Abnormalities of acid–base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients

Lorioli, Laura; Cicalese, Maria Pia; Silvani, Paolo; Assanelli, Andrea; Salvo, Ida; Mandelli, Anna; Fumagalli, Francesca; Fiori, Rossana; Ciceri, Fabio; Aiuti, Alessandro; Sessa, Maria; Roncarolo, Maria‐Grazia; Lanzani, Chiara; Biffi, Alessandra

doi:10.1016/j.ymgme.2015.02.009

Cited by 15 publications

(14 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Psychiatric symptoms may prevail, particularly in adult patients, before the neurologic symptoms develop [ 245 ]. Proximal renal tubular acidosis has been described [ 250 ], with subclinical metabolic acidosis at baseline, worsening to a clinically significant acidosis in the acute setting [ 251 ]. Sulfatides are known to irritate the gallbladder mucosa, potentially leading to gallbladder papillomatosis [ 252, 253 ] and hemobilia [ 254–256 ].…”

Section: Lysosomal Storage Diseases Due To Enzyme Defectsmentioning

confidence: 99%

Lysosomal storage diseases

Ferreira

Gahl

2017

TRD

188

221

View full text Add to dashboard Cite

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.

show abstract

Section: Lysosomal Storage Diseases Due To Enzyme Defectsmentioning

confidence: 99%

Lysosomal storage diseases

Ferreira

Gahl

2017

TRD

188

221

View full text Add to dashboard Cite

show abstract

“…Metachromatic leukodystrophy (MLD‐OMIM 250100) is an autosomal recessive lysosomal storage disorder primarily caused by mutations in the ARSA gene, which encodes for the arylsulfatase A (ARSA) enzyme 1,2 . The lack of enzymatic activity leads to the accumulation of toxic substrates in tissues such as gallbladder, pancreas, kidneys, and, most importantly, myelin‐forming cells; this causes progressive dysfunction of the central (CNS) and peripheral nervous system (PNS) 1,3‐6 …”

Section: Introductionmentioning

confidence: 99%

Metachromatic leukodystrophy: A single‐center longitudinal study of 45 patients

Fumagalli

Zambon

Rancoita

et al. 2021

J of Inher Metab Disea

View full text Add to dashboard Cite

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time‐to‐event analyses were performed to assess time to major disease‐related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late‐infantile, 14 early‐juvenile, 5 late‐juvenile, and 4 adult MLD patients. Thirty‐four were prospectively evaluated (median FU time 43 months). In late‐infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early‐juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late‐infantile and early‐juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late‐infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease‐related milestones (except death) between early‐juvenile and late‐juvenile patients. Late‐juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late‐infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

show abstract

“…A number of AEs have already been reported to be related to the mobilization or apheresis procedure. 9,21,24 We found some AEs to be confined to specific diseases, e.g., metabolic acidosis in MLD, 25 despite the fact that leukapheresis and plerixafor rather carry a risk of alkalosis. 26,27 The frailty of WAS patients, who showed the highest rate of AEs, is not surprising, as thrombocytopenia, immunodeficiency, immune dysregulation, and auto-inflammatory manifestations can understandingly be exacerbated by mobilizing drugs and other procedures.…”

Section: Discussionmentioning

confidence: 76%

Peripheral blood stem and progenitor cell collection in pediatric candidates for ex vivo gene therapy: a 10-year series

Canarutto

Tucci

Gattillo

et al. 2021

Molecular Therapy - Methods & Clinical Development

View full text Add to dashboard Cite

Hematopoietic stem and progenitor cell (HSPC)-based gene therapy (GT) requires the collection of a large number of cells. While bone marrow (BM) is the most common source of HSPCs in pediatric donors, the collection of autologous peripheral blood stem cells (PBSCs) is an attractive alternative for GT. We present safety and efficacy data of a 10year cohort of 45 pediatric patients who underwent PBSC collection for backup and/or purification of CD34 + cells for ex vivo gene transfer. Median age was 3.7 years and median weight 15.8 kg. After mobilization with lenograstim/plerixafor (n = 41) or lenograstim alone (n = 4) and 1À3 cycles of leukapheresis, median collection was 37 Â 10 6 CD34 + cells/kg. The procedures were well tolerated. Patients who collected R7 and R13 Â 10 6 CD34 + cells/kg in the first cycle had pre-apheresis circulating counts of at R42 and R86 CD34 + cells/mL, respectively. Weight-adjusted CD34 + cell yield was positively correlated with peripheral CD34 + cell counts and influenced by female gender, disease, and drug dosage. All patients received a GT product above the minimum target, ranging from 4 to 30.9 Â 10 6 CD34 + cells/kg. Pediatric PBSC collection compares well to BM harvest in terms of CD34 + cell yields for the purpose of GT, with a favorable safety profile.

show abstract

Abnormalities of acid–base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients

Cited by 15 publications

References 12 publications

Lysosomal storage diseases

Lysosomal storage diseases

Metachromatic leukodystrophy: A single‐center longitudinal study of 45 patients

Peripheral blood stem and progenitor cell collection in pediatric candidates for ex vivo gene therapy: a 10-year series

Contact Info

Product

Resources

About