Clinical characteristics of 111 cases with mucopolysaccharidosis ⅣA / 中华儿科杂志

Objective: To analyze the clinical characteristics of patients with Mucopolysaccharidosis ⅣA (MPS ⅣA). Methods: A retrospective study was conducted on 111 patients with MPS ⅣA in Xinhua Hospital of Shanghai Jiao Tong University School of Medcine from December 2008 to August 2020, confirmed by enzyme activity and genetic testing. General situation, clinical manifestations and enzyme activity test results were analyzed. According to the clinical manifestations, it can be divided into severe, intermediate and mild group. The independent sample t test was used to compare the birth body length and weight of children with that of normal boys and girls, and group comparisons of enzyme activities were evaluated by median test. Results: One hundred and eleven unrelated patients, 69 males and 42 females, were classified into 3 subtypes: severe (n=85), intermediate (n=14), and mild (n=12). The age at symptom onset were 1.6 (1.0, 3.0) years, and at diagnosis were 4.3 (2.8, 7.8) years. Skeletal manifestations were observed in all patients and consisted mainly of pectus carinatum (96/111, 86.5%), motor dysfunction (78/111, 70.3%), spinal deformity (71/111, 64.0%), growth retardation (64/111, 57.7%), joint laxity (63/111, 56.8%) and genu valgum (62/111, 55.9%). Eighty-eight patients (88/111, 79.3%) with MPS ⅣA were also along with non-skeletal manifestations, mainly including snoring (38/111, 34.2%), coarse faces (34/111, 30.6%), and visual impairment (26/111, 23.4%). The most common skeletal manifestation was pectus carinatum (79 cases), and non-skeletal manifestation was snoring (30 cases) and coarse faces (30 cases) in severe patients, pectus carinatum (13 cases) and snoring (5 cases) in intermediate type, motor dysfunction (11 cases) and snoring (3 cases) and visual impairment (3 cases) in mild patients. The height and weight of severe patients began to fall below -2 s at 2-<5 years and 5-<7 years, respectively. At the age of 10-<15 years, the standard deviation score of the height of severe patients reached (-6.2±1.6) s in males and (-6.4±1.2) s in females, and the score of weight got (-3.0±1.1) s in males and (-3.5±0.5) s in females. The height of intermediate patients began to fall below -2 s at the age of 7-<10 years, and the standard deviation score of height were -4.6 s and -3.6 s in 2 males, and -4.6 s and -3.8 s in 2 females at the age of 10-<15 years. The weight remained within -2 s in 72.0% (18/25) of intermediate patients compared to age-matched healthy children. In the mild patients with MPS ⅣA, the mean standard deviation score of height and weight was within -2 s. The enzyme activities of mild patients (2.02 (1.05, 8.20) nmol/(17 h·mg)) were both significantly higher than that of intermediate (0.57 (0.47, 0.94) nmol/(17 h·mg)) and severe (0.22 (0, 0.59) nmol/(17 h·mg)) patients (Z=9.91, 13.98, P=0.005, 0.001), and the enzyme activity of intermediate patients was significantly higher than that of severe patients (Z=8.56, P=0.010). Conclusions: The clinical manifestations of MPS ⅣA are charactered by pectus carinatum, motor function impairment, spinal deformity and growth retardation. The clinical characteristics, growth rate and enzyme activity differ among the 3 subtypes of MPS ⅣA.

Manejo anestésico de una gestante con síndrome de Morquio / Anesthetic Management for a pregnant woman with Morquio syndrome Sobre los autores:

