Management of Acute and Chronic Complications of Lysosomal Storage Diseases in Children and Adults: Current Practice and Future Opportunities

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 45058

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Special Issue Editors


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Guest Editor
Adult Inherited Metabolic Department, Salford Royal NHS Foundation Trust, Manchester M6 8HD, UK
Interests: lysosomal storage diseases; mucopolysaccharidosis; cardiovascular risk; fucosidosis; mucolipidosis I, II, III and IV; secondary mitochondrial dysfunction; transition process; GM1 gangliosidosis; hematopoietic stem cell transplantation; hormonal dysfunction
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Co-Guest Editor
Paediatrics and Child Health Department, University of Pretoria, Pretoria, South Africa
Interests: lysosomal storage diseases; mucopolysaccharidosis; morquio syndrome; enzyme replacement therapy; neurodegeneration; niemann pick c; alpha-mannosidosis; pompe disease; transition process; wearable technology; neuronal ceroid lipofuscinosis; lysosomal acid lipase deficiency

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Co-Guest Editor
Adult Inherited Metabolic Diseases, The Mater Missericordiae University Hospital, Dublin, Ireland
Interests: gaucher disease; fabry disease; metachromatic leukodystrophy; krabbe disease; niemann pick disease; farber disease; GM2 gangliosidosis; clinical genetics; neurogenetics; genetic counselling; therapeutic options; biomarkers; neuropathophysiology

Special Issue Information

Dear Colleagues,

Lysosomal Storage Diseases (LSDs) consist of a group of more than 70 inherited metabolic conditions caused by defects in genes that encode proteins involved in lysosomal homeostasis.  

The diseases manifest with clinical symptoms in childhood, although attenuated forms may present for the first time with subtle symptoms in adolescence or adulthood. The spectrum of clinical symptoms varies but the clear genotype–phenotype correlation is not well described for many of these conditions. Intrafamilial heterogeneity has been commonly observed but is not well understood.

Earlier diagnosis and advances in treatment have much improved the prognosis and life expectancy of patients with LSDs over the last decades, meaning that more than 90% of these patients will survive beyond the age of 20 years. The increased survival has created a number of new issues and challenges: the development of long-term age-related complications, the metabolic progression of the underlying LSD, and the lack of data on the natural history of the disease. These new challenges require the care of adolescent LSD patients being transferred from metabolic paediatricians to metabolic physicians specialised in treating adults to an increasing extent, including the development and coordination of a multidisciplinary team for each individual LSD in tertiary centres.

This Special Issue of the Journal of Clinical Medicine aims to attract original research articles, reviews, and short communications on understanding recent advances in diagnosing and managing acute and chronic complications of LSDs.

Dr. Karolina M. Stepien
Prof. Christian J. Hendriksz
Prof. Gregory Pastores
Guest Editors

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Keywords

  • COVID-19
  • adult-onset
  • neurocognitive dysfunction
  • airways management
  • cardiovascular risk
  • pain management
  • dysostosis multiplex
  • pregnancy
  • hematopoietic stem cell transplantation
  • gene therapy
  • adverse reactions
  • molecular chaperones
  • transition to adult services

Published Papers (19 papers)

