Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex.

Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual ß-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis.

Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model.

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-ß-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0-7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.

Molecular genetic assay of mucopolysaccharidosis IVA in South China.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Molecular mutational analysis was performed by PCR product sequencing for fourteen exons and exon-intron boundaries of GALNS gene in 21 patients from 19 unrelated families with severe MPS IVA in South China. We identified fifteen different mutations, including 10 reported mutations (p.P125L, p.G290S, p.M318R, p.G340D, p.L366P, p.R386C, p.A392V, c.1243-1G>C, p.L440RfsX54 and p.X523E) and five novel mutations (p.N177S, p.G290R, p.F306S, p.W403_T404delinsCS, p.W520X). All five novel mutations were inherited from parents of the patients and not found in 100 normal control alleles. Three mutations, p.M318R, p.L366P and p.R386C were common, accounting for 36.8% of mutant alleles investigated. One patient homozygous of p.A392V and the other two unrelated patients homozygous of p.L366P presented classical disease course. The results show that the GALNS gene has a different mutational spectrum in South China as compared to other regions. The p.A392V and p.L366P mutations were associated with severe phenotype of MPS IVA.

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.

Morquio disease: the role of cartilage canals in the pathogenesis of chondrogenic dwarfism.

Chondrogenic dwarfism in Morquio disease (mucopolysaccharidosis IV) has been suggested to be strongly linked to the abnormal lysosomal storage of cartilaginous extracellular matrix waste products within chondrocytes and fibroblasts. The specific genetic defects of enzymes of the keratan sulfate and chondroitin-6-sulfate metabolism have been detected at the molecular level and importantly contributed to the current knowledge on the phenotype of this rare metabolic disorder. However, the pathogenesis of this epiphyseal centered progressive skeletal disease does not seem to be fully explained by the dysfunction of the chondrocyte cytoplasm that presents with vacuolar changes in adult patients. I propose that the accumulation of extracellular matrix degradation product-laden macrophages within epiphyseal cartilage canals during the early postnatal period causes dysregulation in the synchronized process of the neoformation and resorption of the maturing radial growing epiphyses. Similarly, the resorption of pannus tissue following the microtraumatisation of weight-bearing joints and epiphysis-type bones becomes impacted. If the hypothesis is valid, the early pathogenesis in Morquio disease could be because of the inadequate regression of cartilage canals and impaired resorption and restitution of pannus tissue.

Mucopolisacaridosis tipo IV-B. A propósito de un caso / Mucopolysacharidosis type IV-B. A case report

Debido a la deficiencia de las enzimas encargadas de hidrolizar los glicoaminoglicanos intralisosomales se producen las mucopolisacaridosis como errores innatos del metabolismo. Se presenta el caso de un varón de 8 años de edad que fuera hospitalizado por bronconeumonía a germen desconocido – de la comunidad- en estado grave, que exhibía rasgos fenotípicos evocadores del síndrome de Morquio: patrón dismórfico facial, baja talla, máculas hipocrómicas diseminadas por toda la economía y hábito esquelético típico. Diagnóstico que se confirmó bioquímicamente por la ausencia de la enzima β-galactosidasa. Se exponen puntos de vista respecto al particular y se contrasta con la literatura sobre la entidad (AU)

Owing to the deficiency of enzymes responsible of intralysosomal hydrolysis of glycosaminoglycans are produced the mucopolysaccharidosis as inherited metabolic disorders. We repot the case of 8 years old male, who was hospitalized by severe community-acquired bronchopneumonia caused by unknown germ and shown phenotypical pattern of Morquio syndrome: dysmorphic facial pattern, hypochromic spots throughout the economy, short stature and typical skeletal habitus. The diagnose was biochemicaly confirmed by lack of β-galactosidase enzyme. Points of view regarding to the illness are commented taking into account the literature (AU)

Conferencia: En el Centenario de las dos primeras contribuciones latinoamericanas originales a la medicina universal: Enfermedad de Ayerza y Enfermedad de Morquio II / Conference: In the centenary of the two first original Latin American contributions to the universal medicine: Ayerzas disease and Morquio II disease

En el centenario (1901-2001) de las descripciones princeps de las dos primeras contribuciones originales latinoamericanas a la medicina universal se recuerda la hecha por Abel Ayerza (1861-1918) de los Cardíacos negros o Enfermedad de Ayerza. Se hace una breve síntesis de la historia de la individualización de dicha entidad dando las características esenciales del síndrome. A continuación se recuerda la descripción por Luis Morquio (1868-1935) del Bloqueo aurículoventricular completo congénito y familiar o Enfermedad de Morquio II. Se hace una síntesis de su individualización, su herencia autosómica dominante, su variedad etiológica, así como la historia de uno de los primeros casos descritos con implantación de marcapaso permanente con total éxito y excelente evolución hasta hoy. (AU)

Immunohistochemical localization of keratan sulfate in the chinchilla inner ear.