Introducción: El síndrome de Morquio es una enfermedad hereditaria autosómica recesiva con distintos grados de afectación al metabolismo de los glúcidos, lo que genera incapacidad para romper los enlaces de las cadenas largas de glucosamiglicanos, esto provoca acumulación de mucopolisacáridos en distintos tejidos del cuerpo humano. Objetivo: Describir el manejo anestésico de una gestante con síndrome de Morquio. Presentación del caso: Gestante primigesta de 30 años de edad, de raza negra, de 103 cm de estatura y 33 Kg de peso. Acude a consulta preoperatoria por presentar embarazo a término, baja talla y se realizó interrupción del embarazo por vía alta. Se procede a la valoración preanestésica donde se recoge antecedentes de enfermedad genética e ingreso previo por presentar cifras elevadas de tensión arterial. La paciente padecía de alergia a la dipirona. Conclusiones: Los pacientes con mucopolisacaridosis tienen una alta incidencia de dificultad para la ventilación y la intubación endotraqueal asociada con insuficiencia cardiopulmonar. La afectación de la columna presenta dificultades adicionales para los anestesiólogos. Cualquier cirugía electiva requiere una evaluación preoperatoria de los factores de riesgo anestesiológicos y la disponibilidad de un espectro de equipos para el manejo de las vías respiratorias. La anestesia debe ser realizada por un equipo con experiencia en el manejo de la vía aérea(AU)

Introduction: Morquio syndrome is an autosomal recessive hereditary disease that affects, to different extents, carbohydrate metabolism, which obstructs the ability to break bonds of long chains of glycosaminoglycans, causing mucopolysaccharides accumulation in different tissues of the human body. Objective: To describe the anesthetic management of a pregnant woman with Morquio syndrome. Case presentation: This is the case of a 30-year-old primigravid pregnant woman, of black skin, 103 cm of height and 33 kg of weight. She came for preoperative consultation because she was pregnant at term and had low body size; the pregnancy was terminated through the abdominal route. A preanesthetic assessment was performed, which permitted to observe a history of genetic disease and previous admission for high blood pressure. The patient was allergic to dipyrone. Conclusions: Among patients with mucopolysaccharidosis, there is a high incidence of difficulty for ventilation and endotracheal intubation associated with cardiopulmonary insufficiency. Spinal involvement represents additional difficulties for anesthesiologists. Any elective surgery requires preoperative assessment of anesthesiologic risk factors and the availability of a spectrum of airway management equipment. Anesthetic managment should be performed by a team experienced in airway management(AU)

Evaluación neuropsicológica de un adulto colombiano diagnosticado con Síndrome de Morquio B / Neuropsychological assessment of a Colombian adult diagnosed with Morquio B Syndrome

Resumen El síndrome de Morquio B es una enfermedad rara y de baja prevalencia, por lo cual poco se ha estudiado sobre el funcionamiento neuropsicológico y estado cognitivo de quienes lo padecen. Este estudio de caso presenta los resultados del funcionamiento en atención, memoria, lenguaje, gnosias, praxias y funciones ejecutivas de un adulto colombiano diagnosticado con este síndrome. Se encontró que el paciente puede adquirir nuevo conocimiento; muestra memoria visoespacial y de trabajo verbal conservadas; repite, lee y escribe información sencilla que es conocida para él; sigue órdenes simples a partir de comandos verbales; muestra habilidades viso perceptuales y grafomotoras; tiene un desarrollo normal de pensamiento abstracto y asociativo, y es capaz de planear y solucionar problemas. Sin embargo, presenta dificultades en atención visual sostenida, atención audio-verbal, velocidad de procesamiento, lenguaje comprensivo, repetición y escritura al dictado de frases completas, flexibilidad cognitiva, y fluidez verbal semántica y fonológica. Se discute como factores más relevantes del funcionamiento cognitivo del paciente la relación entre el síndrome de Morquio B y la gangliosidosis GM1, y la falta de entrenamiento en el manejo de información de alta complejidad, dada su condición de desescolarización.

Abstract Since Morquio B syndrome is a low-prevalence rare disease, scarce evidence about neuropsychological functioning and cognitive status in diagnosed people is known. This case study shows the results of functioning in attention, memory, language, gnosias, praxias, and executive functions in a Colombian man diagnosed with this syndrome. It was found that the patient is capable of acquiring new information and exhibits preserved visuospatial and verbal working memory; he is also able to repeat, read and write simple information as long as it is familiar to him, and is capable of following simple verbal instructions with no difficulty; moreover, he displays preserved visuospatial and graphomotor abilities, has a normal development of abstract and associative thinking, and is able to plan and solve problems. Nonetheless, he exhibits difficulties in audio-verbal and sustained visual attention, as well as in processing speed, comprehensive language, repetition and writing of complete phrases, cognitive flexibility, and semantic and phonological verbal fluency. It is discussed the association between Morquio B syndrome and gangliosidosis GM1 as well as the lack of training in the management of highly complex information due to unschooling of this patient as the two most relevant factors of his cognitive functioning.

