Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the gene.

Methylmalonyl-coA epimerase (MCE) follows propionyl-coA carboxylase and precedes methylmalonyl-coA mutase in the pathway converting propionyl-coA to succinyl-coA. MCE deficiency has previously been described in six patients, one presenting with metabolic acidosis, the others with nonspecific neurological symptoms or asymptomatic. The clinical significance and biochemical characteristics of this rare condition have been incompletely defined.

UPLC-MS/MS detection of disaccharides derived from glycosaminoglycans as biomarkers of mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are a group of disorders resulting from primary defects in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Depending on the specific enzyme defect, the catabolism of one or more GAGs is blocked leading to accumulation in tissues and biological fluids. GAG measurements are important for high-risk screening, diagnosis, monitoring treatment efficacy, and patient follow up.

Novel microdeletions affecting the GNAS locus in pseudohypoparathyroidism: characterization of the underlying mechanisms.

Context: Pseudohypoparathyroidism type Ia (PHP1A) is a rare endocrine disorder characterized by hypocalcemia, hyperphosphatemia, multiple hormonal resistance, and features of Albright hereditary osteodystrophy. When the phenotype is present but not associated with hormonal resistance, it is called psedopseudohypoparathyroidism (PPHP). Both entities have been associated to GNAS haploinsufficiency, and are mostly caused by inherited inactivating mutations at GNAS gene that codes for the stimulatory alpha subunit of G protein, although the cause remains unidentified in approximately 30% of patients.

Toward a functional definition of a "rare disease" for regulatory authorities and funding agencies.

Background: The designation of a disease as "rare" is associated with some substantial benefits for companies involved in new drug development, including expedited review by regulatory authorities and relaxed criteria for reimbursement. How "rare disease" is defined therefore has major financial implications, both for pharmaceutical companies and for insurers or public drug reimbursement programs. All existing definitions are based, somewhat arbitrarily, on disease incidence or prevalence.

Urinary biomarker investigation in children with Fabry disease using tandem mass spectrometry.

Background: Fabry disease is an X-linked lysosomal storage disorder affecting both males and females with tremendous genotypic/phenotypic variability. Concentrations of globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3)/related analogues were investigated in pediatric and adult Fabry cohorts. The aims of this study were to transfer and validate an HPLC-MS/MS methodology on a UPLC-MS/MS new generation platform, using an HPLC column, for urine analysis of treated and untreated pediatric and adult Fabry patients, to establish correlations between the excretion of Fabry biomarkers with gender, treatment, types of mutations, and to evaluate the biomarker reliability for early detection of pediatric Fabry patients.

Application of a policy framework for the public funding of drugs for rare diseases.

Background: In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs.

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa.

Purpose: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.

Methods: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months).

An evaluation framework for funding drugs for rare diseases.

Objectives: For rare diseases it may be difficult to generate data from randomized trials to support funding of a drug. Enzyme replacement therapies for diseases of inherited metabolic enzyme deficiency provide an example of this dilemma. The Ontario Public Drug Programs convened the Drugs for Rare Diseases Working Group to develop a policy for assessing these drugs.

Erythropoietic protoporphyria: spectrum of three cases.

Background: Erythropoietic protoporphyria is a rare photodermatosis of childhood, and the diagnosis can be delayed. A deficient ferrochelatase enzyme leads to accumulation of protoporphyrins in the dermis, causing phototoxic burning.

Objective: To report three cases with great variability in severity of symptoms and age at diagnosis.

Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy.

Objectives: Anderson-Fabry disease (AFD) is a lysosomal storage disease, which can involve the heart, mimicking hypertrophic cardiomyopathy (HCM). The underlying mechanism of disease in AFD is an infiltrative, diffuse process, whereas HCM is a primary heart muscle condition with patchy distribution, which may prompt differences in myocardial mechanics. The aim of this study was to assess myocardial mechanics in AFD according to the presence of left ventricular hypertrophy (LVH) compared to nonobstructive HCM (NHCM) and healthy controls.

Urinary globotriaosylsphingosine-related biomarkers for Fabry disease targeted by metabolomics.

Fabry disease is a lysosomal storage disorder caused by deficiency of α-galactosidase A, resulting in glycosphingolipid accumulation in organs and tissues, including plasma and urine. Two disease-specific Fabry biomarkers have been identified and quantified in plasma and urine: globotriaosylceramide (Gb(3)) and globotriaosylsphingosine (lyso-Gb(3)). The search continues for biomarkers that might be reliable indicators of disease severity and response to treatment.

An improved method for glycosaminoglycan analysis by LC-MS/MS of urine samples collected on filter paper.

Background: Mucopolysaccharidoses are complex lysosomal storage disorders caused by any of eleven different enzyme deficiencies resulting in the accumulation of substrates, mainly glycosaminoglycans (GAGs), in various tissues and biological fluids.

