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Mucopolysaccharidosis 1H

Hurler Syndrome

Mucopolysaccharidosis type 1H (MPS1H), also known as Hurler syndrome, Hurler's disease or gargoylism, is the most severe form of mucopolysaccharidosis type 1.


Presentation

MPS1H presents as a multisystem disorder in the early childhood [3]. Most important manifestation is developmental delay which becomes evident by the end of first year of life. There is also progressive mental deterioration. The systemic manifestations are classified as:

Short Stature
  • 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]
  • 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.[rarediseases.about.com]
  • Patients with MPS1H are usually short-statured. Joint stiffness: Joint stiffness occurs by the age of 2 years and is progressive. There is a characteristic claw-hand deformity due to phalangial dysostosis.[symptoma.com]
Pathologist
  • Hurler’s syndrome; [updated 5/15/11} Jul 19; Available from: Kelly Hungaski MS/CCC-SLP has been practicing as an ASHA certified speech language pathologist for the last 16 years.[smartspeechtherapy.com]
  • At each clinic visit, the patients underwent comprehensive physical and neurodevelopmental evaluations performed over the course of 4–6 h by a team of specialists including neurodevelopmental pediatricians, speech-language pathologists, physical and occupational[ojrd.biomedcentral.com]
Splenomegaly
  • Attenuated Patients Stiffened Joints Skeletal Abnormalities Carpal Tunnel Syndrome Cardiac (Valvular) Disease Recurrent Ear, Nose, and Throat Infections Obstructive Airway Disease/Sleep Apnea Corneal Clouding Spinal Cord Compression Hepatosplenomegaly/Splenomegaly[mps1disease.com]
  • […] 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/snoring (51.6%) Splenomegaly[oncofertility.northwestern.edu]
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]
Macroglossia
  • […] epiglottis, a deep cranial fossa that narrows nasopharynx, hypoplastic mandible, ankylosis of temporomandibular joint, infiltration of pharyngeal tissues and tracheal cartilages, intraluminal narrowing of the conductive airways and excessive secretions, macroglossia[joacp.org]
  • […] 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]
  • Physical characteristics that may have contributed to feeding difficulties included macroglossia ( n  13; 29.5%), and palate abnormalities ( n  9; 20.5%). Ten patients (22.7%) had gingival hypertrophy.[ojrd.biomedcentral.com]
  • Direct laryngoscopy evidenced in 5 out of 19 patients macroglossia, oropharyngeal and supraglottis redundant tissue, thickened epiglottis, and reduced tracheal and bronchial diameter.[hindawi.com]
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]
  • In these patients ERT has been shown to improve quality of life and ameliorate hepatomegaly, apnea, joint restrictions, and other somatic symptoms [ 3 – 5 ].[ojrd.biomedcentral.com]
  • Ultrasound of the abdomen revealed hepatomegaly with fatty infiltration and umbilical hernia with bowel loops and omentum as contents. Echocardiogram showed mitral valve prolapse with moderate mitral regurgitation.[joacp.org]
  • Abnormal enlargement of the liver (hepatomegaly), is often observed in association with a protruding abdomen in infants with I-cell disease.[rarediseases.org]
Hearing Impairment
  • Hearing impairment. Mental retardation. Inguinal hernias. Joint stiffness and skeletal deformities Coronary heart disease. Hepatosplenomegaly. Diagnosis: Exams and Tests: Electrocardiogram (EKG). Genetic testing for the alpha-L-iduronidase gene.[medigoo.com]
  • Surgical incision in the eardrum can correct hearing impairment. In order to avoid complications, surgery has also been recommended for all inguinal hernias. Ear infections caused by pharyngeal tonsils needs to be excised for better outcomes.[patienthelp.org]
  • Hearing impairment. Umbilical hernias and inguinal hernias. Joint stiffness and skeletal deformities. Cardiomyopathy and coronary heart disease. Hepatosplenomegaly.[patient.info]
Hirsutism
  • Affected individuals exhibit severe mental retardation, clouding of the corners of the eyes, deafness, hirsutism (hairiness), enlarged liver and spleen, dwarfism with hunched back, short limbs and clawed hands, a large head with wide-set eyes, heavy brow[britannica.com]
  • Affected individuals exhibit severe mental retardation , clouding of the corners of the eyes, deafness , hirsutism (hairiness), enlarged liver and spleen , dwarfism with hunched back, short limbs and clawed hands, a large head with wide-set eyes, heavy[britannica.com]
  • Other manifestations include organomegaly, hernias and hirsutism.[orpha.net]
  • Other findings included sacral dimples ( n  8), Mongolian spots ( n  7), hirsutism ( n  6), hemangiomas ( n  3), and café au lait spots ( n  1). Neuromuscular manifestations Most patients presented with neuromuscular abnormalities.[ojrd.biomedcentral.com]
Skeletal Dysplasia
  • In 1919, while training in paediatrics, Hurler described a syndrome of corneal clouding, dwarfing skeletal dysplasia, spinal malalignment and mental retardation.[whonamedit.com]
  • Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age three years, linear growth ceases. Intellectual disability is progressive and profound. Hearing loss is common.[ldnz.org.nz]
  • Dysplasia Society, Southeastern Regional Genetics Group Disclosure: Nothing to disclose.[emedicine.medscape.com]
  • Dysplasia Society , Southeastern Regional Genetics Group Disclosure: Nothing to disclose.[emedicine.medscape.com]
  • Skeletal abnormalities include: a short stature, degenerative joint disease and a skeletal dysplasia referred to as dysostosis multiplex [ 5 , 6 ]. The pathophysiology of the bone disease is still not well understood.[ojrd.biomedcentral.com]
Coxa Valga
  • The epiphyseal centers are not well developed, the pelvis is poorly formed with small femoral heads and coxa valga. The clavicles are short, thick and irregular and the ribs are oar shaped. Phalanges are shortened and trapezoidal in shape.[themedicalbiochemistrypage.org]
  • The major joints show limitation of movement and deformities develop in flexion at the hips and knees with deformities like coxa valga, genu valgum and pes planovalgus.[medcaretips.com]
Joint Deformity
  • In patients with hand, foot and joint deformities, surgical treatment is quite helpful in correcting the abnormality. Corneal clouding can be treated by corneal transplant.[symptoma.com]
  • Some individuals with MPS I have short stature and joint deformities (contractures) that affect mobility. Most people with the severe form of the disorder also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray.[ghr.nlm.nih.gov]
Short Neck
  • Others: Other features may include short neck, subluxation of vertebral bodies, thick and coarse body hair and thickened skin. MPS1H is a genetic disease which can be diagnosed either in the prenatal period or after the birth of the baby.[symptoma.com]
  • Head and neck findings included short neck with limited movement, macrocephaly, coarse facial features, depressed nasal bridge [Figure 1] with copious oral secretions and flexion deformity seen at elbows, wrists and knee joints.[joacp.org]
  • Hurler patients have a short neck and odontoid hypoplasia (decreased ossification of the odontoid bone which is the anterior process of the second vertebra).[themedicalbiochemistrypage.org]
  • Respiratory issues secondary to sleep apnea, large tonsils/adenoids and a short neck have also been reported. Cardiac and respiratory issues should be considered when planning interventions.[smartspeechtherapy.com]
Frontal Bossing
  • Head is enlarged with frontal bossing and scaphocephalic skull due to premature closure of cranial sutures. A large mouth with thick lips may also be present. There is slight protrusion of the eyes.[symptoma.com]
Low Forehead
Slurred Speech
  • Other symptoms may include: slurred speech difficulty swallowing muscle cramps muscle weakness and/or twitching tremors unsteady walk memory problems difficulty understanding things and reasoning mental health problems, such as experiencing psychotic[sharecare.com]
  • speech, dysphagia, urinary incontinence, and sleep 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]
Tremor
  • Other symptoms may include: slurred speech difficulty swallowing muscle cramps muscle weakness and/or twitching tremors unsteady walk memory problems difficulty understanding things and reasoning mental health problems, such as experiencing psychotic[sharecare.com]

