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Mucopolysaccharidosis 1

MPSI

Mucopolysaccharidosis 1 is a rare lysosomal storage disease provoked by mutations of the gene encoding for alpha-L-iduronidase, an enzyme required for the breakdown of determined glycosaminoglycans. Depending on the severity of the disease, patients may be diagnosed with Scheie syndrome, Hurler Scheie syndrome or Hurler syndrome.


Presentation

In general, MPS 1 is a multisystem disorder that follows a progressive course. Although coarse facial features, short stature, skeletal dysplasia reminiscent of dysostosis multiplex, cardiac and respiratory disease as well as corneal clouding are universal, there are considerable differences regarding the clinical presentation of MPS-IS and MPS-IH patients. These especially refer to the involvement of the central nervous system and corresponding deficits. Thus, these entities shall be presented separately.

Clinical presentation is particularly heterogeneous in MPS-IS patients. Median age at symptom onset is 5 years, but due to rather mild symptoms and insufficient awareness of the disease, most patients are not diagnosed with MPS-IS until late adolescence [3]. Joint contractures, cardiac valve abnormalities and corneal clouding are most frequently reported and about half of MPS-IS patients present the complete symptom triad [7]. Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly. Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty. MPS-IS patients are of normal intelligence; the absence of cognitive developmental delays at the age of two years has been proposed as a clinical feature to distinguish MPS-IS from MPS-IH.

Children suffering from MPS-IH develop first symptoms during their first year of life, and the disease is usually confirmed within months afterwards [3]. Affected individuals may present with any of those symptoms listed for MPS-IS. However, disease progression occurs rapidly and additional symptoms manifest early in life. The major difference between MPS-IH and less severe forms of the disease is profound intellectual disability due to neuronal loss, premature closure of cranial sutures, and possibly hydrocephalus and increased intracranial pressure. Developmental delays, hearing loss and macroglossia contribute to severely reduced language acquisition. Coarse facial features are more pronounced than in MPS-IS patients and may be accompanied by facial and body hypertrichosis. Besides corneal clouding, glaucoma and retinopathy may develop and may eventually cause complete vision loss. Of note, visual impairment may also result from central nervous system involvement. Skeletal dysplasia is striking and although neonates may appear healthy, radiographic studies may reveal signs of dysostosis multiplex at birth. Atlantoaxial subluxation and stenosis of the spinal canal are observed in about a third of MPS-IH patients and results in spinal cord compression and early cervical myelopathy [8]. Vertebral hypoplasia may be observed along the spinal column.

