[Neuro-otological manifestations in Fabry disease-a retrospective single center study]. / Neurootologische Manifestationen bei Morbus Fabry ­ eine retrospektive Analyse.

BACKGROUND: Fabry disease (FD) is one of the X­linked lysosomal storage diseases that can affect any organ. They have a specific lysosomal dysfunction in common, which results in substrate accumulation in lysosomes instead of metabolite degradation. Due to the deficiency/absence of α­galactosidase, globotriaosylceramides (Gb3) are deposited in lysosomes of the organs. In addition to acroparesthesia, angiokeratomas, autonomic dysfunction, vortex keratopathies, ischemic cerebral or cardiac complications and chronic renal failure, also vestibulocochlear dysfunctions with sudden or progressive asymmetric hearing loss, tinnitus and vertigo may be observed. PATIENTS AND METHODS: In this retrospective study, 33 patients (men = 16 and women = 17) with FD were evaluated. All patients presented to us in interdisciplinary cooperation as part of routine examinations by the specialized center for lysosomal storage diseases of the in-house department of nephrology. This presentation is carried out as a screening examination independent of neuro-otological symptoms. RESULTS: The mean age at diagnosis was 34.76 (±11.55) years. The first presentation in our ENT department was at 40.45 (±11.71) years. We were able to demonstrate a significant correlation between neurological symptoms or apoplexy and hearing loss (p = 0.001) and between cardiac manifestations and hearing loss (p = 0.024). CONCLUSION: Hearing loss is a potential symptom of Fabry disease and is not limited to the classic male phenotype. Due to possible positive correlations with neurological and cardiological manifestations of the disease, routine ENT screening examinations should be carried out to be able to identify and treat neuro-otological deficits at an early stage. In addition, FD should also be considered and tested as a differential diagnosis, especially in younger patients with sudden unilateral or bilateral hearing loss and a family history.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

The surgical management of spinal disorders in lysosomal storage diseases: a systematic review.

BACKGROUND: The skeletal manifestations of lysosomal storage diseases (LSDs) are largely refractory to available therapeutic modalities. Consequently, there is an increasing need to manage their spinal deformities. The aim was to perform a systematic review to answer the questions, "What are the reported indications for surgery for spinal deformity in patients with LSDs?" and "what are the published surgical management strategies?". METHODS: Articles that made reference to at least one LSD, a spinal abnormality and surgical management were included. Extracted study data included: study type, sample size, methodology and year of publication. The following clinical information was collected: demographics, spinal abnormalities, and surgical indications, details and outcomes. RESULTS: Thirty-seven articles were included, with 23 describing surgical management of craniocervical manifestations seen in mucopolysaccharidosis. Radiological evidence of myelopathy at the craniocervical junction and/or progressive clinical neurological compromise were accepted as surgical indications. Prophylactic surgery was proposed by some authors. The recommended surgical technique and whether to stabilise and/or decompress varied between articles and LSD types. Twenty-one articles discussed thoracolumbar pathology, including thoracolumbar kyphosis and scoliosis. Radiological severity, progression of deformity, and presence of neurological deterioration were discussed as surgical indications. Most papers recommended circumferential arthrodesis via combined anterior and posterior approaches. CONCLUSION: The surgical management of spinal disorders in LSDs remains controversial. Centres managing these patients should be encouraged to have a standardised system of reporting outcomes, to facilitate recommendations for management of the spinal manifestations.

Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review.

We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed, Ovid, and clinicaltrials.gov were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, 22 case series with 2678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2663) in NIHF cases that were tested for any LSD, and 8.2% (177/2151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis, and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.

Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach.

More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences. Also under study is the possibility to block substrate accumulation upstream, by promoting a decrease of its synthesis. This concept is known as substrate reduction therapy and may be triggered by several molecules, such as small interfering RNAs (siRNAs). siRNAs promote RNA interference, a naturally occurring sequence-specific post-transcriptional gene-silencing mechanism, and may target virtually any gene of interest, inhibiting its expression. Still, naked siRNAs have limited cellular uptake, low biological stability, and unfavorable pharmacokinetics. Thus, their translation into clinics requires proper delivery methods. One promising platform is a special class of liposomes called stable nucleic acid lipid particles (SNALPs), which are characterized by high cargo encapsulation efficiency and may be engineered to promote targeted delivery to specific receptors. Here, we review the concept of SNALPs, presenting a series of examples on their efficacy as siRNA nanodelivery systems. By doing so, we hope to unveil the therapeutic potential of these nanosystems for targeted brain delivery of siRNAs in LSDs.