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Research

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15 pages, 933 KiB  
Article
Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis—A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients
by Luise Sophie Ammer, Nicole Maria Muschol, René Santer, Annika Lang, Sandra Rafaela Breyer, Phillip Brenya Sasu, Martin Petzoldt and Thorsten Dohrmann
J. Clin. Med. 2022, 11(13), 3650; https://doi.org/10.3390/jcm11133650 - 24 Jun 2022
Cited by 1 | Viewed by 1260
Abstract
Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. [...] Read more.
Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. This retrospective study includes ML patients who underwent anaesthesia in two centres between 2008 and 2022. We reviewed patients’ demographics, medical history, disease manifestations, as well as procedure- and outcome-related data. A total of 12 patients (7 MLII, 2 ML intermediate, 3 MLIII) underwent 44 anaesthesia procedures (per patient: median 3, range 1–11). The median age was 3.3 years (range 0.1–19.1). At least one complication occurred in 27.3% of the anaesthesia procedures. The vast majority of complications (94%) occurred in children with MLII and ML intermediate. A predicted difficult airway was found in 100% and 80% of the MLII and ML intermediate patients, respectively. Accordingly, most complications (59%) occurred during the induction of anaesthesia. Altogether, respiratory complications were the most frequent (18%), followed by difficult airway management (14%). The risk for anaesthesia-related complications is alarmingly high in patients with ML, particularly in those with MLII and ML intermediate. Multidisciplinary risk–benefit analysis and thoughtful anaesthesia planning are crucial in these patients. Full article
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11 pages, 2702 KiB  
Article
Secondary Hyperparathyroidism in Children with Mucolipidosis Type II (I-Cell Disease): Irish Experience
by Ritma Boruah, Ahmad Ardeshir Monavari, Tracey Conlon, Nuala Murphy, Andreea Stroiescu, Stephanie Ryan, Joanne Hughes, Ina Knerr, Ciara McDonnell and Ellen Crushell
J. Clin. Med. 2022, 11(5), 1366; https://doi.org/10.3390/jcm11051366 - 02 Mar 2022
Cited by 2 | Viewed by 1565
Abstract
Mucolipidosis type II (ML II) is an autosomal recessive lysosomal targeting disorder that may present with features of hyperparathyroidism. The aim of this study was to describe in detail the clinical cases of ML II presenting to a tertiary referral centre with biochemical [...] Read more.
Mucolipidosis type II (ML II) is an autosomal recessive lysosomal targeting disorder that may present with features of hyperparathyroidism. The aim of this study was to describe in detail the clinical cases of ML II presenting to a tertiary referral centre with biochemical and/or radiological features of hyperparathyroidism. There were twenty-three children diagnosed with ML II in the Republic of Ireland from July 1998 to July 2021 inclusive (a 23-year period). The approximate incidence of ML II in the Republic of Ireland is, therefore, 1 per 64,000 live births. Medical records were available and were reviewed for 21 of the 23 children. Five of these had been identified as having biochemical and/or radiological features of hyperparathyroidism. Of these five, three children were born to Irish Traveller parents and two to non-Traveller Irish parents. All five children had radiological features of hyperparathyroidism (on skeletal survey), with evidence of antenatal fractures in three cases and an acute fracture in one. Four children had biochemical features of secondary hyperparathyroidism. Three children received treatment with high dose Vitamin D supplements and two who had antenatal/acute fractures were managed with minimal handling. We observed resolution of secondary hyperparathyroidism in all cases irrespective of treatment. Four of five children with ML II and hyperparathyroidism died as a result of cardiorespiratory failure at ages ranging from 10 months to 7 years. Biochemical and/or radiological evidence of hyperparathyroidism is commonly identified at presentation of ML II. Further studies are needed to establish the pathophysiology and optimal management of hyperparathyroidism in this cohort. Recognition of this association may improve diagnostic accuracy and management, facilitate family counseling and is also important for natural history data. Full article
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11 pages, 1131 KiB  
Article
Impact of Intravenous Trehalose Administration in Patients with Niemann–Pick Disease Types A and B
by Moein Mobini, Shabnam Radbakhsh, Francyne Kubaski, Peyman Eshraghi, Saba Vakili, Rahim Vakili, Manijeh Khalili, Majid Varesvazirian, Tannaz Jamialahmadi, Seyed Ali Alamdaran, Seyed Javad Sayedi, Omid Rajabi, Seyed Ahmad Emami, Željko Reiner and Amirhossein Sahebkar
