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MPS-IIIA mice acquire autistic behaviours with age
In this study, we investigated whether a mouse model of MPS-IIIA exhibited ASD-like symptoms. The BTBR T+Itpr3tf/J inbred mouse model of autism was used as a positive control. Male MPS-IIIA and BTBR mice were less sociable compared with unaffected C57BL/6 male mice in the reciprocal social approach test administered at 20  weeks of age. Alternations in the frequency of social interactions was not evident at earlier stages of the disease course, suggesting an acquisition of ASD-like social behaviours. Stereotypical behaviours were not evident in male MPS-IIIA mice in the marble-burying test nor was the quality of nes t con...
Source: Journal of Inherited Metabolic Disease - March 8, 2018 Category: Internal Medicine Source Type: research

Clinical glycomics for the diagnosis of congenital disorders of glycosylation
AbstractClinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG. This review provides an introduction into protein glycosylation and presents the different ...
Source: Journal of Inherited Metabolic Disease - March 1, 2018 Category: Internal Medicine Source Type: research

Mulberries in the urine: a tell-tale sign of Fabry disease
This report emphasizes the usefulness of urinary microscopic findings in the early diagnosis of Fabry disease. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - February 27, 2018 Category: Internal Medicine Source Type: research

Natural history of neurological abnormalities in cerebrotendinous xanthomatosis
ConclusionWe provide estimates for the neurological progression of CTX, categorizing neurological abnormalities according to time and probability of development. Our approach may be applicable to other rare disorders. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - February 26, 2018 Category: Internal Medicine Source Type: research

A SEPSECS mutation in a 23-year-old woman with microcephaly and progressive cerebellar ataxia
AbstractMutations in theSEPSECS gene are associated with pontocerebellar hypoplasia type 2D. Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare autosomal recessive neurodegenerative disorders, mainly affecting pons and cerebellum. Patients have severe motor and cognitive impairments and often die during infancy. Here, we report a 23-year-old woman with slowly progressive cerebellar ataxia and cognitive impairment, in whom a homozygous missense mutation in theSEPSECS gene (c.1321G>A; p.Gly441Arg) was identified with whole exome sequencing. Our findings underline that defects in selenoprotein synthesis can ...
Source: Journal of Inherited Metabolic Disease - February 20, 2018 Category: Internal Medicine Source Type: research

Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations
AbstractX-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in thePHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40  years. Dental disease (63%), nephrocalcinosis ...
Source: Journal of Inherited Metabolic Disease - February 19, 2018 Category: Internal Medicine Source Type: research

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies
We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived fromaldehyde dehydrogenase 5a1−/− (aldh5a...
Source: Journal of Inherited Metabolic Disease - February 19, 2018 Category: Internal Medicine Source Type: research

Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients
AbstractThe implementation of whole-exome sequencing in clinical diagnostics has generated a need for functional evaluation of genetic variants. In the field of inborn errors of metabolism (IEM), a diverse spectrum of targeted biochemical assays is employed to analyze a limited amount of metabolites. We now present a single-platform, high-resolution liquid chromatography quadrupole time of flight (LC-QTOF) method that can be applied for holistic metabolic profiling in plasma of individual IEM-suspected patients. This method, which we termed “next-generation metabolic screening” (NGMS), can detect>10,000 features in ...
Source: Journal of Inherited Metabolic Disease - February 16, 2018 Category: Internal Medicine Source Type: research

The functional genomics laboratory: functional validation of genetic variants
AbstractCurrently, one of the main challenges in human molecular genetics is the interpretation of rare genetic variants of unknown clinical significance. A conclusive diagnosis is of importance for the patient to obtain certainty about the cause of the disease, for the clinician to be able to provide optimal care to the patient and to predict the disease course, and for the clinical geneticist for genetic counseling of the patient and family members. Conclusive evidence for pathogenicity of genetic variants is therefore crucial. This review gives an introduction to the problem of the interpretation of genetic variants of ...
Source: Journal of Inherited Metabolic Disease - February 14, 2018 Category: Internal Medicine Source Type: research

Fast and accurate quantitative organic acid analysis with LC-QTOF/MS facilitates screening of patients for inborn errors of metabolism
In conclusion, we present a LC-QTOF/MS method for fast and accurate quantitative organic acid analysis which facilitates screening of patients for IEMs. Extension of the panel of metabolites is easy which makes this application a promising technique in metabolic diagnostics/laboratories. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - February 12, 2018 Category: Internal Medicine Source Type: research

Insulin-resistance in glycogen storage disease type Ia: linking carbohydrates and mitochondria?
DiscussionIncreased plasma ACs and abnormal UOA profile suggest mitochondrial impairment in GSDIa. Correlation data suggest a possible connection between mitochondrial impairment and IR. We hypothesized that mitochondrial overload might generate by-products potentially affecting the insulin signaling pathway, leading to IR. On the basis of the available data, the possible pathomechanism for IR in GSDIa is proposed. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - February 12, 2018 Category: Internal Medicine Source Type: research

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Source: Journal of Inherited Metabolic Disease - February 9, 2018 Category: Internal Medicine Source Type: research

Biochemical markers and neuropsychological functioning in distal urea cycle disorders
This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3  years and older, with ASD (n = 64), ASA (n = 65) and ARGD (n = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24;...
Source: Journal of Inherited Metabolic Disease - February 8, 2018 Category: Internal Medicine Source Type: research

Targeted versus untargeted omics — the CAFSA story
ConclusionOur genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either throughPOLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - February 8, 2018 Category: Internal Medicine Source Type: research

Hepatocellular carcinoma in Gaucher disease: an international case series
AbstractGaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cir...
Source: Journal of Inherited Metabolic Disease - February 8, 2018 Category: Internal Medicine Source Type: research