Morquio Research Articles

Inflammatory process and oxidative/nitrative stress: in vivo study in mucopolysaccharidosis type IV A patients under long-term enzyme replacement therapy

Mucopolysaccharidosis type IV A (MPS IVA) is an inborn error of the metabolism (IEM) caused by a deficiency of the enzyme N-acetylgalactosamine 6-sulfate sulfatase (GALNS). Since 2014, enzyme replacement therapy (ERT) is the recommended treatment for these patients. It is known that the inflammatory response is closely related to antioxidant defenses and oxidative stress, and literature shows involvement of oxidative stress in the pathogenesis of IEM. The aim of this study is to investigate the mechanisms of oxidative/nitrative stress and inflammation in patients with MPS IVA under long-term ERT. In the present work we investigate parameters of oxidative/nitrative stress in plasma and urine of MPS IVA patients under long-term ERT and controls, such as plasmatic nitrate/nitrite levels using the LDH Method, urinary di-tyrosine levels by fluorometric method, plasmatic content of sulfhydryl groups, urinary oxidized guanine species by ELISA kit and the plasmatic total antioxidant status. We next evaluated the plasmatic pro and anti-inflammatory cytokines concentration (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α) and the expression of factors and enzymes Nrf-2, NF-κβ and HO-1, main mediators between inflammation and oxidative stress. In concern to the oxidative/nitrative stress parameters, there was no significant difference between the groups MPS IVA patients under long-term ERT and controls, showing that there is no overproducing of RNS, no protein damage, no DNA/RNA oxidative damage and no modification in the non-enzymatic antioxidant capacity of a tissue to prevent the damage associated to free radical processes in these patients. It was also verified no significant difference between the MPS IVA patients under long-term ERT and controls groups regarding the production of proinflammatory cytokines. About anti-inflammatory cytokines, IL 10 was shown to be elevated in MPS IVA patients under long-term ERT in comparison to the control group. We next evaluated the genic expression of Nrf-2, NF-κβ and HO-1and there was no significant difference between the MPS IVA patients under long-term ERT and control groups. In conclusion, MPS IVA patients under long term ERT are not in an inflammatory state and there is no alteration in genic expression in the genes analyzed which are involved in oxidative stress and inflammatory pathways. It is,however, important to consider that absence of imbalance of antioxidant defenses in MPS IVA patients under long term ERT is so far preliminary it is supported by methodologies that are not highly sensitive nor very accurate. Further experiments in future using state-of-the-art methodologies will corroborate these findings. Nevertheless, our results demonstrated the protective effect of the treatment in relation to the parameters studied and the importance of starting treatment in the early stages of the disease.

Real-world impact of enzyme replacement therapy on endurance in patients with MPS IVA

Real-world impact of enzyme replacement therapy on endurance in patients with MPS IVA

Substrate reduction therapy for Morquio syndrome type A: An evaluation

Substrate reduction therapy for Morquio syndrome type A: An evaluation

A case of a presumed diagnosis of Morquio syndrome

A case of a presumed diagnosis of Morquio syndrome

Pregnancy with Morquio syndrome type A: What are patients' perspectives and has enzyme replacement therapy (ERT) changed them?

Pregnancy with Morquio syndrome type A: What are patients' perspectives and has enzyme replacement therapy (ERT) changed them?