J. Clin. Med. 2022, 11(1), 247; https://doi.org/10.3390/jcm11010247 - 04 Jan 2022
Cited by 11 | Viewed by 2493
Abstract
Background and Aims: Niemann–Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an [...] Read more.
Background and Aims: Niemann–Pick disease (NPD) types A (NPA) and B (NPB) are caused by deficiency of the acid sphingomyelinase enzyme, which is encoded by the SMPD1 gene, resulting in progressive pathogenic accumulation of lipids in tissues. Trehalose has been suggested as an autophagy inducer with therapeutic neuroprotective effects. We performed a single-arm, open-label pilot study to assess the potential efficacy of trehalose treatment in patients with NPA and NPB patients. Methods: Five patients with NPD type A and B were enrolled in an open-label, single-arm clinical trial. Trehalose was administrated intravenously (IV) (15 g/week) for three months. The efficacy of trehalose in the management of clinical symptoms was evaluated in patients by assessing the quality of life, serum biomarkers, and high-resolution computed tomography (HRCT) of the lungs at the baseline and end of the interventional trial (day 0 and week 12). Results: The mean of TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients after intervention at W12 compared to the baseline W0, although the difference was not statistically significant. The serum levels of lyso-SM-509 and lyso-SM were decreased in three and four patients out of five, respectively, compared with baseline. Elevated ALT and AST levels were decreased in all patients after 12 weeks of treatment; however, changes were not statistically significant. Pro-oxidant antioxidant balance (PAB) was also decreased and glutathione peroxidase (GPX) activity was increased in serum of patients at the end of the study. Imaging studies of spleen and lung HRCT showed improvement of symptoms in two patients. Conclusions: Positive trends in health-related quality of life (HRQoL), serum biomarkers, and organomegaly were observed after 3 months of treatment with trehalose in patients with NPA and NPB. Although not statistically significant, due to the small number of patients enrolled, these results are encouraging and should be further explored. Full article
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12 pages, 2126 KiB  
Article
Hyo-Mental Angle and Distance: An Important Adjunct in Airway Assessment of Adult Mucopolysaccharidosis
by Chaitanya Gadepalli, Karolina M. Stepien and Govind Tol
J. Clin. Med. 2021, 10(21), 4924; https://doi.org/10.3390/jcm10214924 - 25 Oct 2021
Cited by 2 | Viewed by 3124
Abstract
Background: Mucopolysaccharidosis (MPS) is a rare congenital lysosomal storage disorder with complex airways. High anterior larynx is assessed by thyromental distance (TMD) nasendoscopy. A simpler method to assess this hyoid bone is described. The distance between the central-hyoid and symphysis of the mandible [...] Read more.
Background: Mucopolysaccharidosis (MPS) is a rare congenital lysosomal storage disorder with complex airways. High anterior larynx is assessed by thyromental distance (TMD) nasendoscopy. A simpler method to assess this hyoid bone is described. The distance between the central-hyoid and symphysis of the mandible (hyo-mental distance; HMD) and inclination of this line to the horizontal axis (hyo-mental angle; HMA) in neutrally positioned patients is investigated. Methods: HMA, HMD in MPS, and non-MPS were compared, and their correlation with height and weight were assessed. Results: 50 adult MPS patients (M = 32, F = 18, age range = 19–66 years; mean BMI = 26.8 kg/m2) of MPS I, II, III, IV, and VI were compared with 50 non-MPS (M = 25, F = 25; age range = 22–84 years; mean BMI = 26.5 kg/m2). Mean HMA in MPS was 25.72° (−10 to +50) versus 2.42° (−35 to +28) in non-MPS. Mean HMD was 46.5 (25.7–66) millimeters in MPS versus 41.8 (27–60.3) in non-MPS. HMA versus height and weight showed a moderate correlation (r = −0.4, p < 0.05) in MPS and no significant correlation (r < 0.4, p > 0.05) in non-MPS. HMD versus height and weight showed no correlation (r < 0.4, p > 0.05) in both groups. Conclusions: HMA seems more acute in MPS despite nearly the same HMD as non-MPS, signifying a high larynx, which may be missed by TMD. Full article
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12 pages, 4089 KiB  
Article
COVID-19 Pandemic and Patients with Rare Inherited Metabolic Disorders and Rare Autoinflammatory Diseases—Organizational Challenges from the Point of View of Healthcare Providers
by Ewa Tobór-Świętek, Jolanta Sykut-Cegielska, Mirosław Bik-Multanowski, Mieczysław Walczak, Dariusz Rokicki, Łukasz Kałużny, Joanna Wierzba, Małgorzata Pac, Karina Jahnz-Różyk, Ewa Więsik-Szewczyk and Beata Kieć-Wilk
