Morquio Research Articles

Successful desensitization of elosulfase alfa–induced anaphylaxis in a pediatric patient with Morquio syndrome

Successful desensitization of elosulfase alfa–induced anaphylaxis in a pediatric patient with Morquio syndrome

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients

PurposeMain symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. Material and methodsMRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. ResultsThe deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p<0.005). ConclusionMPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.

Evaluation of oral manifestations of patients with mucopolysaccharidosis IV and VI: clinical and imaging study

The aim of this study is to assess oral manifestations in patients with mucopolysaccharidosis IV (MPS IVA) and mucopolysaccharidosis VI (MPS VI). Seventeen patients were assessed, nine with MPS IVA and eight with MPS VI, treated at the Medical Genetics Outpatient Clinic of Hospital Universitário Alcides Carneiro (HUAC) in Campina Grande, Paraíba State, Brazil. Assessments included clinical and intraoral examinations, analysis of occlusal function, and panoramic X-rays. Among all, 64.7% of the patients had unerupted teeth and 52.9% of them had enamel hypoplasia. Regarding the temporomandibular joint, 88.2% of the patients showed flattening of the mandibular condyle, 52.9% showed condylar hypoplasia, and all of them showed decreased mobility. Enamel hypoplasia was observed only in patients with MPS IVA (p<0.05). On the other hand, only MPS VI patients presented with anterior open bite, restricted mouth opening (p<0.05), and a higher rate of unerupted teeth, hyperplastic tooth follicle, and condylar defects (p<0.05). Enamel hypoplasia was observed only in patients with MPS IVA, whereas anterior open bite was observed only in patients with MPS VI. Abnormal findings in the maxillomandibular complex were more frequent in patients with MPS VI. The relevant frequency of MPS VI and IVA in the sample allows us to compare the changes occurring in both groups of patients, therefore enabling us to further comprehend the oral manifestations in specific types of MPS.

Non-invasive pulmonary function test on Morquio patients

Morquio patients, in many cases, present with severe tracheal narrowing and restrictive lung problems making them susceptible to high mortality arising from sleep apnea and related complications. Tracheal obstruction with growth imbalance, short neck, adeno and tonsillar hypertrophy, large mandible, and/or pectus carinatum also contributes to the challenges in managing the airway with intubation and extubation due to factors intrinsic to Morquio syndrome. Taken together, these issues lead to serious respiratory distress and life-threatening complications during anesthetic procedures. Furthermore, patients with Morquio syndrome frequently cannot perform standard pulmonary function tests as a result of their distinctive skeletal dysplasia and chest deformity, thus making diagnosis of incipient pulmonary disease difficult. In many cases, conventional spirometry is too difficult for patients to complete, deriving from issues with cooperation or clinical circumstance. Therefore, it is an unmet challenge to assess pulmonary insufficiency with standard pulmonary function test (PFT) with minimal effort. Non-invasive PFT such as respiratory inductance plethysmography, impulse oscillometry system, and pneumotachography were described in Morquio patients as compared with spirometry. Findings from our previous study indicate that these non-invasive tests are a reliable approach to evaluate lung function in a larger range of patients, and provide valuable clinical information otherwise unobtainable from invasive tests. In conclusion, the present study describes the utility of non-invasive (PFT) to accommodate a broad range of patients including intolerance to effort-dependent PFT.

A second reported malignancy in a patient with Morquio syndrome.

Morquio syndrome is a rare lysosomal storage disease that affects multiple organ systems. However, it is rarely associated with malignancy. We present the case of a 30-year old man with Morquio syndrome associated with gastric adenocarcinoma. This case also demonstrates two other findings that have not been previously described in patients with Morquio syndrome - malrotation of brainstem and cerebellum, without clinical neurologic deficit, and persistence of fetal lobulation in the kidneys.

Mucopolysaccharidoses: A rare cause for bilateral cloudy cornea

There are many different causes for corneal clouding/opacification which include both local ophthalmic causes as well as systemic causes. Mucopolysaccharidosis is a rare cause. Hence, we present a case of mucopolysaccharidosis type IV, who presented with bilateral corneal clouding and other systemic features of this storage disorder.