Síndrome de Morquio, enfermedad de interés para la odontopediatría: presentación de un caso / Morquio syndrome, a disease of interest for pediatric dentistry: case report

El Síndrome de Morquio es un trastorno de almacenamiento de mucopolisacáridos se caracteriza principalmente por estatura corta y afectación ósea grave, pero el coeficiente intelectual es normal. La prevalencia es rara se estima que afecta a uno de cada 200.000 nacimientos hombres y mujeres por igual. La MPS IV A y B son enfermedades autosómicas recesivas con esto queremos decir que ambos progenitores son portadores del mismo gen afectado el cual se encuentra alterado produciendo así una deficiencia en la producción de la enzima. Las manifestaciones esqueléticas en esta displasia son retardo en el crecimiento, hipoplasia del odontoides, cifosis toracolumbar, displasia de cadera, genu valgo, manchas cutáneas y laxitud articular, en cuando a cuestiones dentales tenemos: el esmalte es delgado, rugoso e hipoplásico afectando dientes deciduos como permanentes. Se presenta el caso de un paciente masculino de 8 años 3/12 presentando MPS el cual requiere un protocolo de rehabilitación lo cual se realiza en el área de odontopedriatría del Hospital del Niño DIF.

Morquio syndrome is a mucopolysaccharide storage disorder is mainly characterized by short stature, severe bone involvement, but IQ is normal. The prevalence is rare is estimated to affect one in every 200,000 births men and women alike. The MPS IV A and B are autosomal recessive diseases with this we mean that both parents are carriers of the same gene affected which is altered thus producing a deficiency in the production of the enzyme. The skeletal manifestations in this dysplasia are growth retardation, hypoplasia of the odontoid, thoracolumbar kyphosis, hip dysplasia, genu valgus, skin blemishes and joint laxity, then dental issues are: the enamel is thin rugged and hypoplastic affecting deciduous theeth as permanent. The case of a male patient presenting eight years 3/12 MPS which requires a rehabilitation protocol which is done in the dental area of Hospital del Niño DIF is presented.

Enfermedad de Morquio en un niño / Morquio disease in a child

Se presenta el caso clínico de un niño de 8 años de edad, con antecedentes de infecciones respiratorias repetidas, atendido en el centro de salud de Archidona hacía 4 años, y desde aquí fue remitido hacia el hospital de la ciudad de Tena, donde le indicaron algunos exámenes complementarios que no concluyeron el diagnóstico. Posteriormente fue trasladado al Hospital Pediátrico Baca Ortiz y los resultados de los exámenes efectuados, como pruebas enzimáticas y el análisis cromosómico o cariotipo, confirmaron el diagnóstico de enfermedad de Morquio. Se dieron orientaciones generales, se indicó tratamiento sintomático y fisioterapia en el área de salud; asimismo, se brindó asesoramiento genético a la madre

The case report of an 8 years boy with history of repeated breathing infections is presented. He was assisted 4 years ago in the health center of Archidona, and he was referred to the hospital of Tena city, where some complementary exams that didn't conclude the diagnosis were indicated. Later on he was transferred to Baca Ortiz Pediatric Hospital and the results of the exams, as enzymatic tests and the chromosomal analysis or cariotype, confirmed the diagnosis of Morquio disease. Some general orientations were given, symptomatic treatment and physiotherapy in the health area was indicated; also, a genetic advice was offered to the mother

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.

