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Hydrops fetalis is an abnormal accumulation of fluid in two or more foetal compartments which is easily detected using prenatal ultrasonography. It can be categorised into immune and non-immune. The non-immune hydrops can result from various aetiologies, including cardiovascular, respiratory, genitourinary infections, chromosomal anomalies and metabolic causes. The metabolic causes, including lysosomal storage disorders (LSD), are increasingly being recognised as the causes of non-immune hydrops. The hydrops fetalis associated with metabolic disorders is usually severe with huge ascites, hepatosplenomegaly, thick skin, renal abnormalities, increased nuchal translucency, renal abnormalities and skeletal deformities. In this report, we describe a case of LSD, that is, galactosialidosis presenting as non-immune hydrops and its diagnosis. In utero diagnosis of the disorder without an index case is challenging. The definitive diagnosis is important for planning and management of future conceptions., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To present a case report of mucolipidosis type IV (ML4) and review the literature for all of the ophthalmic abnormalities associated with this disease., Methods: A systematic review of the literature using PubMed/Medline was conducted, and with the addition of the current case report, the eye and ocular adnexa findings of 93 patients with ML4 are summarized., Results: The most common ophthalmic findings reported among the 93 patients included corneal clouding (90.3%), strabismus (58.1%), optic nerve pallor (52.2%), retinal dystrophy/pigmentary changes (50.5%), and retinal vascular attenuation (38.9%). Other less commonly reported findings included nystagmus, photophobia, ocular pain, excessive lacrimation, ptosis, and cataracts., Conclusions: The ophthalmic findings discussed in the current case report and literature review serve as indicators for ML4. Early diagnosis of ML4 is important in forming a multidisciplinary management plan, genetic counseling strategy, and maximizing the visual development of affected individuals. [ J Pediatr Ophthalmol Strabimus . 2022;59(5):332-337.] .

Sialidosis is a rare autosomal recessive hereditary disease caused by NEU1 gene mutations. A 25-year-old woman developed generalized tonic-clonic seizures since teenage, followed by progressive visional decline and limb myoclonus. Her sister had similar presentations. Both patients were products of a consanguineous marriage. Electroencephalography (EEG) revealed extensive paroxysmal spiky beta brush. Somatosensory evoked potentials (SEP) after stimulation of median nerves demonstrated giant SEP and C-reflex support the cortical origin of myoclonus. Genetic tests confirmed that both sisters carried the known pathogenic homozygous mutation of c.544A > G in exon 3 of the NEU1 gene. The diagnosis of sialidosis type 1 was then made. This suggests that neurophysiological abnormalities, especially spiky beta brush on EEG, might facilitate the early diagnosis of sialidosis type 1.

This single-centre retrospective study reports our management of carpal tunnel syndrome in 52 children (103 hands) with mucopolysaccharidoses and mucolipidoses. All except one were bilateral. The median age at surgery was 4 years (range 1.5 to 12). The diagnosis of carpal tunnel syndrome was confirmed by an electromyogram (EMG) in all patients; 38% of these presented without any clinical signs. Surgical neurolysis was performed in all hands, combined with epineurotomy in 52 hands (50%) and flexor tenosynovectomy in 75 hands (73%). Surgery was bilateral in 98% of children (102 hands). The mean follow-up was 12 years (range 1 to 19) and the EMG was normalized in 78% of hands. Ten patients suffered recurrence, eight of whom required further surgery. Screening for carpal tunnel syndrome is essential for the management of children mucopolysaccharidoses and mucolipidoses. Surgical treatment should be carried out early with follow-up by EMG to detect recurrence. Level of evidence: IV.

Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 in vitro . NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death in vitro . ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects in vitro . More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies in vitro and in vivo . Knockdown of LKB1 reversed the effect elicited by shNEU1 in vitro . In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Trichohepatoenteric syndrome (THES) is a very rare autosomal recessive genetic disorder, which is characterized by intractable diarrhea during infancy, dysmorphic features, immunodeficiency, and a failure to thrive. There are still significant difficulties for patients and clinicians in terms of the management of THES, even though its molecular basis has been uncovered in the last decade. In this article, we have presented two cases relating to siblings that have been diagnosed with the condition. Concerning one of the patients, we described a novel variation (c.2114 + 5G > A) in the TTC37 gene and a mild clinical course; meanwhile, the other one was clinically diagnosed with THES at 17 years of age, but they had seizures and died suddenly. These cases expand the spectrum of clinical findings in relation to THES., (© 2021 Wiley Periodicals LLC.)