J. Clin. Med. 2021, 10(21), 4862; https://doi.org/10.3390/jcm10214862 - 22 Oct 2021
Cited by 8 | Viewed by 1745
Abstract
COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one [...] Read more.
COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one year of coronavirus pandemic has impacted the treatment of patients with IMD and AD in Poland. Surveys were distributed to all healthcare providers that coordinate the treatment of IMD and AD patients. Thirty-two responders (55%) answered the survey. They provide care to 1726 patients with IMD/AD, including 246 patients on dedicated treatment. In 35% of units, the regular appointments were disrupted, primarily because of patient infection. In 18 hospitals, remote visits were implemented, but only 66.6% of patients used this form of consultation. In 14/32 hospitals, administration of the therapy was delayed (median: 17.4 days). Forty-four patients suffered from SARS-COV-2 infection, in majority with mild symptoms. However, four adult patients developed complications, and one died following a SARS-COV-2 infection. Although most hospitals managed to maintain regular visits during the pandemic, more comprehensive implementation of telemedicine and switch to oral therapy or home infusions would be a reasonable solution for the current epidemic situation. Full article
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10 pages, 1342 KiB  
Article
Plasma Neurofilament Light (NfL) in Patients Affected by Niemann–Pick Type C Disease (NPCD)
by Andrea Dardis, Eleonora Pavan, Martina Fabris, Rosalia Maria Da Riol, Annalisa Sechi, Agata Fiumara, Lucia Santoro, Maximiliano Ormazabal, Romina Milanic, Stefania Zampieri, Jessica Biasizzo and Maurizio Scarpa
J. Clin. Med. 2021, 10(20), 4796; https://doi.org/10.3390/jcm10204796 - 19 Oct 2021
Cited by 6 | Viewed by 1908
Abstract
(1) Background: Niemann–Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe [...] Read more.
(1) Background: Niemann–Pick type C disease (NPCD) is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. The clinical presentation is characterized by visceral and neurological involvement. Apart from a small group of patients presenting a severe perinatal form, all patients develop progressive and fatal neurological disease with an extremely variable age of onset. Different biomarkers have been identified; however, they poorly correlate with neurological disease. In this study we assessed the possible role of plasma NfL as a neurological disease-associated biomarker in NPCD. (2) Methods: Plasma NfL levels were measured in 75 healthy controls and 26 patients affected by NPCD (24 NPC1 and 2 NPC2; 39 samples). (3) Results: Plasma NfL levels in healthy controls correlated with age and were significantly lower in pediatric patients as compared to adult subjects (p = 0.0017). In both pediatric and adult NPCD patients, the plasma levels of NfL were significantly higher than in age-matched controls (p < 0.0001). Most importantly, plasma NfL levels in NPCD patients with neurological involvement were significantly higher than the levels found in patients free of neurological signs at the time of sampling, both in the pediatric and the adult group (p = 0.0076; p = 0.0032, respectively). Furthermore, in adults the NfL levels in non-neurological patients were comparable with those found in age-matched controls. No correlations between plasma NfL levels and NPCD patient age at sampling or plasma levels of cholestan 3β-5α-6β-triol were found. (4) Conclusions: These data suggest a promising role of plasma NfL as a possible neurological disease-associated biomarker in NPCD. Full article
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10 pages, 290 KiB  
Article
Gastrointestinal Manifestations in Mucopolysaccharidosis Type III: Review of Death Certificates and the Literature
by Sophie Thomas, Uma Ramaswami, Maureen Cleary, Medeah Yaqub and Eva M. Raebel
J. Clin. Med. 2021, 10(19), 4445; https://doi.org/10.3390/jcm10194445 - 27 Sep 2021
Cited by 3 | Viewed by 2279
Abstract
Background: Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections [...] Read more.
Background: Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections have been reported as frequent and as the most common cause of death, but gastrointestinal (GI) manifestations have not been acknowledged as a cause of concern. The aim of this study was to determine the incidence of GI problems as a primary cause of death and to review GI symptoms reported in published studies. Methods: Causes of death from 221 UK death certificates (1957–2020) were reviewed and the literature was searched to ascertain reported GI symptoms. Results: GI manifestations were listed in 5.9% (n = 13) of death certificates. Median (IQR) age at death was 16.7 (5.3) years. Causes of death included GI failure, GI bleed, haemorrhagic pancreatitis, perforation due to gastrostomies, paralytic ileus and emaciation. Twenty-one GI conditions were reported in 30 studies, mostly related to functional GI disorders, including diarrhoea, dysphagia, constipation, faecal incontinence, abdominal pain/distension and cachexia. Conclusions: GI manifestations may be an under-recognized but important clinical feature of MPS III. Early recognition of GI symptoms and timely interventions is an important part of the management of MPS III patients. Full article