Lysosomal Storage Disorders Shed Light on Lysosomal Dysfunction in Parkinson's Disease.

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson's disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.

Aortopathies in mouse models of Pompe, Fabry and Mucopolysaccharidosis IIIB lysosomal storage diseases.

INTRODUCTION: Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. METHODS: We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/- mice for FD, 5 NAGLU-/- mice for MPS IIIB, 5 GAA-/- mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. RESULTS: Compared to their correspondent WT mice: GAA-/- mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs 1.02mm, p-value 0.04); GLA-/- mice showed greater diameters of aortic annulus (1.35mm vs. 1.22mm, p-value = 0.01), sinus of Valsalva (1.6mm vs. 1.38mm, p-value<0.01), ascending aorta (1.57mm vs. 1.34mm, p-value<0.01), aortic arch (1.36mm vs. 1.22mm, p-value = 0.03) and descending aorta (1.29mm vs. 1.11mm, p-value<0.01); NAGLU-/- mice showed greater diameters of sinus of Valsalva (1.46mm vs. 1.31mm, p-value = 0.05), ascending aorta (1.42mm vs. 1.29mm, p-value<0.01), aortic arch (1.34mm vs. 1.28mm, p-value<0.01) and descending aorta (1.18mm vs. 1.1mm, p-value 0.01). CONCLUSIONS: We evaluated for the first time the aortic diameters in 3 LSD mouse models and identified different aortopathy patterns, in concordance with recent human findings. Our results are relevant in view of using KO mouse models for efficiently testing the efficacy of new therapies on distinct cardiovascular aspects of LSDs.

Impact of COVID-19 related healthcare crisis on treatments for patients with lysosomal storage disorders, the first Italian experience.

The direct and indirect effects of Coronavirus Disease-19 (COVID-19) pandemic, on Italian patients with lysosomal storage disorders receiving therapy, were analyzed by a phone questionnaire. No proved COVID-19 emerged among 102 interviewed. No problems were reported by patients receiving oral treatments. Forty-nine% of patients receiving enzyme replacement therapy in hospitals experienced disruptions, versus 6% of those home-treated. The main reasons of missed infusions were fear of infection (62.9%) and re-organization of the infusion centers (37%).

Lysosomal storage disease spectrum in nonimmune hydrops fetalis: a retrospective case control study.

OBJECTIVES: Nonimmune hydrops fetalis (NIHF) accounts for 90% of hydrops fetalis cases. About 15% to 29% of unexplained NIHF cases are caused by lysosomal storage diseases (LSD). We review the spectrum of LSD and associated clinical findings in NIHF in a cohort of patients referred to our institution. METHODS: We present a retrospective case-control study of cases with NIHF referred for LSD biochemical testing at a single center. Cases diagnosed with LSD were matched to controls with NIHF and negative LSD testing and analyzed according to the STROBE criteria to the extent the retrospective nature of this study allowed. RESULTS: Between January 2006 and December 2018, 28 patients with NIHF were diagnosed with a LSD. Eight types of LSD were diagnosed: galactosialidosis 8/28 (28.6%), sialic acid storage disease (SASD) 5/28 (17.9%), mucopolysaccharidosis VII 5/28 (17.9%), Gaucher 4/28 (14.3%), sialidosis 2/28 (7.1%), GM1 gangliosidosis 2/28 (7.1%), Niemann-Pick disease type C 1/28 (3.6%), and mucolipidosis II/III 1/28 (3.6%). Associated clinical features were hepatomegaly 16/21 (76.2%) vs 22/65 (33.8%), P < .05, splenomegaly 12/20 (60.0%) vs 14/58 (24.1%), P < .05, and hepatosplenomegaly 10/20 (50.0%) vs 13/58 (22.4%) P < .05. CONCLUSION: The most common LSD in NIHF were galactosialidosis, SASD, mucopolysaccharidosis VII, and Gaucher disease. LSD should be considered in unexplained NIHF cases, particularly if hepatomegaly, splenomegaly, or hepatosplenomegaly is visualized on prenatal ultrasound.

Pulmonary involvement in selected lysosomal storage diseases and the impact of enzyme replacement therapy: A state-of-the art review.