Coarse Facial Features
  • Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly.[symptoma.com]
  • facial features Communicating hydrocephalus (fluid on the brain) Abnormally shaped teeth Life expectancy Life expectancy varies significantly for people with MPS I.[mps1disease.com]
  • Patients may also have coarse facial features, although this is usually milder than that seen in MPSI or MPSII.[genedx.com]
  • Some of the symptoms include: Abnormal bones in the spine Claw hand Cloudy corneas Deafness Halted growth Heart valve problems Joint disease, including stiffness Intellectual disability that gets worse over time in severe MPS I Thick, coarse facial features[medlineplus.gov]
  • 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]
Short Stature
  • Clinical features and disease severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities and facial dysmorphism.[news-medical.net]
  • Other causes of general learning disability and short stature. Investigations [ 1, 3 ] Diagnosis: The urine GAGs pattern, confirmed by iduronidase enzyme assay, is diagnostic.[patient.info]
  • 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]
  • This leads to complex and heterogeneous symptoms, and MPS 1 patients may present with coarse facial features, short stature, skeletal dysplasia, cardiac and respiratory disease as well as corneal clouding.[symptoma.com]
  • stature, dysostosis multiplex, hepatosplenomegaly, corneal clouding, umbilical or inguinal hernia, generally normal mental development with psychotic symptoms later in life, and death by age 25 years.[icd10data.com]
Developmental Delay
  • Those suffering from the most severe form of the disease, which may be referred to as Hurler syndrome, also show developmental delays and intellectual disability.[symptoma.com]
  • Developmental delay may plateau, but then the child’s developmental skills may regress.[medicalhomeportal.org]
  • The most severe form of MPS I, Hurler syndrome affects the brain and spinal cord in children, resulting in medical and cognitive challenges that can include developmental delay, progressive mental decline, loss of physical function, impaired language[armagen.com]
  • Some children with mucopolysaccharidosis type I (MPS I) have developmental delays.[babysfirsttest.org]
  • Clinical features of MPS IIID include hyperactivity, aggressiveness, and developmental delays. Mental abilities decline as the disease progresses.[egl-eurofins.com]
Inguinal Hernia
  • Umbilical hernias and inguinal hernias. Joint stiffness and skeletal deformities. Cardiomyopathy and coronary heart disease. Hepatosplenomegaly.[patient.info]
  • hernia, generally normal mental development with psychotic symptoms later in life, and death by age 25 years.[icd10data.com]
  • Children with MPS I often have no signs or symptoms of the condition at birth, although some have a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia).[ghr.nlm.nih.gov]
  • Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly.[symptoma.com]
  • Early Signs of MPS I include: Soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia) Large head (macrocephaly) Distinctive facial features that appear “coarse” Varying degrees of developmental delay and learning[babysfirsttest.org]
Recurrent Otitis Media
  • Typical clinical findings at various ages include: 0 - 6 months Chronic rhinitis Recurrent otitis media or "glue ear" with thick cerumen Umbilical or inguinal hernia Above normal growth and head size 6 months -12 years Distinctive facial gestalt, with[medicalhomeportal.org]
  • otitis media Impaired hearing Recurrent sinopulmonary infections Upper airway obstruction Sleep apnea Reduced pulmonary function Cardiac abnormalities and valvular disease Hepatosplenomegaly Umbilical and inguinal hernias Reduced joint range of motion[biomarin.com]
  • Recurrent respiratory infections were noted in 11 of the 27 patients (41%) and recurrent otitis media was seen in 19 (70%), all with documented conductive hearing loss and requiring pressure-equalizing tubes.[jamanetwork.com]
  • otitis media Consideration of sleep study Cranial imaging, preferentially MRI, including assessment of possible hydrocephalus Assessment of spinal cord and peripheral nerve involvement Developmental assessment Consultation with a clinical geneticist[ncbi.nlm.nih.gov]
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]
  • In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression.[neurology.testcatalog.org]
Respiratory Insufficiency
  • Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty.[symptoma.com]
  • Clinical features and severity of symptoms of MPS IVA are widely variable, but may include skeletal dysplasia, short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal.[neurology.testcatalog.org]