11 pages, 759 KiB  
Article
Molecular Diagnosis of Pompe Disease in the Genomic Era: Correlation with Acid Alpha-Glucosidase Activity in Dried Blood Spots
by Fanny Thuriot, Elaine Gravel, Katherine Hodson, Jorge Ganopolsky, Bojana Rakic, Paula J. Waters, Serge Gravel and Sébastien Lévesque
J. Clin. Med. 2021, 10(17), 3868; https://doi.org/10.3390/jcm10173868 - 28 Aug 2021
Cited by 3 | Viewed by 2338
Abstract
Measurement of alpha-glucosidase activity on dried blood spots has been the main method to screen for Pompe disease, but a paradigm shift has been observed in recent years with the incorporation of gene panels and exome sequencing in molecular diagnostic laboratories. An 89-gene [...] Read more.
Measurement of alpha-glucosidase activity on dried blood spots has been the main method to screen for Pompe disease, but a paradigm shift has been observed in recent years with the incorporation of gene panels and exome sequencing in molecular diagnostic laboratories. An 89-gene panel has been available to Canadian physicians since 2017 and was analyzed in 2030 patients with a suspected muscle disease. Acid alpha-glucosidase activity was measured in parallel in dried blood spots from 1430 patients. Pompe disease was diagnosed in 14 patients, representing 0.69% of our cohort. In 7 other patients, low enzyme activities overlapping those of Pompe disease cases were attributable to the presence of pseudodeficiency alleles. Only two other patients had enzymatic activity in the Pompe disease range, and a single heterozygous pathogenic variant was identified. It is possible that a second variant could have been missed; we suggest that RNA analysis should be considered in such cases. With gene panel testing increasingly being performed as a first-tier analysis of patients with suspected muscle disorders, our study supports the relevance of performing reflex enzymatic activity assay in selected patients, such as those with a single GAA variant identified and those in whom the observed genotype is of uncertain clinical significance. Full article
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16 pages, 296 KiB  
Article
Assessment of Dysphonia in Children with Pompe Disease Using Auditory-Perceptual and Acoustic/Physiologic Methods
by Kelly D. Crisp, Amy T. Neel, Sathya Amarasekara, Jill Marcus, Gretchen Nichting, Aditi Korlimarla, Priya S. Kishnani and Harrison N. Jones
J. Clin. Med. 2021, 10(16), 3617; https://doi.org/10.3390/jcm10163617 - 16 Aug 2021
Cited by 2 | Viewed by 2798
Abstract
Bulbar and respiratory weakness occur commonly in children with Pompe disease and frequently lead to dysarthria. However, changes in vocal quality associated with this motor speech disorder are poorly described. The goal of this study was to characterize the vocal function of children [...] Read more.
Bulbar and respiratory weakness occur commonly in children with Pompe disease and frequently lead to dysarthria. However, changes in vocal quality associated with this motor speech disorder are poorly described. The goal of this study was to characterize the vocal function of children with Pompe disease using auditory-perceptual and physiologic/acoustic methods. High-quality voice recordings were collected from 21 children with Pompe disease. The Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) scale was used to assess voice quality and ratings were compared to physiologic/acoustic measurements collected during sustained phonation tasks, reading of a standard passage, and repetition of a short phrase at maximal volume. Based on ratings of grade, dysphonia was present in 90% of participants and was most commonly rated as mild or moderate in severity. Duration of sustained phonation tasks was reduced and shimmer was increased in comparison to published reference values for children without dysphonia. Specific measures of loudness were found to have statistically significant relationships with perceptual ratings of grade, breathiness, asthenia, and strain. Our data suggest that dysphonia is common in children with Pompe disease and primarily reflects impairments in respiratory and laryngeal function; however, the primary cause of dysphonia remains unclear. Future studies should seek to quantify the relative contribution of deficits in individual speech subsystems on voice quality and motor speech performance more broadly. Full article
