This phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, which causes cirrhosis and severe dyslipidemia, showed that enzyme replacement lessened ...multiple disease-related hepatic and lipid abnormalities.
Lysosomal acid lipase deficiency (Online Mendelian Inheritance in Man number, 278000)
1
is an autosomal recessive storage disease that is caused by mutations in the
LIPA
gene.
2
In infants, progression of the disease (historically known as Wolman’s disease) is very rapid, with death typically occurring by 6 months of age.
2
In older patients, progression of the disease (historically known as cholesteryl ester storage disease) leads to cirrhosis and other complications in childhood or later in life.
3
Common features in infants, children, and adults include elevated serum aminotransferase levels, dyslipidemia, hepatomegaly, liver fibrosis, and cirrhosis.
3
–
5
Awareness of the disease is low, . . .
Galactosemia is a carbohydrate metabolism disorder often caused by galactose-1-phosphate uridyl transferase (GALT) deficiency. Detecting GALT deficiency involves measuring intra-erythrocyte enzyme ...activity. We aimed to create a robust liquid chromatography-mass spectrometry (LC-MS/MS) method to assess GALT activity in dried blood spot (DBS) samples. We validated this method and compared it to the fluorometric approach. We investigated the impact of K2EDTA and lithium heparin tubes on enzyme activity to identify the best sample collection tube. We also assessed the reaction-stopping method. The developed approach employed 13C6-galactose-1-phosphate as a substrate and UDP-N-acetylglycosamine as an internal standard (IS). The mean ± SD value for GALT activity of DBS samples was determined as 6.37 ± 1.96 μmol/gHb/hour. The linear range was 0.4-50 μM (2.4-310% of normal) in the DBS method. The % coefficient of variation (%CV) values were less than 15 for intra-day and inter-day repeatability studies. Over 90% recovery was achieved in recovery studies, and no ion suppression from matrix was detected. DBS samples were quite stable for 31 days under different storage conditions. Enzyme activity results reported as <3.5 U/g Hb by fluorometric method, were quantitatively determined for even very low concentrations by LC-MS/MS method.
Background. Methylmalonyl CoA epimerase (MCE) deficiency was first reported in 2006 and only a few cases have been reported so far. The clinical spectrum of MCE deficiency ranges from asymptomatic to ...lifethreatening metabolic decompensation attacks. Case. Herein we report a patient diagnosed with MCE deficiency with recurrent acute metabolic ketoacidosis attacks and moderate MMA-uria that persisted in periods without decompensation. At presentation, organic acid profiles were dominated by increased 3 hydroxybutyrate. Conclusions. 3-Oxothiolase deficiency as a main ketolysis defects disorder was initially suspected. However, the subsequently repeated organic acid analyses demonstrated mild and persistent elevation of methylmalonic acid. This report provides a new phenotype of the clinical and biochemical characterization of MCE deficiency.
Cystinosis is an autosomal recessive disorder characterized by the accumulation of cystine in lysosomes, causing irreversible damage to organs, especially the kidneys. Intracellular leukocyte cystine ...concentrations are used to diagnose cystinosis and to monitor cysteamine treatment. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method without derivatization capable of measuring leukocyte intracellular cystine concentrations.
During development, the effects of using three different protein precipitation agents were evaluated in terms of sensitivity and the matrix effect, with 12% trichloroacetic acid providing the highest sensitivity. The effects of different blood collection tubes were also assessed in terms of recovery, matrix effect, and protein content. Compared to other methods, our method was quicker (run time of 3 min), was linear over the range 0.078–100 μM, and had lower limits of detection (0.0192 μM) and quantification (0.0582 μM). The intra-day and inter-day reproducibility %CVs were ≤10%. and the method had excellent recovery rates (94%–106%). Other parameters including matrix selectivity, injection carryover, leukocyte lysate stability were also validated and met the acceptance criterias of European Medicines Agency (EMA) Guideline. The assay was successfully applied to quantify cystine leukocyte concentration in healthy and cystinosis patients.
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•Faster analysis time, lower detection and quantitation limit than prior methods.•A non-derivatized simple pretreatment method.•Unique study to determine the effect of blood collection tubes.•First study showing the effect of protein precipitation agents.
Biotinidase deficiency is an autosomal recessive inherited neurocutaneous disorder. Clinically untreated patients with BD can present with variable neurological and dermatological signs, such as ...seizures, hypotonia, feeding problems, developmental delay, hearing loss, optic atrophy ataxia, alopecia, and skin rash. Clinical findings of patients with partial BD reported in the literature show that it can occur from infancy to adulthood. Outcomes of newborn screening programs support the fact that biotin treatment started after birth prevents patients with biotinidase deficiency from developing symptoms. Presence of late-onset cases with different clinical findings indicates that there is still much to learn about BD.