Aim: To describe the ophthalmologic findings on the largest cohort of patients with sialidosis type I due to deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and to introduce a quantitative neuroretinal image analysis approach to the associated 'macular cherry-red spot'., Methods: Seven patients with sialidosis type I (mutations in NEU1 ) and one with galactosialidosis (mutations in CTSA ) were included. All patients underwent detailed ophthalmological examinations. The reflectivity of macular optical coherence tomography (OCT) was measured using greyscale analysis (Fiji) and compared with age-matched healthy volunteers. Four patients were evaluated over a time of 1.5+0.5 years., Results: The mean age of the patients at their first visit was 27.5+9.8 years. All patients had a macular cherry-red spot, clear corneas and visually non-significant lenticular opacities. The mean visual acuity was LogMar 0.4 (20/50)+0.4 (20/20 to 20/125). Six patients had good visual function. Optic atrophy was present in two individuals with reduced acuity. A significant increase in macular reflectivity was present in all patients compared to age-matched controls (p<0.0001)., Conclusion: Most of our patients (75%) have preserved visual acuity, even in adulthood. The presence of optic atrophy is associated with poor visual acuity. Increased macular reflectivity by OCT greyscale measurements is noted in all patients, although the underlying biological basis is unknown. These findings complement the current methods for examining and monitoring disease progression, especially in patients for whom visualisation of the cherry-red spot is not entirely clear., Trial Registration Number: NCT00029965., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sialidosis, a rare autosomal recessive disorder, is caused by a deficiency of NEU1 encoded enzyme alpha-N-acetyl neuraminidase. We report a premature male with neonatal-onset type II sialidosis which was associated with left ventricular dysfunction. The clinical presentation and subsequent progression which culminated in his untimely death at 16 months of age are succinctly described. Early-onset cardiovascular involvement as noted in this patient is not well characterised. The case report is supplemented by a comprehensive review of the determinants, characteristics, and the clinical course of cardiovascular involvement in this rare condition.

Mucolipidosis (ML) II and III are complex lysosomal storage disorders characterized by progressive multisystem pathology which can pose challenges to the anesthetist and increase the risks associated with general anesthesia. We sought to review the management of patients with ML II and III undergoing anesthesia in our institution in order to better define recommendations for the preoperative assessment and optimization of these children. We further elected to analyze the conduct of anesthesia, intraoperative management, and perioperative complications that our patients had experienced in order to allow improved informed consent and anesthetic planning. We performed a retrospective examination of the medical notes of those patients who had undergone anesthesia in our institution to identify their clinical features, anesthetic technique, airway management, and perioperative complications. Five children underwent 11 episodes of anesthesia. Fiber-optic or videolaryngoscopy was utilized in six out of seven intubations, with four out of seven requiring a change from the method initially chosen to enable intubation. Four of the five patients had an abnormal echocardiogram. Three patients had radiological evaluation of their cervical spine, with two demonstrating abnormalities. One patient had changes suggesting instability at the atlantoaxial junction. Children and babies with ML II and III present multisystem challenges to the anesthetist. Multidisciplinary planning and assessment, followed by a discussion of risk, should proceed any elective surgery. These complex children should undergo elective anesthesia delivered by an experienced (pediatric) anesthetist in an appropriate tertiary center with on-site pediatric ENT and critical care support., (© 2020 John Wiley & Sons Ltd.)