15 pages, 947 KiB  
Article
Disease Manifestations in Mucopolysaccharidoses and Their Impact on Anaesthesia-Related Complications—A Retrospective Analysis of 99 Patients
by Luise Sophie Ammer, Thorsten Dohrmann, Nicole Maria Muschol, Annika Lang, Sandra Rafaela Breyer, Ann-Kathrin Ozga and Martin Petzoldt
J. Clin. Med. 2021, 10(16), 3518; https://doi.org/10.3390/jcm10163518 - 10 Aug 2021
Cited by 5 | Viewed by 1564
Abstract
Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and [...] Read more.
Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and adults with MPS undergoing anaesthesia from 2002 until 2018. We retrieved the patients’ demographics, medical history, clinical manifestations, and indication by each anaesthesia. Multivariable mixed-effects logistic regression was calculated for a clinical model based on preoperative predictors preselected by lasso regression and another model based on disease subtypes only. Of the 484 anaesthesia cases in 99 patients, 22.7% experienced at least one adverse event. The clinical model resulted in a better forecast performance than the subtype-model (AICc 460.4 vs. 467.7). The most relevant predictors were hepatosplenomegaly (OR 3.10, CI 1.54–6.26), immobility (OR 3.80, CI 0.98–14.73), and planned major surgery (OR 6.64, CI 2.25–19.55), while disease-specific therapies, i.e., haematopoietic stem cell transplantation (OR 0.45, CI 0.20–1.03), produced a protective effect. Anaesthetic complications can best be predicted by surrogates for advanced disease stages and protective therapeutic factors. Further model validation in different cohorts is needed. Full article
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16 pages, 4437 KiB  
Article
New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside
by Aditi Korlimarla, Jeong-A Lim, Paul McIntosh, Kanecia Zimmerman, Baodong D. Sun and Priya S. Kishnani
J. Clin. Med. 2021, 10(15), 3395; https://doi.org/10.3390/jcm10153395 - 30 Jul 2021
Cited by 8 | Viewed by 2888
Abstract
Background: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. Methods: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) [...] Read more.
Background: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. Methods: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. Results: Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18–79 years, median age: 51.55 years; 35 females; 53 on ERT). Conclusion: GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles. Full article
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9 pages, 590 KiB  
Article
Attention Deficits and ADHD Symptoms in Adults with Fabry Disease—A Pilot Investigation
by Nadia Ali, Amanda Caceres, Eric W. Hall and Dawn Laney
J. Clin. Med. 2021, 10(15), 3367; https://doi.org/10.3390/jcm10153367 - 29 Jul 2021
Cited by 1 | Viewed by 2168
Abstract
The present pilot study examines subjective reported symptoms of attention-deficit/hyperactivity (AD/H) in adults with Fabry disease (FD) in comparison with existing normative control data. Existing data from 69 adults with FD via the Achenbach System of Empirically Based Assessment Adult Self-Report questionnaire were [...] Read more.
The present pilot study examines subjective reported symptoms of attention-deficit/hyperactivity (AD/H) in adults with Fabry disease (FD) in comparison with existing normative control data. Existing data from 69 adults with FD via the Achenbach System of Empirically Based Assessment Adult Self-Report questionnaire were analyzed. The results demonstrated a higher prevalence of AD/H symptoms in adults with FD than in the general United States population, with a roughly equal endorsement of Inattention/Attention Deficit symptoms (AD), Hyperactivity-Impulsivity (H-I) symptoms, and Combined Inattention/hyperactivity-impulsivity (C) symptoms. No gender differences were observed. While all subjects endorsing H-I symptoms fell into the symptomatic range on the AD/H scale, only two-thirds of subjects endorsing AD did so. This suggests that attention difficulties with FD are not solely explained by ADHD. Adults with FD who endorsed the AD, H-I, and C symptoms were also more likely to report mean adaptive functioning difficulties. These findings support the growing literature regarding attention difficulties in adults with FD, as well as suggesting a previously unrecognized risk of AD/H symptoms. Future research involving the objective assessment of ADHD in adults with FD is recommended. When serving adults with FD clinically, healthcare professionals should address multiple areas of care, including physical, psychological, and cognitive arenas. Full article
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Review