Mucopolysaccharidosis type 4 (Morquio syndrome): A case report

Abstract Introduction Mucopolysaccharidosis (MPS) IVA (Morquio syndrome) is a rare lysosomal storage disease, that is caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to an autosomal recessive mutation in the GALNS gene. Herein, we present a MPS IVA case without regular follow-up, whose enzyme replacement was planned to start at age 30 for the first time, so as to attract attention to this rare disease. Clinical Case A 30-year-old female patient diagnosed with MPS IVA, that was evaluated due to corneal clouding referred to the Marmara University endocrinology outpatient clinic for enzyme replacement. On admission, she complains of impaired vision, hearing loss, hypoglycemic symptoms and numbness of hands and feet. While she was normal for about 2 years after birth, she was noticed for delays in crawling and walking from 2–3 year of age. However, she had definitive diagnosis of MPS-IVA at the age of 9 years, with low enzymatic analysis and genetic mutation in the GALNS gene located on chromosome 16q24.3. She operated on for bilateral glaucoma and cerebellar mass when she was 17. Her parents were third degree consanguineous, and she had one healthy younger brother. On physical examination, blood pressure: 99/67 mmHg, pulse: 72/min, temperature: 36°C, SpO2:99. She was in a wheelchair. Her height was 92 cm, weight was 30 kg, BMI: 25.6 kg/m2. Disproportionate short stature, coarse facial features, hypertelorism, genu valgum, pectus carinatum, kyphoscoliosis, were detected. Her neuromotor development was normal. Laboratory findings were unremarkable except for vitamin D hypovitaminosis. Radiographic findings were dysostosis multiplex, include abnormally shaped vertebral bodies with anterior beaking, posterior scalloping, platyspondyly and dens hypoplasia, thoracolumbar kyphosis, short, broad metacarpals, acetabular dysplasia, genu valgum, pectus carinatum, paddle-shaped ribs and short, and thick clavicles (Fig 1). Bone densitometry results were in osteoporotic range BMD at the femoral neck was 0.491 g/cm2, Z score was -2.8 and at the lumbar spine was 0.707 g/cm2, Z score was -3.6. She continued the 6-min walk test with the help of a walker and knee pad for 2.37 minutes and walked 3.4 meters. Echocardiography demonstrated that ejection fraction was 65%, normal left ventricular systolic function, no ventricular segmental wall motion defect, aortic 3 cusps, mild to moderate aortic valvular regurgitation, mild mitral valvular regurgitation. Pectus carinatum was detected on thorax CT imaging, whereas a restrictive disease pattern was not observed in PFT and DLCO. Bilateral severe mixed hearing loss was detected. Recombinant human GALNS (elosulfase alfa), 2.0 mg/kg/week, was planned to administer IV in 4 hr. Conclusion Because of the progressive nature of MPS- IVA, early diagnosis and early initiation of enzyme replacement therapy are critical to prevent cumulative systemic manifestations of the patient, especially the skeletal system.

Clinical Characteristics of a Patient with Mucopolysaccharidosis Type IVA (Morquio Syndrome)

Mucopolysaccharidosis (MPS) type IVA (Morquio syndrome) is a hereditary lysosomal storage disease caused by deficiency of N-acetylglucosamine-6-sulfate sulfatase. This enzyme deficiency leads to specific glycosaminoglycans (keratan sulfate and chondroitin-6sulfate) accumulation mainly in the bone and cartilage tissues, as well as in the cardiovascular, respiratory systems, and visual systems. Patients with MPS IVA look healthy at birth, however, they develop typical spine deformities (kyphoscoliosis), pectus carinatum, wrists hypermobility with decreased muscle strength and loss of fine motor skills, valgus deformation of lower limbs during the first years of life. Pathological changes in cardiovascular and respiratory systems, visual and acoustic analyzers can be revealed. Early diagnosis of the disease is crucial for timely initiation of enzyme replacement therapy. Thus, low incidence of the disease and its heterogeneous clinical picture complicates diagnosis. Consequently, patients with MAS IVA often become severely disabled as early as adolescence. Patients with severe form and without treatment die before the age of 30 due to complications of respiratory system diseases, valvular heart apparatus involvement, and cervical myelopathy.

A pictorial review of the radiographic skeletal findings in Morquio syndrome (mucopolysaccharidosis type IV).

Morquio syndrome, also known as Morquio-Brailsford syndrome or mucopolysaccharidosis type IV (MPS IV), is a subgroup of mucopolysaccharidosis. It is an autosomal recessive lysosomal storage disorder. Two subtypes of Morquio syndrome have been identified. In MPS IVA, a deficiency in N-acetylgalactosamine-6-sulfate sulfatase interrupts the normal metabolic pathway of degrading glycosaminoglycans. Accumulated undigested glycosaminoglycans in the tissue and bones result in complications leading to severe skeletal deformity. In MPS IVB, a deficiency in beta-galactosidase results in a milder phenotype than in MPS IVA. Morquio syndrome presents a variety of clinical manifestations in a spectrum of mild to severe. It classically has been considered a skeletal dysplasia with significant skeletal involvement. However, the extraskeletal features can also provide valuable information to guide further work-up to assess the possibility of the disorder. Although the disease involves almost all parts of the body, it most commonly affects the axial skeleton, specifically the vertebrae. The characteristic radiologic findings in MPS IV, such as paddle-shaped ribs, odontoid hypoplasia, vertebral deformity, metaphyseal and epiphyseal bone dysplasia, and steep acetabula, are encompassed in the term "dysostosis multiplex," which is a common feature among other types of MPS and storage disorders. Myelopathy due to spinal cord compression and respiratory airway obstruction are the most critical complications related to mortality and morbidity. The variety of clinical features, as well as overlapping of radiological findings with other disorders, make diagnosis challenging, and delays in diagnosis and treatment may lead to critical complications. Timely imaging and radiologic expertise are important components for diagnosis. Gene therapies may provide robust treatment, particularly if genetic variations can be screened in utero.