Workup

MPS1H is a genetic disease which can be diagnosed either in the prenatal period or after the birth of the baby. A number of laboratory, as well as radiological investigations, are helpful to determine the diagnosis of the disease.

  • Laboratory investigations: The laboratory workup consists of an examination of lymphocytes in blood smear for abnormal cytoplasmic inclusions as well as enzyme levels of L-iduronidase in cultured fibroblasts and leukocytes. Urinary levels of dermatin sulfate and heparin sulfate are also measured.
  • Prenatal diagnosis: Prenatal diagnosis is established by measuring enzyme levels in amniotic cells or chorionic villi cells.
  • Radiology: Radiography of the skeleton showing gibbus deformity of the lower spine and characteristic dysostosis of bones. Echocardiography is done to detect heart valve abnormalities.
Ground Glass Appearance
  • Corneal clouding: There is ground glass appearance of the cornea due to corneal clouding which may begin during the first year of life. It may lead to blindness. Degeneration of the retina is also common.[symptoma.com]

Treatment

Treatment of MPS1H involves palliative and curative elements [5]. Enzyme replacement therapy with L-iduronidase is helpful in improving pulmonary function [6] [7]. The walking ability of the person is also improved. In addition, it reduces the carbohydrate storage in organs [8].
In patients with hand, foot and joint deformities, surgical treatment is quite helpful in correcting the abnormality [9]. Corneal clouding can be treated by corneal transplant. Some studies have shown decreased corneal opacity and improved vision even with enzyme replacement therapy [10].

Prognosis

Children with MPS1H have a poor prognosis. Mostly, they develop skeletal as well as nervous system abnormalities. The organ systems may also be involved leading to organ dysfunction. Patients may die at an early age.

