William G. Mackenzie

Mucopolysaccharidosis Type IVA (Morquio A Disease): Clinical Review and Current Treatment: A Special Review

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio A, is a rare, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), which catalyzes a step in the catabolism of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). It leads to accumulation of the KS and C6S, mainly in bone and cornea, causing a systemic skeletal chondrodysplasia. MPS IVA has a variable age of onset and variable rate of progression. Common presenting features include elevation of urinary and blood KS, marked short stature, hypoplasia of the odontoid process, pectus carinatum, kyphoscoliosis, genu valgum, laxity of joints and corneal clouding; however there is no central nervous system impairment. Generally, MPS IVA patients with a severe form do not survive beyond the third decade of life whereas those patients with an attenuated form may survive over 70 years. There has been no effective therapy for MPS IVA, and care has been palliative. Enzyme replacement therapy (ERT) and hematopoietic stem cell therapy (HSCT) have emerged as a treatment for mucopolysaccharidoses disorders, including Morquio A disease. This review provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA and describes potential perspectives of ERT and HSCT. The issue of treating very young patients is also discussed.

An independent assessment of two clubfoot-classification systems.

We conducted an independent assessment of two clubfoot-classification systems. In a blinded trial, two orthopaedists scored 55 feet by using the classification systems developed by Pirani et al. and by Dimeglio et al. Thirty-seven of the feet were also scored by a physical therapist. By using the 10-point classification described by Pirani, the two physician examiners tallied total scores that were within one point of one another 89% of the time. The mean difference between the scores assigned by the two examiners was 0.6 points. For the 20-point classification described by Dimeglio et al., total scores tallied by the two physician examiners were within two points of one another 91% of the time. The mean difference between the scores assigned by the two physician examiners was 1.4 points. Correlation coefficients were 0.90 (p = 0.0001) for the Pirani classification, and 0.83 (p = 0.0001) for the Dimeglio classification. Correlation coefficients were much lower for the first 15 feet scored and were also lower when the therapists scores were included. Overall, both classification systems had very good interobserver reliability after the initial learning phase.

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed.

Pathogenesis of Morquio A syndrome: An autopsied case reveals systemic storage disorder

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase, which results in systemic accumulation of glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. Accumulation of these GAGs causes characteristic features as disproportionate dwarfism associated with skeletal deformities, genu valgum, pigeon chest, joint laxity, and kyphoscoliosis. However, the pathological mechanism of systemic skeletal dysplasia and involvement of other tissues remain unanswered in the paucity of availability of an autopsied case and successive systemic analyses of multiple tissues. We report here a 20-year-old male autopsied case with MPS IVA, who developed characteristic skeletal features by the age of 1.5 years and died of acute respiratory distress syndrome five days later after occipito-C1-C2 cervical fusion. We pathohistologically analyzed postmortem tissues including trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae. The postmortem tissues relevant with clinical findings demonstrated 1) systemic storage materials in multiple tissues beyond cartilage, 2) severely vacuolated and ballooned chondrocytes in trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification, 3) appearance of foam cells and macrophages in lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow, and 4) storage of chondrotin-6-sulfate in aorta. This is the first autopsied case with MPS IVA whose multiple tissues have been analyzed pathohistologically and these pathological findings should provide a new insight into pathogenesis of MPS IVA.

International guidelines for the management and treatment of Morquio A syndrome.

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non‐skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom‐based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome.

Anesthetic care and perioperative complications of children with Morquio syndrome.

Objectives:  Our objective was to make recommendations based on our experience and findings from this study regarding the anesthetic care of children with Morquio syndrome (MS). We emphasize information not readily available in the Anesthesiology literature.

Objective evaluation of knee laxity in children.