The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The mechanisms balancing proteostasis in glomerular cells are unknown. Mucolipidosis (ML) II and III are rare lysosomal storage disorders associated with mutations of the Golgi-resident GlcNAc-1-phosphotransferase, which generates mannose 6-phosphate residues on lysosomal enzymes. Without this modification, lysosomal enzymes are missorted to the extracellular space, which results in lysosomal dysfunction of many cell types. Patients with MLII present with severe skeletal abnormalities, multisystemic symptoms, and early death; the clinical course in MLIII is less progressive. Despite dysfunction of a major degradative pathway, renal and glomerular involvement is rarely reported, suggesting organ-specific compensatory mechanisms., Methods: MLII mice were generated and compared with an established MLIII model to investigate the balance of protein synthesis and degradation, which reflects glomerular integrity. Proteinuria was assessed in patients. High-resolution confocal microscopy and functional assays identified proteins to deduce compensatory modes of balancing proteostasis., Results: Patients with MLII but not MLIII exhibited microalbuminuria. MLII mice showed lysosomal enzyme missorting and several skeletal alterations, indicating that they are a useful model. In glomeruli, both MLII and MLIII mice exhibited reduced levels of lysosomal enzymes and enlarged lysosomes with abnormal storage material. Nevertheless, neither model had detectable morphologic or functional glomerular alterations. The models rebalance proteostasis in two ways: MLII mice downregulate protein translation and increase the integrated stress response, whereas MLIII mice upregulate the proteasome system in their glomeruli. Both MLII and MLIII downregulate the protein complex mTORC1 (mammalian target of rapamycin complex 1) signaling, which decreases protein synthesis., Conclusions: Severe lysosomal dysfunction leads to microalbuminuria in some patients with mucolipidosis. Mouse models indicate distinct compensatory pathways that balance proteostasis in MLII and MLIII., (Copyright © 2020 by the American Society of Nephrology.)

Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal hydrolase N-acetylglucosamine- 1-phosphotransferase, a key enzyme in the synthesis of the mannose-6-phosphate targeting signals on lysosomal enzymes. Patients with MLII alpha/beta present coarse facial features, cessation of statural growth, important skeletal manifestations, impaired neuromotor development and cardiorespiratory involvement. All children appear to have cardiac involvement, but severe dilated cardiomyopathy is uncommon. In this report we describe the case of an 11-month-old girl who is affected by a MLII. Analysis of the GNPTAB gene identified at a heterozygous level the previously described gene variants c. 2693delA p(Lys898Serfs*13) and c. 2956C>T p(Arg986Cys). Her main clinical features were coarse face with gingival hypertrophy, dysostosis multiplex, recurrent respiratory infection and an early onset of dilated cardiomyopathy, an uncommon feature for MLII. To our knowledge, dilated cardiomyopathy has been previously described in literature in only two cases of MLII and in one patient affected by MLIII., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Objective: Type I sialidosis (ST-1) is a rare autosomal recessive inherited disorder. To date, there has been no study on ST-1 patients in mainland China., Methods: We reported in detail the cases of five Chinese ST-1 patients from two centers, and summarized all worldwide cases. Then, we compared the differences between Chinese and foreign patients., Results: A total of 77 genetically confirmed ST-1 patients were identified: 12 from mainland China, 23 from Taiwan, 10 from other Asian regions, and 32 from European and American regions. The mean age of onset was 16.0 ± 6.7 years; the most common symptoms were myoclonus seizures (96.0%), followed by ataxia (94.3%), and blurred vision (67.2%). Compared to other groups, the onset age of patients from mainland China was much younger (10.8 ± 2.7 years). The incidence of visual impairment was lower in patients from other Asian regions than in patients from mainland China and Taiwan (28.6% vs. 81.8%-100%). Cherry-red spots were less frequent in the Taiwanese patients than in patients from other regions (27.3% vs. 55.2%-90.0%). Furthermore, 48 different mutation types were identified. Chinese mainland and Taiwanese patients were more likely to carry the c.544A > G mutation (75% and 100%, respectively) than the patients from other regions (only 0%-10.0%). Approximately 50% of Chinese mainland patients carried the c.239C > T mutation, a much higher proportion than that found in the other populations. In addition, although the brain MRI of most patients was normal, 18 F-FDG-PET analysis could reveal cerebellar and occipital lobe hypometabolism., Interpretation: ST-1 patients in different regions are likely to have different mutation types; environmental factors may influence clinical manifestations. Larger studies enrolling more patients are required., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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., (© 2020 John Wiley & Sons, Ltd.)