Lysosomal storage disorders (LSDs) are multisystemic, progressive and clinically very heterogeneous. Respiratory complications are not regarded as the principal problems of LSDs, but significantly impact morbidity. In this review, we focus on pulmonary complications observed in late-onset LSDs, their milder forms that are recognised in adulthood. We also discuss the effects of enzyme replacement therapy (ERT) on the respiratory system in patients with particular LSDs. We searched the PubMed database, retrieving research papers on pulmonary complications of LSDs currently treated with ERT (the conditions are abbreviated GD3; NPDB; LOPD; MPS I, II, IVA, VI; and FD) and the effects of such treatment. Although some studies indicated that ERT was helpful in terms of reducing chest computed tomography abnormalities, infection frequency and organomegaly, the data are not conclusive, and the mechanism of action of ERT in the respiratory system remains unclear for some LSDs including late-onset Pompe disease and Gaucher disease type III. The optimal timing of treatment for pre-symptomatic or symptomatic patients, treatment duration and whether such treatment modulates inflammation (as has been suggested in patients with Fabry disease), remain to be explored.

[Loss of motoric function in a three-year-old boy with lysosomal storage disease].

This case report describes a three-year-old boy with delayed development of language, who developed erythema migrans. Soon after peroral antibiotics was initiated, he also had loss of motoric function, and he developed ataxia. Neuroborreliosis was diagnosed, and antibiotic treatment was changed to intravenous. There was no gain of his motoric skills. A test was made for lysosomal storage disease, and neuronal ceroid lipofuscinosis type 2 was found. The patient started intraventricular enzyme substitution treatment as the first patient in Denmark. Treatment has shown to reduce the progression of functional decline.

Large animal models contribute to the development of therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are a group of 70 monogenic disorders characterized by the lysosomal accumulation of a substrate. As a group, LSDs affect ~1 in 5000 live births; however, each individual storage disease is rare, limiting the ability to perform natural history studies or to perform clinical trials. Perhaps in no other biomedical field have naturally occurring large animal (canine, feline, ovine, caprine, and bovine) models been so essential for understanding the fundamentals of disease pathogenesis and for developing safe and effective therapies. These models were critical for the development of hematopoietic stem cell transplantation in α- and ß- mannosidosis, fucosidosis, and the mucopolysaccharidoses; enzyme replacement therapy for fucosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis; and small molecule therapy in Niemann-Pick type C disease. However, their most notable contributions to the biomedical field are in the development of gene therapy for LSDs. Adeno-associated viral vectors to treat nervous system disease have been evaluated in the large animal models of α-mannosidosis, globoid cell leukodystrophy, GM1 and GM2 gangliosidosis, the mucopolysaccharidoses, and neuronal ceroid lipofuscinosis. This review article will summarize the large animal models available for study as well as their contributions to the development of central and peripheral nervous system dysfunction in LSDs.

Oncogenic effects of germline variants in lysosomal storage disease genes.

PURPOSE: Clinical and experimental evidence has suggested pathobiological crosstalk between lysosomal storage diseases (LSDs) and cancer. We aimed to elucidate the association between germline variants in LSD genes and cancer. METHODS: We performed aggregate rare variant association analysis of potentially pathogenic variants (PPVs) in 42 LSD genes and >30 histological types of cancer using genome sequencing data from 2567 cancer patients (Pan-Cancer cohort) and 2504 healthy individuals (1000 Genomes cohort) and exome sequencing data from 53,105 individuals without cancer (ExAC cohort). RESULTS: PPVs were significantly enriched in the Pan-Cancer cohort compared with the 1000 Genomes cohort (PPV prevalence, 20.7% vs. 13.5%; P = 8.7 × 10-12). Cancer risk was higher in individuals with a greater number of PPVs (P = 7.3 × 10-12). Population structure-adjusted optimal sequence kernel association test (SKAT-O) revealed 37 significantly associated cancer type-LSD gene pairs. These results were supported by the consistent tendency toward enrichment of PPVs in cancer patients compared with the ExAC cohort. Cancer developed earlier in PPV carriers than in wild-type patients. Analysis of tumor transcriptomic data from the pancreatic adenocarcinoma cohort revealed 508 genes differentially expressed according to PPV carrier status, which were highly enriched in the core signaling pathways of pancreatic cancer. CONCLUSION: Carriers of PPVs in LSD genes are at increased risk of cancer.

Myopathy and scleromyxedema.

