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Mucopolysaccharidosis

MPS

Mucopolysaccharidosis (MPS) is a general term referring to a group of hereditary lysosomal storage diseases, in which the progressive accumulation of glycosaminoglycans causes a variety of symptoms. According to the current classification, there are seven types of MPS, and they are caused by deficiencies of lysosomal enzymes. Common symptoms include mental retardation, characteristic facial features, and further anomalies of the skeletal system.

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Presentation

There is a considerable overlap of clinical features of distinct types of MPS, and they may be impossible to distinguish based on clinical findings alone. Furthermore, patients suffering from a certain type of MPS may present with subtle changes or severe alterations, so the spectrum of disease presentation is broad - even among those carrying defects of the same gene.

Most commonly, MPS induces mental disability, malformations of the skeletal system, and corneal clouding. Mental retardation may be accompanied by developmental delays and may become apparent in infancy; it may or may not progress throughout life. However, MPS patients may also be of normal intelligence. Malformations of the locomotor system may comprise, but are not limited to, short stature, short neck, lumbar kyphosis, scoliosis, pectus carinatum, genu valgum, and pes cavus [1]. In late stages of the disease, life-threatening spinal cord compression may occur, especially in those suffering from severe skeletal dysplasia [2] [3]. Many patients also have joint contractures. While they may present coarse facial features, the latter rarely prompt a diagnostic workup. Corneal clouding was mentioned as another symptom characteristic of MPS and may be associated with glaucoma, retinal degeneration, and optic nerve swelling with subsequent atrophy. These complications may result in visual impairment and even blindness [4].

Beyond neurological, orthopedic, and ophthalmological findings, macroglossia, tonsillar hypertrophy, otitis media and conductive hearing loss, upper airway obstruction, valvular heart disease, hepatosplenomegaly, and bowel dysfunction are frequently reported [4] [5].

