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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
  • […] 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]
  • 200mg, 400mg syrup: 100mg/ml Dosage Initially 10mg/day orally, increasing slowly to 20-30mg/kg/day in divided doses 40. 40 Adverse effect drowsiness, diplopia, vertigo, araxia, blurred vision, GI upset, skin reaction, lymphadenopathy, eosinophilia, splenomegaly[slideshare.net]
Sleep Apnea
  • Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea . Many affected individuals also have heart disease, often involving enlarged or diseased heart valves.[en.wikipedia.org]
  • For sleep apnea, CPAP and Bilevel PAP are non-invasive options if the patient can adjust to wearing the mask and mouthpiece at night.[medicalhomeportal.org]
  • apnea, severe respiratory compromise, or cor pulmonale Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema; retinal degeneration Hearing impairment – Deafness Musculoskeletal disease – Short stature; joint stiffness; symptoms of[emedicine.medscape.com]
  • 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 Cloudy corneas and vision loss.[centogene.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]
  • Patients also develop hepatosplenomegaly, frequent ear infections, and a thickening of the vocal cords and airway that leads to hoarseness and sleep apnea. Umbilical and inguinal hernias may also develop and may reappear after surgical correction.[invitae.com]
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]
  • Mucopolysaccharidosis IVA should be suspected in an individual with the following findings 29 : Marked disproportionate short stature with short trunk and normal limbs Respiratory complications (sleep apnea, endurance limitations, snoring) Cardiac valve[centogene.com]
Respiratory Insufficiency
  • The mucopolysaccharidoses are a group of hereditary disorders pathologically characterized by tissue accumulation of glycosaminoglycans due to deficient lysosomal metabolism which often leads to progressive airway stenosis and respiratory insufficiency[ncbi.nlm.nih.gov]
  • Respiratory insufficiency and sleep apnea-hypopnea syndrome, together with cardiovascular compromise and joint problems, are the main causes of morbidity and mortality.[actapediatrica.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]
Hepatomegaly
  • 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]
  • The patient was a 2-yr-old girl presenting with skeletal deformity, hepatomegaly, and delayed motor development.[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]
  • 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]
Hydrops Fetalis
  • 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 its rarest form, Sly syndrome causes children to be born with hydrops fetalis , in which extreme amounts of fluid are retained in the body. Survival is usually a few months or less. Most children with Sly syndrome are less severely affected.[en.wikipedia.org]
  • 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]
  • The most severe form is characterized by hydrops fetalis and premature or very early death.[centogene.com]
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]
  • behavior MPS II (mild form) – Similar features, but with much slower progression; normal intelligence and no hydrocephalus; hearing impairment and loss of hand function MPS III – The most common MPS disorder; severe central nervous system (CNS) involvement[emedicine.medscape.com]
  • 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]
  • However, a clear association between EEG, CNS and the history of seizures was not established.[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]
  • […] sure he is safe when he has seizure episode.[slideshare.net]
  • Keywords: Hunter syndrome, mucopolysaccharidosis II, lysosomal storage disorder, developmental delay, cognitive impairment, neurology, neurological symptoms, seizures, spinal cord compression, neuronopathic[touchneurology.com]
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]
  • 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]
  • 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]
  • Communicating hydrocephalus may occur without ventriculomegaly, due to the thickened arachnoid membrane. Presence of acute behavioral changes, headaches, and vomiting should trigger an evaluation of hydrocephalus.[medicalhomeportal.org]
  • Neurological symptoms may include mild to moderate mental retardation by age 3, communicating hydrocephalus, nerve entrapment, corneal clouding, and some loss of peripheral and night vision.[slideshare.net]
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]
  • gait with frequent falls Qualitative urine glycosaminoglycan (GAG) analysis demonstrates keratan sulfate and chondroitin 6-sulfate.[centogene.com]
Sleep Disturbance
  • The high frequency of frontal lobe seizures causes sleep fragmentation, which may result in sleep disturbances observed in at least a small percentage of MPS patients.[ncbi.nlm.nih.gov]
  • The major features of MPS III include the following: Onset of symptoms is usually between 2 and 6 years Presenting symptoms include hyperactive, aggressive and destructive behaviors and sleep disturbances Mental development abnormalities starts slowly[centogene.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]
Papilledema
  • Angina; valvular dysfunction; hypertension; congestive heart failure Pulmonary disease – Airway obstruction, potentially leading to sleep apnea, severe respiratory compromise, or cor pulmonale Ophthalmologic disease – Corneal clouding; glaucoma; chronic papilledema[emedicine.medscape.com]
  • Glaucoma and chronic papilledema Deafness Middle ear infections, deformity of the ossicles, and abnormalities of the inner ear.[slideshare.net]
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]
  • 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]
  • 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]
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]
  • 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]
  • 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]
  • Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span.[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]
  • 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 glycosaminoglycan[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]
  • We report a case of a 5-year-old boy with developmental delay and behaviour problems admitted to the Department of Paediatrics due to chronic hypertransaminasemia.[ncbi.nlm.nih.gov]
Coarse Facial Features
  • 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 glycosaminoglycan[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]
  • Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span.[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]
  • 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]
  • Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance.[ncbi.nlm.nih.gov]
Diarrhea
  • 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]
  • 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]
  • 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]
  • Most children with MPS type IIIA have severe neurological impairment by age 6 years Recurrent or chronic diarrhea and seizures occurs in some MPS III patients.[centogene.com]
