Secondary Hyperparathyroidism in Children with Mucolipidosis Type II (I-Cell Disease): Irish Experience.

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.

Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

BACKGROUND: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. METHODS: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. RESULTS: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. CONCLUSIONS: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.

Mucolipidoses Overview: Past, Present, and Future.

Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.

Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome.

Mucolipidosis II α/beta (MLII) is an autosomal recessive disease in which a gene mutation leads to improper targeting of lysosomal enzymes with an end result of accumulation of lysosomes in the mitochondria resulting in a dysfunctional mitochondria. 1 Leigh syndrome (LS) is a rare progressive neurodegenerative disorder associated with dysfunctional mitochondria and oxidative phosphorylation. 4 Both disease processes typically present in infancy. 3 7 Herein, we present a case of an infant diagnosed with both mucolipidosis II and Leigh syndrome. Genetic analysis in this case revealed two mutations (NDUFA12 c.178C > T p.Arg60* and GNPTAB c.732_733delAA) on the long arm of chromosome 12 as the etiology of MLII and LS in this neonate, respectively. We are unaware of any previously published cases of the presence of these two diseases occurring in the same patient. The complex clinical presentation of this case led to a delay in the diagnosis, and we believe that the clinical phenotypes of these two conditions were likely worsened. The genetic alterations presented in this case occurred as a result of mutations on chromosome 12. We suggest further investigation into the potential overlap in the pathophysiology, specifically the inheritance pattern, linkage disequilibrium, mitochondrial-lysosomal interaction, or crosstalk contributing to both diseases.

Hip Morphology in Mucolipidosis Type II.

Mucolipidosis type II (MLII) is a rare lysosomal storage disorder caused by defective trafficking of lysosomal enzymes. Severe skeletal manifestations are a hallmark of the disease including hip dysplasia. This study aims to describe hip morphology and the natural course of hip pathologies in MLII by systematic evaluation of plain radiographs, ultrasounds and magnetic resonance imaging (MRI). An international two-centered study was performed by retrospective chart review. All MLII patients with at least one pelvic radiograph were included. A total of 16 patients were followed over a mean of 3.5 years (range 0.2-10.7 years). Typical age-dependent radiographic signs identified were femoral cloaking (7/16), rickets/hyperparathyroidism-like changes (6/16) and constrictions of the supra-acetabular part of the os ilium (16/16) and the femoral neck (7/16). The course of acetabular and migration indexes (AI, MI) significantly increased in female patients. However, in the overall group, there was no relevant progression of acetabular dysplasia with a mean AI of 23.0 (range 5°-41°) and 23.7° (range 5°-40°) at the first and last assessments, respectively. Better knowledge on hip morphology in MLII could lead to earlier diagnosis, improved clinical management and enables assessment of effects of upcoming therapies on the skeletal system.

A neonate with mucolipidosis II and transient secondary hyperparathyroidism.

Background Mucolipidosis II α/ß (ML II) is an autosomal recessive disease associated with the abnormality of lysosomal enzyme trafficking. Case presentation We present an unusual patient with: (a) marked skeletal anomalies with secondary hyperparathyroidism; (b) serum intact parathyroid hormone level normalized by 7 weeks but abnormally elevated serum alkaline phosphate persisted; and (c) two mutations identified in the GNPTAB gene. One mutation, c.3503_3504delTC, is the most common mutation in ML II. However, the second mutation, c.2896delA, is a rare mutation for which clinical presentation has not been described previously.

Characterization of mesenchymal stem cells in mucolipidosis type II (I-cell disease).

Mucolipidosis type II (ML-II, I-cell disease) is a fatal inherited lysosomal storage disease caused by a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase. A characteristic skeletal phenotype is one of the many clinical manifestations of ML-II. Since the mechanisms underlying these skeletal defects in ML-II are not completely understood, we hypothesized that a defect in osteogenic differentiation of ML-II bone marrow mesenchymal stem cells (BM-MSCs) might be responsible for this skeletal phenotype. Here, we assessed and characterized the cellular phenotype of BM-MSCs from a ML-II patient before (BBMT) and after BM transplantation (ABMT), and we compared the results with BM-MSCs from a carrier and a healthy donor. Morphologically, we did not observe differences in ML-II BBMT and ABMT or carrier MSCs in terms of size or granularity. Osteogenic differentiation was not markedly affected by disease or carrier status. Adipogenic differentiation was increased in BBMT ML-II MSCs, but chondrogenic differentiation was decreased in both BBMT and ABMT ML-II MSCs. Immunophenotypically no significant differences were observed between the samples. Interestingly, the proliferative capacity of BBMT and ABMT ML-II MSCs was increased in comparison to MSCs from age-matched healthy donors. These data suggest that MSCs are not likely to cause the skeletal phenotype observed in ML-II, but they may contribute to the pathogenesis of ML-II as a result of lysosomal storage-induced pathology.

Clinical and radiological findings in Brazilian patients with mucolipidosis types II/III.