Rhinorrhea
  • Rhinorrhea is common. Sleep apnea as a result of obstructive airway disease and possibly CNS involvement occurs in attenuated MPS I. Gastrointestinal system.[ncbi.nlm.nih.gov]
Diarrhea
  • 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]
  • Atypical microbial infections of digestive tract may contribute to diarrhea in mucopolysaccharidosis patients: a MPS I case study.[ncbi.nlm.nih.gov]
  • The most frequently reported adverse reactions included: chills, vomiting, nausea, arthralgia, diarrhea, tachycardia, abdominal pain, blood pressure increased, and oxygen saturation decreased.[biomarin.com]
  • Patients may also have diarrhea. Aortic valve disease may occur. Upper and lower respiratory tract infections can be frequent. Developmental delay may become apparent by age 1-2 years, with a maximum functional age of 2-4 years.[en.wikipedia.org]
  • Hearing loss Poor peripheral vision Diarrhea Sleep apnea Although respiratory and cardiac complications can contribute to premature death. Persons with MPS II B may live into their 50s or beyond.[wikidoc.org]
Macroglossia
  • Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty.[symptoma.com]
  • […] 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), and a large tongue (macroglossia[ghr.nlm.nih.gov]
  • MPS IH is the most severe and has an early onset consisting of skeletal deformities, coarse facial features, hepatosplenomegaly, macrocephaly, cardiomyopathy, hearing loss, macroglossia, and respiratory tract infections.[neurology.testcatalog.org]
  • On examination, child had dysmorphic features such as frontal bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli,[jcor.in]
  • This type of deposit can as well be seen on the pharynx walls and, when in association with macroglossia and mandible abnormalities (occasionally they are seen on MPS cases), there is the risk of progressive obstruction of upper airways and sleep apnea[arquivosdeorl.org.br]
Hepatosplenomegaly
  • Symptoms may include dwarfism, hepatosplenomegaly, gargoyle-like facies, corneal clouding, cardiac complications, and noisy breathing.[icd10data.com]
  • Clinical features and disease severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities and facial dysmorphism.[news-medical.net]
  • Symptoms include, macrocephaly, excessive accumulation of fluid in the brain, hepatosplenomegaly, sleep apnea, cornea clouding, spinal cord compression and cognitive impairment. Severe MPS I occurs in approximately 1 in 100,000 newborns.[raredr.com]
  • Symptoms may include DWARFISM; hepatosplenomegaly; thick, coarse facial features with low nasal bridge; corneal clouding; cardiac complications; and noisy breathing.[doctor.am]
  • Hepatosplenomegaly. Dysostosis multiplex: enlarged skull, enlarged but shortened bones, malformed pelvis, and other skeletal defects. Mucopolysaccharidosis I-Hurler (MPS I-H) Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form MPS.[patient.info]
Hepatomegaly
  • Joint stiffness, corneal clouding, umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Death tends to be in their 20s.[patient.info]
  • 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]
  • Further common findings are coarse facial features, carpal tunnel syndrome, umbilical and inguinal hernia, and hepatomegaly.[symptoma.com]
  • Features include short-trunk dwarfism, short neck, joint hypermobility, respiratory disease, cardiac disease, impaired vision with corneal clouding, hearing loss, dental abnormalities, hepatomegaly, and elevated urinary keratan sulfate.[invitae.com]
  • The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function.[neurology.testcatalog.org]
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]
  • […] 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]
  • It is genetically determined, generating skeletal deformities, corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism, hirsutism and hydrocephaly.[journals.lww.com]
  • […] bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli, abdominal distension, umbilical hernia, noisy breathing, and hirsutism[jcor.in]
  • The main features observed were: normal appearance at birth with a progressive coarse facies, progressive neurological deterioration, corneal clouding, gibbous lumbar vertebrae, hirsutism, joint contractures, hepatosplenomegaly, short stature, and skeletal[scielo.br]
Hypertrichosis
  • Coarse facial features are more pronounced than in MPS-IS patients and may be accompanied by facial and body hypertrichosis. Besides corneal clouding, glaucoma and retinopathy may develop and may eventually cause complete vision loss.[symptoma.com]