Chronic Diarrhea
  • Most children with MPS type IIIA have severe neurological impairment by age 6 years Recurrent or chronic diarrhea and seizures occurs in some MPS III patients.[centogene.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]
Dental Caries
  • Mothers' SOC of children/adolescents with MPS was associated with dental caries experience in their children. Improving mothers' SOC should contribute to a better quality of life for their children.[ncbi.nlm.nih.gov]
  • Dental Dental caries and abscessed teeth occur easily because the teeth are poorly formed and have fragile enamel, which causes susceptibility to infection and decay.[medicalhomeportal.org]
  • Mouth and Throat Sore on lips Color/ cracks/ ulceration Oral cavity Mucus membrane color Gum-bleeding/ ulceration/ swelling Missing teeth Dental caries Tongue Odor from mouth Difficulty in swallowing Tonsils Absent Pink color, no cracks and ulceration[slideshare.net]
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]
Heart Failure
  • Despite the common pharmacologic treatment and implementation of enzyme replacement therapy with galsulfase the patient died at the age of 38 years because of decompensation of chronic heart failure.[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]
  • Those with multiple organ system involvement may have the following presentations: CNS disease – Hydrocephalus; cervical spine myelopathy Cardiovascular disease – Angina; valvular dysfunction; hypertension; congestive heart failure Pulmonary disease –[emedicine.medscape.com]
  • Other cardiac problems include: Thickening of the mitral and aortic valves leading to regurgitation or stenosis Myocardial thickening that contributes to heart failure Cardiac arrhythmias that lead to heart block, resulting in the need for a permanent[medicalhomeportal.org]
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]
  • impairment – Deafness Musculoskeletal disease – Short stature; joint stiffness; symptoms of peripheral nerve entrapment Findings from examination may include the following: MPS IH – Corneal clouding, hepatosplenomegaly, skeletal deformities (dysostosis[emedicine.medscape.com]
  • Audiology (see Services below for relevant providers) Refer at the time of diagnosis and for annual visits to determine the degree, cause, and progression of hearing impairment.[medicalhomeportal.org]
Hirsutism
  • […] much slower progression; normal intelligence and no hydrocephalus; hearing impairment and loss of hand function MPS III – The most common MPS disorder; severe central nervous system (CNS) involvement and only minimal somatic involvement; coarse hair, hirsutism[emedicine.medscape.com]
  • 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]
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]
  • In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and[mdpi.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]
  • Subspecialist Collaborations & Other Resources Pediatric Ophthalmology (see Services below for relevant providers) Refer for initial evaluation and periodic management of visual acuity, corneal opacity, optic nerve abnormalities, and peripheral vision[medicalhomeportal.org]
Visual Impairment
  • These complications may result in visual impairment and even blindness.[symptoma.com]
  • Patients may suffer from glaucoma, severe visual impairment with retinal degeneration, optic nerve compression and atrophy, and the loss of peripheral vision.[medicalhomeportal.org]
  • 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
  • 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]
Skeletal Dysplasia
  • Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias.[ncbi.nlm.nih.gov]
  • The pathogenesis and treatment of systemic skeletal dysplasia in MPS IVA remains an unmet challenge.[ncbi.nlm.nih.gov]
  • 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. GAGs were quantified by spectrometry method with 1,9-dimethylen blue in 24-hour urine samples.[ncbi.nlm.nih.gov]
  • 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]
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]
  • […] and micrognathia; corneal clouding, joint stiffness, and heart disease MPS IS - Aortic valve disease, corneal clouding, and joint stiffness; normal intelligence and stature MPS II (severe) – Pebbly ivory skin lesions on the back, arms, and thighs; coarse[emedicine.medscape.com]
  • 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]
  • Short and often claw-like hands, progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function. Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea .[en.wikipedia.org]
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]
  • 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]
  • 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]
Genu Valgum
  • 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]
  • valgum, short stature, spinal curvature, odontoid hypoplasia, ligamentous laxity, and atlantoaxial instability MPS IV (mild) – Much slower progression of skeletal dysplasia MPS VI – Features very similar to MPS IH MPS VII – Features similar to MPS IH[emedicine.medscape.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]
  • valgum, hypermobile joints Waddling gait with frequent falls Qualitative urine glycosaminoglycan (GAG) analysis demonstrates keratan sulfate and chondroitin 6-sulfate.[centogene.com]
Coxa Valga
  • 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]
  • Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT.[journals.lww.com]
  • Affected individuals usually present with unusual skeletal features including short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, gibbus, scoliosis, genu valgus, coxa valga, and flaring of the lower ribs.[genedx.com]
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]
  • 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]
  • Other problems include carpal tunnel syndrome or other nerve compression, stiff joints, claw hands and deformed feet, a short neck, and aortic valve disease. Some affected individuals also have obstructive airway disease and sleep apnea.[en.wikipedia.org]
  • 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)[en.wikipedia.org]
  • Physical Exam General Look for coarsening of facial features resulting in a remarkably consistent appearance that involves a short nose, flat face, thick lips and gums and large head (relatively elongated front to back with a prominent forehead).[medicalhomeportal.org]
  • lips, and enlarged mouth and tongue) Corneal clouding Degeneration of retina Decreased visual acquity Short stature with disproportionate short trunk Short stature but proportionate trunk Dysplasia (abnormal bone size and shape or other skeletal abnormalities[slideshare.net]
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]
  • Increased accumulation of mucopolysaccharides leads to characteristic facial features such as thickened lips, enlarged tongue, a full lower aspect of the face, depressed nasal bridge, thickened eyebrows, and frontal bossing.[invitae.com]

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]
  • Coarsening of facial features and enlargement of the liver and spleen occur over the first few months, leading to diagnosis usually by 18 months.[medicalhomeportal.org]
  • , liver and bone lesions.[slideshare.net]

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