Background: Children suffering from mucopolysaccharidoses (subtypes I, II, III, IV, VI, and VII) or mucolipidoses often require anesthesia, but are at high risk for perioperative adverse events. However, the impact of the disease subtype and the standard of care for airway management are still unclear., Aims: This study aimed to assess independent risk factors for perioperative adverse events in individuals with mucopolysaccharidoses/mucolipidoses and to analyze the interaction with the primary airway technique implemented., Methods: This retrospective study included individuals with mucopolysaccharidoses/mucolipidoses who underwent anesthesia at two high-volume centers from 2002 to 2016. The data were analyzed in a multivariate hierarchical model, accounting for repeated anesthesia procedures within the same patient and for multiple events within a single anesthesia., Results: Of 141 identified inpatients, 67 (63 mucopolysaccharidoses and 4 mucolipidoses) underwent 269 anesthesia procedures (study cases) for 353 surgical or diagnostic interventions. At least one perioperative adverse event occurred in 25.6% of the cases. The risk for perioperative adverse events was higher in mucopolysaccharidoses type I (OR 8.0 [1.5-42.7]; P = .014) or type II (OR 8.8 [1.3-58.6]; P = .025) than in type III. Fiberoptic intubation through a supraglottic airway was associated with the lowest risk for perioperative adverse events and lowest conversion rate. Direct laryngoscopy was associated with a significantly higher risk for airway management problems than indirect techniques (estimated event rates 47.8% vs 10.1%, OR 24.05 [5.20-111.24]; P < .001). The risk for respiratory adverse events was significantly higher for supraglottic airway (22.6%; OR 31.53 [2.79-355.88]; P = .001) and direct laryngoscopy (14.8%; OR 14.70 [1.32-163.44]; P = .029) than for fiberoptic intubation through a supraglottic airway (2.1%)., Conclusions: The disease subtype and primary airway technique were the most important independent risk factors for perioperative adverse events. Our findings indicate that in MPS/ML children with predicted difficult airway indirect techniques should be favored for the first tracheal intubation attempt., (© 2019 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy, was first described by Davidson et al. in 1978. Till date, only a handful of cases with MVID have been described in English literature. It is an autosomal recessive disorder with no sex predisposition and more commonly noted in countries with prevalent consanguineous marriages. These patients usually present with intractable secretory diarrhea in early days of life. The pathognomonic findings of MVID are villous atrophy along with the formation of intracellular microvillous inclusions on electron microscopy. Till date, no curative therapy exists, and prognosis mainly depends upon parenteral nutrition. Small bowel transplantation is one of the treatment options. Clinician and pathologist should consider the possibility of MVID in the differential diagnosis of chronic intractable diarrhea in an infant. Herein, authors are describing a case of intractable diarrhea with MVID phenotype diagnosed in a 3-mo-old male child who presented with intractable diarrhea in an outside hospital, and the diagnostic workup was performed by the authors on endoscopic biopsy sample.

Mucolipidosis (ML) is a rare lysosomal storage disorder with a wide spectrum of disease severity according to the type. Sleep-disordered breathing is recognized as a characteristic feature of ML but objective data are scarce. The aim of the study was to describe sleep data and medical management in children with ML α/β. All patients with ML α/β followed at a national reference center of ML were included. Five patients had ML II, one patient had ML III and one patient had ML II-III. One patient was started on noninvasive ventilation (NIV) to allow extubation after prolonged invasive mechanical ventilation. The six other patients underwent sleep study at a median age of 1.8 years (range 4 months-17.4 years). Obstructive sleep apnea (OSA) was observed in all patients with a median apnea-hypopnea index (AHI) of 36 events/hr (range 5-52) requiring continuous positive airway pressure (CPAP) or NIV. CPAP/NIV resulted in an improvement of nocturnal gas exchange and was continued in all patients with an excellent compliance. Two patients died. Systematic sleep studies are recommended at time of diagnosis in ML. CPAP or NIV are effective treatments of OSA, well tolerated, and may contribute to improve the quality of life of patients and caregivers., (© 2019 Wiley Periodicals, Inc.)

