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NORD is very grateful to Hudson Freeze, PhD, Professor and Director, Genetic Disease Program, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, for assistance in the preparation of this report.
PMM2-CDG, formerly known as congenital disorder of glycosylation type 1a, is a rare multisystem disorder that involves a normal, but complex, chemical process known as glycosylation. Glycosylation is the process by which sugar chains (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins. Glycoproteins have varied important functions within the body and are essential for the normal growth and function of numerous tissues and organs. PMM2-CDG can affect virtually any part of the body, although most cases usually have an important neurological component. PMM2-CDG is associated with a broad and highly variable range of symptoms and can vary in severity from mild cases to severe, disabling or life-threatening cases. Most cases are apparent in infancy. PMM2-CDG is caused by mutations of the phosphomannomutase-2 (PMM2) gene and is inherited as an autosomal recessive condition.
PMM2-CDG belongs to a group of disorders known as the congenital disorders of glycosylation (CDG). CDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken, et al. More than 50 different forms of CDG have been reported in the ensuing years. PMM2-CDG is the most common form. Several different names have been used to describe these disorders including carbohydrate-deficient glycoprotein syndromes. Recently, researchers have proposed a classification system that names each subtype by the official abbreviation of its defective gene followed by a dash and CDG. Congenital disorder of glycosylation type 1a is now known as PMM2-CDG. CDG are a rapidly growing disease family and information about these disorders is constantly changing.
In order to help characterize and clarify this disorder, researchers have divided PMM2-CDG into three stages. These stages are based upon the symptoms at different periods of life. They are: the infantile multisystem stage; the late-infantile and childhood ataxia-intellectual disability stage; and the adult stable disability stage.
The symptoms associated with PMM2-CDG are broad and highly variable. The specific symptoms present, severity and prognosis can vary greatly from one person to another depending upon several factors such as the specific organ system involved. Therefore, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
INFANTILE MULTISYSTEM STAGE
This phase is primarily characterized by feeding problems, neuromuscular abnormalities, severe developmental delay, symptoms resulting from episodes of internal organ failure, and/or additional physical abnormalities (e.g., squinting facial appearance, inverted nipples, fat pads above the buttocks).
Some researchers break down the infantile multisystem stage into two distinct clinical presentations. One presentation is a non-fatal neurological form characterized by psychomotor retardation, underdevelopment (hypoplasia) of the cerebellum, and crossed eyes. Later on, symptoms of abnormal nerve development may occur as could problems with eyesight. The second presentation is potentially fatal as it affects the neurological system and various internal organs. All organs except the lungs can become affected. Mortality is approximately 20% in the first 5 years.
Most infants with PMM2-CDG exhibit normal birth weight. However, they may be slightly smaller than normal. Newborns may also appear sluggish and have an abnormally weak sucking response. Throughout their first year of life, affected infants may demonstrate little interest in nursing or bottle-feeding, have repeated episodes of diarrhea, vomit frequently, and/or fail to gain weight or grow at the expected rate (failure to thrive). In many cases, growth is significantly impaired. Infants and children may have also an increased (sometimes pronounced) susceptibility to infection.
Newborns with PMM2-CDG may also exhibit many neuromuscular abnormalities. Their arms and legs (limbs) may appear abnormally thin and weak and may fail to extend normally. In addition, affected infants may exhibit severely diminished muscle tone (generalized hypotonia), so that they appear "floppy," have little or no control of head movements, and/or exhibit decreased reflexes (hyporeflexia).
Most infants with PMM2-CDG also exhibit additional physical abnormalities. Some have a distinctive facial appearance (minor facial dysmorphism) characterized by an abnormally prominent jaw; a nose with an unusually high bridge; an unequal, inward deviation of both eyes (bilateral internal strabismus and esotropia); a squinting facial appearance; large ears; and/or other facial abnormalities. Additional characteristic physical abnormalities may include inverted nipples; abnormally thick, dimpled skin, particularly on the thighs and buttocks ("peau d’orange" meaning "skin of orange"); an abnormal fat distribution on the body including prominent pads of fat under the skin (subcutaneous) above the buttocks; fat deposits around the external genitals (e.g., penis and scrotum in males, labia majora in females); and/or abnormal streaks of fat on the lower limbs.