Method: We developed and validated a urine filter paper methodology for the analysis of GAGs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for mucopolysaccharidoses type I, type II and type VI patients. We focused on 2 objectives: first, its applicability to high-risk screening, and secondly, to facilitate the collection and shipping of samples to reference centers as part of diagnostic investigation, as well as from treated patients needing to be monitored for assessment of the efficacy of treatment.

Source document verification in the Mucopolysaccharidosis Type I Registry.

PURPOSE: The Mucopolysaccharidosis Type I (MPS I) Registry is an international observational database that tracks the natural history and the outcomes of patients with MPS I. The Registry was a regulatory requirement following the approval of laronidase enzyme replacement therapy for MPS I in 2003. All data are collected voluntarily after informed consent from the patient or family.

Impact of measures to enhance the value of observational surveys in rare diseases: the Fabry Outcome Survey (FOS).

Background: Disease registries are an important source of information on the natural history of rare diseases and the response to new therapies in a real-world setting. The value of the information, however, is directly related to the completeness of the data entered for each patient over the course of time. The Fabry Outcome Survey (FOS) is a Shire Human Genetic Therapies-sponsored, physician-directed registry of patients with Fabry disease, a rare, multisystem, lysosomal storage disorder, established in 2001.

X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.

X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection.

Hunter disease eClinic: interactive, computer-assisted, problem-based approach to independent learning about a rare genetic disease.

Background: Computer-based teaching (CBT) is a well-known educational device, but it has never been applied systematically to the teaching of a complex, rare, genetic disease, such as Hunter disease (MPS II).

Aim: To develop interactive teaching software functioning as a virtual clinic for the management of MPS II.

Implementation And Results: The Hunter disease eClinic, a self-training, user-friendly educational software program, available at the Lysosomal Storage Research Group (http://www.

Efficient analysis of urinary glycosaminoglycans by LC-MS/MS in mucopolysaccharidoses type I, II and VI.

Mucopolysaccharidoses (MPSs) are complex storage disorders caused by specific lysosomal enzyme deficiencies, resulting in the accumulation of glycosaminoglycans (GAGs) in urine, plasma, as well as in various tissues. We devised and validated a straightforward, but accurate and precise tandem mass spectrometry methodology coupled to high performance liquid chromatography (LC-MS/MS) for the quantification of GAGs in urine. The method is applicable to the investigation of patients with MPS I, II, and VI, by quantifying dermatan sulfate (DS) and heparan sulfate (HS) in urine.

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants).

Late-onset GM2 gangliosidosis is an autosomal recessive, neurodegenerative, lysosomal storage disease, caused by deficiency of ß-hexosaminidase A (Hex A), resulting from mutations in the HEXA (Tay-Sachs variant) or the HEXB (Sandhoff variant) genes. The enzyme deficiency in many patients with juvenile or adult onset forms of the disease results from the production of an unstable protein, which becomes targeted for premature degradation by the quality control system of the smooth endoplasmic reticulum and is not transported to lysosomes. In vitro studies have shown that many mutations in either the α or β subunit of Hex A can be partially rescued, i.

Case report: Long-term outcome post-heart transplantation in a woman with Fabry's disease.

Fabry's disease is an X-linked recessive disorder that results from the deficiency of alpha-galactosidase A and causes the accumulation of globotriaosylceramide (Gb3) in different tissues. It leads to a rare form of cardiomyopathy which may be complicated by end-stage heart failure and need to heart transplant. Our group described the first case of heart transplant in a woman with cardiomyopathy secondary to Fabry's disease about 12 years ago.

How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

Background: Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb(3)), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb(3)), is increased in patients with the disease. Until now, lyso-Gb(3) was not detectable in urine, possibly because of the presence of interfering compounds.

Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I.

Scheie syndrome is the most attenuated and rarest form of mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder. Only small patient series have previously been reported. Using natural history data from the uniquely large population of 78 Scheie patients enrolled in the MPS I Registry, we characterized the onset and prevalence of clinical manifestations and explored reasons for delayed diagnosis of the disease.

Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease.

Objectives: To investigate a 4-year prospective clinical trial of agalsidase alfa in children with Fabry disease, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A.

Study Design: Seventeen (16 boys, 1 girl; age range, 7.3 to 18.

An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH.

A validated disease severity scoring system for Fabry disease.

Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques.

Substrate reduction therapy in juvenile GM2 gangliosidosis.

Substrate reduction therapy (SRT) is considered to be a potential therapeutic option for juvenile GM2 gangliosidosis (jGM2g). We evaluated the efficacy of SRT in jGM2g, assessing neurological, neuropsychological and brain magnetic resonance imaging (MRI) outcomes over a 24-month period of treatment. In an open-label and single-center study, five jGM2g patients (mean age 14.