Anaesthetic challenges and perioperative management of a child with morquio syndrome posted for atlanto axial fusion and decompression: A case report

Anaesthetic challenges and perioperative management of a child with morquio syndrome posted for atlanto axial fusion and decompression: A case report

First report of preimplantation genetic diagnosis of mucopolysaccharidoses IVA and HLA typing for hematopoietic stem cell transplantation

BackgroundMucopolysaccharidoses IVA is an autosomal recessive lysosomal storage disease resulting in skeletal and cartilage dysplasia. Hematopoietic stem cell transplantation is a good therapeutic option for MPS IV. Here we report the first application of PGD test for MPS IVA and HLA with the purpose of HSCT for the affected son in a family with consanguineous marriage. Haplotype analysis of linked STR markers in GALNS gene and HLA loci as well as variant detection by cycle sequencing were included in our PGD test.ResultsTwo out of nine embryos were transferrable. The second embryo transfer was successful and resulted in the pregnancy of one healthy and HLA matched girl.ConclusionsPreimplantation genetic diagnosis could be considered as a noninvasive clinical option for families with a mucopolysaccharidoses IVA patient to have a healthy child that is HLA-matched with the patient in need of hematopoietic stem cell transplantation. In lack of an appropriate hematopoietic stem cell donor the importance of preimplantation genetic diagnosis is much more significant too.

First Case of Prenatal Diagnostics of Type IV Mucopolysaccharidosis (Morquio Syndrome) in Azerbaijan Republic

In one of the regions of Azerbaijan Republic while clinic examination with doctor-pediatrician, doctor-neurologist and doctor-geneticist a girl of 5 years of age was identified as suspicious of mucopolysaccharidosis. N-acetyl-galactosamin-6-sulfatase enzyme analysis has shown low activity of 0,1 μmol/L at norm of >0,2 μmol/L/h. Molecular-genetic analysis of GALNS gene identified substitution of Adenine nucleotide with Guanine nucleotide in 1283 (с.1283 A>G) position accompanied with amino acid change Gln428Arg (Morquio A; OMIM®: 253000). These results correspond to the presence of MPS IVA type. With the consent of both parents and at the term of 16-17-week pregnancy transabdominal amniocentesis was carried out. At the level of DNA, isolated from fibroblasts from amniotic liquid, we have got heterozygous carriage of a с.1283 A>G mutation of GALNS gene, that says of a healthy fetus. We plan to carry out prenatal diagnostics to all families of reproductive age, who have got affected children diagnosed with MPS.

Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy.

Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA.

Abnormal Fundus Autofluorescence in Eyes with Morquio Syndrome

Abnormal Fundus Autofluorescence in Eyes with Morquio Syndrome

Comparison of growth dynamics in different types of MPS: an attempt to explain the causes

BackgroundMucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficient activity of enzymes responsible for the catabolism of glycosaminoglycans (GAGs), resulting in progressive damage to various tissues and organs. Affected individuals present with skeletal deformities, bone growth impairment, joint stiffness and frequently mental retardation.ResultsThe objective of the study was to summarise over 30 years of observations of the growth dynamics in patients with different types of MPS, performed at the Children’s Memorial Health Institute (CMHI, Warsaw, Poland). A retrospective analysis of anthropometric data collected from 1989 to 2020 was performed for 195 patients with MPS I, MPS II, MPS III, MPS IVA and MPS VI. Mean values for birth body length were statistically significantly greater than in the general population. The mean z-scores for other MPS groups showed that until the 24th month of life, the growth pattern for all patients was similar, and the average z-scores for body height were greater than in reference charts. Afterwards, growth patterns began to differentiate for MPS groups.ConclusionsThe long-term follow up showed that the growth pattern in patients with all types of mucopolysaccharidoses significantly deviates from the general population. Patients with MPS IVA had the most severe growth impairments compared to other patients in the study group. Neuropathic MPS I and II demonstrated severe growth impairments compared to other patients in this study. Patients with MPS III showed the mildest growth impairments compared to other MPS patients and reached the 3rd percentile last.