Analysis of clinical features and GALNS gene mutation in a patient with mucopolysaccharidosis type IV A / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect potential mutation of galactosamine-6-sulfate (GALNS) gene in a Chinese girl affected with mucopolysaccharidosis type IV A (Morquio A syndrome).</p><p><b>METHODS</b>The patient was diagnosed by assaying the activities of mucopolysaccharidosis-related enzymes in leukocytes. Potential mutation in the GALNS gene was detected with PCR and Sanger sequencing.</p><p><b>RESULTS</b>The patient was characterized by short stature, skeletal deformities, normal intelligence, and auditory dysfunction. The activities of GALNS enzymes were low. A compound heterozygous missense mutation, c.1094G>T (p.Gly365Val)/c.938C>T (p.Thr313Met), was detected in the GALNS gene. The mutations were respectively inherited from her father and mother. Among them, the c.1094G>T (p.Gly365Val) mutation was not reported previously.</p><p><b>CONCLUSION</b>The mutations c.1094G>T (p.Gly365Val)/c.938C>T (p.Thr313Met) probably underlie the pathogenesis of the disease in our patient.</p>

Albuminuria en paciente con Enfermedad de Morquio Tipo A. Reporte de un caso / Albuminuria in patient with MorquioÆs disease Type A. A case report

La Enfermedad de Morquio (MPS IV-A) es producida por dos defectos enzimáticos diferentes. Desde que la terapia de sustitución enzimática (TSE) se encuentra disponible para algunas EDL y en desarrollo para otras, este grupo de patologías han despertado un gran interés en la comunidad científica debido a que la misma parecería una alternativa terapéutica prometedora para cambiar el curso evolutivo de los pacientes afectados. Se presenta un caso con presencia de albuminuria

Morquio's disease (MPS IV-A) is produced by two different enzymatic defects. Since enzymatic replacement therapy (ERT) is available for some LDD and others under development, this group of diseases have created great interest within the scientific community due to the fact that promising therapeutic alternative will be available to change disese course of affected patient. We present a case with albuminuria.

Cuantificación de actividad enzimática en leucocitos para el diagnóstico de mucopolisacaridosis tipo II y tipo IVA / Quantification of enzymatic activity in leukocytes for the diagnosis of mucopolysaccharidosis type II and type IVA

INTRODUCCIÓN: La mucopolisacaridosis tipo II y tipo IVA son enfermedades causadas por la deficiencia de las enzimas iduronato 2 sulfato sulfatasa y galactosamina 6 sulfato sulfatasa respectivamente. El depósito resultante de glucosaminoglicanos produce manifestaciones clínicas variadas. Aunque se han propuesto varias alternativas diagnósticas, tales como el examen físico, la cuantificación de glucosaminoglicanos en orina y la cuantificación de la actividad enzimática en leucocitos, la utilidad diagnóstica de esta última no ha sido estudiada en la práctica clínica rutinaria. La posibilidad de ofrecer terapia de reemplazo enzimático a estos pacientes obliga a evaluar la utilidad de la cuantificación de actividad enzimática para confirmar el diagnóstico de estas entidades. OBJETIVO: Evaluar la utilidad diagnóstica de la cuantificación de actividad enzimática de la iduronato 2 sulfato sulfatasa en leucocitos para la confirmación diagnóstica de la MPS tipo II y la galactosamina 6 sulfato sulfatasa en leucocitos para la confirmación diagnóstica de la MPS tipo IVA. Esta revisión no contempla la evaluación de la utilidad diagnóstica del examen físico, glucosaminoglicanos en orina o pruebas moleculares. METODOLOGÍA: Se realizó una búsqueda de las revisiones panorámicas y sistemáticas de los últimos cinco años y estudios de validez diagnóstica, cohortes descriptivas y series de casos sin límite de fecha en MEDLINE, EMBASE, Cochrane, DARE, LILACS y Google. Los artículos debían estar en texto completo, en inglés o español. Se excluyeron artículos que describieran mutaciones o manifestaciones clínicas de un sistema u órgano específico. Los estudios con criterios de elegibilidad fueron evaluados por dos revisores independientes. A los estudios incluidos se extrajo información sociodemográfica, clínica y métodos diagnósticos empleados. RESULTADOS: No se encontró ninguna revisión panorámica, sistemática o estudio de validez diagnóstica para MPS tipo II o IVA. Se incluyeron 3 estudios de serie de casos para MPS tipo II y 13 series de casos para MPS tipo IVA. El 100% de los estudios de MPS tipo II incluyeron la cuantificación enzimática como prueba confirmatoria. El 63.6% (7/11) de las series de casos de MPS tipo IVA incluyeron la cuantificación enzimática en leucocitos como prueba confirmatoria, el 18.1% (2/11) no la incluyeron por falta de disponibilidad de la tecnología y el otro 18.1% (2/11) por publicación del artículo antes de la fecha de introducción de la tecnología. CONCLUSIONES: La cuantificación de la actividad enzimática de la iduronato 2 sulfato sulfatasa y la galactosamina 6 sulfato sulfatasa en leucocitos representa una tecnología diagnóstica útil para confirmar MPS tipo II y MPS tipo IVA respectivamente en pacientes con sospecha clínica de dichas entidades.(AU)