  • Facial and body hypertrichosis are often seen by age 24 months, at which time the scalp hair is coarse, straight, and thatch-like. Hepatosplenomegaly. Protuberance of the abdomen caused by progressive hepatosplenomegaly is common [ Clarke 1997 ].[ncbi.nlm.nih.gov]
Hearing Impairment
  • Hearing impairment. Umbilical hernias and inguinal hernias. Joint stiffness and skeletal deformities. Cardiomyopathy and coronary heart disease. Hepatosplenomegaly.[patient.info]
  • 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 local providers) Refer at the time of diagnosis and for annual visits to determine the degree, cause, and progression of hearing impairment.[medicalhomeportal.org]
  • The severe form of MPS I is known as Hurler syndrome or MPS I H : Children affected with the severe form may have mental retardation, short stature, stiff joints, speech and hearing impairment, heart disease, and a shortened lifespan.[verywell.com]
  • Hearing impairment, most commonly in the high frequency range, is likely caused by a combination of eustachian tube dysfunction, dysostosis of the ossicles of the middle ear, and eighth nerve involvement. ENT (otolaryngologic). Rhinorrhea is common.[ncbi.nlm.nih.gov]
Hearing Problem
  • By the age of three growth usually slows down significantly and intellectual and hearing problems become apparent.[verywell.com]
  • Pediatricians, surgeons, specialists who assess and treat heart problems (cardiologists), specialists who assess and treat hearing problems (audiologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat[rarediseases.org]
Corneal Opacity
  • 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]
  • Tukey's multiple comparison test demonstrated a statistically significant difference in IOP between the mild and severe corneal opacity groups, but not between mild and moderate, or moderate and severe corneal opacity groups.[nature.com]
  • opacity, and central nervous system (CNS) involvement).[tandfonline.com]
Joint Stiffness
  • Joint stiffness and contractures limit mobility. Cardiac disease affects all children with MPS I-H. Death occurs before the age of 10 years.[patient.info]
  • Additional signs and symptoms that may develop include: Enlarged head Chronic nasal discharge Retinal degeneration Splenomegaly Enlarged abdominal organs Skeletal dysplasia Joint stiffness The cause of MPS I is inherited genetic mutations on chromosome[medicinenet.com]
  • Within the first year, skeletal deformities, joint stiffness, and developmental delay may become apparent.[medicalhomeportal.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]
  • […] 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]
Skeletal Dysplasia
  • Skeletal dysplasia is striking and although neonates may appear healthy, radiographic studies may reveal signs of dysostosis multiplex at birth.[symptoma.com]
  • Additional signs and symptoms that may develop include: Enlarged head Chronic nasal discharge Retinal degeneration Splenomegaly Enlarged abdominal organs Skeletal dysplasia Joint stiffness The cause of MPS I is inherited genetic mutations on chromosome[medicinenet.com]
  • Mucopolysaccharidosis type IVA or Morquio syndrome A is a lysosomal storage disorder characterized by skeletal dysplasia due to excessive storage of keratan sulfate.[genedx.com]
  • Dysplasia Society, Southeastern Regional Genetics Group Disclosure: Nothing to disclose.[emedicine.medscape.com]
  • Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis.[novapublishers.org]
Macrocephaly
  • Symptoms include, macrocephaly, excessive accumulation of fluid in the brain, hepatosplenomegaly, sleep apnea, cornea clouding, spinal cord compression and cognitive impairment. Severe MPS I occurs in approximately 1 in 100,000 newborns.[raredr.com]
  • 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]
  • Early Signs of MPS I include: Soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia) Large head (macrocephaly) Distinctive facial features that appear “coarse” Varying degrees of developmental delay and learning[babysfirsttest.org]
  • The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function.[neurology.testcatalog.org]
Genu Valgum
  • Bone deformities like kyphosis or gibbus, scoliosis, genu valgum, pes cavus have been described and may cause gait disturbances. Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss.[symptoma.com]
  • 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]
  • Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum.[novapublishers.org]
  • valgum, hypermobile joints Waddling gait with frequent falls Qualitative urine glycosaminoglycan (GAG) analysis demonstrates keratan sulfate and chondroitin 6-sulfate.[centogene.com]