Proteoglycan (PG) synthesis begins with the sequential addition of a “linker chain”, made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps ...two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in
XYLT1
, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.
Recommendations on phenylketonuria in Turkey Coşkun, Turgay; Çoker, Mahmut; Mungan, Neslihan Önenli ...
The Turkish journal of pediatrics,
2022, Letnik:
64, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Phenylketonuria (PKU), is an autosomal recessive disease leading to the conversion defect of phenylalanine (Phe) into tyrosine. Severe neurocognitive and behavioral outcomes are observed in untreated ...cases. The present paper aims to review clinical experiences and expert recommendations in diagnosis, treatment, and follow-up of pediatric PKU patients in Turkey.
Two advisory board meetings were held in the year 2016 and 2017 with contributions of four leading experts in this field, and an online update meeting was held for final decisions about statements, and conclusions in January 2021. Considering management gaps in diagnosis, treatment, and follow-up of PKU, discussion points are defined. The Committee members then reviewed the Turkish and general literature and the final statements were formulated.
The diagnostic cut-off for dried blood spots should remain at 2 mg/dl. Treatment cut-off value is acceptable at 6 mg/dl. Compliance with an ideal follow-up list is strongly recommended. Total protein intake should not be limited. Age-related safe levels of protein intake should be encouraged with an additional 40% from L-amino acids supplements, a 20% compensatory factor to account for the digestibility and utilization of amino acids from the supplement, and a further 20% compensation to optimize Phe control. Cognitive impairment and intelligence quotient evaluations should be performed at least twice before 3 years of age. In pregnant women, the target Phe level should be < 5 mg/dl, and they should be followed-up weekly in the first trimester, then every 2 weeks after organogenesis. Novel pharmacological treatments are promising, but some of them have limitations for our country.
Early diagnosis and treatment initiation; determination and standardization of diagnostic and treatment thresholds; treatment modalities and follow-up parameters are significant steps in treating PKU in the long term. PKU follow-up is a dynamic process with uncertainties and differences in clinical practice.
This review by a panel of pediatric metabolic disease specialists aimed to provide a practical and implementable guidance document to assist clinicians in best clinical practice in terms of ...recognition, diagnosis and management of patients with acid sphingomyelinase deficiency (ASMD). The participating experts consider the clinical suspicion of ASMD by the physician to be of utmost importance in the prevention of diagnostic delay and strongly suggest the use of a diagnostic algorithm including/starting with dried blood spots assay in the timely diagnosis of ASMD in patients presenting with hepatosplenomegaly and a need for increased awareness among physicians in this regard to consider ASMD in the differential diagnosis. In anticipation of the introduction of enzyme replacement therapy, raising awareness of the disease among physicians to prevent diagnostic delay and further investigation addressing natural history of ASMD across the disease spectrum, potential presenting characteristics with a high index of suspicion, as well as biomarkers and genotype-phenotype correlations suggestive of poor prognosis seem important in terms of implementation of best practice patterns.
Background Recently, urinary excretion of the tetrasaccharide 6-α-D-glucopyranosyl-maltotriose (Glc4) has been proposed as a marker for the diagnosis and monitoring of Pompe disease (PD). We aimed to ...determine the reference intervals and reliable decision-making levels of urine tetrasaccharide concentrations for the diagnosis of infantile- and late-onset Pompe patients in the Turkish population. Methods In this study, nine patients with PD (five of them with late-onset PD LOPD) and 226 healthy individuals (aged 0-64 years) were included. Urine Glc4 concentrations were determined using the ultra-high-performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method. Results Our data showed that the urine tetrasaccharide levels decreased with age in healthy individuals (p < 0.001, r = -0.256). It was higher especially during the first year of life compared to that in the elder subjects. The tetrasaccharide level of Pompe patients was higher compared to that of healthy controls of the same age: 99 ± 68 mmol/mol creatinine for infantile onset vs. 4.0 ± 3.0 mmol/mol creatinine for healthy controls of the same age group and 12.1 ± 17.4 mmol/mol creatinine for late onset vs. 1.7±1.2 mmol/mol creatinine for healthy controls of the same age group. Conclusions The results of this study showed that the reference intervals of tetrasaccharide in urine changed over time; therefore, it is critically important to define age-based decision levels for the diagnosis of LOPD.
Vestronidase alfa is an enzyme replacement therapy for mucopolysaccharidosis VII (MPS VII). In this open-label, phase 1/2 study, three subjects with MPS VII received intravenous vestronidase alfa ...administered every other week (QOW) for 14 weeks (2 mg/kg), followed by 24-week forced-dose titration (1, 4, and 2 mg/kg QOW; 8 weeks each), 36-week continuation (2 mg/kg), and long-term extension (4 mg/kg). Vestronidase alfa was well tolerated and led to dose-responsive, sustained reductions in urinary glycosaminoglycan excretion.
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