This study was designed to measure objectively knee laxity in children. Physical examination and the KT 1000 arthrometer were used to test the knee laxity of 150 healthy, uninjured children between 6 and 18 years of age. Data from the knee examinations and the KT 1000 measurements were compared and statistically analyzed to determine the change in knee laxity with age, laxity differences between boys and girls, and the correlation between the KT1000 measurements and subjective tests for laxity described by Carter and Wilkinson. There was no statistical difference in knee laxity between boys and girls of similar ages. We found that knee laxity, determined by measuring the millimeters of tibial translation using the KT 1000 arthrometer, was significantly greater in younger children.

Severe Tibial Growth Retardation in Total Fibular Hemimelia After Limb Lengthening

Seven patients with total fibular hemimelia who underwent limb-lengthening procedures prior to skeletal maturity were evaluated for tibial and femoral growth after lengthening. The average preoperative follow-up was 6.5 years and all patients were followed to skeletal maturity. Thirteen segments (eight tibiae and five femora) were lengthened by three methods (Wagner, Ilizarov, and modified Ilizarov). The average preoperative limb-length discrepancy was 9.7 cm, and the average projected limb-length discrepancy at skeletal maturity was 12.5 cm. The average tibial lengthening was 6.7 cm (range, 5.3-10) with an average percentage of lengthening of 26% (range, 19-40%). The average postoperative growth rate of the tibia was 80% (range, 70-100%) and of the femur, 83% (range, 70-90%) of the normal side. Five tibiae showed a decrease in the average preoperative growth rate from 82.5% (range, 70-100%) to 39% (range, 26-54%) of the normal side. Two tibiae had no longitudinal growth after lengthening. The average postoperative growth rate of the femur decreased from 83% (range, 70-90%) to 61% (range, 26-125%). In one patient there was an increase in the rate of growth of the femur. These findings suggest that limb lengthening in skeletally immature children with total fibular hemimelia results in severe growth retardation of the tibia after lengthening. The subsequent growth of the tibia after lengthening in patients with total fibular hemimelia is unpredictable.

Femoral forces during limb lengthening in children.

A system was designed to measure forces during femoral lengthening using force transducers on an Ilizarov femoral frame. Measurements were made in three teenaged subjects overnight and during weight bearing. A progressive increase in axial load secondary to distraction was seen, forces peaking at 428, 447, and 673 N for the three subjects. Little change in force transmitted by the frame was observed during weight bearing. Measurements taken before and after each individual lengthening showed no change in axial force or bending moment (p > 0.01). A diurnal variation of axial load was found (p < 0.01). Forces at midnight were greater than in the morning in all the subjects, with a mean difference of 113 N (p < 0.01). Distraction forces measured in the femur during distraction are greater than those previously measured in the tibia. Evidence exists that the callus is stiff and may be the origin of these forces.

Mucopolysaccharidosis IVA: Correlation between genotype, phenotype and keratan sulfate levels

Mucopolysaccharidosis IVA (MPS IVA) is caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to systemic skeletal dysplasia because of excessive storage of keratan sulfate (KS) in chondrocytes. In an effort to determine a precise prognosis and personalized treatment, we aim to characterize clinical, biochemical, and molecular findings in MPS IVA patients, and to seek correlations between genotype, phenotype, and blood and urine KS levels. Mutation screening of GALNS gene was performed in 55 MPS IVA patients (severe: 36, attenuated: 13, undefined: 6) by genomic PCR followed by direct sequence analysis. Plasma and urine KS levels were measured by ELISA method. Genotype/phenotype/KS correlations were assessed when data were available. Fifty-three different mutations including 19 novel ones (41 missense, 2 nonsense, 4 small deletions, 1 insertion, and 5 splice-site) were identified in 55 patients and accounted for 93.6% of the analyzed mutant alleles. Thirty-nine mutations were associated with a severe phenotype and ten mutations with an attenuated one. Blood and urine KS concentrations in MPS IVA patients were age-dependent and markedly higher than those in age-matched normal controls. Plasma and urine KS levels in MPS IVA patients with the severe phenotype were higher than in those with an attenuated form. This study provides evidence for extensive allelic heterogeneity of MPS IVA. Accumulation of mutations as well as clinical descriptions and KS levels allows us to predict clinical severity more precisely and should be used for evaluation of responses to potential treatment options.