Coxa Valga
  • 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]
  • The femoral heads are small and coxa valga is common. Involvement of the femoral heads and acetabula leads to progressive and debilitating hip deformity.[ncbi.nlm.nih.gov]
Short Neck
  • Airway evaluation: abnormal neck anatomy, short neck with limited mobility, hyromental and thyromentonian distance less than 6 cm, severely limited jaw protrusion, mouth opening inferior to 6 cm, mallampati IV and snoring.[omicsonline.org]
  • Features include short-trunk dwarfism, short neck, joint hypermobility, respiratory disease, cardiac disease, impaired vision with corneal clouding, hearing loss, dental abnormalities, hepatomegaly, and elevated urinary keratan sulfate.[invitae.com]
  • On examination, child had dysmorphic features such as frontal bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli,[jcor.in]
  • 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]
  • However, laryngoscopy and intubation in these cases is often complicated by the presence of craniofacial abnormalities, a short neck, stiffening of the temporomandibular joint, a large tongue, and an anteriorly positioned larynx. 10 Should the airway[jamanetwork.com]
Thick Lips
  • The early signs usually are coarsening of facial features with enlarged mouth, thick lips, and eye problems that progressively become worse.[medicinenet.com]
  • 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 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]
  • 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]
Hypertelorism
  • On examination, child had dysmorphic features such as frontal bossing, hypertelorism, saddle nose, low-set ears, macroglossia, short stature, short neck, kyphosis of lumbar spine, pigeon chest, widening of wrist, bowing of legs, doubling of malleoli,[jcor.in]
  • In a significant number of cases, 2,9 the initial diagnosis might be suspected from the ENT consultation with a special emphasis on anamnesis and examination (prominent torus frontalis, hypertelorism, sunken nasal dorsum, anteverted nostrils, thickened[elsevier.es]
  • Patients present with characteristic coarse facial features, hypertelorism, and a flattened nasal dorsum.[jamanetwork.com]
Frontal Bossing
  • Radiology of skull, face, chest, long bones, and spine showed short stubby small bones, frontal bossing, thick ribs, thickened metaphyses of long bones, spinal thoracolumbar kyphosis highly suggestive of MPS (type IV).[jcor.in]
Myelopathy
  • Patients may develop myelopathy, but this condition does generally not manifest before puberty.[symptoma.com]
  • Odontoid hypoplasia is the most serious skeletal finding because, in combination with ligamentous laxity and mucopolysaccharide deposition, it may result in atlantoaxial subluxation, cervical myelopathy or even death.[genedx.com]
  • Joint stiffness, corneal clouding, umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Death tends to be in their 20s.[patient.info]
  • Abnormalities, Ocular Hypertension and Glaucoma [ 4 ] • Central and Peripheral Nervous System–Related Symptoms: is not typically associated with progressive impairment of mental status, but Carpal Tunnel Syndrome, Communicating Hydrocephalus and Compressive Myelopathy[omicsonline.org]
  • 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]
Sleep Disturbance
  • Sleep disturbances due to respiratory insufficiency may be experienced and patients may claim a hearing loss. Some patients present with macroglossia. Patients may develop myelopathy, but this condition does generally not manifest before puberty.[symptoma.com]
  • The MPS I registry reports the following findings in individuals with Hurler syndrome [2] : Coarse facial features (86.4%) Corneal clouding (70.9%) Heaptomegaly (70.0%) Kyphosis/gibbus (70.0%) Hernias (58.9%) Airway-related symptoms, such as sleep disturbances[oncofertility.northwestern.edu]
  • 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]
  • This disorder may be recognized in childhood by developmental delays, behavioural difficulties, sleep disturbances and dementia.[rheumatology.oxfordjournals.org]
Psychomotor Regression
  • Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed.[adc.bmj.com]
Abnormal Gait
  • Hypermobile joints and an abnormal gait with a tendency to fall may also be presenting features. Unlike other mucopolysaccharidoses (MPS) intelligence is often preserved.[genedx.com]
Cognitive Developmental Delay
  • MPS-IS patients are of normal intelligence; the absence of cognitive developmental delays at the age of two years has been proposed as a clinical feature to distinguish MPS-IS from MPS-IH.[symptoma.com]