A typical presentation of mucopolysaccharidosis. Morquio's syndrome [type IV-B]: a morbid entity

Mucopolysaccharidosis [MPS] are a group of metabolic disorders of the lysosomal storage disease family caused by the absence or malfunctioning of lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to abnormal accumulation of heparan sulfate, dermatan sulfate, and keratan sulfate. Morquio's syndrome is a rare autosomal-recessive mucopolysaccharidosis. This syndrome is characterized by a reduced activity of N-acetylgalactosamine-6-sulfate-sulfatase [type A], or beta-galactosidase [type B]. This deficiency leads to a lysosomal storage disease with accumulation of keratan sulfate and chondroitin-6-sulfate in connective tissue, skeletal system and teeth. The general phenotype includes coarse facies, corneal clouding, hepatosplenomegaly, joint stiffness, hernias, dysostosis multiplex, lower limb alignment problems, mucopolysaccharides excretion in the urine and metachromatic staining in peripheral leukocytes and bone marrow. Consequently, aortic valvular disease, gastrointestinal disease and dental abnormalities occur. Clinical manifestations of mucopolysaccharidosis depend on the type of disease. We report a case of morquio's syndrome in a child, solely diagnosed on the basis of history and physical examination of the case reported. The clinical features and complications of the case and review of the literature are discussed

Presentación de un caso clínico de mucopolisacaridosis Tipo IV, síndrome de Morquio / Presentation of a clinical case of mucopolysaccharidosis type IV, Morquio syndrome

Se presenta el caso de un paciente de 16 años de edad, con el diagnostico de mucopolisacaridosis (MPS) tipo IV-A, con una breve revisión teórica del curso y progresión crónica de esta enfermedad multi-sistémica, que se manifiesta con amplia signo sintomatología, hallazgos de laboratorio y anomalías radiológicas. El objetivo es documentar el caso y difundir a la comunidad médica boliviana, la importancia de los errores innatos del metabolismo, consideradas enfermedades "raras", que a criterio nuestro, sufren un sub-diagnóstico debido a las pocas publicaciones científicas sobre el tema en el medio.

We report the case of a patient 16 years old with a diagnosis of mucopolysaccharidosis (MPS) type IV- A, with a brief theoretical review of chronic course and progression of this multisystem disease, which manifests with extensive signs symptoms, findings are presented, with laboratory and radiological reported abnormalities. The aim is to document the event and communicated to Bolivian medical community, the importance of inborn errors of metabolism, considered "rare" diseases, which in our opinion; suffer a sub- diagnosis because of the few Bolivian scientific publications on the topic.

The Burden Endured by Caregivers of Patients With Morquio A Syndrome: Results From an International Patient-Reported Outcomes Survey

Abstract This international survey performed by direct personal interview or mail evaluated the global burden among primary caregivers of patients with Morquio A syndrome. Collected outcomes included self-reported time spent on caregiving, proportion of daily activities (from the Mucopolysaccharidosis Health Assessment Questionnaire) requiring caregiver assistance, and how the patient's age and wheelchair use affect these. In addition, the impact of caregiving on the caregivers' relationship with family and friends, physical and mental health, and employment status and income was evaluated. Caregiver burden increased with disease progression. Adult patients always using a wheelchair required substantially more caregiving time and complete assistance with a larger proportion of daily activities than more mobile patients. In children, this was less apparent. Caregivers suffered physically and emotionally and their family and social life and financial situation were considerably impacted. Improvements in patient mobility may substantially reduce the level of caregiver support and the burden of caregiving.