OBJECTIVE: The present study aims to provide orientation for clinicians and radiologists to recognize the most prevalent findings leading to diagnosis in mucolipidosis from a description of the natural history of five Brazilian cases. MATERIALS AND METHODS: We conducted an observational and retrospective study of five patients with clinical and radiological diagnosis of mucolipidosis. Clinical evaluation consisted of information obtained from records and including physical, neurologic, and dysmorphic evaluations. Radiologic studies consisted of complete skeletal radiographs of all patients. Enzyme assessment was performed for confirmation of the diagnosis. RESULTS: The five patients were referred for genetic evaluation due to disproportionate short stature with short trunk accompanied by waddling gait. Age at referral varied from 11 months to 28 years. The most prevalent findings were joint restriction (4/5 patients), neuropsychomotor developmental delay (3/5), coarse facies (2/5), hypertrophic cardiomyopathy (2/5), and mental retardation (1/4 patients). The most common radiological findings were anterior beaking of the vertebral bodies (5/5), shallow acetabular fossae (5/5), epiphyseal dysplasia (5/5), platyspondyly (4/5), pelvic dysplasia (4/5), decreased bone mineralization (4/5), scoliosis (3/5), wide and oar-shaped ribs (3/5), generalized epiphyseal ossification delay (3/5), and hypoplasia of basilar portions of ilea (3/5). Enzyme assessment showed α-iduronidase, α-mannosidase, ß-glucuronidase, hexosaminidase A, and total hexosaminidase increased in plasma and normal glycosaminoglycans concentration. One patient was clinically classified as ML II and four patients as ML III. CONCLUSIONS: The follow-up of five patients showed the typical clinical and radiological findings allowing the diagnosis, thus improving clinical management and providing adequate genetic counseling. Clinicians and radiologists can take advantage of the information from this work, enhancing their differential diagnosis ability.

I-Cell Disease (Mucolipidosis II): A Case Series from a Tertiary Paediatric Centre Reviewing the Airway and Respiratory Consequences of the Disease.

BACKGROUND: Inclusion cell disease (I-cell) is a rare autosomal recessive metabolic disease involving multiple organ systems, associated with a severely restricted life expectancy. No curative therapy is currently available, with management aimed at symptom palliation. METHODS: We present a retrospective, single-centre, case series of children referred to a tertiary paediatric metabolic service. The clinical presentation, demographics, genetics and natural history of the condition are investigated. RESULTS: Five patients with I-cell disease were referred over a 10-year period. All patients were born with dysmorphic features and had a family history of I-cell disease on further exploration. Phenotypic variation was seen within patients with the same genetic profile. Airway problems were common with 100% of the documented sleep oximetry studies suggesting sleep-disordered breathing. Of the two patients who had tracheal intubation anaesthetic difficulties we encountered, one required intraoperative reintubation, and one suffered a failed intubation with subsequent death. All five patients required oxygen therapy with the use of CPAP and BiPAP also seen. Feeding issues were almost universal with four of the five patients requiring nasogastric feeding. Four patients had died in the 10-year period with a mean life expectancy of 36 months. Cause of death for three of the four patients was respiratory failure. CONCLUSIONS: Airway problems, including sleep-disordered breathing, were ubiquitous in this cohort of children. Any intervention requiring a general anaesthetic needs careful multidisciplinary consideration due to significant associated risks and possibly death. Management as a result is generally non-surgical and symptomatic. This case series demonstrates universal involvement of the airway and respiratory systems, an important consideration when selecting meaningful outcomes for future effectiveness studies of novel therapies.

A Lifetime of Adventures in Glycobiology.

My initial research experience involved studying how bacteria synthesize nucleotide sugars, the donors for the formation of cell wall polysaccharides. During this time, I became aware that mammalian cells also have a surface coat of sugars and was intrigued as to whether these sugars might be arranged in specific sequences that function as information molecules in biologic processes. Thus began a long journey that has taken me from glycan structural analysis and determination of plant lectin-binding preferences to the biosynthesis of Asn-linked oligosaccharides and the mannose 6-phosphate (Man-6-P) lysosomal enzyme targeting pathway. The Man-6-P system represents an early example of a glycan serving as an information molecule in a fundamental cellular function. The remarkable advances in the field of glycobiology since I entered have uncovered scores of additional examples of oligosaccharide-lectin interactions mediating critical biologic processes. It has been a rewarding experience to participate in the efforts that have established a central role for glycans in biology.

A potential strategy for reducing cysts in autosomal dominant polycystic kidney disease with a CFTR corrector.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers, raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR), conventionally used to manage cystic fibrosis in reducing renal cyst growth. VX-809 reduced cyst growth in Pkd1-knockout mice and in proximal, tubule-derived, cultured Pkd1 knockout cells. VX-809 reduced both basal and forskolin-activated cAMP levels and also decreased the expression of the adenylyl cyclase AC3 but not of AC6. VX-809 also decreased resting levels of intracellular Ca2+ but did not affect ATP-stimulated Ca2+ release. Notably, VX-809 dramatically decreased thapsigargin-induced release of Ca2+ from the endoplasmic reticulum (ER). VX-809 also reduced the levels of heat shock proteins Hsp27, Hsp70, and Hsp90 in mice cystic kidneys, consistent with the restoration of cellular proteostasis. Moreover, VX-809 strongly decreased an ER stress marker, the GADD153 protein, and cell proliferation but had only a small effect on apoptosis. Given that administration of VX-809 is safe, this drug potentially offers a new way to treat patients with ADPKD.