Splenomegaly
  • […] lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and other skeletal irregularities, thickened skin, enlarged organs such as liver (hepatomegaly) or spleen (splenomegaly[en.wikipedia.org]
Short Stature
  • His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities.[ncbi.nlm.nih.gov]
  • In a resource poor setting, we report a case of Hunter syndrome, severe subtype, based on global development delay, coarse facies, short stature, hepatosplenomegaly and dysostosis multiplex on X-ray with unusual large congenital inguinal hernia.[ncbi.nlm.nih.gov]
  • MPS patients present with several somatic manifestations, including short stature, musculoskeletal abnormalities, and cardiorespiratory dysfunction, and several primary and secondary neurological signs and symptoms.[ncbi.nlm.nih.gov]
  • A typical clinical presentation includes such symptoms and characteristics as short stature, facial dysmorphism, skeletal deformities, pulmonary dysfunction, joint stiffness and contractures, myocardial hypertrophy, neurological symptoms, and mental retardation[ncbi.nlm.nih.gov]
  • Abstract A 25-year-old female was referred for short stature and joint deformities. Except for previous corneal transplantation, her medical history was unremarkable.[ncbi.nlm.nih.gov]
Dysostosis
  • Skeletal X-rays revealed characteristic signs of dysostosis multiplex in the older brother at the initiation of treatment that were unchanged two years later, whereas the younger brother showed only slight findings of dysostosis multiplex throughout the[ncbi.nlm.nih.gov]
  • In a resource poor setting, we report a case of Hunter syndrome, severe subtype, based on global development delay, coarse facies, short stature, hepatosplenomegaly and dysostosis multiplex on X-ray with unusual large congenital inguinal hernia.[ncbi.nlm.nih.gov]
  • There were no pronounced signs of dysostosis multiplex on radiographs. The only difference when compared with his healthy twin brother was lower IQ (Termann-Merrill 98 vs. 118) and mild deformity of one vertebrae.[ncbi.nlm.nih.gov]
  • Very few patients had the skeletal features of classical dysostosis multiplex. CONCLUSIONS: Radiologists should appreciate the wide phenotypic variability of MPS IVA and VI.[ncbi.nlm.nih.gov]
  • Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, cervical spinal canal stenosis with or without spinal cord compression and myelopathy, and bone abnormalities in the skull and spine (dysostosis multiplex) are typical imaging[ncbi.nlm.nih.gov]
Developmental Delay
  • He had mild dysmorphic features with prominent speech developmental delays and, to a lesser extent, motor developmental delays.[ncbi.nlm.nih.gov]
  • Affected subjects present developmental delay, attention deficit disorder, uncontrollable hyperactivity, and aggressive behavior, followed by progressive dementia and death in late adolescence.[ncbi.nlm.nih.gov]
  • Abstract We report a patient with stage 3 ganglioneuroblastoma who initially presented with clinical and laboratory features consistent with mucopolysaccharidosis including coarse facial features, developmental delay, and an elevated quantitative urine[ncbi.nlm.nih.gov]
  • The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay.[ncbi.nlm.nih.gov]
  • The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia.[ncbi.nlm.nih.gov]
Coarse Facial Features
  • Abstract We report a patient with stage 3 ganglioneuroblastoma who initially presented with clinical and laboratory features consistent with mucopolysaccharidosis including coarse facial features, developmental delay, and an elevated quantitative urine[ncbi.nlm.nih.gov]
  • The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia[ncbi.nlm.nih.gov]
  • He did not develop coarse facial features, joint disease, or organomegaly, and his cardiac function remained normal. There were no pronounced signs of dysostosis multiplex on radiographs.[ncbi.nlm.nih.gov]
  • We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG.[ncbi.nlm.nih.gov]
  • Physical examination revealed obesity, mildly coarse facial features and stocky hands. He showed mental retardation and mild motor delay. The clinical picture strongly suggested mucopolysaccharidosis.[ncbi.nlm.nih.gov]
Pain
  • The MHQ global and domains mean scores were: global, 56.68 16.17; hand function, 64.17 21.62; activities of daily living, 46.87 27.78; school performance, 56.01 32.69; pain, 79.33 30.87; aesthetics, 77.81 11.16; and satisfaction, 74.57 27.16.[ncbi.nlm.nih.gov]
  • Patient 4 was diagnosed at 17 months of age when presented lower limb pain at night, respiratory allergy and repeated upper airways infections.[ncbi.nlm.nih.gov]
  • Health-related quality of life (HRQoL) tools that utilize patient reported outcomes to address patient parameters such as symptoms (pain, fatigue, psychological health), functioning (activity and limitations), or quality of life, have been used to supplement[ncbi.nlm.nih.gov]
  • Important themes to emerge were- the fear of dying associated with obstructive sleep apnoea, difficulties communicating at school due to the delayed acquisition of language, chronic pain and restricted mobility, physical differences and restricted participation[ncbi.nlm.nih.gov]
  • Symptoms included nodular soft-tissue masses located around joints, with episodes of painful swelling of the masses and pain that ended spontaneously within 3 days. Pelvic radiography showed multiple soft-tissue masses and some bone erosion.[en.wikipedia.org]
Sleep Apnea
  • Respiratory problems, sleep apnea, and heart disease may develop in adolescence. Some persons with MPS I H-S need continuous positive airway pressure during sleep to ease breathing.[en.wikipedia.org]
  • The airway may become narrow in some people with MPS I, causing frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea).[ghr.nlm.nih.gov]
  • apnea Ear infections and hearing loss Numbness and tingling in fingers or feet Heart disease Stiff joints and trouble moving Hernias, which look like a bulge around the belly button or in the groin Diarrhea Enlarged liver or spleen Your child might not[webmd.com]