Cervical spine surgery in MPS IVA: a single center experience

To assess the effect of high doses of corticosteroids in patients hospitalized for exacerbation of chronic obstructive pulmonary disease (COPD).A prospective cohort study was conducted on patients hospitalized with COPD between January and March 2015, grouped according to the glucocorticoid dosage administered (cutoff, 40 mg of prednisone/day). We compared the results of hospital stay, readmission and mortality at 3 months of discharge.We analyzed 87 patients. The median daily dose was 60 mg of prednisone (interquartile range, 46.67–82.33 mg/day), and the administration route was intravenous in 96.6% of the cases. We established a relative risk (RR) for hospital stays longer than 8 days of 1.095 (95% CI 0.597–2.007; p = .765) when steroid dosages greater than 40 mg/day were employed. In these patients, the hazard ratio (HR) for readmission in the 3 months after discharge was 0.903 (95% CI 0.392–2.082; p = .811), and the mortality was 1.832 (95% CI 0.229–16.645; p = .568). Neither the RR nor the HR varied in a statistically significant manner after adjusting for confounding factors.A daily dose greater than 40 mg of prednisone in patients hospitalized for COPD exacerbation was not associated with a shorter hospital stay or a reduction in readmissions or mortality at 3 months.Evaluar el efecto de las dosis altas de corticoides en pacientes ingresados por exacerbación de una enfermedad pulmonar obstructiva crónica (EPOC).Estudio de cohortes prospectivo de enfermos hospitalizados con EPOC entre enero y marzo de 2015, agrupados en función de la dosis de glucocorticoides recibida (punto de corte: 40 mg de prednisona/día). Se compararon los resultados de estancia hospitalaria, y de reingreso y mortalidad a los 3 meses del alta.Se analizaron 87 pacientes. La mediana de la dosis diaria recibida fue de 60 mg de prednisona/día (rango intercuartílico: 46,67-82,33 mg/día); la vía de administración fue endovenosa en el 96,6% de los casos. Se estableció un riesgo relativo (RR) de estancia superior a 8 días de 1,095 [intervalo de confianza (IC) 95%: 0,597-2,007; p = 0,765] cuando se usaban dosis de esteroides superiores a 40 mg/día. Además, en estos pacientes la hazard ratio (HR) para el reingreso durante los 3 meses siguientes al alta fue de 0,903 [IC 95%: 0,392-2,082; p = 0,811] y la mortalidad de 1,832 [IC 95%: 0,229-16,645; p = 0,568]. Ni el RR ni las HR observadas variaron de forma estadísticamente significativa tras el ajuste por factores de confusión.Una dosis superior a 40 mg diarios de prednisona en pacientes ingresados por exacerbación de EPOC no se asocia a una menor estancia hospitalaria ni a una disminución del reingreso y de la mortalidad a los 3 meses.

Is joint pain a criteria for ERT indication in adult patients with MPS IVA and VI, even without significant visceral involvement?

Is joint pain a criteria for ERT indication in adult patients with MPS IVA and VI, even without significant visceral involvement?

Muscle Weakness: A Misleading Presentation in Children With Distinctive Syndromic Entities (Clinical Case Reports).

Marked ligamentous hyperlaxity and muscle weakness/wasting associated with awkward gait are the main deficits confused with the diagnosis of myopathy. Seven children (6 boys and 1 girl with an average age of 8 years) were referred to our department because of diverse forms of skeletal abnormalities. No definitive diagnosis was made, and all underwent a series of sophisticated investigations in other institutes in favor of myopathy. We applied our methodology through the clinical and radiographic phenotypes followed by targeted genotypic confirmation. Three children (2 boys and 1 girl) were compatible with the diagnosis of progressive pseudorheumatoid chondrodysplasia. The genetic mutation was correlated with the WISP 3 gene actively expressed by articular chondrocytes and located on chromosome 6. Klinefelter syndrome was the diagnosis in 2 boys. Karyotyping confirmed 47,XXY (aneuploidy of Klinefelter syndrome). And 2 boys were finally diagnosed with Morquio syndrome (MPS type IV A) as both showed missense mutations in the N-acetylgalactosamine-sulfate sulfatase gene. Misdiagnosis can lead to the initiation of a long list of sophisticated investigations.

