Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions.

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS).

Precision Treatment of Patients With GI Cancer Using Pre-emptive Genotyping/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil.

Purpose: The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.

Validation of an LC-MS/MS method for urinary homovanillic and vanillylmandelic ACIDS and application to the diagnosis of neuroblastoma.

Background: Urinary catecholamine metabolites are well-established biomarkers for neuroblastoma (NB). Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are the most frequently measured metabolites within SIOPEN - Catecholamine Working Group laboratories. Here, we evaluated the performance of a new LC-MS/MS in vitro diagnostic (IVD) kit for HVA and VMA to facilitate inter-laboratory harmonization.

Urinary Catecholamines Predict Relapse During Complete Remission in High-Risk Neuroblastoma.

Purpose: Urinary catecholamine metabolites are well-known biomarkers for the diagnosis (Dx) of neuroblastoma, but their clinical significance in determining therapy response during treatment is not well established. Therefore, catecholamines are not included in criteria for assessing response and complete remission (CR). This study investigated the use of urinary catecholamines in response monitoring and predicting survival outcomes.

Acid sphingomyelinase deficiency and Gaucher disease in adults: Similarities and differences in two macrophage storage disorders.

The lysosomal storage diseases chronic visceral acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are both macrophage storage disorders with overlapping clinical manifestations. We compared cross-sectional data on visceral, hematological, and biochemical manifestations of untreated adult patients with chronic visceral ASMD ( = 19) and GD1 ( = 85). Spleen volume, liver volume, and bone marrow fat fraction did not significantly differ between the two disease groups ( >0.

Natural disease course of chronic visceral acid sphingomyelinase deficiency in adults: A first step toward treatment criteria.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype.

All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved, the cells that are most expansion prone and the extent of expansion. Furthermore, whether these diseases share a common expansion mechanism is unclear.

Lethal Capecitabine Toxicity in Patients With Complete Dihydropyrimidine Dehydrogenase Deficiency Due to Ultra-Rare Variants.

A DPD deficiency should be considered in case of severe toxicity even in the absence of common risk variants in DPYD.

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.

Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome.

All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved, the cells that are most expansion prone and the extent of expansion. Furthermore, whether these diseases share a common expansion mechanism is unclear.

Early Risk Stratification for Natural Disease Course in Fabry Patients Using Plasma Globotriaosylsphingosine Levels.

Background: Fabry disease is a very heterogeneous X-linked lysosomal storage disease. Disease manifestations in the kidneys, heart, and brain vary greatly, even between patients of the same sex and with the same disease classification (classical or nonclassical). A biomarker with a strong association with the development of disease manifestations is needed to determine the need for Fabry-specific treatment and appropriate frequency of follow-up because clinical manifestations of the disorder may take decennia to develop.

Development of a Biosimilar of Agalsidase Beta for the Treatment of Fabry Disease: Preclinical Evaluation.

Background And Objective: Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients.

Severe dilated cardiomyopathy as an unusual clinical presentation in an infant with sialidosis type II.

We report a unique case of an infant with a severe dilated cardiomyopathy as the clinical presentation of sialidosis type II (OMIM 256550), a rare autosomal recessive inherited lysosomal storage disease that is characterized by partial or complete deficiency of α-neuraminidase, following mutations in the gene neuraminidase 1 (), located on the short arm of chromosome 6 (6p21.3). Accumulation of metabolic intermediates leads to severe morbidity, especially myoclonus, gait disturbances, cherry-red macules with secondary loss of visual acuity, impaired color vision and night blindness, and sometimes additional neurological findings such as seizures.

Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4.

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C.

Multi-omics in classical galactosemia: Evidence for the involvement of multiple metabolic pathways.

Classical galactosemia (CG) is one of the more frequent inborn errors of metabolism affecting approximately 1:40.000 people. Despite a life-saving galactose-restricted diet, patients develop highly variable long-term complications including intellectual disability and movement disorders.

The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain.

Background: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism.

Aim: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype.

Methods: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases.

Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study.

In clinical practice, 25-30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine-related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype-based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency.

β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity.

β-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid to β-alanine and β-aminoisobutyric acid, ammonia and CO. To date, only a limited number of genetically confirmed patients with a complete β-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified β-ureidopropionase deficient individuals.

Children with atopic dermatitis show increased activity of β-glucocerebrosidase and stratum corneum levels of glucosylcholesterol that are strongly related to the local cytokine milieu.

Background: Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), β-glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD.

Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes.

Background: The therapeutic use of [I]meta-iodobenzylguanidine ([I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake.

Preemptive screening of DPYD as part of clinical practice: high prevalence of a novel exon 4 deletion in the Finnish population.

Capecitabine is a fluoropyrimidine that is widely used as a cancer drug for the treatment of patients with a variety of cancers. Unfortunately, early onset, severe or life-threatening toxicity is observed in 19-32% of patients treated with capecitabine and 5FU. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of 5FU and a DPD deficiency has been shown to be a major determinant of severe fluoropyrimidine-associated toxicity.