  • ERT may improve growth, joint movement, sleep apnea, respiratory function, pain levels, vision, and liver/spleen enlargement.[babysfirsttest.org]
  • Shapiro J, Strome M, Crocker AC: Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol 94:458–461, 1985. PubMed Google Scholar 31.[link.springer.com]
Tonsillar Hypertrophy
  • Beyond neurological, orthopedic, and ophthalmological findings, macroglossia, tonsillar hypertrophy, otitis media and conductive hearing loss, upper airway obstruction, valvular heart disease, hepatosplenomegaly, and bowel dysfunction are frequently reported[symptoma.com]
Hoarseness
  • Vocal cords can also enlarge, resulting in a deep, hoarse voice. The airway may become narrow in some people with MPS I, causing frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea).[ghr.nlm.nih.gov]
Snoring
  • The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia[ncbi.nlm.nih.gov]
Nasal Congestion
Hepatomegaly
  • The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development.[ncbi.nlm.nih.gov]
  • The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia[ncbi.nlm.nih.gov]
  • In our case, MPS IIIB was diagnosed at an early age because recurrent wheezing and otitis media in conjunction with hepatomegaly were recognised as more than trivial findings.[ncbi.nlm.nih.gov]
  • CONCLUSIONS: Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.[ncbi.nlm.nih.gov]
  • Sustained IDS expression had a profound effect on normalization of GAG in all tested tissues and on prevention of hepatomegaly.[ncbi.nlm.nih.gov]
Hydrops Fetalis
  • Keywords Live Birth Consanguineous Parent Mucopolysaccharidosis Hunter Syndrome Hydrops Fetalis These keywords were added by machine and not by the authors.[doi.org]
  • Three cases of non-immune hydrops fetalis born to consanguineous parents were thought to be due to beta-glucuronidase deficiency (MPS VII) on the basis of placental histology and enzyme studies on both parents but no living cases of MPS VII were ascertained[ncbi.nlm.nih.gov]
  • The severe neonatal form is the most common type of this syndrome, characterized by hydrops fetalis (abnormal accumulation of fluid in various tissues of the body) and dysmorphic features.[news-medical.net]
  • If the disorder causes hydrops fetalis, stillbirth or death in the neonatal period is likely. Patients may also succumb to cardiac or respiratory failure, or fall into a vegetative state during later stages of life.[symptoma.com]
  • In rare cases, some newborn infants with Sly syndrome may experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis). MPS VII is currently in clinical trial.[rarediseases.org]
Aggressive Behavior
  • Affected subjects present developmental delay, attention deficit disorder, uncontrollable hyperactivity, and aggressive behavior, followed by progressive dementia and death in late adolescence.[ncbi.nlm.nih.gov]
  • In the syndrome's second stage, aggressive behavior, hyperactivity, profound dementia, and irregular sleep may make children difficult to manage, particularly those who retain normal physical strength.[en.wikipedia.org]
  • Affected individuals may experience seizures, unsteady gait, and aggressive behavior. Affected individuals may eventually lose the ability to walk. Accumulation of heparan sulfate may occur.[rarediseases.org]
Seizure
  • Long term video-EEG monitoring (LT-VEEGM) demonstrated sleep-related hypermotor seizures consistent with NFLE. No case of sleep-related hypermotor seizures has ever been reported to date in MPS.[ncbi.nlm.nih.gov]
  • Although the five patients with history of seizures did not present a distinctive EEG anomaly, four of them presented some structural alteration in the imaging studies.[ncbi.nlm.nih.gov]
  • The amount of literature on the prevalence, pathophysiology, clinical features, and management of epileptic seizures in patients with MPS is limited.[ncbi.nlm.nih.gov]
  • Tonic–clonic seizures are the most common type of seizure in Hunter syndrome, but absent and myoclonic seizures have also been reported. 15 It is possible that absence seizures (petit mal) are under-reported; neurologists should be aware of this and seek[touchneurology.com]
  • There was no history of constipation, diarrhea, vomiting, bleeding, jaundice, seizure, weight loss or loss of appetite or of consciousness. His bladder habit was normal. The scholastic performance was poor.[omicsonline.org]
Communicating Hydrocephalus
  • In patients with this disorder, craniocervical compression, carpal tunnel syndrome, and communicating hydrocephalus are common. Traditionally, hydrocephalus occurring in patients with MPS VI has been treated with shunt placements.[ncbi.nlm.nih.gov]
  • Communicating hydrocephalus can be effectively treated by insertion of a ventriculoperitoneal shunt, which can improve motor development in early stages of the disease. 17 It is suggested that nerve conduction studies be performed in patients every 1[touchneurology.com]
  • Neurological symptoms may include mild to moderate intellectual disability by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision.[en.wikipedia.org]
  • Mps iia usually occurs between 2 and 4 years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 and 15 years.[icd9data.com]
  • Focal or diffuse white matter lesions, ventriculomegaly, communicating hydrocephalus, and eventually cerebral atrophy may be visualized by magnetic resonance imaging. Laboratory analyses of urine samples.[symptoma.com]
Sleep Disturbance
  • KEYWORDS: Epilepsy; Mucopolysaccharidosis; Sleep disturbances[ncbi.nlm.nih.gov]
  • Reported sleep disturbances include difficulty initiating or maintaining sleep, decreased rapid eye movement sleep and sleep onset insomnia. 15,17 Seizures and seizure-like behaviours also occur early in the disease.[touchneurology.com]
  • disturbance.[ 16 ] A syrinx is present in 30–70% of cases of CM-I.[ 15 ] Table 1 Diagnostic quick reference for Chiari I malformation and variants.[surgicalneurologyint.com]
