Última actualización:
February 02, 2021
Años publicados: 1986, 1988, 1990, 1996, 1998, 2005
Pseudo-Hurler polydystrophy (mucolipidosis type III) is a rare genetic metabolic disorder characterized by a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. This defective enzyme ultimately results in the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are similar, but less severe than those of I-cell disease (mucolipidosis type II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with pseudo-Hurler polydystrophy. Additional symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild intellectual disability, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait.
This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Defective lysosomal enzymes associated with pseudo-Hurler polydystrophy leads to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
In most cases, children with pseudo-Hurler polydystrophy do not exhibit symptoms until 2-4 years of age. Specific symptoms and rate of progression may vary from case to case although the disorder is often slowly progressive.
Initial symptoms may include stiffness of the hands and shoulders. In some cases, claw-like deformities of the hands may occur. These symptoms may progress to cause difficulty with specific tasks (e.g., getting dressed). Eventually, carpal tunnel syndrome may develop. Carpal tunnel syndrome is a neurological disorder characterized by compression of the median nerve, which passes through the carpal tunnel inside the wrist (peripheral nerve entrapment). Symptoms of this disorder affect the hand and wrist and may include pain, numbness, loss of feeling in the fingertips, and/or unusual sensation such as burning or «pins and needles.»
Additional symptoms associated with pseudo-Hurler polydystrophy may include side-to-side curvature of the spine (scoliosis), degeneration of the hip, joints that are permanently fixed in a bent or flexed position (contractures), and short stature. Progressive degeneration of the hip and joint contractures may cause difficulty walking or force affected individuals to walk with a characteristic waddling gait.
Affected children may also develop coarse facial features, clouding (opacity) of the surface of the eye (cornea), abnormalities affecting the nerve-rich membrane (retina) lining the eyes (mild retinopathy), and irregular curvature of the cornea (hyperopic astigmatism).
Although many children with pseudo-Hurler polydystrophy have normal intelligence, some may develop mild intellectual disability or learning disabilities. In some cases, affected children develop aortic insufficiency, a cardiovascular condition in which the aortic valve weakens preventing the valve from shutting and allowing backflow of blood from the major artery of the body (aorta) into one of the chambers of the heart (left ventricle). Symptoms of aortic insufficiency may include palpitations, fatigue, shortness of breath, and chest pain.
Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.
Investigators have determined that pseudo-Hurler polydystrophy is caused by disruption or changes (mutations) in the UDP-N-acetylglucosamine-1-phosphotransferase gene known as GNPTAB located on the long arm of chromosome 4 (4q21-q23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated «p» and a long arm designated «q». Chromosomes are further sub-divided into many bands that are numbered. For example, «chromosome 4q21-q23» refers to bands 21-23 on the long arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Investigators have determined that variant pseudo-Hurler polydystrophy (mucolipidosis IIIC) results from mutations in the GlcNAc-phosphotransferase -subunit gene located on chromosome 16.
The symptoms of pseudo-Hurler polydystrophy result from a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. Due to this defect, certain lysosomal enzymes fail to reach their proper destination (i.e., lysosomes). Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Lysosomal enzymes are mistakenly secreted outside cells resulting in elevated lysosomal enzymes in the serum and fluids of affected individuals. The failure of lysosomal enzymes to reach the lysosomes within cells results in the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells, which, in turn, results in the symptoms of the disorder.
Pseudo-Hurler polydystrophy affects males and females in equal numbers. The prevalence of the disorder is unknown. Pseudo-Hurler polydystrophy is often misdiagnosed making it difficult to determine its true frequency in the general population. One estimate places the frequency at 1 in 1 million births.
As a group, lysosomal storage diseases are believed to have an estimated frequency of about one in every 5,000 live births. Although the individual diseases are rare, the group together affects many people around the world.
A diagnosis of pseudo-Hurler polydystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. A variety of specialized tests may confirm a diagnosis. These tests include detecting elevated lysosomal enzyme activity in serum or decreased enzyme levels in white blood cells or cultured connective tissue cells (fibroblasts).
Treatment
There is no definitive treatment for pseudo-Hurler polydystrophy. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, cardiologists, eye specialists, and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.
Surgery may be used to treat a variety of symptoms associated with pseudo-Hurler polydystrophy including carpal tunnel syndrome, skeletal malformations, and degeneration of the hip. Corneal transplantation has been performed with mixed results. Physical therapy and exercise may improve joint stiffness. Heart valve replacement may be necessary in some cases.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Researchers are studying biphosphonate therapy such as pamidronate for the treatment of individuals with pseudo-Hurler polydystrophy. Initial studies have demonstrated improvement of symptoms in some individuals with pseudo-Hurler syndrome. More research is necessary to determine the long-term safety and effectiveness of biphosphonate therapy for individuals with pseudo-Hurler-polydystrophy.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Muenzer J, Wedehase B. Mucolipidosis II and III. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:472-3.
Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:3469-80.
Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:164-5.
Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:942.
JOURNAL ARTICLES
Steet RA, Hullin R, Kudo M, et al. A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. Am J Med Genet. 2005;132:369-75.
Robinson C, Baker N, Noble J, et al. The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment. J Inherit Metab Dis. 2002;25:681-93.
Pourjavan S, Fryns JP, Van Hove JL, Poorthuis BJ, Casteels I. Ophthalmological findings in a patient with mucolipidosis III (pseudo-Hurler polydystrophy). A case report. Bull Soc Belge Ophthalmol. 2002;19-24.
Tylki-Szymanska A, Czartoryska B, Groener JE, Lugowska A. Clinical variability in mucolipidosis III (pseudo-Hurler polydystrophy). Am J Med Genet. 2002;15:214-8.
Raas-Rothschild A, Cormier-Daire V, Bao M, et al. Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC). J Clin Invest. 2000;105:673-81.
Haddad FS, Hill RA, Vellodi A. Orthopaedic manifestations of mucolipidosis III: an illustrative case. J Pediatr Orthop B. 2000;9:58-61.
Hetherington C, Harris NJ, Smith TW. Orthopaedic management in four cases of mucolipidosis type III. J R Soc Med. 1999;92:244-6.
Haddad FS, Jones DH, Vellodi A, Kane N, Pitt MC. Carpal tunnel syndrome in the mucopolysaccharidoses and mucolipidoses. J Bone Joint Surg Br. 1997;79:576-82.
Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M. Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci. 1997;146:167-72.
FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:252600; Last Update:3/30/2005. Available at: https://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=252600 Accessed on: 3/30/2005.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:252605; Last Update:5/30/2003. Available at: https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=252605 Accessed on: 3/30/2005.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
View reportMedlinePlus has information about this condition that may include a description, frequency, causes, inheritance, and links to more information. The information is written for the public, including patients, caregivers and families. MedlinePlus is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).
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