Delivery and assessment of a CRISPR/nCas9-based genome editing system on in vitro models of mucopolysaccharidoses IVA assisted by magnetite-based nanoparticles

Mucopolysaccharidosis IV A (MPS IVA) is a lysosomal disorder caused by mutations in the GALNS gene. Consequently, the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate accumulate in the lysosomal lumen. Although enzyme replacement therapy has shown essential advantages for the patients, several challenges remain to overcome, such as the limited impact on the bone lesion and recovery of oxidative profile. Recently, we validated a CRISPR/nCas9-based gene therapy with promising results in an in vitro MPS IVA model. In this study, we have expanded the use of this CRISPR/nCas9 system to several MPS IVA fibroblasts carrying different GALNS mutations. Considering the latent need to develop more safety vectors for gene therapy, we co-delivered the CRISPR/nCas9 system with a novel non-viral vector based on magnetoliposomes (MLPs). We found that the CRISPR/nCas9 treatment led to an increase in enzyme activity between 5 and 88% of wild-type levels, as well as a reduction in GAGs accumulation, lysosomal mass, and mitochondrial-dependent oxidative stress, in a mutation-dependent manner. Noteworthy, MLPs allowed to obtain similar results to those observed with the conventional transfection agent lipofectamine. Overall, these results confirmed the potential of CRISPR/nCas9 as a genome editing tool for treating MPS IVA. We also demonstrated the potential use of MLPs as a novel delivery system for CRISPR/nCas9-based therapies.

Efficacy of Intravenous Elosulfase Alfa for Mucopolysaccharidosis Type IVA: A Systematic Review and Meta-Analysis.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were −0.260, −0.102, −0.182, −0.360, −0.408, −0.587, −0.293, −0.311, and −0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.

Chest wall deformities and their possible associations with different genetic syndromes.

Our primary objective was to identify discrete and syndromic cases of Pectus excavatum (PE) and Pectus carinatum (PC). We also intended to highlight the significance of further genetic exploration in clinically suspected syndromic cases of PC and PE. Pectus excavatum (PE) and Pectus carinatum (PC) are the most common morphological chest wall deformities. Although various hypotheses have been put forth, the pathogenesis of both entities is largely unknown. Clinicians often refer such cases for further genetic evaluation to exclude an associated underlying connective tissue disorder or a syndrome. Additionally, a detailed anamnesis with focused family history and thorough dysmorphological physical examination was done. PE and PC are considered isolated abnormalities if there is the absence of features of other syndromes, eliminating the need for further genetic evaluations. It is believed that the pattern of inheritance of these non-syndromic isolated PE and PC cases with positive family history could be multifactorial in nature. The recurrence risk of such isolated cases is thought to be low. Further diagnostic studies are indicated as PE and PC could be a part of a syndrome. Among the many syndromes, the most common monogenic syndromes associated with PE and PC are Marfan's and Noonan's. After obtaining the consent, we compiled a database of the patients who presented with chest wall deformities during the period 2017-2019. We selected 70 cases with PC and PE deformities to identify the discrete and syndromic PC and PE cases. During the study, we perused the cytogenetic and/or molecular analyses, that had been conducted to confirm the clinically suspected syndromic cases. We also scrutinized for the presence of PC and PE cases that are associated with the rare syndrome (s). Various genetic abnormalities were identified in 28 (40%) of the 70 cases that had been diagnosed with chest wall abnormalities. Along with PE and PC, other thoracic wall abnormalities were also identified, such as the broad chest, bell-shaped thorax, and elongated or enlarged thorax. One case of a rare genetic disorder of Morquio syndrome associated with PC was also identified. Novel (previously unpublished) genomic variants are reported here. It is important to delve deeper when encountering cases of PE and PC by conducting a further genetic exploration of such cases to identify syndromic associations that cause other structural and functional disorders, diagnosis of which might be missed during the early developmental period. Early identification of such disorders may help us correcting the defects, slowing the progression of disease processes, and preparing better to deal with the potential outcome.

The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome

BackgroundMucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon–intron boundaries of the GALNS gene in patients from 23 unrelated families.ResultsWe report 11 variants that include eight missense variants: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site variant: (c.121-7C > G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_841delACA). Of these, three missense variants (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. Interestingly, we observed a higher than anticipated prevalence of p.P77R variant in our cohort (n = 14/25, 56%). Haplotype analysis in cases with p.P77R variant and 63 ethnicity matched healthy population controls suggested a 4 SNP haplotype block present in cases compared to controls (likelihood ratio test p-value = 1.16 × 10–13), thereby suggesting p.P77R variant as a founder variant in the Gujarati-Indian population. Furthermore, age of mutation analysis suggested the variant to have arisen approximately 450 years ago in the population.Conclusionp.P77R variant in the GLANS gene is likely to be a founder variant in MPS IVA patients of Gujarati-Indian ancestry and appeared approximately 450 years ago in the population. To our knowledge, this is the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.