Mental Deterioration
  • MPS III presents with progressive mental deterioration, speech delay and behavioural problems with subtle somatic features, which can often lead to misdiagnosis with idiopathic developmental/speech delay, attention deficit/hyperactivity disorder or autism[ncbi.nlm.nih.gov]
  • Behavioral disorders, mental deterioration, and a loss of motor skills are the principal features. Hirsutism, macrocephaly, and limited joint movements. Four types, each with a different enzyme deficiency, are recognized: a, b, c and d.[icd9data.com]
Waddling Gait
  • 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[ncbi.nlm.nih.gov]
  • Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance.[ncbi.nlm.nih.gov]
Diarrhea
  • The most frequently reported adverse reactions included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased.[biomarin.com]
  • Initial manifestations include: frequent respiratory tract infections (in particular otitis media); umbilical and inguinal hernia; intractable diarrhea; hepatosplenomegaly; and skin lesions resembling an orange peel (on the shoulder, back and thighs).[orpha.net]
  • , including runny nose, sinus infections, and sleep apnea Ear infections and hearing loss Numbness and tingling in fingers or feet Heart disease Stiff joints and trouble moving Hernias, which look like a bulge around the belly button or in the groin Diarrhea[webmd.com]
  • Mps iia usually occurs between 2 and 4 years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 and 15 years.[icd9data.com]
  • Diet A dietician can help you create a nutrition plan to help your baby control diarrhea and constipation, which may occur in those with severe MPS I.[babysfirsttest.org]
Abdominal Pain
  • The most frequently reported adverse reactions included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased.[biomarin.com]
Chronic Diarrhea
  • Mps iia usually occurs between 2 and 4 years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 and 15 years.[icd9data.com]
Failure to Thrive
  • […] to thrive, intellectual disability, and developmental delay.[ 5 12 ] The extensive storage of these glycosaminoglycans is also known to cause meningeal thickening.[ 4 ] Intraoperatively, our patient was noted to have thickened arachnoid membrane, which[surgicalneurologyint.com]
Widely Spaced Teeth
  • The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia[ncbi.nlm.nih.gov]
  • Other possible features include pulmonary compromise, valvular heart disease, hearing loss, hepatomegaly, fine corneal clouding, and widely spaced teeth with abnormally thin enamel with increased risk of caries formation.[genedx.com]
  • They also tend to look similar: Shorter than average, with stocky build Large head, bulging forehead Thick lips, widely spaced teeth, and large tongue Short, flat nose with wide nostrils Thick, tough skin Short, broad hands with curving fingers Knock-knees[webmd.com]
Dental Caries
  • CONCLUSION: Mothers' SOC of children/adolescents with MPS was associated with dental caries experience in their children.[ncbi.nlm.nih.gov]
Heart Failure
  • An adult Caucasian woman, who displayed very few symptoms up to her late thirties, was diagnosed with mucopolysaccharidosis type VI (MPS VI) after her hospitalization due to acute heart failure originating mainly from valve disease.[ncbi.nlm.nih.gov]
  • The younger sibling has never received any cardiovascular drugs, whereas the older one has been using β-blockers and diuretics in addition to enzyme therapy to cope with heart failure.[ncbi.nlm.nih.gov]
Hearing Impairment
  • During 36 months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling.[ncbi.nlm.nih.gov]
  • The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema.[icd9data.com]
  • Neurological signs and symptoms that may be evident in patients having either the neuronopathic or non-neuronopathic phenotypes include seizures, optic nerve compression, hearing impairment, sleep apnoea, hydrocephalus, carpal tunnel syndrome, spinal[touchneurology.com]
Hirsutism
  • Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex.[orpha.net]
  • Hirsutism, macrocephaly, and limited joint movements. Four types, each with a different enzyme deficiency, are recognized: a, b, c and d.[icd9data.com]
Skeletal Dysplasia
  • The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge.[ncbi.nlm.nih.gov]
  • Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias.[ncbi.nlm.nih.gov]
  • PURPOSE: Main 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.[ncbi.nlm.nih.gov]
  • PATIENT CONCERNS: The patient was a 17-year-old girl with growth retardation, hearing loss, and severe skeletal dysplasia(scoliosis and chicken breast), and was evaluated to have normal nervous system function and intelligence by physicians.[ncbi.nlm.nih.gov]
  • The patient showed a wide spectrum of symptoms including skeletal dysplasia and short stature with elevated glycosaminoglycans (GAGs) in urine.[ncbi.nlm.nih.gov]
Joint Stiffness
  • A typical clinical presentation includes such symptoms and characteristics as short stature, facial dysmorphism, skeletal deformities, pulmonary dysfunction, joint stiffness and contractures, myocardial hypertrophy, neurological symptoms, and mental retardation[ncbi.nlm.nih.gov]
  • The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia.[ncbi.nlm.nih.gov]
  • These may include joint stiffness, heart problems, corneal clouding and hearing loss. Individuals with Hurler/Scheie syndrome usually have variable clinical symptoms of intermediate severity between the mildest and most severe forms of MPS I.[luriechildrens.org]
  • Restricted breathing, joint stiffness, and heart disease are also common. Children with the more, severe form of Morquio syndrome may not live beyond their twenties or thirties.[en.wikipedia.org]
  • Symptoms usually become apparent between three and eight years of age and include coarse facial features, corneal clouding, joint stiffness, short stature and hepatosplenomegaly. Survival to adulthood is common.[news-medical.net]
Macrocephaly
