https://europepmc.org/articles/PMC5293636?pdf=render

Mucopolysaccharidosis IVA and glycosaminoglycans.

Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy.

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA.

/pdf/mucopolysaccharidosis-iva-diagnosis-treatment-and-management-5e4gwzcwqw.pdf

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

Background
Musculoskeletal involvement in Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) contributes significantly to morbidity and mortality. While the spinal manifestations of the disorder have received considerable attention in the literature, there have been few reported studies to date to guide the management of the orthopedic problems associated with the lower and upper extremities.

https://online.boneandjoint.org.uk/doi/pdf/10.1007/s11832-014-0601-4

Orthopedic management of the extremities in patients with Morquio A syndrome.

Clinical characteristics The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA typically have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, genu valgum (knock-knee), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease. Diagnosis/testing The diagnosis of MPS IVA is established in a proband by identification of low N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity in cultured fibroblasts or leukocytes or by identification of biallelic pathogenic variants in GALNS on molecular genetic testing. Management Treatment of manifestations: Enzyme replacement therapy (elosulfase alfa) is available, although the data on long-term effects of this treatment on the skeletal and non-skeletal features of MPS IVA are limited. Evaluation and management of individuals with MPS IVA are best undertaken by multiple specialists, coordinated by a physician specializing in the care of persons with complex medical problems. Physiatrists, physical therapists, and occupational therapists help optimize mobility and autonomy. Psychological support can optimize coping skills and quality of life; educational professionals can optimize the learning environment for a medically fragile individual. Upper-extremity management may include stabilizing external wrist splints or partial or complete wrist fusion. Surgical intervention is often required for lower-extremity malalignment, hip subluxation and/or hip pain, upper cervical spine instability, and/or progressive thoracolumbar kyphosis. Cardiac valve involvement may require valve replacement. Bacterial endocarditis prophylaxis is recommended for those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis. Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids; diffuse narrowing of the airway may require positive airway pressure and/or tracheostomy. All affected individuals should receive influenza and pneumococcal immunizations as well as routine immunizations. Anesthesia management by an experienced anesthesiologist. Potential pre- and postoperative anesthetic concerns secondary to spine anomalies and difficult airway management need to be anticipated. Optimize nutrition and provide adequate vitamin D and calcium. The outcome following keratoplasty for corneal opacification varies. Dental care to prevent cavities and orthodontic management as needed. Hearing loss is often treated initially with ventilation tubes and later with hearing aids. School accommodations as needed to prevent physical injury. Surveillance: For all individuals: physical examination at least every six months. Annual assessment of: pain severity; disease burden including quality of life and activities of daily living, endurance tests to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems; upper and lower extremities for functionality and malalignment, hips for dysplasia/subluxation, and thoracolumbar spine for kyphosis. Neurologic examination every six months to assess for spinal cord compression; yearly whole-spine MRI in neutral position and cervical spine flexion-extension MRI if the results are inconclusive; spine radiographs every two to three years. Annual assessment of heart rate; electrocardiogram and echocardiogram every one to three years depending on disease course. Polysomnography every three years to assess for obstructive sleep apnea; annual pulmonary function in children older than age five years until growth stops, then every two to three years. Monitor nutritional status using MPS IVA-specific growth charts. Perform vision and eye exam at least annually, dental evaluation every six to 12 months, and annual audiogram. For those on enzyme replacement therapy: annual assessment of pain, disease burden parameters, and pulmonary function tests; urine keratan sulfate or total glycosaminoglycans every six months. Agents/circumstances to avoid: Excessive weight gain; beta blockers. Genetic counseling MPS IVA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GALNS pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GALNS pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Mucopolysaccharidosis Type IVA

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype–phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.

/pdf/morquio-a-syndrome-associated-mutations-a-review-of-3751k4m23y.pdf

April B. Ryles

Papers

Morquio A Syndrome-Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus-Specific Database