Etiology

There are no specific etiological or causative factors for MPS1H. It is classified as one of the lysosomal storage disorders and is genetic in origin. The disease is transferred as an autosomal recessive trait which means that the affected person should have two defective copies of the IDUA gene. This gene is responsible for the synthesis of the enzyme alpha-L-iduronidase [1]. If both the parents have a single mutated copy of the gene (i.e. both parents are unaffected carriers) there is a 25% chance in each of their children to have MPS1H.

Epidemiology

MPS1H is an autosomal recessive disorder which affects both sexes equally. The annual incidence of this syndrome in the United States is 1 case per 100, 000 cases. The prevalence of the disease in the UK was estimated to be about 1.07 cases per 100, 000 births from the years 1981 to 2003 [2].

Sex distribution
Age distribution

Pathophysiology

MPS1H is a metabolic disorder in which there is abnormal accumulation of metabolites of glycosaminoglycans in different cells of the body either due to the absence or a deficiency of a specific lysosomal enzyme alpha-L-iduronidase required for the degradation of glycosaminoglycans, dermatin sulfate and heparin sulfate resulting in organ dysfunction. Genetic mutations in the IDUA gene located on chromosome 4 site 4p16.3 result in the absence or a deficiency of the enzyme and lead to the development of Hurler syndrome.

Glycosaminoglycans are essential components of the extracellular matrix, connective tissue, and joint fluid. The degradation of these macromolecules is brought about by the lysosomal enzyme alpha-L-iduronidase. This breakdown process is essential for normal tissue growth and tissue homeostasis. If there is accumulation of these compounds within the cells it causes cell, tissue and organ dysfunction. In addition, there is an increased urinary excretion of heparin sulfate and dermatin sulfate.

Prevention

MPS1H is a genetic disorder. There is no preventive measure against it.

Summary

MPS1H is a genetic metabolic disorder characterized by the deficiency of a lysosomal enzyme alpha-L-iduronidase. This enzyme is responsible for the breakdown of muccopolysaccharides also known as glycosaminoglycans. The deficiency of this enzyme therefore results in the accumulation of muccopolysaccharides in the body. MPS1H is an autosomal recessive disorder that is passed from parents to offsprings. If both the parents carry the defective gene, there is a 25% chance of developing the disease in each of their children. The disease affects many systems of the body. The most common manifestations are physical and mental growth retardation in children usually by the end of first year. Death mostly occurs by the age of 10 years due to organ damage.

Patient Information

MPS1H is a genetic disease which occurs due to the absence or deficiency of an enzyme alpha-L-iduronidase which results in accumulation of certain substances in the body leading to organ dysfunction. The disease runs in families and is transmitted from parents to their offspring. The syndrome manifests as abnormalities in various systems of the body as skeletal and mental abnormalities, joint and bone deformities as well as heart problems. There is no specific treatment of the disease and the affected children usually have a poor prognosis.

References

Article

  1. Muller KB, Pereira VG, Martins AM, D'Almeida V. Evaluation of alpha-iduronidase in dried blood spots is an accurate tool for mucopolysaccharidosis I diagnosis. Journal of clinical laboratory analysis. 2011;25(4):251-254.
  2. Moore D, Connock MJ, Wraith E, Lavery C. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. Orphanet journal of rare diseases. 2008;3:24.
  3. D'Aco K, Underhill L, Rangachari L, et al. Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry. European journal of pediatrics. Jun 2012;171(6):911-919.
  4. Pastores GM. Musculoskeletal complications encountered in the lysosomal storage disorders. Best practice & research. Clinical rheumatology. Oct 2008;22(5):937-947.
  5. Muenzer J, Wraith JE, Clarke LA, International Consensus Panel on M, Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. Jan 2009;123(1):19-29.
  6. Pastores GM. Laronidase (Aldurazyme): enzyme replacement therapy for mucopolysaccharidosis type I. Expert opinion on biological therapy. Jul 2008;8(7):1003-1009.
  7. Clarke LA, Wraith JE, Beck M, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. Jan 2009;123(1):229-240.
  8. Giugliani R, Rojas VM, Martins AM, et al. A dose-optimization trial of laronidase (Aldurazyme) in patients with mucopolysaccharidosis I. Molecular genetics and metabolism. Jan 2009;96(1):13-19.
  9. Arn P, Wraith JE, Underhill L. Characterization of surgical procedures in patients with mucopolysaccharidosis type I: findings from the MPS I Registry. The Journal of pediatrics. Jun 2009;154(6):859-864 e853.
  10. Caceres-Marzal C, Garcia-Reymundo M, Solana J, de Arevalo B, Vaquerizo J, Galan E. Decreased corneal opacity and improved vision in a patient with mucopolysaccharidosis I (Hurler-Scheie) treated with enzyme replacement therapy (laronidase, Aldurazyme). American journal of medical genetics. Part A. Jul 1 2008;146A(13):1768-1770.

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Last updated: 2019-07-11 20:40