Workup

Most patients suffering from MPS 1 have a family history of complaints consistent with this disease. Even if such data are not available, findings of general, ophthalmological and neurological examination, as well as radiographic studies, may prompt a strong suspicion of mucopolysaccharidosis. Clinical features of distinct types of mucopolysaccharidosis may overlap, though, and a target-oriented workup is necessary. The assessment of glycosaminoglycan excretion in urine is helpful to diagnose and distinguish related entities. Qualitative and quantitative analyses should be performed; MPS 1 patients typically excrete excess dermatan and heparan sulfate. However, this approach has limited sensitivity and it is strongly recommended to either determine IDUA activity or to employ molecular biological techniques to demonstrate gene defects consistent with MPS 1. With regards to the former, IDUA activity may be evaluated in leukocytes, dried blood spots or fibroblasts. Recently, a modified IDUA assay has been described that allows for the precise quantification of residual IDUA activity, and such results may enable the physician to predict the course of the disease [5].

Enlargement of the Spleen
  • Stiffened joints Skeletal (bone) Carpal tunnel syndrome Heart (valve) disease Recurrent upper airway infections Lung disease/sleep apnea Corneal clouding Spinal cord compression Enlarged liver and spleen Hernia (inguinal or umbilical) Hearing loss Delayed[mps1disease.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]
  • […] 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]
  • In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression.[neurology.testcatalog.org]
  • Symptoms of MPS I MPS II Abnormal bones, including shortened stature and spine problems Intellectual disabilities Heart disease Enlarged liver and spleen Joint stiffness Vision or hearing loss Depression Chronic Pain Shortened lifespan Prevalence / Incidence[sangamo.com]
Enlargement of the Liver
  • 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]
  • 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]
Trophoblastic Cells
  • Biological diagnosis relies on detection of increased urinary excretion of DS and HS and the demonstration of the enzymatic deficiency (in plasma, leucocytes, fibroblasts, trophoblastic cells or amniocytes).[orpha.net]

Treatment

Enzyme replacement therapy and hematopoietic stem cell transplantation are the mainstays of treatment of attenuated MPS 1 and MPS-IH, respectively. Hematopoietic stem cell transplantation has been shown to improve the neurological outcome and to increase survival times in patients suffering from the most severe form of the disease. Nevertheless, long-term follow-ups revealed disease progression years after the successful realization of this procedure [6]. Stem cell transplantation should be performed as early as possible, ideally in infants aged less than four months. Due to morbidity and mortality associated with this therapeutic measure, it is currently not recommended for MPS-IHS and MPS-IS patients. Enzyme replacement therapy consists of weekly administration of 100 U/kg recombinant IDUA (laronidase; Aldurazyme®) per kg body weight; this compound has obtained approval for MPS 1 treatment in 2003 [9]. Patients should be prepared for intravenous laronidase application with antihistamines and/or antipyretics that are to be administered one hour prior to treatment with recombinant IDUA. Of note, laronidase is also given to patients diagnosed with MPS-IH after stem cell transplantation. Although the compound does not cross the blood-brain barrier and thus cannot prevent glycosaminoglycan accumulation within the central nervous system, it is likely to have a positive effect on the patient's quality of life [10].

In any case, supportive care should be provided to MPS 1 patients. It should be adjusted to the individual needs of the affected person and may comprise physiotherapy, orthopedic measures, provision of hearing aids, analgesia, prophylactic administration of antibiotics, supplementation of oxygen, and psychological support. Surgical interventions may become necessary to remedy joint contractures, skeletal deformities, cardiac valve insufficiency or stenosis, spinal cord compression, and other pathological conditions. A multidisciplinary team is required to support the patient and their family, and this team should be consulted in regular follow-ups. Periodic performance of pulmonary function tests, echocardiography, and neurological evaluation, among others, are of major importance to estimate disease progression and the patient's risk of complications.

Prognosis

As has been indicated above, only confirmation of nonsense mutations on both alleles allows for the prediction of a patient’s phenotype from their genotype. If so, the patient is likely to develop MPS-IH. Otherwise, the heterogeneity of underlying phenotypes has not yet allowed for establishing unequivocal genotype-phenotype correlation [2]. In contrast, residual activity of IDUA directly correlates with the outcome. Quantification of low IDUA activity requires a very sensitive assay, but has been achieved: Dutch researchers have proven MPS-IS patients to show residual IDUA activity of 0.8% of control values, while MPS-IHS and MPS-IH were associated with a residual activity of 0.3% and <0.2%, respectively [5]. Still, more extensive studies on this subject are required to provide general reference ranges.