Hearing Loss in Patients With Morquio Syndrome: Protocol for a Scoping Review.

BackgroundMild to moderate hearing loss is common in patients with mucopolysaccharidosis (MPS) IVA. The hearing loss can be conductive, sensorineural, or mixed. However, in these patients, the mixed form is frequent, attributed to the combination of conductive and neurosensory elements, with slowly progressive evolution. Conductive hearing loss may be secondary to recurrent upper respiratory tract infections, serous otitis media, and deformities of the ear ossicles due to the accumulation of glycosaminoglycans (GAGs). Meanwhile, the sensorineural form is mainly attributed to the accumulation of GAGs in the auditory system.ObjectiveThe aim of this scoping review is to understand the extent and type of evidence in relation to the physiopathology, classification, epidemiology, and clinical management of hearing loss and the effect of therapy for hearing loss in patients with MPS IVA.MethodsThis scoping review includes participants across all genders and of no particular age group who are diagnosed with MPS IVA and develop hearing loss as a comorbidity. No exclusion criteria (country, language, or document type) will be applicable. The information sources will include experimental and quasi-experimental, analytical observational, observational, and qualitative studies. Unpublished literature will not be covered. Grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening the literature, paper selection, and data extraction, and this process will be performed blindly. When all manuscripts have been selected, disagreements that arise between the 2 reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer. Results will be reported with descriptive statistics and information will be displayed in a diagrammatic or tabular manner, as explained in the JBI guidelines.ResultsThe literature search was performed in November 2021 in MEDLINE, LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), the Cochrane Library, ScienceDirect, Google Scholar, and OpenGrey; a total of 780 results were retrieved. Completion of the review is expected in mid-2022.ConclusionsThis scoping review will be the first to describe the extent of the information regarding the development of hearing loss in the MPS IVA population. The data gathered by this review may lead to an understanding of the grade of hearing loss in this population and allow for the assessment of possible interventions according to the disease pattern.International Registered Report Identifier (IRRID)PRR1-10.2196/32986

Vertebral Pathology and Vertebrogenic Myelopathy in Patients with Mucopolysaccharoidosis Type IV A (Morquio Syndrome)

Background: Upper cervical spine instability in patients with Morquio´s syndrome is of common occurrence. Dysplastic odontoid is one of the prominent aetiologies behind the development of atlanto-axial instability which eventually leads to morbid vertebrogenic myelopathy. Material and Methods: We describe 10 children (7 boys and 3 girls) with the phenotype/genotype of Morquio´s syndrome (MPS IVA). Lumbar kyphosis occurs at the age of six months, followed by apparent waddling gait at the age of 3 years. Clinical phenotype and genotype are the baseline tools to set up a crystal clear long term management. Firstly, we proceed via clinical assessment of C1-2 instability. The latter is carried out with full dynamic lateral cervical spine radiographs. Instability can be visualized through the precise interpretations of the anatomical structures around the atlanto-axial segments. 3D sagittal CT scan has been applied to further localize the exact pathology. In 7 cases, there was an initial myelopathy at the level of the cranio-vertebral junction. Results: The most threatening complication of MPS IVA is the vertebrogenic myelopathy. The latter emerged as a notorious complication in connection with atlanto-axial instability and progressive thickening of the spinal cord due to accumulation of Glycosaminoglycan (GAGs). Vertebrogenic myelopathy have been encountered in seven children. All underwent decompression and stabilization of the cervical spine Conclusion: Patients with MPS IV, in their first year of life usually manifest growth deficiency and lumbar kyphosis, but unfortunately passed unnoticed by most of the paediatricians. Progressive dysplasia of the acetabulae is the reason behind the waddling gait. The misconception of generalized ligamentous hyper laxity accompanied with waddling gait were the main incentives of confusion among most of the paediatricians and physicians. Thereby, the false diagnosis of Duchenne Muscular dystrophy has been falsely considered by some colleagues. The purpose of this paper is threefold. First, overlooking the early mal-development of the backbone (lumbar kyphosis) is not a simple mistake. Second, marked ligamentous hyperlaxity warrants the attention toward cervical ligaments, and as ligaments are the main supporters of the craniocervical junction and spine stability, such abnormality demands prompt clinical attention. Third, is to assess the vertebral pathology and vertebrogenic myelopathy from the standpoint of syndromic assessment and the efficiency of decompression and stabilization operations.