Progression of Polysomnographic Abnormalities in Mucolipidosis II (I-Cell Disease).

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.

Early characteristic radiographic changes in mucolipidosis II.

BACKGROUND: Although mucolipidosis type II has similar metabolic abnormalities to those found in all the mucopolysaccharidoses and mucolipidoses, there are distinctive diagnostic radiographic changes of mucolipidosis II in the perinatal/newborn/infant period. OBJECTIVE: To describe the early characteristic radiographic changes of mucolipidosis II and to document when these changes manifest and resolve. MATERIALS AND METHODS: We retrospectively reviewed radiographs and clinical records of 19 cases of mucolipidosis II from the International Skeletal Dysplasia Registry (1971-present; fetal age to 2½ years). A radiologist with special expertise in skeletal dysplasias evaluated the radiographs. RESULTS: The most common abnormalities were increased vertebral body height (80%, nonspecific), talocalcaneal stippling (86%), periosteal cloaking (74%) and vertebral body rounding (50%). Unreported findings included sacrococcygeal sclerosis (54%) and vertebral body sclerosis (13%). Rickets and hyperparathyroidism-like (pseudohyperparathyroidism) changes (rarely reported) were found in 33% of cases. These changes invariably started in the newborn period and resolved by 1 year of age. The conversion from these early infantile radiographic features to dysostosis multiplex changes occurred in 41% of cases, and within the first year after birth. CONCLUSION: Several findings strongly suggest the diagnosis of mucolipidosis II, including cloaking in combination with one or more of the following radiographic criteria: talocalcaneal stippling, sacrococcygeal or generalized vertebral body sclerosis, vertebral body rounding, or rickets/hyperparathyroidism-like changes in the perinatal/newborn/infancy period. These findings are not found in the other two forms of mucolipidosis nor in any of the mucopolysaccharidoses.

Airway management considerations in children with I-cell disease.

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.

Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.

Craniosynostosis in a child with I-cell disease: The need for genetic analysis before contemplating surgery in craniosynostosis.

We are reporting a rare case of I-cell disease presenting with craniosynostosis. An 11-month-old child presented with abnormal head shape, developmental delay and bent bones. We planned for corrective surgery for craniosynostosis, but on genetic analysis I-cell disease was confirmed. After explaining the prognosis of I-cell disease, parents denied surgery. This case report emphasizes the fact that syndromic evaluation of craniosynostosis is very much essential before proceeding for corrective surgery.

Systemic accumulation of undigested lysosomal metabolites in an autopsy case of mucolipidosis type II; autophagic dysfunction in cardiomyocyte.

Mucolipidosis type II is an autosomal recessive lysosomal storage disease caused by N-acetylglucosamine-1-phosphotransferese deficiency. We report here pathological findings of an autopsy case of mucolipidosis type II. The patient was an 8-year-old boy with mucolipidosis type II and was complicated with hypertrophic cardiomyopathy. He suddenly developed progressive respiratory failure and finally died. At autopsy, systemic accumulation of undigested lysosomal metabolites was prominent, particularly in the heart, lungs, and dorsal root ganglion. In cardiomyocyte, LC3, an autophagy marker, was positive in the cytoplasm. Ubiquitin, p62, K48 polyubiquitin, and K63 polyubiquitin were also positive in the cytoplasm. Our findings suggest that autophagic dysfunction might be associated with the cardiomyopahty of mucolipidosis type II.

Difficult intubation management in a child with I-cell disease.

I-cell disease (mucolipidosis II) is a rare metabolic disorder resulting from the deficiency of a specific lysosomal enzyme, N-acetylglucosamine-1-phosphotransferease. Developmental delay and growth failure are common presentations of I-cell disease. Psychomotor deterioration is rapid and progressive. Some physical signs such as hip dislocations, inguinal hernia, hepatomegaly, joint limitation, and skin changes may be present at birth. Coarse facial features and skeletal abnormalities become more conspicuous with time. The life expectancy of children with this condition is poor, with death usually occurring around the fifth year. A case report of the anesthetic management of gingivectomy with multiple dental extractions in a 5-year-old Omani female with I-cell disease is presented. The problems faced and their management during anesthesia are described.

I-Cell Disease (Mucolipidosis II) Presenting as Neonatal Fractures: A Case for Continued Monitoring of Serum Parathyroid Hormone Levels.

A severe form of I-cell disease (mucolipidosis II) can present in the newborn period as multiple fractures. The bone disease in these patients is believed to be due to hyperparathyroidism. We report a case where bone disease was present at birth but the parathyroid hormone levels were initially normal and did not increase until 37 d of age. Supplemention with vitamin D was needed to normalize the parathyroid hormone levels despite adequate intake of vitamin D, calcium and phosphorus. We suggest that in patients with I-cell disease, continued evaluation for hyperparathyroidism may be necessary despite initial normal parathyroid hormone levels.