Caracterización clínica, estudios genéticos, y manejo de la Mucopolisacaridosis tipo IV A / Mucopolysaccharidosis type IV A (Morquio Syndrome type A): clinical features, genetic studies, preventive management of complications and genetic counseling

Introducción: la Mucopolisacaridosis tipo IV A (OMIM #253000), es una enfermedad autosómica recesiva que pertenece al grupo de enfermedades de depósito lisosomal, esta fue descrita inicialmente por Luis Morquio, cuya etiología es la deficiencia de la enzima N-acetil-galactosamina-6-sulfato sulfatasa, favoreciendo el depósito intracelular de queratán sulfato y condroitin-6-sulfato, llevando al espectro de manifestaciones clínicas que caracterizan este síndrome como son: baja talla, anormalidades vertebrales, opacidades corneales, inteligencia conservada, entre otras. Mediante radiografía de tórax y de extremidades inferiores se pueden observar las vértebras ovoides o en cuña y alteraciones en huesos largos, respectivamente. Objetivo: revisar sobre las generalidades de la MPS IV A, sus características clínicas, complicaciones, los estudios genéticos, la asesoría genética y su manejo preventivo. Conclusiones: las pruebas de laboratorio como el test de cloruro de cetilpiridinio o la albúmina ácida son esenciales para el diagnóstico. En cuanto al tratamiento hasta la fecha no existe una terapia de reemplazo enzimático por ello los cuidados son preventivos, y el manejo de estas personas debe ser interdisciplinario (medicina, nutrición, psicología, entre otros).

Background: mucopolysaccharidosis IV A (OMIM # 253000), belongs to the group of lysosomal storage diseases, this was first described by Luis Morquio, whose etiology is a deficiency of the enzyme N-acetylgalactosamine-6-sulfate sulfatase, favoring the deposit intracellular queratán sulfate and chondroitin-6-sulfate, leading to the spectrum of clinical manifestations that characterize this syndrome are short stature, vertebral abnormalities, corneal opacities, preserved intelligence, among others. X-ray can see the vertebrae ovoid or wedge, and alterations in long bones. Objetive: make a general overview of MPS IV A, its clinical features, complications, genetic testing, genetic counseling and preventive management. Conclusions: laboratory tests as test test cetylpyridinium chloride or acid albumin essential for diagnosis. As for treatment to date there is no enzyme replacement therapy are therefore preventive care, and management of these people should be interdisciplinary (medicine, nutrition, psychology, etc.).

Analysis of GALNS gene mutation in thirty-eight Chinese patients with mucopolysaccharidosis type IVA / 中华儿科杂志

<p><b>OBJECTIVE</b>Mucopolysaccharidosis (MPS) type IVA (MPS IVA) is an autosomal recessive lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) needed to degrade glycosaminoglycanes (GAGs), accumulation of GAGs in the tissue resulting in disorder of function. So far, the small number of articles about clinical study of Chinese MPS IVA were published and only one paper about gene mutation analysis was published. This study aimed to investigate the mutation spectrum and characteristic of GALNS gene in Chinese patients with MPS IVA who were diagnosed in our hospital.</p><p><b>METHOD</b>Thirty-eight patients from 36 families (male 17, female 21) were diagnosed as MPS IVA by GALNS activity determination [(0.85 ± 1.33) nmol/(17 h·mg)] and clinical symptoms during 2006-2012. The average age of diagnosis was (5.7 ± 3.6) years. Mutation analysis of GALNS gene performed performed by PCR-direct DNA sequencing for 38 patients. PCR-restriction fragment length polymorphism analysis was used for validating novel mutation, and also to assess amino acid conservation for novel missense variants in five different species. PolyPhen-2 tool was used to predict the possible impact of missense mutations on the structure and function of the human GALNS protein, etc. Analysis of GALNS activity and gene mutation in amniotic fluid were performed to provide the prenatal diagnosis for some families with MPS type IVA.</p><p><b>RESULT</b>(1) Thirty-eight kinds of mutation in GALNS gene were identified in 38 patients of them, 71% were missense mutations. p. M318R was a hot-spot mutation (21%) tested. Five kinds of mutation i.e., p. P163H, p.G168L, p. A324E, p. L366P and p. F452L were only found in Chinese patients with MPS IVA. Eighteen kinds of novel mutation were detected including p. E315K, p.G304D, p.R251Q, p.Y240C, p.G161E, p.N32D, p.L390P, p. D60E, p. P420S, W403C/T404S, p.L454P, for p.W405X, p. M1I, c.409_ c.420del12, c.1176_1178del3, c.1046delG, c.1188delG and IVS9-2A>C. (2) The polymorphism of novel missense variants were ruled out by the PCR-restriction fragment length polymorphism analysis and no related mutations were found in 50 normal controls. A splice site mutation IVS9-2A>C had been validated by reverse transcription PCR direct sequencing. The amino acid of mutant position of 10 kinds of missense variants are highly conserved and only p. L454 is moderately conserved position. These missense variants were predicted to cause damage to the structure and function of human GALNS protein possibly according to the PolyPhen-2 tool, so these novel missense variants may be disease-causing mutations. (3) Prenatal diagnosis was provided for 7 families and three fetuses were diagnosed as MPS IVA.</p><p><b>CONCLUSION</b>The GALNS gene mutation spectrum in Chinese patients with MPS IVA is really different from that in other countries, five kinds of mutation were only found in Chinese patients with MPS IVA. The reports of hot-spot mutation in Chinese patients were also different, and should be analyzed by more data of gene mutation analysis and epidemiological study.</p>