The patient experience of elosulfase alfa treatment for MPS IVA (Morquio syndrome type A): beyond traditional measures

The patient experience of elosulfase alfa treatment for MPS IVA (Morquio syndrome type A): beyond traditional measures

Multi-stakeholder engagement leading to access to treatment for MPS IVA (Morquio syndrome type A), a model for the ultra rare disease community

Multi-stakeholder engagement leading to access to treatment for MPS IVA (Morquio syndrome type A), a model for the ultra rare disease community

Elosulfase alfa treatment and changes in physical functioning and disability in Morquio syndrome type A

Elosulfase alfa treatment and changes in physical functioning and disability in Morquio syndrome type A

Activities of daily living for patients with Morquio syndrome type A

Activities of daily living for patients with Morquio syndrome type A

Injectable microgels development for sustained GALNS enzyme replacement therapy for Morquio syndrome type A

Injectable microgels development for sustained GALNS enzyme replacement therapy for Morquio syndrome type A

Echocardiographic assessment of Morquio syndrome type A mice

Echocardiographic assessment of Morquio syndrome type A mice

Sub-analysis of long-term elosulfase alfa treatment outcomes in adults with Morquio syndrome type A

Sub-analysis of long-term elosulfase alfa treatment outcomes in adults with Morquio syndrome type A

Lysosomal storage diseases.

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.

Spine malformation complex in 3 diverse syndromic entities: Case reports.

Rationale:Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity.Patients concerns:Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes.Diagnoses:We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A).Interventions:Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively.Outcomes:The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex.Lesons:Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and (c) the diagnosis.

Mucopolysaccharidosis IVA and glycosaminoglycans.

Mucopolysaccharidosis IVA (MPS IVA; Morquio A: OMIM 253000) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). C6S and KS are mainly produced in the cartilage. Therefore, the undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. Chondrogenesis, the earliest phase of skeletal formation, is maintained by cellular interactions with the ECM, growth and differentiation factors, signaling pathways, and transcription factors in a temporal-spatial manner. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. The unique skeletal features are distinguished by a disproportional short stature, odontoid hypoplasia, spinal cord compression, tracheal obstruction, pectus carinatum, kyphoscoliosis, platyspondyly, coxa valga, genu valgum, waddling gait, and laxity of joints. In spite of many descriptions of these unique clinical features, delay of diagnosis still happens. The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge. In this review article, we comprehensively describe historical aspect, property of GAGs, diagnosis, screening, pathogenesis, and current and future therapies of MPS IVA.

Four novel mutations in the N-acetylgalactosamine-6-sulfate sulfatase gene among Egyptian patients with Morquio A disease

Morquio A disease (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS) encoded by the GALNS gene. This deficiency leads to a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing their accumulation within the lysosomes and consequently prominent skeletal and visceral abnormalities.Clinical evaluation and biochemical GALNS enzyme activity determination were carried out for the patients from four unrelated Egyptian families. Mutational analysis was performed to PCR products by sequencing of the 14 exons and exon-intron boundaries of GALNS gene for the 4 patients.Sequence analysis revealed four novel mutations; three nonsense mutations (p.Q12X, p.Q220X, p.Y254X) and one missense mutation, p.D40G. All four patients were offspring of consanguineous marriages and were homozygous for the corresponding mutation. The activity of the GALNS enzyme was below normal reference range in all of them. The p.Q12X and p.Y254X were associated with severe MPS IVA phenotype.Molecular analysis of GALNS gene revealed four novel mutations in four different Morquio A Egyptian patients.