  • The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia[ncbi.nlm.nih.gov]
  • Hirsutism, macrocephaly, and limited joint movements. Four types, each with a different enzyme deficiency, are recognized: a, b, c and d.[icd9data.com]
  • Macrocephaly develops during infancy and infants initially grow at normal or above average rates.[orpha.net]
  • Some symptoms (hernia, macrocephaly, respiratory infections, and limited hip abduction) become apparent early in infancy but the complete clinical picture develops during the second year of life.mucopolysaccharidosis (mps) i-s synonyms: scheie syndrome[icd10data.com]
  • Individuals with MPS I may have a large head ( macrocephaly ), a buildup of fluid in the brain (hydrocephalus), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," an enlarged liver and spleen (hepatosplenomegaly[ghr.nlm.nih.gov]
Genu Valgum
  • Abstract A 16-year-old boy with widening of the large joints of the extremities and bilateral genu valgum had been extensively treated with oral vitamin D, with little clinical benefit.[ncbi.nlm.nih.gov]
  • 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[ncbi.nlm.nih.gov]
  • Clinical features include short trunk dwarfism, dysostosis multiplex, progressive spinal deformity, short neck, pectus carinatum, genu valgum, pes planus, and odontoid hypoplasia with varying degrees of severity.[icd9data.com]
  • Malformations of the locomotor system may comprise, but are not limited to, short stature, short neck, lumbar kyphosis, scoliosis, pectus carinatum, genu valgum, and pes cavus.[symptoma.com]
  • Symptoms may include growth retardation, a prominent lower face, an abnormally short neck, knees that are abnormally close together (knock knees or genu valgum), flat feet, abnormal sideways and front-to-back or side-to-side curvature of the spine (kyphoscoliosis[rarediseases.org]
Platyspondyly
  • 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[ncbi.nlm.nih.gov]
  • The most common bony changes were hypo/dysplastic odontoid; cervical platyspondyly with anterior inferior beaking; thoracic posterior end plate depressions and lumbar posterior scalloping.[ncbi.nlm.nih.gov]
  • […] beta-galactosidase deficiency mucopolysaccharidosis (mps) iv b this type is caused by beta-galactosidase (ec 3.2.1.23) deficiency and is marked a milder phenotype consisting of dysostosis multiplex, pectus carinatum, odontoid hypoplasia, kyphosis, genua valga, platyspondyly[icd9data.com]
  • Beyond the clinical findings described above, imaging often reveals macrocephaly, atlantoaxial dislocation, wedge-shaped vertebral bodies and platyspondyly, spatulate ribs, bullet-shaped metacarpals, as well as hypoplastic epiphyses and thickened diaphyses[symptoma.com]
Corneal Opacity
  • Regardless of phenotype, all patients had various degrees of infiltrated facies, short stature, dysostosis multiplex, joint contractures, and corneal opacity typical of the disease.[ncbi.nlm.nih.gov]
  • The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema.[icd9data.com]
  • Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present.[orpha.net]
  • opacities, clawhand, aortic valve disease, normal stature, mild or absent intellectual impairment, and nearly normal life span, depending on cardiac complications.[icd10data.com]
Visual Impairment
  • These complications may result in visual impairment and even blindness.[symptoma.com]
  • impairment, and deafness, usually leading to death within the first decade of life.[ 8 ] The advent of allogeneic hematopoietic stem cell transplantation from bone marrow, peripheral blood, or unrelated umbilical cord has resulted in the reversal of[surgicalneurologyint.com]
Retinal Pigmentation
  • CONCLUSION: Our multimodal analysis reported here attempted to contribute to the knowledge of the natural history of GAG deposition in the eye, focusing on the retina and retinal pigment epithelium.[ncbi.nlm.nih.gov]
Short Neck
  • Initial physical examination revealed the presence of a coarse facies, short neck, kyphosis, restricted joint movements and deformities, and cardiac murmur besides a normal intellect.[ncbi.nlm.nih.gov]
  • Figure 1: shows Coarse facial features with depressed nasal bridge, a short neck, long philtrum. Figure 2: showing dorso lumbar scoliosis with anterior breaking at D12, L1,2,3 with ovoid shaped vertebra.[omicsonline.org]
  • Clinical features include short trunk dwarfism, dysostosis multiplex, progressive spinal deformity, short neck, pectus carinatum, genu valgum, pes planus, and odontoid hypoplasia with varying degrees of severity.[icd9data.com]
  • Malformations of the locomotor system may comprise, but are not limited to, short stature, short neck, lumbar kyphosis, scoliosis, pectus carinatum, genu valgum, and pes cavus.[symptoma.com]
  • Affected children may also have an abnormally large head (macrocephaly), a short neck and broad chest, delayed tooth eruption, progressive hearing loss, and enlargement of the liver and spleen (hepatosplenomegaly).[rarediseases.org]
Thick Lips
  • These symptoms may include kyphosis (curvature of the spine causing a “lump on the back”), joint stiffness, coarse facial features (flattened nose bridge, thick lips and an enlarged tongue), corneal clouding, hearing loss, heart problems, an enlarged[luriechildrens.org]
  • They also tend to look similar: Shorter than average, with stocky build Large head, bulging forehead Thick lips, widely spaced teeth, and large tongue Short, flat nose with wide nostrils Thick, tough skin Short, broad hands with curving fingers Knock-knees[webmd.com]
  • Physical symptoms generally include coarse or rough facial features (including a flat nasal bridge, thick lips, and enlarged mouth and tongue), short stature with disproportionately short trunk (dwarfism), dysplasia (abnormal bone size and/or shape) and[en.wikipedia.org]
Frontal Bossing
  • Anteroposterior and lateral X-rays of the skull showed an calvarial thickening and depressed bridge of nose with frontal bossing with hypopneumatised mastoid ( Figure 3 ).[omicsonline.org]