Clinical, radiologic, and genetic features of Korean patients with Mucopolysaccharidosis IVA / 소아과

PURPOSE: Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is rare lysosomal storage disorder caused by N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. Only a few MPS IVA cases have been reported in the Korean literature; there is a paucity of research about clinical or radiologic findings for this disorder. Therefore, we studied clinical findings, radiological features, and genetic data of Korean MPS IVA patients for determining factors that may allow early diagnosis and that may thus improve the patients' quality of life. METHODS: MPS IVA was confirmed via assay for enzymatic activity of leukocytes in 10 patients. The GALNS gene was analyzed. Patients' charts were retrospectively reviewed for obtaining clinical features and evaluated for radiological skeletal surveys, echocardiography, pulmonary function test, and ophthalmologic test results. RESULTS: Nine patients had severe clinical phenotype, and 1 had an intermediate phenotype, on the basis of clinical phenotype criteria. Radiologic findings indicated skeletal abnormalities in all patients, especially in the hips and extremities. Eight patients had an odontoid hypoplasia, and 1 showed mild atlantoaxial subluxation and cord myelopathy. Genetic analysis indicated 10 different GALNS mutations. Two mutations, c.451C>A and c.1000C>T, account for 37.5% (6/16) and 25% (4/16) of all mutations in this samples, respectively. CONCLUSION: An understanding of the clinical and radiological features involved in MPS IVA may allow early diagnosis of MPS IVA. Adequate evaluations and therapy in the early stages may improve the quality of life of patients suffering from skeletal abnormalities and may reduce life-threatening effects of atlantoaxial subluxation.

GLB1 gene mutation and clinical characteristics of a patient with mucopolysaccharidosis type IVB / 中华儿科杂志

<p><b>OBJECTIVE</b>To report the results of clinical characteristics, enzyme activity determination and mutation analysis of GLB1 gene in a Chinese patient with mucopolysaccharidosis (MPS) type IVB (Morquio B disease).</p><p><b>METHOD</b>A 14-year-old Chinese boy with MPS type IVB was firstly diagnosed by blood leucocytes galactosamine-6-sulfate sulfatase (GALNS) and β-galactosidase (GLB1) determination, who was characterized by short stature, multiplex skeletal abnormalities, difficulty in walking. PCR-sequencing analysis was applied to detect the mutations in GLB1 of the patient.</p><p><b>RESULT</b>The patient was characterized by dwarfism, pectus carinatum, kyphosis, normal intelligence, and no neurologic damage of spasms, linguistic capacity and so on. The patient had normal GALNS enzyme activity and very low GLB1 enzyme activity [5.03 nmol/(h·mg) vs. normal value 118 - 413 nmol/(h·mg) ] in leukocytes. A compound heterozygous missense mutations c.442C > T(p.R148C)/c.1454A > G(p.Y485C) in GLB1 gene were detected in this patient. The mutation p.Y485C is a novel variant. With the method of gene analysis of new variant, the mutation p.Y485C was considered to be a pathogenic mutation.</p><p><b>CONCLUSION</b>The MPS IVB patient showed severe multiple skeletal deformities, normal intelligence, no neurologic damage and very low GLB1 enzyme activity, who carries compound heterozygous mutations p.R148C/p.Y485C. The mutation p.Y485C in GLB1 gene may be a novel pathologic mutation of MPS type IVB.</p>

