Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.

Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier.

The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review.

Background: Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C-bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients.

Tremors in cats: 105 cases (2004-2023).

Although tremors are common neurological presentations, there is little known about their clinical features and underlying etiologies in cats. The aim of this study was to evaluate the clinical features, and underlying diagnoses in cats with tremors. We hypothesized that the results of this study would provide clinically useful information for clinicians when evaluating cats with tremors.

Multimodal Blood-Based Biomarker Panel Reveals Altered Lysosomal Ionic Content in Alzheimer's Disease.

Lysosomal storage disorders (LSDs) and adult neurodegenerative disorders like Alzheimer's disease (AD) share various clinical and pathophysiological features. LSDs are characterized by impaired lysosomal activity caused by mutations in key proteins and enzymes. While lysosomal dysfunction is also linked to AD pathogenesis, its precise role in disease onset or progression remains unclear.

Epidemiology and early predictors of Fabry nephropathy: evaluation of long-term outcomes from a national Fabry centre.

Background: Fabry disease is a rare genetic lysosomal storage disorder, whereby the accumulation of sphingolipids consequently leads to kidney structural damage and dysfunction. We explored the epidemiology of chronic kidney disease (CKD) among patients with Fabry disease at a major UK referral centre in Greater Manchester serving over 7 million people, to inform early predictors of kidney disease and possible treatment planning.

Methods: Data were sourced from the electronic records of registered participants from November 2020 to February 2022 of adults diagnosed with Fabry disease, with at least 1 year of follow-up.

Splenomegaly and progressive neurologic involvement: Think about Niemann-Pick type C disease.

Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disease with visceral organ involvement and neurological and psychiatric symptoms. This study presents the clinical and laboratory findings of NPC cases involving three novel variants.

Methods: The clinical and laboratory findings were reviewed retrospectively between February 2006 and December 2022.

The use of nanocarriers in treating Batten disease: A systematic review.

The neuronal ceroid lipofuscinoses, commonly known as Batten disease, are a group of lysosomal storage disorders affecting children. There is extensive central nervous system and retinal degeneration, resulting in seizures, vision loss and a progressive cognitive and motor decline. Enzyme replacement and gene therapies are being developed, and mRNA and oligonucleotide therapies are more recently being considered.

Morpholine Anchored Fluorogenic Toolkit: Unveiled Disease Allied Protein Fibrillation in Lysosomal Compartment of Live-Cell and Drosophila Models.

The aberrant accumulation of cytotoxic protein aggregates is a hallmark of various neurodegenerative and non-neurodegenerative ailments, necessitating the development of sensitive and selective tools for their detection. Herein, we report a series of morpholine-anchored fluorescent probes, denoted as SC-nmor (n = 2, 4, 6), designed for facile visualization of protein aggregates. These probes display notable changes in their photophysical properties upon binding with protein aggregates, owing to their high sensitivity to the fibrillar microenvironment.

Preclinical efficacy and safety of adeno-associated virus 5 alpha-galactosidase: A gene therapy for Fabry disease.

We developed a novel adeno-associated virus 5 gene therapy (AAV5-GLA) expressing human alpha-galactosidase A (GLA) under the control of a novel, small and strong, liver-restricted promoter. We assessed the preclinical potential of AAV5-GLA for treating Fabry disease, an X-linked hereditary metabolic disorder resulting from mutations in the gene encoding GLA that lead to accumulation of the substrates globotriaosylceramide and globotriaosylsphingosine, causing heart, kidney, and central nervous system dysfunction. Effects of intravenously administered AAV5-GLA were evaluated in (1) GLA-knockout mice aged 7-8 weeks (early in disease) and 20 weeks (nociception phenotype manifestation) and (2) cynomolgus macaques during an 8-week period.

Intrathecal or intravenous AAV9-IDUA/RGX-111 at minimal effective dose prevents cardiac, skeletal and neurologic manifestations of murine MPS I.

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of α-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 10 to 10 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration.

Screening for Fabry Disease-Related Mutations Among 829 Kidney Transplant Recipients.

: Fabry disease (FD) is a genetic lysosomal storage disease caused by a pathogenic variant in GLA gene coding for a functional alpha-galactosidase A enzyme whose disfunction leads to globotriaosylceramide (Gb3) accumulation in cells, which results in multiple organ disorders. The aim of this study was to identify mutations associated with Fabry disease among 829 kidney transplant recipients and to investigate the correlation between the factors such as age, dialysis vintage, eGFR, proteinuria and corticosteroid dose and the deviations in alpha-galactosidase A and lyso-Gb3 levels. Dry blood spot samples were collected for genetic analysis.

Case Report: A Novel Homozygous Variant of the Gene in Rare Pycnodysostosis.

Pycnodysostosis (PD) is a rare autosomal recessive skeletal dysplasia from impaired bone resorption due to osteoclastic dysfunction. The features of PD are deformity of the skull, maxilla, and phalanges; osteosclerosis; and bone fragility. We describe the case of a patient with complaints of multiple fractures of the lower extremities in the anamnesis and pain in the lower extremities, cervical spine, and shoulder girdle during physical exertion.

Health care costs of home care enzyme replacement therapy for patients with lysosomal storage diseases in Germany.