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in the MCOLN1 gene causes an alteration of the protein mucolipin-1 that results in the accumulation of lipids and proteins in cytoplasmic vacuoles derived from lysosomes. Visual impairment results mainly from corneal clouding and retinal degeneration. The involvement of the corneal epithelium has been proposed following clinical observation and confirmed by ultrastructural studies of the cornea. We present the case of a child of French Canadian origin affected by mucolipidosis type IV who showed abnormal optical coherence tomography imaging of the cornea, typical skin cell inclusions on electronic microscopy, and a novel pathogenic mutation., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Introduction: Carpal tunnel syndrome (CTS) in children represents a complex challenge for the hand surgeon because of its rarity, poor patient cooperation, frequently associated malformation syndromes and mental retard, atypical symptoms and nuanced and poor sensitivity of instrumental tests. The most frequently associated causes with the CTS in children are rare congenital malformations and diseases, requiring an overall assessment of the young patient and a high degree of suspicion for the potentially associated canalicular syndrome. On the other hand, the associated syndromes may be the main ally for a diagnosis that starts from the knowledge of the literature and the surgeon's suspicion by observing the child wailing. Early diagnosis and decompression treatment is mandatory., Materials and Methods: The authors report a case series of 26 children and analyze the etiology and diagnostic algorithms. Patient assessment was based on complete clinical examination and medical history collection of these young patients with the involvement of the family and educators., Results: In all 26 patients treated, along an average period of 23 months (minimum 12, maximum 30), no signs of recurrence or persistence of median nerve disturbances were recorded., Conclusions: In conclusion, we believe that anamnesis, a careful physical examination and analysis of instrumental examinations, should be accompanied by a thorough knowledge of rare diseases in the context of congenital malformations. The carpal tunnel syndrome, while well known and treated by each orthopedic surgeon, reveals a mysterious aspect in the context of the "fabulous" world of childhood illnesses, even more difficult than rare congenital diseases.

Background: Mucolipidosis type III α/β or γ (MLIII) are rare autosomal recessive diseases, in which reduced activity of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-PTase) leads to intra-lysosomal accumulation of different substrates. Publications on the natural history of MLIII, especially the milder forms, are scarce. This study provides a detailed description of the disease characteristics and its natural course in adult patients with MLIII., Methods: In this retrospective chart study, the clinical, biochemical and molecular findings in adult patients with a confirmed diagnosis of MLIII from three treatment centres were collected., Results: Thirteen patients with MLIII were included in this study. Four patients (31%) were initially misdiagnosed with a type of mucopolysaccharidosis (MPS). Four patients (31%) had mild cognitive impairment. Six patients (46%) needed help with activities of daily living (ADL) or were wheelchair-dependent. All patients had dysostosis multiplex and progressive secondary osteoarthritis, characterised by cartilage destruction and bone lesions in multiple joints. All patients underwent multiple orthopaedic surgical interventions as early as the second or third decades of life, of which total hip replacement (THR) was the most common procedure (61% of patients). Carpal tunnel syndrome (CTS) was found in 12 patients (92%) and in eight patients (61%), CTS release was performed., Conclusions: Severe skeletal abnormalities, resulting from abnormal bone development and severe progressive osteoarthritis, are the hallmark of MLIII, necessitating surgical orthopaedic interventions early in life. Future therapies for this disease should focus on improving cartilage and bone quality, preventing skeletal complications and improving mobility.

A 2-month-old male with dysmorphic facies, neonatal thrombocytopenia, left congenital cataract, and long bone abnormalities became hypotensive with ST depression on induction of anesthesia for congenital cataract repair. Echocardiogram demonstrated decreased left ventricular function (ejection fraction 46%), mild mitral valve regurgitation (MR), and regional wall motion abnormalities. The left coronary artery could not be visualized. Subsequent cardiac catheterization confirmed atresia of the left main coronary artery. The patient underwent cardiac surgery with coronary artery bypass grafting of the left internal mammary artery to the left anterior descending coronary artery. His postoperative course was uncomplicated, his ventricular function normalized, and he was discharged home. Over the next few months, he developed progressive, severe MR refractory to medical management. Repeat cardiac catheterization revealed stenosis of the right proximal coronary artery, raising concern for progressive coronary involvement. In addition to dysmorphic features and failure to thrive, there were profound developmental delays and a finding of vacuolated lymphocytes on blood smear, which led to a diagnosis of mucolipidosis II (Inclusion [I]-cell disease). The patient was referred for mitral valve replacement, which was successful; however, ongoing respiratory issues attributed to the progression of I-cell disease led to a prolonged hospitalization with placement of a tracheostomy. Reports of coronary anomalies in patients with I-cell disease are rare. An association between mucopolysaccharidosis syndromes and coronary artery abnormalities has been established and is supported by this case report, highlighting the importance of considering the potential for coronary artery involvement with I-cell disease and other similar storage diseases.

Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1 -/- ), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In order to identify the cortical changes in patients with Sialidosis type 1, diffusion tensor imaging and resting state fMRI were acquired from 11 patients and 11 sex/age matched normal controls after clinical evaluations. The neuroimages from each participant were normalized and parcellated according to the Automatic Anatomical Labeling. Both the mean diffusivity and the corresponding functional connectivity were calculated from each cortical region. The white matter tract integrity was examined. The difference between patients and controls was examined using Student's t-test and between patients with either homozygous or heterozygous mutations by Mann-Whitney U test, both at a threshold of 0.05. Increased mean diffusivity throughout the brain can be noticed in the patients, together with a compromised white matter tracts integrity. The most severely affected cortical regions are in the occipital lobe. Decreased functional connectivity was from the temporal and occipital lobes to the hippocampus and parahippocampus. In contrast, connectivity from thalamus was enhanced. Diffused cortical atrophy with posterior focal lesions was noticed. We concluded that MRI observed functional changes in the posterior cortical pathways in the patients with Sialidosis. The observation might be related to the cortical blindness due to an altered neural network and a compromised visual pathway in the patients.

Congenital diarrheas correspond to a severe and low frequency digestive disease, with a high mortality. They start a few days or months after birth, leading to intestinal insufficiency and dependence on parenteral nutrition. It must be highly suspected in newborns or infants with diarrhea and severe electrolyte disorders. The diagnosis is based on clinical, endoscopic, histologic and eventually genetic findings. Treatment is supportive with intensive correction of electrolyte imbalances as well as parenteral nutrition., Objective: To present a case report of congenital diarrhea identified as microvillous inclusion disease presenting in the neonatal period., Case Report: Male patient currently 3 years of age, son of consanguineous parents. At 10 days of age presents a severe secretory diarrhea, requiring treatment in a critical care unit and parenteral nutrition. Initially he also presented with Fanconi syndrome, which improved afterwards. The suspicion of congenital microvillous inclusion was confirmed later by optic and electronic microscopy, and inmunohistochemistry. A succesful evolution was later achieved maintaining home parenteral nutrition after discharge., Conclusion: We present the first known case in Chile of congenital diarrhea due to microvillous inclusión disease and his evolution.

Abstract: Mucolipidosis II (Inclusion cell or I-cell disease) is an autosomal recessive lysosomal storage disorder clinically comparable to the mucopolysaccharidoses (MPS), characterized by progressive respiratory and neurologic deterioration. Sleep problems, especially obstructive sleep apnea (OSA) and disrupted sleep architecture, are observed in other lysosomal storage diseases but have not been described in mucolipidosis II. We report the progression of polysomnographic abnormalities in a child with mucolipidosis II, demonstrated by worsening sleep-related hypoventilation, OSA, and sleep state fragmentation despite advancing PAP therapy. Background slowing and reduction in spindle activity on limited EEG may reflect progressive CNS disease affecting thalamic neurons., (© 2016 American Academy of Sleep Medicine)

Mucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1(-/-) mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1(-/-) retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1(-/-) mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1(-/-) mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin-1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation., Patients and Methods: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013., Results: All debuted in the first month of life, with a median age of three days (range, 3-30 days), and had secretory diarrhea dependent on parenteral nutrition, with fasting fecal volume of 150-200ml/kg/day. Light microscopy of duodenal biopsy samples showed varying degrees of villous atrophy without cryptic hyperplasia, accumulation of PAS positive material in the cytoplasm of enterocytes brush border, and anti-CD10 immunostaining was suggestive of intracytoplasmic inclusions. Diagnostic confirmation was performed with electron microscopy. Two of them had a genetic study, and showed mutations in MYO5B gene. Three died and three are alive; two of them with an intestinal transplantation and the third waiting for a multivisceral transplantation., (Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.

Inclusion-cell disease (mucolipidosis II/I-cell disease) is a lysosomal storage disease characterized by a constellation of physical findings which complicate airway management. There is currently a deficit of published literature describing appropriate strategies for acute management of these children's airways. This paper details emergency and anesthetic airway management concerns and potential solutions in a small series of children with I-cell disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

We report on a boy with severe pulmonary arterial hypertension associated with mucolipidosis, a rare lysosomal storage disorder. During diagnostic catheterisation, we found increased endothelin-1 levels, but normal big endothelin-1-levels (the precursor form of endothelin-1), which suggests impaired degradation of endothelin-1 rather than increased synthesis. As endothelin-1 degradation takes place in the lysosome, it appears likely that lysosomal dysfunction caused by the underlying disease contributes to the development of pulmonary arterial hypertension in this patient.