Jump to: Research

6 pages, 221 KiB  
Review
Healthcare Transition in Inherited Metabolic Disorders—Is a Collaborative Approach between US and European Centers Possible?
by Jessica I. Gold and Karolina M. Stepien
J. Clin. Med. 2022, 11(19), 5805; https://doi.org/10.3390/jcm11195805 - 30 Sep 2022
Viewed by 1117
Abstract
Inherited metabolic diseases (IMDs) are rare heterogenous genetic conditions. Advanced technology and novel therapeutic developments have led to the improved life expectancy of patients with IMDs. Long-term, they require close surveillance from specialist adult metabolic providers. Healthcare transition (HCT) is the planned, purposeful [...] Read more.
Inherited metabolic diseases (IMDs) are rare heterogenous genetic conditions. Advanced technology and novel therapeutic developments have led to the improved life expectancy of patients with IMDs. Long-term, they require close surveillance from specialist adult metabolic providers. Healthcare transition (HCT) is the planned, purposeful process of preparing adolescents for adult-centered medical care and has been recognized globally as a necessary component of care for IMDs. Two recent surveys outlined barriers to the HCT in the US and the UK. The limited knowledge of IMDs among adult physicians was one of the barriers. Some work on specialty curriculum has started and aims to improve the structured training and awareness of rare diseases. Other barriers included social and legal aspects of adulthood, social, vocational and educational support for young adults, care fragmentation and insurance coverage. Although various HCT tools are available, they cannot always be standardized for IMDs. Despite the remarkable differences in the healthcare systems and physicians’ training, collaboration among metabolic centers is possible. International rare disease alliance may enhance the patients’ management via guidelines development and standardized training for adult metabolic providers. Full article
9 pages, 240 KiB  
Review
Do Not Miss the (Genetic) Diagnosis of Gaucher Syndrome: A Narrative Review on Diagnostic Clues and Management in Severe Prenatal and Perinatal-Lethal Sporadic Cases
by Aleksandra Jezela-Stanek, Grazina Kleinotiene, Karolina Chwialkowska and Anna Tylki-Szymańska
J. Clin. Med. 2021, 10(21), 4890; https://doi.org/10.3390/jcm10214890 - 23 Oct 2021
Cited by 1 | Viewed by 1738
Abstract
With a growing number of proved therapies and clinical trials for many lysosomal storage disorders (LSDs), a lot of hope for many patients and families exists. However, there are sometimes cases with poor prognosis, fatal outcomes when our efforts must be directed towards [...] Read more.
With a growing number of proved therapies and clinical trials for many lysosomal storage disorders (LSDs), a lot of hope for many patients and families exists. However, there are sometimes cases with poor prognosis, fatal outcomes when our efforts must be directed towards a prompt and correct genetic diagnosis, which offers the only possibility of providing the family with appropriate prevention and treatment. To address this issue, in this article, we present the clinical and genetic hallmarks of the lethal form of Gaucher disease (PLGD) and discuss the potential management. We hope that this will draw attention to its specific manifestations (such as collodion-baby phenotype, ichthyosis, arthrogryposis), which differ from best-known GD complications and ensure appropriate diagnostic assessment to provide families at risk with reliable counselling and treatment to avoid the medical complication of GD. Full article
19 pages, 3063 KiB  
Review
A Systematic Review and Meta-Analysis of Enzyme Replacement Therapy in Late-Onset Pompe Disease
by Alícia Dorneles Dornelles, Ana Paula Pedroso Junges, Tiago Veiga Pereira, Bárbara Corrêa Krug, Candice Beatriz Treter Gonçalves, Juan Clinton Llerena, Jr., Priya Sunil Kishnani, Haliton Alves de Oliveira, Jr. and Ida Vanessa Doederlein Schwartz
J. Clin. Med. 2021, 10(21), 4828; https://doi.org/10.3390/jcm10214828 - 21 Oct 2021
Cited by 11 | Viewed by 3458
Abstract
Pompe disease (PD) is a glycogen storage disorder caused by deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for late-onset PD (LOPD). Methods: We [...] Read more.
Pompe disease (PD) is a glycogen storage disorder caused by deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for late-onset PD (LOPD). Methods: We systematically searched the MEDLINE (via PubMed), Embase, and Cochrane databases for prospective clinical studies evaluating ERT for LOPD on pre-specified outcomes. A meta-analysis was also performed. Results: Of 1601 articles identified, 22 were included. Studies were heterogeneous and with very low certainty of evidence for most outcomes. The following outcomes showed improvements associated with GAA ERT, over a mean follow-up of 32.5 months: distance walked in the 6-min walking test (6MWT) (mean change 35.7 m (95% confidence interval [CI] 7.78, 63.75)), physical domain of the SF-36 quality of life (QOL) questionnaire (mean change 1.96 (95% CI 0.33, 3.59)), and time on ventilation (TOV) (mean change −2.64 h (95% CI −5.28, 0.00)). There were no differences between the pre- and post-ERT period for functional vital capacity (FVC), Walton and Gardner-Medwin Scale score, upper-limb strength, or total SF-36 QOL score. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Considering the limitations imposed by the rarity of PD, our data suggest that GAA ERT improves 6MWT, physical QOL, and TOV in LOPD patients. ERT was safe in the studied population. PROSPERO register: 135102. Full article
