At-Risk Testing for Pompe Disease Using Dried Blood Spots: Lessons Learned for Newborn Screening.

Pompe disease (GSD II) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid-α-glucosidase (GAA, EC 3.2.1.

Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and β-thalassemias in dried blood spots.

A fast and reliable method for the determination of hemoglobinopathies and thalassemias by high-resolution accurate mass spectrometry (HRAM/MS) is presented. The established method was verified in a prospective clinical study (HRAM/MS vs. high-pressure liquid chromatography [HPLC]) of 5335 de-identified newborn samples from the Hamburg area.

Diagnostic strategy for females suspected of Fabry disease.

A total of 11 948 females suspicious of Fabry disease were tested by a combined biochemical and genetic approach. The enzyme activity, together with the concentration of lyso-GL-3 (lyso-Gb3) biomarker in dried blood spots (DBS), substantially improved the diagnostic detection of Fabry disease in females compared to the enzyme activity alone. Abnormal values for both were highly suspicious of Fabry disease (97% positive predictive value [PPV], similar to PPV in males).

Obstructive sleep apnea and craniofacial appearance in MPS type I-Hurler children after hematopoietic stem cell transplantation.

Objectives: Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder characterized by severe multi-systemic organ manifestations including obstructive sleep apnea syndrome (OSAS). Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in severe MPS I (MPS IH, Hurler syndrome). However, the effect of HSCT on OSAS in MPS IH still remains unclear.

Newborn Screening for Lysosomal Storage Disorders: Methodologies for Measurement of Enzymatic Activities in Dried Blood Spots.

All worldwide newborn screening (NBS) for lysosomal storage diseases (LSDs) is performed as a first-tier test by measurement of lysosomal enzymatic activities in dried blood spots (DBS). The currently two available methodologies used for measurement of enzymatic activities are tandem mass spectrometry (MS/MS) and digital microfluidics fluorimetry (DMF-F). In this chapter we summarize the workflows for the two platforms.

Megaphylogeny resolves global patterns of mushroom evolution.

Mushroom-forming fungi (Agaricomycetes) have the greatest morphological diversity and complexity of any group of fungi. They have radiated into most niches and fulfil diverse roles in the ecosystem, including wood decomposers, pathogens or mycorrhizal mutualists. Despite the importance of mushroom-forming fungi, large-scale patterns of their evolutionary history are poorly known, in part due to the lack of a comprehensive and dated molecular phylogeny.

Validity of a rapid and simple fluorometric tripeptidyl peptidase 1 (TPP1) assay using dried blood specimens to diagnose CLN2 disease.

Purpose: CLN2 disease is a genetic disorder caused by dysfunction of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) that belongs to the neuronal ceroid lipofuscinoses (NCL) and leads to epilepsy, dementia, and death in young persons. CLN2 disease has recently become treatable by enzyme replacement, which can only be effective when the disease is diagnosed early. We have investigated the reliability of a test for TPP1 deficiency in dried blood specimens (DBS) to detect CLN2 disease.

Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD).

Background: Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1, the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease.

Low Prevalence Estimates of Late-Onset Glycogen Storage Disease Type II in French-Speaking Belgium are not Due to Missed Diagnoses.

Background: Late-onset glycogen storage disease type II is associated with variable muscle phenotypes. Epidemiological data suggest that its prevalence is lower in Belgium than in bordering countries like The Netherlands.

Objective: We investigated whether such low estimated prevalence is due to missed diagnoses.

A Description of Reference Ranges for Organic Acids in Urine Samples from A Pediatric Population in Iran.

Background: Organic acids refer to a family of compounds that are intermediates in a variety of metabolic pathways. Many organic acids are present in urine from clinically normal individuals. Elevated levels of urine organic acids cause to the organic acidurias, disorders in which some metabolic pathways in organic acid metabolism are blocked.

Best practice in the measurement and interpretation of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2.

Lysosomal acid lipase deficiency (LAL-D) is an inherited, autosomal recessive lysosomal storage disorder characterized by progressive damage in multiple organ systems. Diagnosis is especially important in infants, in whom the course of disease is rapidly lethal without treatment. The recent regulatory approval of recombinant human lysosomal acid lipase (LAL), sebelipase alfa, merits rapid diagnosis in clinical routine, particularly in infants.

Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Unlabelled: Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases.

Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease.

Klüver-Bucy syndrome associated with a recessive variant in HGSNAT in two siblings with Mucopolysaccharidosis type IIIC (Sanfilippo C).

Klüver-Bucy syndrome (KBS) comprises a set of neurobehavioral symptoms with psychic blindness, hypersexuality, disinhibition, hyperorality, and hypermetamorphosis that were originally observed after bilateral lobectomy in Rhesus monkeys. We investigated two siblings with KBS from a consanguineous family by whole-exome sequencing and autozygosity mapping. We detected a homozygous variant in the heparan-α-glucosaminidase-N-acetyltransferase gene (HGSNAT; c.

Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis.

Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death.

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness.

Objective: We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation.

Methods: DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry.

Tolerability, safety, and pharmacokinetics of the novel cathepsin A inhibitor SAR164653 in healthy subjects.

Cathepsin A (CathA) is a lysosomal protein where it forms a stable complex with neuraminidase and ß-galactosidase. CathA also has enzymatic activity and is involved in the degradation of many peptides. CathA was recently discovered as a target for heart failure, fostering the development of CathA inhibitors with SAR164653 as a frontrunner.

Congenital Adrenal Hyperplasia with Non-functional Mutations in Both Alleles in a Clinically Unaffected Infant.

Background: Results in neonatal screening programs aiming at detection of congenital adrenal hyperplasia (CAH) can only report elevated levels of 17-hydroxy-progesterone (17-OHP), without being able to differentiate presence or absence of salt loss.

Aim: To predict presence or absence of salt loss in newborn infants with CAH.

Methods: The first specimen of suspected CAH in samples sent from People's Democratic Republic of Laos (Lao PDR) was investigated for known mutations in CAH associated with salt loss.

The Prevalence of Sickle Cell Disease and Its Implication for Newborn Screening in Germany (Hamburg Metropolitan Area).

Sickle cell disease is among hereditary diseases with evidence that early diagnoses and treatment improves the clinical outcome. So far sickle cell disease has not been included in the German newborn screening program despite immigration from countries with populations at risk. To determine the birth prevalence we tested 17,018 newborns.

Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum.

Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.

Combined Serological Detection of Circulating Angiostrongylus vasorum Antigen and Parasite-specific Antibodies in Dogs from Hungary.

The occurrence of the nematode Angiostrongylus vasorum, also known as the French heartworm, is increasingly being reported from various European countries. The adults of this parasite species live in the pulmonary arteries and right cardiac ventricle of wild canids and domestic dogs. Larval stages and eggs in the lungs induce inflammatory verminous pneumonia, causing severe respiratory disease in dogs.

Dried blood spots allow targeted screening to diagnose mucopolysaccharidosis and mucolipidosis.

Background: As patients with different types of mucopolysaccharidosis (MPS) and mucolipidosis (ML) may present with overlapping clinical features - including coarse face, hepatosplenomegaly, bone dysplasia and claw-hand deformities, collectively also called 'MPS-like phenotype', enzymatic and/or molecular genetic analyses are indispensable for accurate diagnosis and applying specific therapy. In this prospective study, we screened patients with symptoms compatible with MPS for MPS I, II (males) and VI.

Methods: Dried blood spots/specimens (DBS) were collected from 200 patients with an MPS-like phenotype and analysed for activities of α-iduronidase (IDUA), iduronate-2-sulphatase (IDS), and arylsulphatase B (ARSB), the enzymes deficient in mucopolysaccharidosis (MPS) type I, II and VI, respectively.

Seroprevalence of some vector-borne infections of dogs in Hungary.

The first comprehensive study on the prevalence of canine vector-borne pathogens (Anaplasma phagocytophilum, Borrelia burgdorferi, Ehrlichia canis, and Dirofilaria immitis) was carried in Hungary because, except for babesiosis and dirofilariosis caused by Dirofilaria repens, there were no data on their regional distribution and prevalence. In 2011 and 2012, 1305 blood samples were collected from randomly selected, apparently healthy pet dogs in 167 localities of 19 counties of Hungary. All sera samples from dogs were screened for simultaneous qualitative detection of circulating antibodies to E.

Combined D2-/L2-hydroxyglutaric aciduria (SLC25A1 deficiency): clinical course and effects of citrate treatment.

Combined D,L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182) is a rare neurometabolic disorder clinically characterized by muscular hypotonia, severe neurodevelopmental dysfunction, and intractable seizures associated with respiratory distress. Biochemically, DL-2HGA patients excrete increased amounts of D- and L-2-hydroxyglutarate (D2HG and L2HG, respectively), with predominance of D2HG, and α-ketoglutarate, and show a decrease in urinary citrate. Impaired function of the mitochondrial citrate carrier (CIC) due to pathogenic mutations within the SLC25A1 gene has been identified as the underlying molecular cause of the disease.

Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies.

Objective: Late-onset Pompe disease is a rare, but potentially treatable metabolic myopathy, and therefore should not be overlooked. However, it is not unusual that patients go undiagnosed for many years. We hypothesized that patients with late-onset Pompe disease may have been overlooked in a population of patients with unclassified neuromuscular disease.