Objectives: Microvillous inclusion disease (MVID) is a cause of intractable diarrhea in infancy. In its classic form, the disease is characterized by a severe persistent watery diarrhea starting within the first days of life. Parenteral nutrition and small bowel transplantation are the only known treatments for the affected children. Histologically, periodic acid-Schiff (PAS) staining shows accumulation of periodic acid-Schiff-positive staining material along the apical pole of enterocytes, whereas transmission electron microscopy exhibits microvillus inclusion bodies within the cytoplasm of enterocytes with rarefied and shortened microvilli and secretory granules. The objective of this work was to explore clinical, morphological, and genetic findings in cases of MVID with unusual presentations., Methods: Clinical, histological, and genetic findings are reported for 8 cases of MVID with atypical presentation., Results: The diarrhea started after several months in 3 cases. It was usually less abundant and 3 patients were weaned off parenteral nutrition. None required intestinal transplantation. Three patients experienced malformations, dysmorphy, sensory disabilities, and severe mental retardation. One had a hydrocephaly. Three patients had a cholestasis with low γ-glutamyl transferase levels. Light microscopy showed histological abnormalities consistent with MVID in all of the cases, but the lesions were sometimes focal or delayed. Transmission electron microscopy retrieved some criteria of MVID in 4 patients. Finally, 6 patients were homozygotes or compound heterozygotes for MYO5B mutations., Conclusions: This study extends the spectrum of MVID to less severe clinical presentations.

Objectives: Intractable diarrhea of infancy (IDI), a group of prolonged diarrheal disorders, is difficult to diagnose and manage. We documented general features of patients and the causes of IDI., Methods: The present retrospective study included 60 hospitalized patients with IDI ages 0 to 24 months during January 2000 to December 2010. Detailed history, laboratory and endoscopic findings, diagnoses, and clinical courses were reviewed. Descriptive analyses were used for statistical evaluation., Results: The male/female ratio was 1.4. The median age at onset of diarrhea was 12 days. A total of 70% and 11% of patients were severely and moderately malnourished, respectively. Carbohydrate malabsorption (CM) and food allergies (n = 11, 18% for both) were the most frequent causes. A total of 16 of the patients (27%) did not have a specific diagnosis. The other diagnoses were infections (n = 5), immune-mediated disorders (IMD) (n = 6), congenital enterocyte defects (CED) (n = 3, 5%), short bowel syndrome (n = 2), cystic fibrosis (n = 2), intestinal pseudoobstruction (n = 1), congenital disorder of glycosylation (n = 1), abetalipoproteinemia (n = 1), and proprotein convertase (PC) 1 deficiency (n = 1). Stool calprotectin level was high in 10 of 19 patients with Crohn disease (n = 3, mean 1116 ± 851 mg/L), food allergy (n = 4, mean 516 ± 288 mg/L), and undefined etiology (n = 3, mean 616 ± 780 mg/L). The mean duration of hospitalization was 76 days., Conclusions: IDI is a heterogeneous group of diarrheal disorders. The most frequent causes were CM and food allergies in our study. Because high levels of calprotectin support inflammation, calprotectin levels may help to discriminate CED and inflammatory causes of IDI.

Sialidosis is a lysosomal storage disease caused by deficit of neuraminidase. It is an autosomal recessive disease, heterogeneous in its onset, presentation and prognosis. We report a case of a male patient with molecular and enzymatic confirmation of the diagnosis. Symptoms began at age 26 with reduced visual acuity, bilateral cherry-red spots and later myoclonus. A brother, now deceased, had the same confirmed disease. We describe the symptoms and clinical findings of the patient, as well review the current knowledge on the topic. With this report, we highlight the importance of a clinical history integrating all the patient's symptoms in order to achieve the diagnosis. In the presence of a cherry-red spot, a comprehensive study is mandatory. Despite being a rare disease, sialidosis carries a significant burden for its patients and its diagnosis should always be considered in the appropriate setting., (2014 BMJ Publishing Group Ltd.)