Patients suffering from MPS-IS may have a near-to-normal life expectancy, but the disease is still associated with considerable morbidity. Individuals affected by MPS-IHS often die in early adulthood. To date, the prognosis of MPS-IH patients is poor. Most patients die within their first decade of life from respiratory or heart failure. Hematopoietic stem cell transplantation is the treatment of choice, and if performed at a very young age when cognitive function is not yet impaired, this therapy may improve survival and neurodevelopment [6].

Etiology

All forms of MPS 1 are caused by mutations in the IDUA gene. This gene is located on the short arm of chromosome 4 and encompasses approximately 18 kb, which include 14 exons that are assembled to a 653-amino acid precursor protein. To date, more than 200 distinct mutations have been described in MPS 1 patients [1]. The majority of known sequence anomalies corresponds to missense mutations, while nonsense mutations and gene variants leading to alternative splicing, deletions and insertions account for minor shares of MPS 1-related defects [2]. Genotype-phenotype correlations have been established insofar as nonsense mutations generally trigger MPS-IH; affected patients carry such mutations on both alleles and are unable to synthesize functional IDUA. In contrast, residual activity of IDUA may be detected in patients with missense mutations of the respective gene, and it may attenuate the severity of the disease. In this context, only trace amounts of functional IDUA are encountered in MPS-IHS patients, while enzymatic activity is maintained to a greater degree in MPS-IS patients. According to the current knowledge, enzymatic activity as assessed in an individual patient determines the course of the disease. Moreover, modifying factors have not been identified so far; all forms of the disease are inherited as an autosomal recessive trait.

Epidemiology

The overall incidence of MPS 1 has been estimated to 1 in 100,000 live births [3]. About 61% of affected neonates develop MPS-IH, while MPS-IHS and MPS-IS account for 23% and 13% of all cases, respectively. In the cited study, the remainder of cases was classified as undetermined. While Caucasians were overrepresented in the MPS 1 Registry, this may be due to most study participants being Europeans or North Americans. A literature review reveals that people of all races and both genders may be affected by the disease.

Sex distribution
Age distribution

Pathophysiology

IDUA is a lysosomal enzyme catalyzing the hydrolytic cleavage of dermatan sulfate and heparan sulfate. In MPS 1 patients, IDUA activity is severely reduced and thus, glycosaminoglycans accumulate in lysosomes. This condition initially disturbs lysosomal function, but the progressive enlargement of these cell organelles eventually has detrimental consequences for the whole cell and the tissue it forms part of. Furthermore, glycosaminoglycans may alter gene expression and thus affect the composition of the extracellular matrix. Recent studies have shown such pathophysiological events to be involved in MPS 1-associated cartilage and bone damage [4], but it is tempting to speculate that these mechanisms also contribute to lesions of other organs. In fact, inappropriate accumulation of dermatan sulfate and heparan sulfate is mainly observed in connective tissue and the wide distribution of connective tissue in the human body explains why affected individuals develop multisystem sequelae.

Prevention

Affected families may benefit from genetic counseling. Furthermore, chorionic villus sampling and amniocentesis allow obtaining specimens suitable for enzyme activity assessment and genetic screens. Thus, prenatal diagnosis of MPS 1 is feasible. In the case of positive results, parents-to-be may be offered the possibility of a premature termination of pregnancy. Neonates born to families with a history of MPS 1 should be tested as early as possible. This way, treatment may be initialized before irreversible organ damage occurs. This is of particular importance for individuals suffering from MPS-IH since this disease requires hematopoietic stem cell transplantation within the first months of life. With regards to milder forms of the disease, pediatricians are encouraged to realize regular examinations, to monitor development and growth, and to refer their patients to specialists if doubts arise.