From the age of approximately four months, most affected infants begin to exhibit delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor developmental delay). Throughout infancy and early childhood, affected children may be severely delayed in achieving certain developmental milestones (e.g., sitting with minimal support, grasping objects, etc.). Although hand coordination may improve during late infancy, skills requiring the coordination of large muscles (gross motor abilities), such as those necessary for crawling, may continue to be delayed.
In most cases, individuals with PMM2-CDG exhibit underdevelopment (hypoplasia) of certain portions of the brain (e.g., the cerebellum). Symptoms indicating such underdevelopment usually become apparent during infancy and may include poor sucking response, abnormal eye movements, lack of coordination, and/or low muscle tone. Hypoplasia of certain portions of the brain may also play a role in the other neuromuscular abnormalities and developmental delays apparent during infancy and childhood.
In many cases, newborns and infants with PMM2-CDG may also have episodes of organ system failure, potentially resulting in life-threatening complications. For example, malfunction of the liver (hepatic dysfunction) may occur. Hepatic abnormalities include increased levels of certain liver enzymes (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and/or abnormal enlargement of the liver (hepatomegaly), possibly in association with unusual enlargement of the spleen (splenomegaly). Affected infants may also have abnormal deposits of fat (hepatic steatosis) and/or unusual accumulations of scar tissue (fibrosis) within the liver.
Because the liver creates many glycoproteins that function in the blood, liver malfunction may lead to problems with blood clotting and, in some cases, heart problems. For example, in some affected infants, abnormally increased amounts of fluid may accumulate between the two layers (pericardial space) of the membranous bag (pericardium) that surrounds the heart (pericardial effusion). The pericardial space normally contains a few small drops of fluid to help lubricate the contractions of the heart. However, if excess fluid accumulates in the pericardial space, the tough outermost layer of the pericardium (fibrous pericardium) may not be able to stretch normally, causing abnormal pressure to build up around the heart (cardiac tamponade). As a result, the heart may not be able to pump blood efficiently to the lungs and the rest of the body (cardiac failure). In most cases, in individuals with PMM2-CDG, such pericardial effusions do not result in life-threatening complications and tend to resolve over time.
Some affected infants may experience episodes of severe gastrointestinal bleeding and/or abnormal accumulation of body fluids in the abdominal cavity (ascites). Symptoms associated with these findings may include shortness of breath, difficulty breathing, chest pain, bloating, and/or cramping. As mentioned above, it is believed that episodes of pericardial effusion, ascites, and/or gastrointestinal bleeding may be due in part to certain blood factor deficiencies exhibited by some infants with PMM2-CDG. Many affected infants periodically exhibit low levels of certain substances in the blood (e.g., factor XI) that help the blood clot (coagulation factors) as well as deficient levels of albumin, a protein that helps regulate the movement of fluid between the bloodstream and tissues.
Some infants with PMM2-CDG may also exhibit kidney (renal) abnormalities. Such abnormalities may include enlarged kidneys (nephromegaly) and/or the presence of numerous small cysts within the kidneys (renal microcysts). Nephrotic syndrome, a condition in which the body secretes too much protein, has also been reported. Nephrotic syndrome can cause swelling (edema) especially of the feet and increase the risk of additional health problems.
Some children with PMM2-CDG may have an underactive thyroid (hypothyroidism). Disease of the heart muscle (cardiomyopathy) and congenital heart anomalies have also been reported. Osteopenia, a condition in characterized by decreased bone mineralization and bone loss, is common and persistent. Some newborns experience abnormal accumulation of fluid in various tissues of the body (hydrops fetalis).
LATE-INFANTILE AND CHILDHOOD ATAXIA-INTELLECTUAL DISABILITY PHASE
In PMM2-CDG, episodes of internal organ failure (e.g., hepatopathy, pericardial effusion, gastrointestinal bleeding, etc.) tend to decline during late infancy and early childhood. However, during this stage of development, several additional symptoms and characteristics may become apparent including varying degrees of intellectual disability, further physical signs of cerebellar hypoplasia, visual impairment, signs of impaired nerve impulse transmission to the legs (peripheral neuropathy), and/or additional abnormalities.
During this second phase of PMM2-CDG, most affected children exhibit intellectual disability, ranging from moderate to severe. The degree of intellectual disability tends to remain stable at this point unless secondary events, such as stroke-like episodes, cause regression in a child’s previous mental capabilities. Although most children have some form of intellectual disability, children have been reported with normal intellectual development or only extremely mild deficiencies.