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16 pages, 8306 KiB  
Review
Atherosclerosis in Fabry Disease—A Contemporary Review
by Ashwin Roy, Hamza Umar, Antonio Ochoa-Ferraro, Adrian Warfield, Nigel Lewis, Tarekegn Geberhiwot and Richard Steeds
J. Clin. Med. 2021, 10(19), 4422; https://doi.org/10.3390/jcm10194422 - 27 Sep 2021
Cited by 6 | Viewed by 2580
Abstract
Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated [...] Read more.
Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population. Full article
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17 pages, 312 KiB  
Review
Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease
by Jonathan Niranjan Rajan, Katharine Ireland, Richard Johnson and Karolina M. Stepien
J. Clin. Med. 2021, 10(18), 4168; https://doi.org/10.3390/jcm10184168 - 15 Sep 2021
Cited by 11 | Viewed by 2940
Abstract
Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in [...] Read more.
Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme. Full article
20 pages, 7139 KiB  
Review
Airway Abnormalities in Adult Mucopolysaccharidosis and Development of Salford Mucopolysaccharidosis Airway Score
by Chaitanya Gadepalli, Karolina M. Stepien, Reena Sharma, Ana Jovanovic, Govind Tol and Andrew Bentley
J. Clin. Med. 2021, 10(15), 3275; https://doi.org/10.3390/jcm10153275 - 24 Jul 2021
Cited by 12 | Viewed by 2433
Abstract
(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of glycosaminoglycans (GAGs). GAGs deposition in tissues leads to progressive airway narrowing and/or tortuosity. Increased longevity of patients has posed newer problems, [...] Read more.
(1) Background: Mucopolysaccharidoses (MPS) are a heterogeneous group of lysosomal storage disorders caused by the absence of enzymes required for degradation of glycosaminoglycans (GAGs). GAGs deposition in tissues leads to progressive airway narrowing and/or tortuosity. Increased longevity of patients has posed newer problems, especially the airway. This study aims to characterise various airway abnormalities in adult MPS from a regional centre and proposes a method to quantify the severity of the airway disease. (2) Methods: Retrospective analysis by case notes review, clinical examination, endoscopy, cross-sectional imaging, 3-dimensional reconstruction, and physiological investigations were used to assess the airway abnormalities. Quantitative assessment of the airway severity was performed a validated questionnaire of 15 parameters to derive Salford Mucopolysaccharidosis Airway Score (SMAS). (3) Results: Thirty-one adult MPS patients (21M/ 9F; median 26.7 years; range 19–42 years) were reviewed. There were 9 MPS I, 12 MPS II, 2 MPS III, 5 MPS IV, 2 MPS VI, and 1 MPS VII. Airway abnormalities in each MPS type are described. Patients scoring more than 35 on SMAS had some form of airway intervention. The area under curve of 0.9 was noted at a score of 25, so SMAS more than 25 may predict a difficult airway and potential to have complications. Pearson’s correlation between SMAS and height, weight, BMI were poor (p < 0.05). (4) Conclusions: Airway abnormalities in adult MPS are varied and complex. Assessment of the airway should be holistic and include multiple parameters. An objective multidimensional score such as SMAS may help to predict and manage difficult airways warranting further investigation and validation. Full article
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14 pages, 821 KiB  
Review
Management of Corneal Clouding in Patients with Mucopolysaccharidosis
by Orlaith McGrath, Leon Au and Jane Ashworth
J. Clin. Med. 2021, 10(15), 3263; https://doi.org/10.3390/jcm10153263 - 24 Jul 2021
Cited by 5 | Viewed by 2535
Abstract
Mucopolysaccharidoses (MPS) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems including the eye. Visual loss occurs in MPS predominantly due to corneal clouding and retinopathy, but the sclera, trabecular meshwork [...] Read more.
Mucopolysaccharidoses (MPS) are a rare group of lysosomal storage disorders characterized by the accumulation of incompletely degraded glycosaminoglycans (GAGs) in multiple organ systems including the eye. Visual loss occurs in MPS predominantly due to corneal clouding and retinopathy, but the sclera, trabecular meshwork and optic nerve may all be affected. Despite the success of therapies such as enzyme replacement therapy (ERT) and hematopoietic stem-cell transplantation (HSCT) in improving many of the systemic manifestations of MPS, their effect on corneal clouding is minimal. The only current definitive treatment for corneal clouding is corneal transplantation, usually in the form of a penetrating keratoplasty or a deep anterior lamellar keratoplasty. This article aims to provide an overview of corneal clouding, its current clinical and surgical management, and significant research progress. Full article
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