Scleromyxedema is a chronic, idiopathic disorder associated with monoclonal gammopathy, and characterized by dermal mucin deposition. However, systemic manifestations are frequent, including neuromuscular symptoms. We herein present a 71-year-old man who developed a vacuolar myopathy in a context of a known scleromyxedema, and we compare our observation with the nineteen other cases found in the medical literature. Such an association (especially with suggestive skin abnormalities) has to be known for two reasons. First, this diagnosis might be quite challenging because the myopathy may precede the typical skin changes. Secondly, conversely to other forms of vacuolar myopathy, some of the symptoms may respond (even partially) to immunomodulatory and/or immunosuppressant therapeutics.

Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities.

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

Neurological manifestations of lysosomal disorders and emerging therapies targeting the CNS.

Lysosomal disorders have been an area of interest since intravenous enzyme replacement therapy was successfully introduced for the treatment of Gaucher's disease in the early 1990s. This treatment approach has also been developed for several other lysosomal disorders, including Fabry's disease, Pompe's disease, lysosomal acid lipase deficiency, and five types of mucopolysaccharidosis. Despite the benefits of enzyme replacement therapy, it has limitations-most importantly, its ineffectiveness in treating the neurological components of lysosomal disorders, as only a small proportion of recombinant enzymes can cross the blood-brain barrier. Development of strategies to improve drug delivery to the CNS is now the primary focus in lysosomal disorder research. This Review discusses the neurological manifestations and emerging therapies for the CNS component of these diseases. The therapies in development (which are now in phase 1 or phase 2 clinical trials) might be for specific lysosomal disorders (enzyme replacement therapy via intrathecal or intracerebroventricular routes or with fusion proteins, or gene therapy) or applicable to more than one lysosomal disorder (haemopoietic stem cell transplantation, pharmacological chaperones, substrate reduction therapy, or stop codon readthrough). The combination of early diagnosis with effective therapies should change the outlook for patients with lysosomal disorders with neurological involvement in the next 5-10 years.

Turning the backbone into an ankylosed concrete-like structure: Case report.

RATIONALE: Progressive restriction of the spinal bio-mechanics is not-uncommon deformity encountered in spine clinics. Congenital spinal fusion as seen in Klippel-Feil-anomaly, progressive non-infectious anterior vertebral fusion, and progressive spinal hyperostosis secondary to ossification of the anterior longitudinal spinal ligament are well delineated and recognized. PATIENT CONCERNS: A 24-year-old girl has history of osteoporosis since her early childhood, associated with multiple axial and appendicular fractures and scoliosis. Recently she presented with episodes of severe back pain, spinal rigidity/stiffness with total loss of spine biomechanics. DIAGNOSES: She was provisionally diagnosed as having osteogenesis imperfecta and was investigated for COL1A1/A2 mutations which have been proven to be negative. Autosomal recessive type of osteogenesis imperfecta was proposed as well, no mutations have been encountered. A homozygous for CTSA gene mutation, the gene associated with Galactosialidosis was identified via whole exome sequencing (Next-Generation Sequencing projects) has been identified. INTERVENTIONS: Early in her life she had a history of frequent fractures of the long bones since she was 4 years which was followed by vertebral fractures at the age of 12 years. She manifested lower serum 25OH-D levels and were associated with lower LS-aBMD Z-scores with higher urinary bone turnover indexes (urinary NTX/Cr). OUTCOMES: Lysosomal storage diseases (LSD) have a strong correlation with the development of osteoporosis. LSD causes skeletal abnormalities results from a lack of skeletal remodeling and ossification abnormalities owing to abnormal deposition of GAGs (impaired degradation of glycosaminoglycans ) in bone and cartilage. 3D reconstruction CT scan of the spine showed diffuse hyperostosis of almost the entire spine (begins at the level of T4- extending downwards to involve the whole thoraco-lumbar and upper part of the sacrum) with total diffuse fusion of the pedicles, the transverse and articular processes, the laminae and the spinous processes. LESSONS: This is the first clinical report of adult patient with a history of osteoporosis and fractures with the late diagnosis of Galactosialidosis. Osteogenesis imperfecta (autosomal dominant and recessive) were the first given diagnoses which proven negative. The pathophysiology of the spine ankylosis in our current patient and its correlation with LSD, antiresorptive medications, vitamin D3 and supplemental calcium is not fully understood. Therefore, further studies are needed to elucidate this sort of correlation.

Biochemical and molecular analyses of infantile sialic acid storage disease in a patient with nonimmune hydrops fetalis.

Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene.