NORD gratefully acknowledges William R. Wilcox, MD, PhD, Medical Genetics Institute, Cedars-Sinai Medical Center; Professor of Pediatrics, UCLA School of Medicine, for assistance in the preparation of this report.
Some symptoms of Marinesco-Sjögren syndrome are often present at birth (congenital) including diminished muscle tone (hypotonia), a condition sometimes referred to as “floppy baby”. Cataracts can also be present at birth, but more often develop rapidly during early childhood. Cataracts occur when the lenses of the eyes become clouded preventing light from being focused onto the retina and thereby affecting vision. In most cases, cataracts affect both eyes (bilateral).
Individuals Marinesco-Sjögren syndrome have difficulties coordinating voluntary movements due to a small cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movements. In most cases, ataxia is usually readily evident around the time a child can sit up.
Affected infants may also exhibit significant delays in reaching developmental milestones that require the coordination of physical (motor) and mental activity (psychomotor development) as well as speech. Muscle weakness may grow progressively worse in adulthood.
As affected individuals age, additional symptoms may become apparent including ataxia that primarily affects the torso (truncal ataxia) and impaired ability to perform rapidly alternating movements (dysdiadochokinesia). The degree of severity of motor dysfunction will vary from one person to another. Many affected individuals eventually can walk with an assistive device such as a walker. Other individuals, however, may require the use of a wheelchair.
The intellectual abilities of individuals Marinesco-Sjögren syndrome can vary greatly. In some individuals intelligence is unaffected; others develop mild to moderate cognitive impairment. Neurological deterioration usually does not occur in Marinesco-Sjögren syndrome or may be extremely slow. In addition, some individuals may have difficulty speaking or slurred speech (dysarthria). Certain symptoms of Marinesco-Sjögren syndrome (e.g., vision problems, speech difficulties) make it easy to underestimate the intelligence of an affected child.
Individuals with Marinesco-Sjögren syndrome usually exhibit growth deficiencies that can ultimately lead to short stature. Short stature refers to individuals who are significantly below average height for a person of the same age and sex. In some cases, affected individuals also have hypergonadotropic hypogonadism, a condition characterized by defective development or function of the ovaries or testes (gonads). Hypergonadotropic hypogonadism causes delays in the start of puberty and the development of secondary sexual characteristics and contributes to the development of short stature.
Less frequently, additional symptoms have been associated with Marinesco-Sjögren syndrome. These symptoms include rapid, involuntary eye movements (nystagmus), misalignment of the eyes (strabismus), and degeneration of the main nerve of the eyes that transmits nerve impulses from the retina to the brain (optic atrophy). A variety of skeletal malformations have been reported including side-to-side curvature of the spine (scoliosis), abnormally short fingers and toes (brachydactyly), and an abnormal “cone-shape” to the end portions of the long bones (cone epiphyses).
Although the severity of Marinesco-Sjögren syndrome can vary from one person to another and some affected individuals may be significantly disabled, lifespan is usually unaffected.
Marinesco-Sjögren syndrome is often caused by mutation of the SIL1 gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and 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 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent 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 percent. The risk is the same for males and females.
Investigators have determined that the SIL1 gene is located on the long arm (q) of chromosome 5 (5q31). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. 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 5q31” refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The SIL1 gene contains instructions for creating (encoding) a protein that has a specific role in the body. A mutation of the SIL1 gene results in the production of a defective protein that cannot carry out its proper function, which, ultimately, results in the signs and symptoms of Marinesco-Sjögren syndrome. Researchers believe that the protein product of the SIL1 gene is involved in protein folding. Protein folding is a normal process in which a protein folds into a three-dimensional structure. This process is required for a protein to carry out its normal function. Defective protein folding is believed to cause abnormal proteins to accumulate in the endoplasmic reticulum, the extensive membrane network located in all cells including muscle cells.
Some individuals with Marinesco-Sjögren syndrome do not have a mutation of the SIL1 gene, which suggests that another gene(s) may also cause the disorder (genetic heterogeneity). The other gene(s) that may play a role in the development of Marinesco-Sjögren syndrome have not been identified.
Marinesco-Sjögren syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The exact incidence of the disorder in the general population is unknown. Marinesco-Sjögren syndrome can affect all ethnic groups (panethnic), but most cases have occurred in isolated populations in rural areas.
A diagnosis of Marinesco-Sjögren syndrome may be suspected based upon the identification of characteristic findings. A diagnosis can be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests including an eye (ophthalmologic) exam to detect cataracts and magnetic resonance imaging (MRI) to detect characteristic changes in the brain (e.g., cerebellar atrophy). Imaging studies of muscle may show significant damage to muscle tissue and the abnormal accumulation of fat and connective tissue.
Molecular genetic testing (which can identify a mutation of the SIL1 gene) is available on a clinical basis. Prenatal diagnosis of Marinesco-Sjögren syndrome is possible if the SIL1 gene mutation is known to run in a family.
There is no specific treatment for individuals with Marinesco-Sjögren syndrome. 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, surgeons, specialists who asses and treat skeletal problems (orthopedists), eye specialists (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Surgery may be necessary to remove cataracts and, in some cases, to implant artificial lenses. Orthotic devices such as walkers may be required. If hypergonadotropic hypogonadism is present, then hormone replacement therapy may be administered around the time puberty is expected.
Early intervention is important in ensuring that children with Marinesco-Sjögren syndrome reach their highest potential. Services that may be beneficial may include special education programs tailored to an individual’s specific needs, occupational therapy, physical therapy, and other medical, social, and/or vocational services.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Anttonen AK, Mahjneh I, Hamalainen RH, et al. The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet. 2005;37:1309-1311.
Senderek J, Krieger M, Stendel C, et al. Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet. 2005;37:1312-1314.
Lagier-Tourenne C, Tranebaerg L, Chaigne D, et al. Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31. Eur J Hum Genet. 2003;11:770-778.
Lagier-Tourenne C, Chaigne D, Gong J, et al. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjögren syndrome. J Med Genet. 2002;39:838-843.
FROM THE INTERNET
Anttonen AK, Lehesjoki AE. Updated:10/07/2008. Marinesco-Sjögren Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org. Accessed On: November 11, 2008.
Palau F. Marinesco-Sjögren Syndrome. Orphanet encyclopedia, June 2006. Available at: www.orpha.net Accessed on: November 11, 2008.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:248800; Last Update:08/28/2008. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248800 Accessed on: November 11, 2008.
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