Keratan sulfate (KS) was immunolocalized in the chinchilla cochlea and vestibular system using indirect immunohistochemistry and a monoclonal antibody (clone 5-D-4) directed against a proteoglycan core antigen. As a positive control, anti-KS Mab reactivity was found in the pericellular matrix and lacuna walls of temporal bone osteocytes. In the cochlea, anti-KS Mab reactivity was abundant in the basal cell layer of the stria vascularis and in the marginal band and Hensen's stripe of the tectorial membrane. Less anti-KS Mab reactivity was present in the cover net, Hardesty's membrane and the upper fibrous zone of the limbal layer of the tectorial membrane. In the vestibular system, anti-KS Mab reactivity was immunolocalized to a portion of the epithelium overlying the cupula of the crista ampullaris, in the apical surface of crista ampullaris epithelium, crista ampullaris stereocilia and in the otoconia. Elucidating the distribution of KS in the cochlea will improve our understanding of cochlear anatomy and is a first step toward understanding the etiology of hearing loss observed in diseases involving KS metabolism, namely, mucopolysaccharidosis type IV (Morquio's syndrome).

Mucopolysaccharidosis IVA: four new exonic mutations in patients with N-acetylgalactosamine-6-sulfate sulfatase deficiency.

We report four new mutations in Japanese patients with mucopolysaccharidosis IVA (MPSIVA) who were heterozygous for a common double gene deletion. A nonsense mutation of CAG to TAG at codon 148 in exon 4 was identified, resulting in a change of Q to a stop codon and three missense mutations. V (GTC) to A (GCC) at codon 138 in exon 4, P (CCC) to S (TCC) at codon 151 in exon 5, and P (CCC) to L (CTC) at codon 151 in exon 5. Introduction of these mutations into the normal GALNS cDNA and transient expression in cultured fibroblasts resulted in a significant decrease in the enzyme activity. V138A and Q148X mutations result in changes of restriction site, which were analyzed by restriction-enzyme assay. P151S and P151L mutations that did not alter the restriction site were detected by direct sequencing or allele specific oligohybridization. Detection of the double gene deletion was initially done using Southern blots and was confirmed by PCR. Haplotypes were determined using seven polymorphisms to the GALNS locus in families with the double gene deletion. Haplotype analysis showed that the common double gene deletion occurred on a single haplotype, except for some variation in a VNTR-like polymorphism. This finding is consistent with a common founder for all individuals with this mutation.

[beta-galactosidosis--GM1 gangliosidosis and Morquio B disease].

beta-galactosidosis is a lysosomal storage disorder caused by a deficiency of acid beta-galactosidase, including to autosomal recessive diseases; GM1-gangliosidosis (neurovisceral form) and Morquio B disease (skeletal form). To date, 26 different mutations in the beta-galactosidase gene have been identified in patients with beta-galactosidosis from various ethnic groups. Transient expression of the mutant genes has confirmed that mutant enzymes responsible for infantile GM1-gangliosidosis have almost no detectable beta-galactosidase activity. But the other three forms (late infantile/juvenile, adult/chronic GM1-gangliosidosis and Morquio B disease) are characterized by specific mutant enzymes with significant residual enzyme activity. Heterogeneous patterns of post-translational processing and maturation in these mutant enzymes are closely related to the phenotypic variations in beta-galactosidosis.

Morquio syndrome (mucopolysaccharidosis IV B) associated with beta-galactosidase deficiency. Report of two cases.

Two male patients, aged 6 and 25, both with normal intelligence and absence of neurological abnormalities, exhibited dysostosis multiplex, dwarfism, odontoid anomalies, cloudy corneas, exessive excretion of keratan sulfate, and abnormal urinary oligosaccharides. Leukocytes and fibroblasts of both patients were deficient in acid beta-galactosidase (beta-gal) and normal in N-acetylgalactosamine-6-sulfate sulfatase, the deficient enzyme in classical Morquio syndrome. The beta-gal deficiency was not due to an endogenous inhibitor, and the parents exhibited intermediate activities. Deficient beta-gal activity was observed toward p-nitrophenyl-beta-galactoside, 4-methylumbelliferyl-beta-galactoside (4 MU-beta-gal), lactose, GM1 ganglioside, keratan sulfate, and asialofetuin (ASF). Under standard assay conditions, the residual activity was similar for all substrates tested. Toward p-nitrophenyl-beta-glactoside, the mutant enzyme behaved as a Km variant.