Workup

Molecular biological analyses are the gold standard of MPS diagnosis and allow for a reliable identification of the type of the disease. However, diagnostic delays of several years are common. While lumbar kyphosis should definitely raise suspicion as to a lysosomal storage disease, most symptoms are non-specific if considered separately. Thus, MPS diagnostics are not usually carried out until the patient or their parents relate a complex medical history comprising several of the events described in the previous paragraph.

MPS diagnostics should include:

  • Imaging studies. Skeletal anomalies are a clinical hallmark of MPS and should be evaluated to assess best treatment options and to prevent severe complications like spinal cord compression. Beyond the clinical findings described above, imaging often reveals macrocephaly, atlantoaxial dislocation, wedge-shaped vertebral bodies and platyspondyly, spatulate ribs, bullet-shaped metacarpals, as well as hypoplastic epiphyses and thickened diaphyses leading to hip dysplasia and deformities of other joints [1] [6]. Focal or diffuse white matter lesions, ventriculomegaly, communicating hydrocephalus, and eventually cerebral atrophy may be visualized by magnetic resonance imaging [6].
  • Laboratory analyses of urine samples. The measurement of total glycosaminoglycans is usually followed by the separation of subfractions for qualitative analyses. The excretion pattern of urinary glycosaminoglycans allows for a tentative diagnosis of a specific type of MPS. In detail, patients suffering from MPS types 1 or 2 are likely to excrete abnormal amounts of heparan sulfate and dermatan sulfate. MPS type 3 is associated with an increased excretion of heparan sulfate, whereas MPS type 4 manifests in elevated concentrations of chondroitin 6-sulfate and keratan sulfate. While urine samples from MPS type 6 patients contain large amounts of dermatan sulfate, MPS type 7 is characterized by high urinary levels of heparan, dermatan, and chondroitin sulfate. Finally, MPS type 9 patients excrete hyaluronan [7].
  • Before molecular biological tools became widely available, the activity of determined lysosomal enzymes was assessed in fibroblasts or leukocytes.
  • Genetic studies to determine the underlying mutation [8].
Enlargement of the Spleen
  • […] liver and spleen, hernias, chronic nasal congestion and ear infections.[luriechildrens.org]
  • Individuals with MPS I may have a large head ( macrocephaly ), a buildup of fluid in the brain (hydrocephalus), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," an enlarged liver and spleen (hepatosplenomegaly[ghr.nlm.nih.gov]
  • […] liver or spleen Your child might not have all of those symptoms.[webmd.com]
  • […] liver and spleen) Clouding of the eye (corneal clouding) Hearing loss Frequent “runny nose" If your baby shows any of these signs, be sure to contact your baby’s health care provider immediately.[babysfirsttest.org]
  • Affected individuals may develop coarse facial features, joint stiffness, short stature, clouding of the corneas, abnormally enlarged liver and/spleen (hepatosplenomegaly), and skeletal and cardiac abnormalities.[rarediseases.org]
Enlargement of the Liver
  • The accumulation of GAGs interferes with the way certain cells and organs in the body function and can lead to a number of serious symptoms including hearing loss, declined cardiac function, obstructive airway disease, enlargement of the liver and spleen[efpia.eu]
  • Affected individuals may develop coarse facial features, joint stiffness, short stature, clouding of the corneas, abnormally enlarged liver and/spleen (hepatosplenomegaly), and skeletal and cardiac abnormalities.[rarediseases.org]

Treatment

MPS is considered potentially treatable with enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction therapy, or gene therapy [9]:

  • With regard to the former, laronidase, idursulfase, and galsulfase have been approved for the treatment of MPS types 1, 2, and 6, respectively. These enzymes are effective in controlling somatic manifestations of MPS, but skeletal anomalies and valvular heart disease don't usually respond to this kind of therapy. Furthermore, neither of these recombinant human enzymes is able to cross the blood-brain-barrier, so MPS-related central nervous system disorders won't be alleviated either.
  • Hematopoietic stem cells of a healthy donor are a life-long source of lysosomal enzymes. Due to morbidity and mortality associated with the procedure, hematopoietic stem cell transplantation is usually reserved for those suffering from severe MPS. It should also be noted that disease progression has been reported years after the successful transplantation of stem cells. In order to improve the outcome, the transplantation should be performed as early as possible, and the donor shouldn't be a carrier of MPS-related mutations [10].
  • To date, substrate reduction and gene therapy remain in experimental stages. Substrate reduction therapy aims at limiting the formation of glycosaminoglycans, thereby reducing the necessity of enzymatic degradation. Promising results have been achieved in cell culture and animal models with rhodamine B and genistein. What's more, the latter has been used in small clinical trials and has been demonstrated to improve joint mobility [11]. Gene therapy of MPS has not yet been realized in men. However, vector-mediated gene transfer has been shown to mitigate peripheral and central symptoms and to prolong survival [9].

Beyond that symptomatic and supportive care should be provided according to the individual needs of the patient.

Prognosis

Severe MPS is usually fatal within the first two decades of life. If the disorder causes hydrops fetalis, stillbirth or death in the neonatal period is likely. Patients may also succumb to cardiac or respiratory failure, or fall into a vegetative state during later stages of life [9]. By contrast, mild forms of the disease are associated with near-to-normal life expectancy.

Etiology

All types of MPS are monogenic disorders. In detail, they are triggered by pathogenic mutations of one of the genes encoding for lysosomal enzymes that are required for the degradation of glycosaminoglycans. Except for MPS type 2, all forms of MPS are inherited in an autosomal recessive manner. The gene related to MPS type 2 is located on the X chromosome, so this disease is classified as an X-linked metabolic disorder [5]. Mutations of the following genes have been associated with single types of MPS:

  • MPS type 1 - IDUA, to be found on 4p16.3, encoding for α-L-iduronidase
  • MPS type 2 - IDS, to be found on Xq28, encoding for iduronate 2-sulfatase
  • MPS type 3 - SGSH, NAGLU, HGSNAT, or GNS, to be found on 17q25.3, 17q21.2, 8p11.21, and 12q14.3, encoding for N-sulfoglucosamine sulfohydrolase, N-acetyl-α-glucosaminidase, heparan-α-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase, respectively
  • MPS type 4 - GALNS or GLB1, to be found on 16q24.3 and 3p22.3, encoding for N-acetylgalactosamine-6-sulfatase and galactosidase β1, respectively
  • MPS type 6 - ARSB, to be found on 5q14, encoding for arylsulfatase B
  • MPS type 7 - GUSB, to be found on 7q11.21, encoding for glucuronidase β
  • MPS type 9 - HYAL1, to be found on 3p21.31, encoding for hyaluronidase 1

Epidemiology

The overall incidence of MPS has been estimated to be 1 in 25,000 life births [5] [6]. Still, the incidence rates vary greatly between distinct types of MPS. The most common type of MPS is MPS type 2, which may account for more than half of all cases [5]. The least common type of MPS is MPS type 9. This disease has been described by Natowicz et al. in 1996, and only four patients have been reported to date [12] [13] [14].

While both males and females may be affected by MPS, MPS type 2 is generally diagnosed in males. This is because the causal mutation is located on the X-chromosome. Nevertheless, heterozygous females have been described to present symptoms characteristic of this type of MPS [5].

Sex distribution
Age distribution

Pathophysiology

Glycosaminoglycans are to found on the cell surface and in the extracellular matrix. They are involved in a myriad of physiological processes, e.g., in ligand-receptor interaction and cell proliferation. In the central nervous system, they are required as promoters of neurogenesis and enhancers of synaptic plasticity. Eventually, they are taken up by endocytosis or autophagy, and the respective vesicles fuse with lysosomes. Glycosaminoglycans may be recycled or degraded in lysosomes, namely be those enzymes that are deficient in MPS patients. Thus, undegraded or partially degraded substrates accumulate in the lysosomes, which initially causes the dysfunction of that organelle but eventually interferes with the function of the whole cell [9].

Via the bloodstream, poorly degraded glycosaminoglycans may reach virtually all tissues and organs. Therefore, all types of MPS are multisystem diseases, even though the activity of the affected enzyme is physiologically limited to determined types of cells [5]. Furthermore, glycosaminoglycans have been speculated to induce the secretion of cytokines, which may mediate degenerative joint disorders [9].

Prevention

Genetic counseling should be offered to affected families, and they should be informed that both a child's genotype and phenotype can be determined prenatally. However, prenatal screens for MPS are not carried out on a routine basis and in the absence of a positive family history, parents may not be aware they carry a pathogenic mutation. Indeed, more than one-fifth of IDS mutations, which account for MPS type 2, are de novo mutations [8]. In this context, and because an early diagnosis is crucial for an optimum outcome, newborn screenings for MPS and other lysosomal storage diseases have been proposed in distinct countries, but no consensus has yet been reached on how to achieve high sensitivity, high specificity, and cost-effectiveness. While some authors prefer the assessment of enzyme activities [15], others favor the measurement of glycosaminoglycan concentrations in blood samples [16]. At the same time, costly follow-ups of false-positive cases have to be avoided [17].

Summary

MPS refers to a group of heterogeneous metabolic disorders. Affected individuals carry mutations of one of eleven genes that encode for lysosomal enzymes involved in the breakdown of glycosaminoglycans. Glycosaminoglycans are - usually highly sulfated - polysaccharides comprising disaccharide repeats, and they may also be referred to as mucopolysaccharides. The type of disaccharide to be found in glycosaminoglycans varies and is the basis of their classification as heparin sulfate/heparan sulfate, chondroitin sulfate/dermatan sulfate, keratan sulfate or non-sulfated hyaluronan. Glycosaminoglycans are part of the synovial fluid, the articular cartilage and bones, of heart valves, cornea and vitreous humor as well as mast cell granules, among others. In MPS patients, they progressively accumulate in the respective tissues but eventually reach the bloodstream and are excreted in urine. Therefore, additional tissues and distant organs are generally involved in the disease, and urine analyses are very useful in MPS diagnostics.