Background: Lysosomal storage diseases (LSDs) can be treated with intravenous enzyme replacement therapy (ERT). ERT is being administered either in specialized clinics or in the home care setting. Studies indicate that home-based ERT can be considered safe and positively effects patient reported outcomes.

Navigating Pompe Disease Assessment: A Comprehensive Scoping Review.

Pompe disease (PD) is a rare progressive autosomal recessive disorder resulting from the deficiency of acid alpha-glucosidase (GAA) enzyme activity. Due to its multisystemic involvement, PD leads to significant morbidity and impacts patients' quality of life. Despite the availability of approved disease-modifying treatments, the prompt diagnosis and management of PD, which are crucial for patient outcomes, still present several challenges.

AMPK protects proximal tubular epithelial cells from lysosomal dysfunction and dedifferentiation induced by lipotoxicity.

Renal proximal tubules are a primary site of injury in metabolic diseases. In obese patients and animal models, proximal tubular epithelial cells (PTECs) display dysregulated lipid metabolism, organelle dysfunctions, and oxidative stress that contribute to interstitial inflammation, fibrosis and ultimately end-stage renal failure. Our research group previously pointed out AMP-activated protein kinase (AMPK) decline as a driver of obesity-induced renal disease.

Genetic spectrum of neuronal ceroid lipofuscinosis & its genotype-phenotype correlation -A single centre experience of 56 cases.

Background: Neuronal ceroid lipofuscinoses (NCLs) are progressive, autosomal recessive lysosomal storage disorders primarily affecting children, marked by seizures, cognitive decline, motor regression, and visual impairment. Limited genetic data exist for South Asian populations, with most studies relying on enzymatic assays or electron microscopy. This study explores the genetic spectrum of NCL and genotype-phenotype correlations in a cohort from South India.

Targeted nanoliposomes to improve enzyme replacement therapy of Fabry disease.

The central nervous system represents a major target tissue for therapeutic approach of numerous lysosomal storage disorders. Fabry disease arises from the lack or dysfunction of the lysosomal alpha-galactosidase A (GLA) enzyme, resulting in substrate accumulation and multisystemic clinical manifestations. Current enzyme replacement therapies (ERTs) face limited effectiveness due to poor enzyme biodistribution in target tissues and inability to reach the brain.

The impact of sphingomyelin on the pathophysiology and treatment response to olipudase alfa in acid sphingomyelinase deficiency.

Acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder caused by pathogenic variants in the gene causing low or absent activity of the enzyme acid sphingomyelinase, resulting in subsequent accumulation of its substrate, sphingomyelin. Signs and symptoms of excessive lysosomal sphingomyelin storage, such as hepatosplenomegaly and pulmonary impairment, and in a subset of patients, progressive neurological manifestations, have long been recognized as hallmarks of the disease. Uncontrolled accumulation of sphingomyelin has important and complex downstream metabolic and immunologic consequences that contribute to the disease burden.

Prospective characterization of early symptom onset and progression in young pediatric patients with variants in the gene across 5 years: Longitudinal data from the Fabry MOPPet Study.

Purpose: This prospective, longitudinal study was designed to determine the natural history of Fabry disease (FD) in early pediatric patients across the disease spectrum.

Methods: In this observational study of children under 5 years of age with variants in the  gene, prospective phenotypic and urinary biomarker data were collected annually over 5 years.

Results: The study population included 40 participants (35 male, 5 female) with variants including 15 with classic pathogenic variants (CFD), 6 with nonclassic pathogenic variants (NFD), and 19 with a variant of uncertain significance.

Drug-refractory epilepsy due to a novel CLN5 mutation: A report of three patients from an Indian family.

Introduction: Neuronal Ceroid Lipofuscinosis (NCL) are a group of lysosomal storage disorders characterised by progressive neurodegeneration caused by an accumulation of ceroid lipopigment in lysosomes of neurons and other cell types. Adult-onset NCL (Kufs disease) differs from childhood forms by its later onset and preserved vision. Type A (Kufs A) presents as progressive myoclonus epilepsy (PME), while Type B (Kufs B) manifests as dementia with motor involvement.

Cardiac dysfunction and altered gene expression in acid ceramidase deficient mice.

Farber disease (FD) is an ultra-rare, autosomal-recessive, lysosomal storage disorder attributed to ASAH1 gene mutations. FD is characterized by acid ceramidase (ACDase) deficiency and the accumulation of ceramide in various tissues. Classical FD patients typically manifest symptoms including lipogranulomatosis, respiratory complications, and neurological deficits, often leading to mortality during infancy.

Sphingolipid Levels and Processing of the Retinyl Chromophore in the Retina of a Mouse Model of Niemann-Pick Disease.

Purpose: Mutations in the gene that encodes the enzyme acid sphingomyelinase (ASMase) are associated with Niemann-Pick disease, a lysosomal storage disorder. Mice that lack ASMase (ASMase-/-) exhibit age-related retinal degeneration and large increases in accumulation of lipofuscin in the retinal pigment epithelium (RPE). We examined which lipid species accumulate in the retina and the RPE of ASMase-/- mice and whether the retinal degeneration is associated with impaired photoreceptor metabolism and retinyl chromophore processing.