Summary

Mucopolysaccharidosis 1, also referred to as MPS 1, is a lysosomal storage disease. MPS 1 is inherited as an autosomal recessive trait and is triggered by distinct mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA). This enzyme is expressed in lysosomes and catalyzes the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. In MPS 1 patients, a functional deficiency of α-L-iduronidase results in the progressive accumulation of glycosaminoglycans in lysosomes, and this condition eventually interferes with cellular, tissue and organ functions. Because this entity affects virtually all organ systems, affected individuals may present complex and heterogeneous symptoms. Depending on the severity of the disease, the following forms of MPS 1 may be distinguished:

  • Scheie syndrome (MPS-IS) follows a chronic but relatively mild course and patients primarily present with skeletal, cardiac and ocular symptoms.
  • Hurler Scheie syndrome (MPS-IHS) describes an intermediate form of MPS 1.
  • Hurler syndrome (MPS-IH) is the most severe form of MPS 1 and patients additionally experience symptoms of central nervous system compromise.

Of note, MPS-IS and MPS-IHS correspond to attenuated MPS 1.

Patient Information

Mucopolysaccharidosis 1 (MPS 1) is a rare genetic disorder. It is provoked by mutations of the gene encoding for the enzyme α-L-iduronidase (IDUA), and this enzyme is required for the breakdown of determined glycosaminoglycans, namely of dermatan sulfate and heparan sulfate. These may be encountered in virtually any tissue and because MPS 1 patients are unable to synthesize functional IDUA, these molecules accumulate within cell organelles called lysosomes. In fact, MPS 1 is commonly classified as a lysosomal storage disease. Eventually, build up of glycosaminoglycans interferes with cellular, tissue and organ function. This leads to complex and heterogeneous symptoms, and MPS 1 patients may present with coarse facial features, short stature, skeletal dysplasia, cardiac and respiratory disease as well as corneal clouding. Those suffering from the most severe form of the disease, which may be referred to as Hurler syndrome, also show developmental delays and intellectual disability.

Hematopoietic stem cell transplantation in early infancy is recommended to patients diagnosed with Hurler syndrome, and these individuals may subsequently receive recombinant IDUA. The latter replaces the defective enzyme and thus allows for partial degradation of glycosaminoglycans. Thereby, the patient's quality of life is improved. Unfortunately, there is no cure for MPS 1 and while mild forms of the disease are associated with a near-to-normal life span, they are also related to significant morbidity. Patients diagnosed with Hurler syndrome may live to their twenties if hematopoietic stem cell transplantation is performed early and successfully.

References

Article

  1. Kwak MJ, Huh R, Kim J, Park HD, Cho SY, Jin DK. Report of 5 novel mutations of the alpha-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I. BMC Med Genet. 2016; 17(1):58.
  2. Terlato NJ, Cox GF. Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature. Genet Med. 2003; 5(4):286-294.
  3. Beck M, Arn P, Giugliani R, et al. The natural history of MPS I: global perspectives from the MPS I Registry. Genet Med. 2014; 16(10):759-765.
  4. Heppner JM, Zaucke F, Clarke LA. Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I. Mol Genet Metab. 2015; 114(2):146-155.
  5. Oussoren E, Keulemans J, van Diggelen OP, et al. Residual alpha-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients. Mol Genet Metab. 2013; 109(4):377-381.
  6. 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.
  7. Thomas JA, Beck M, Clarke JT, Cox GF. Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I. J Inherit Metab Dis. 2010; 33(4):421-427.
  8. Grech R, Galvin L, O'Hare A, Looby S. Hurler syndrome (Mucopolysaccharidosis type I). BMJ Case Rep. 2013; 2013.
  9. Thomas JA, Jacobs S, Kierstein J, Van Hove J. Outcome after three years of laronidase enzyme replacement therapy in a patient with Hurler syndrome. J Inherit Metab Dis. 2006; 29(6):762.
  10. Arranz L, Aldamiz-Echevarria L. Enzyme replacement therapy in Hurler syndrome after failure of hematopoietic transplant. Mol Genet Metab Rep. 2015; 3:88-91.

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Last updated: 2019-07-11 20:45