Rapid prenatal genetic diagnosis of a fetus with a high risk for Morquio A syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To provide rapid and accurate prenatal genetic diagnosis for a fetus with high risk of Morquio A syndrome.</p><p><b>METHODS</b>Based on ascertained etiology of the proband and genotypes of the parents, particular mutations of the GALNS gene were screened at 10th gestational week with amplification refractory mutation system (ARMS), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing.</p><p><b>RESULTS</b>DHPLC screening has identified abnormal double peaks in the PCR products of exons 1 and 10, whilst only a single peak was detected in normal controls. Amplification of ARMS specific primers derived a specific product for the fetus's gene, whilst no similar product was detected in normal controls. Sequencing of PCR products confirmed that exons 1 and 10 of the GALNS gene from the fetus contained a heterozygous paternal c.106-111 del (p.L36-L37 del) deletion and a heterozygous maternal c.1097 T>C (p.L366P) missense mutation, which resulted in a compound heterozygote status.</p><p><b>CONCLUSION</b>The fetus was diagnosed with Morquio A syndrome and a genotype similar to the proband. Termination of the pregnancy was recommended. Combined ARMS, DHPLC and DNA sequencing are effective for rapid and accurate prenatal diagnosis for fetus with a high risk for Morquio A syndrome. Such methods are particularly suitable for early diagnosis when pathogenesis is clear. Furthermore, combined ARMS and DHPLC are suitable for rapid processing of large numbers of samples for the identification of new mutations.</p>

Identification of a novel mutation of GALNS gene from a Chinese pedigree with mucopolysaccharidosis type IV A / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the molecular genetic mechanism of mucopolysaccharidosis type IV A(MPS IV A), and reveal the relationship between the genotype and phenotype, and provide a basis for prenatal gene diagnosis in the future.</p><p><b>METHODS</b>A preliminary diagnosis was made by qualitative detection of urinary glycosaminoglycans of the suspected MPS IV A proband. Then, mutation detection was performed on the proband and her family members with PCR and direct sequencing of the PCR products. After a novel c.1567T to G mutation was detected, Xsp I restriction enzyme digestion and amplification refractory mutation system (ARMS) fast specific identification were established to analyze the sequences of exon 14 in GALNS gene, including 110 randomly selected healthy controls, the proband and other pedigree members. At the same time, bioinformatic approaches for protein secondary, tertiary structure prediction were applied to identify the novel pathologic mutation.</p><p><b>RESULTS</b>The proband's urine GAGs test was a weak positive(± ), and a c.1567T to G heterozygous termination codon mutation in exon 14 and a c.374C to T heterozygous missense mutation in exon 4 were found. The proband was compound heterozygous of the two mutations, so was her younger sister. Her mother was a carrier with only a c.1567T to G heterozygous mutation in exon 14. Her father had a heterozygous mutation of c.374C to T in exon 4. After Xsp I restriction enzyme digestion, healthy controls had three bands including 28 bp, 120 bp and 399 bp, while the proband and her mother had four bands consisting of 28 bp, 120 bp, 148 bp and 399 bp. For amplification by ARMS specific primers, it was negative for the controls, while it was positive for the proband and the carrier. The results of protein secondary and tertiary structure prediction showed that the c.1567T to G mutation located in the stop codon, resulted in stop codon (TAG) changing to glutamic acid (GAG), with the peptide chain extending 92 amino acid residues, and secondary and tertiary protein structure change, which were not found in the controls. The result of enzyme assay showed that the activity of GALNS enzyme in the affected child was 8.3 nmol/17h/mg pr, which was obviously lower than the normal value (the normal range is 41.9-92.1 nmol/17h/mg pr).</p><p><b>CONCLUSION</b>These results illustrate that the c.1567 T to G is a novel pathologic mutation, which is the main cause of the disease in this family.</p>