPS I. The remaining case was a heterozygote for the latter condition. The false-positive rate was 0.0018% and the positive predictive value was 80%. Conclusion: Postanalytical interpretive tools can drastically reduce false-positive outcomes, with preliminary evidence of no greater risk of false-negative events, still to be verified by long-term surveillance

Disorder of cerebellar foliation in Walker's lissencephaly and neu-laxova syndrome.

A diffuse disorder of cerebellar foliation was found in eight infants and one fetus with Walker's lissencephaly. The cerebellar cortex consisted of fused and irregularly distorted folia. In the white matter, trilaminated rings of cortex were concentrically arranged around blood vessels and mesenchymal tissue. The normal relative position of the different classes of cortical nerve cells was preserved. Cells of the external granular layer invaded the meninges and migrated along penetrating blood vessels. We believe that this foliation disorder is caused by a defect in the external basal lamina that allows adjacent folia to be fused and sulci obliterated by intrameningeal ectopias of external granule layer cells. Physical forces applied during development probably contribute to the distortion of the gyral pattern. There was a volumetric reduction of the neocerebellum, which might also be a consequence of the basal lamina defect. The cerebellum of a fetus with the Neu-Laxova syndrome showed the same abnormalities as in Walker's lissencephaly. It is postulated that these two conditions belong to a class of prenatal developmental disorders that involves a defect of the extracellular matrix

Estudo de prevalência em recém-nascidos por deficiência de biotinidase

INTRODUÇÃO: A deficiência de biotinidase é um erro inato do metabolismo caracterizado principalmente por ataxia, crise convulsiva retardo mental, dermatites, alopécia e susceptibilidade a infecções. É atribuída a esta deficiência enzimática a forma tardia de deficiência múltipla das carboxilases. Com o objetivo de verificar a prevalência da deficiência de biotinidase e validar o teste de triagem neonatal considerando a relação custo/benefício, elaborou-se estudo prospectivo na população de recém-nascidos no Estado do Paraná. MATERIAL E MÉTODO: Em um período de 8 meses foram triados 125.000 recém-nascidos. A amostra sangüínea foi a mesma obtida para os testes de triagem para fenilcetonúria e hipotireoidismo congênito, submetida ao teste semiquantitativo colorimétrico para atividade de biotinidase. As amostras consideradas suspeitas foram repetidas em duplicatas do mesmo cartão de papel de filtro, e as que permaneceram alteradas solicitou-se novo cartão. O teste quantitativo colorimétrico da doença foi realizado nos casos em que a segunda amostra testada em duplicata sugeriu deficiência de biotinidase. RESULTADOS: A taxa de repetição em duplicata variou de 0,9% a 0,5% do total de exames realizados por mês. A taxa de reconvocação do segundo cartão foi de 0,17%, sendo que destes 212 casos, 30% não retornaram o segundo cartão solicitado. Foram identificados 2 casos, um de deficiência total de biotinidase e outro de deficiência parcial. A prevalência da doença na população de estudo foi de 1:62.500 nascidos-vivos. A sensibilidade do teste semiquantativo colorimétrico foi calculada em 100% e a especificidade 99,88%. CONCLUSÃO: A prevalência da doença no Estado do Paraná foi de 1:125.000 nascidos-vivos para deficiência total da enzima, levando-se em consideração que 30% de casos suspeitos que repetiram novo teste. O teste semiquantitativo colorimétrico foi considerado efetivo em identificar os casos afetados, com sensibilidade de 100% e especificidade de 99,88%. A relação custo/benefício foi satisfatória, permitindo a inclusão do teste de detecção de deficiência de biotinidase no programa de triagem neonatal do Estado do Paraná

Estudo de prevalência em recém-nascidos por deficiência de biotinidase Neonatal screening for biotinidase deficiency

INTRODUÇÃO: A deficiência de biotinidase é um erro inato do metabolismo caracterizado principalmente por ataxia, crise convulsiva retardo mental, dermatites, alopécia e susceptibilidade a infecções. É atribuída a esta deficiência enzimática a forma tardia de deficiência múltipla das carboxilases. Com o objetivo de verificar a prevalência da deficiência de biotinidase e validar o teste de triagem neonatal considerando a relação custo/benefício, elaborou-se estudo prospectivo na população de recém-nascidos no Estado do Paraná. MATERIAL E MÉTODO: Em um período de 8 meses foram triados 125.000 recém-nascidos. A amostra sangüínea foi a mesma obtida para os testes de triagem para fenilcetonúria e hipotireoidismo congênito, submetida ao teste semiquantitativo colorimétrico para atividade de biotinidase. As amostras consideradas suspeitas foram repetidas em duplicatas do mesmo cartão de papel de filtro, e as que permaneceram alteradas solicitou-se novo cartão. O teste quantitativo colorimétrico da doença foi realizado nos casos em que a segunda amostra testada em duplicata sugeriu deficiência de biotinidase. RESULTADOS: A taxa de repetição em duplicata variou de 0,9% a 0,5% do total de exames realizados por mês. A taxa de reconvocação do segundo cartão foi de 0,17%, sendo que destes 212 casos, 30% não retornaram o segundo cartão solicitado. Foram identificados 2 casos, um de deficiência total de biotinidase e outro de deficiência parcial. A prevalência da doença na população de estudo foi de 1:62.500 nascidos-vivos. A sensibilidade do teste semiquantativo colorimétrico foi calculada em 100% e a especificidade 99,88%. CONCLUSÃO: A prevalência da doença no Estado do Paraná foi de 1:125.000 nascidos-vivos para deficiência total da enzima, levando-se em consideração que 30% de casos suspeitos que repetiram novo teste. O teste semiquantitativo colorimétrico foi considerado efetivo em identificar os casos afetados, com sensibilidade de 100% e especificidade de 99,88%. A relação custo/benefício foi satisfatória, permitindo a inclusão do teste de detecção de deficiência de biotinidase no programa de triagem neonatal do Estado do Paraná.<br>INTRODUCTION: Biotinidase deficiency is an inheritable disorder of biotin metabolism. This disorder fulfills major criteria for consideration for newborn screening: the affected children do not show clinical signs in the newborn period; the disease is highly disabling; treatment is effective in preventing neurological sequelae if undertaken promptly. MATERIAL AND METHODS: Screening of 125,000 infants born in Paraná State was carried out to establish the prevalence of biotinidase deficiency. A simple colorimetric procedure was used to detect two infants with biotinidase deficiency (1:62,500), one of them with profound deficiency (1:125,000) and the other with partial deficiency (1:125,000) of the enzyme. RESULTS: There were no known false-negative test results and 0.12% were false-positive, defined by further blood samples which were negative upon repeated testing. Sensitivity was 100% and specificity was 99.88%. Repeat blood samples could not be obtained in 63 (30%) suspected cases. CONCLUSIONS: Newborn screening for biotinidase is useful in identifying affected children, is inexpensive and allows early intervention, which may prevent irreversible neurological damage