A total of seven types of MPS are distinguished to date, namely MPS types 1 to 9, except for types 5 and 8, which are no longer considered distinct entities. It should be noted that subtypes are differentiated in case of MPS type 1 (Scheie syndrome, Hurler Scheie syndrome, Hurler syndrome), MPS type 3 (Sanfilippo syndromes A to D), and MPS type 4 (types 4A and 4B, which are also referred to as Morquio A and Morquio B). MPS types 6 and 7 are also known as Maroteaux-Lamy syndrome and Sly syndrome, respectively. MPS type 9 is a rare entity that may also be referred to as Natowicz syndrome. All types of MPS have been associated with determined genetic defects, so molecular biological studies have become the gold standard for their diagnosis.

Patient Information

Mucopolysaccharidosis (MPS) is a general term referring to a group of hereditary disorders. The cells of MPS patients are unable to properly degrade glycosaminoglycans, compounds to be found in joints and bones, heart valves, ocular tissues and others. This is due pathogenic mutations of those genes that encode for the enzymes required for the breakdown of glycosaminoglycans. Consequently, glycosaminoglycans - which may also be referred to as mucopolysaccharides - accumulate within cells, reach the bloodstream, are distributed throughout the body, and interfere with the function of multiple tissues and organs.

The spectrum of disease presentation is broad. The clinical hallmarks of MPS are mental retardation, short stature and further anomalies of the skeleton, and visual impairment, but between individual patients, there are considerable differences regarding the symptoms and their severity. Thus, the diagnosis cannot be made based on clinical findings alone. Because glycosaminoglycans are excreted in urine, the analysis of urine samples is very useful in the workup of a suspected case. The tentative diagnosis can be confirmed once the activity of the deficient lysosomal enzyme is measured or the underlying mutation is determined.

Treatment options depend on the type of MPS. There are at least seven variants of the disease, and enzyme replacement therapy is available for only three of them. Patients suffering from severe MPS may undergo hematopoietic stem cell transplantation, but the procedure is associated with significant morbidity and mortality. New therapeutic approaches are substrate reduction therapy and gene therapy, but to date, they remain in the experimental stage. In sum, the prognosis of an individual patient largely depends on the severity of their disease: While those affected by mild MPS may have a near-to-normal life expectancy, severe MPS is often fatal before adulthood.

References

Article

  1. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011; 50 Suppl 5:v26-33.
  2. Charrow J, Alden TD, Breathnach CA, et al. Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome. Mol Genet Metab. 2015; 114(1):11-18.
  3. Horovitz DD, Magalhaes Tde S, Pena e Costa A, et al. Spinal cord compression in young children with type VI mucopolysaccharidosis. Mol Genet Metab. 2011; 104(3):295-300.
  4. Ferrari S, Ponzin D, Ashworth JL, et al. Diagnosis and management of ophthalmological features in patients with mucopolysaccharidosis. Br J Ophthalmol. 2011; 95(5):613-619.
  5. Khan SA, Peracha H, Ballhausen D, et al. Epidemiology of mucopolysaccharidoses. Mol Genet Metab. 2017; 121(3):227-240.
  6. Palmucci S, Attina G, Lanza ML, et al. Imaging findings of mucopolysaccharidoses: a pictorial review. Insights Imaging. 2013; 4(4):443-459.
  7. Langereis EJ, Wagemans T, Kulik W, et al. A Multiplex Assay for the Diagnosis of Mucopolysaccharidoses and Mucolipidoses. PLoS One. 2015; 10(9):e0138622.
  8. Pollard LM, Jones JR, Wood TC. Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. J Inherit Metab Dis. 2013; 36(2):179-187.
  9. Noh H, Lee JI. Current and potential therapeutic strategies for mucopolysaccharidoses. J Clin Pharm Ther. 2014; 39(3):215-224.
  10. Aldenhoven M, Wynn RF, Orchard PJ, et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study. Blood. 2015; 125(13):2164-2172.
  11. Marucha J, Tylki-Szymanska A, Jakobkiewicz-Banecka J, et al. Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression-targeted isoflavone therapy (GET IT). Am J Med Genet A. 2011; 155a(9):2257-2262.
  12. Imundo L, Leduc CA, Guha S, et al. A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis. J Inherit Metab Dis. 2011; 34(5):1013-1022.
  13. Natowicz MR, Short MP, Wang Y, et al. Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med. 1996; 335(14):1029-1033.
  14. Triggs-Raine B, Salo TJ, Zhang H, Wicklow BA, Natowicz MR. Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Proc Natl Acad Sci U S A. 1999; 96(11):6296-6300.
  15. Burlina AB, Polo G, Salviati L, et al. Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy. J Inherit Metab Dis. 2018; 41(2):209-219.
  16. Tomatsu S, Fujii T, Fukushi M, et al. Newborn screening and diagnosis of mucopolysaccharidoses. Mol Genet Metab. 2013; 110(1-2):42-53.
  17. Minter Baerg MM, Stoway SD, Hart J, et al. Precision newborn screening for lysosomal disorders. Genet Med. 2017.

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Last updated: 2018-06-22 02:10