Language and motor development can be affected and significantly delayed. Most affected children do not develop normal speech patterns. Intellectual disability, severe development delays, cerebellar ataxia, and/or other abnormalities contribute to communication limitations. In most cases, however, affected children may begin to develop their own communication methods through the use of signs, expressions, and gestures. Most children with this disorder tend to be outgoing and sociable.
Additional symptoms associated with underdevelopment (hypoplasia) of certain portions of the brain (e.g., the cerebellum) also become apparent during this stage of PMM2-CDG. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. Such symptoms may include progressive balance problems (disequilibrium) and further impairment of the ability to coordinate voluntary movements (cerebellar ataxia). Cerebellar ataxia and other symptoms due to such hypoplasia tend to stabilize during later childhood or early adolescence.
Individuals with PMM2-CDG continue to exhibit severe psychomotor developmental delays throughout childhood. For example, although some children may learn toilet habits, they tend to do so much later than expected. In addition, although some affected children may learn to feed themselves, most require regular assistance. Many affected children are unable to walk without assistance.
In approximately 50 percent of children with PMM2-CDG, infections and fevers may trigger stroke-like episodes characterized by sluggishness (lethargy) and unresponsiveness to the environment (stupor), sudden unconsciousness, seizures, temporary blindness, paralysis on one side of the body (hemiplegia), and/or coma. In most cases, recovery may occur from such episodes within a few hours or days. However, in other cases, such episodes may be characterized by tissue damage and loss (necrosis) in part of the brain due to a lack of blood supply (cerebral infarction). Cerebral infarction may sometimes result in permanent damage, causing regression in a child's previous mental capabilities.
In addition, many infants and children with PMM2-CDG periodically exhibit low levels of certain substances in the blood that help the blood clot (coagulation factors, such as factor XI) or prevent abnormal blood clotting (coagulation inhibitors, such as antithrombin III, protein C, protein S, and heparin cofactor II). The stroke-like episodes and cerebral infarctions sometimes occurring in children with PMM2-CDG may be due in part to coagulation factor and coagulation inhibitor deficiencies. In addition, some affected children may be predisposed to the development of clots within blood vessels (thromboses).
Approximately half of affected children experience seizures during such stroke-like episodes. However, in some cases, affected children may also experience seizures outside of these episodes (epilepsy). Epilepsy is a condition characterized by recurrent episodes of uncontrolled electrical disturbances in the brain that may cause spasms, convulsions, and/or other symptoms. In some cases, seizures may develop as early as the second or third month. Seizures usually respond to anti-seizure medications.
During this stage of development, children with PMM2-CDG may also begin to exhibit abnormalities of the peripheral nervous system (i.e., the motor and sensory nerves outside the brain and spinal cord). Due to loss or deficiency of the fatty coverings (myelin) around these nerve fibers (demyelination), nerve impulses may not be appropriately conducted from the brain and spinal cord to the extremities (peripheral neuropathy). Myelin, a substance made up of fatty materials and protein, enables effective transmission of nerve impulses from the brain and spinal cord by serving as an electrical insulator. As a result, the muscles in the arms and, in particular, the legs may become progressively weak and thin (atrophied).
Infants and children with PMM2-CDG may also exhibit various abnormalities of the eyes during this stage. In addition to the bilateral inward deviation present during early infancy, affected children may also exhibit wandering eye movements and progressive degeneration of the colored (pigmented) layer of the nerve-rich membrane lining the eyes (progressive tapetoretinal degeneration, retinitis pigmentosa type). Progressive tapetoretinal degeneration may lead to poor night vision, restriction of visual fields, and/or difficulty with glare. Nearsightedness (myopia) and cataracts may also occur. The degree of visual impairment may vary from case to case, depending upon the combination and severity of various visual abnormalities present.
Additional symptoms that may develop during this stage include skeletal malformations and abnormally fixed joints that occur when thickening and shortening of tissue such as muscle fibers cause deformity and restrict the movement an affected area (joint contractures).
Adult Stable Disability Stage
Most individuals with PMM2-CDG enter a period of general stabilization and adaptation. According to the medical literature, at this phase of development, the coordination and balance difficulties (cerebellar ataxia) due to cerebellar hypoplasia generally have stabilized; stroke-like episodes typically have ceased; and convulsive episodes in those who exhibit epilepsy may begin to decrease. In addition, in most cases, episodes of internal organ failure have not occurred for some time, liver function has stabilized, and fat pads and other subcutaneous abnormalities (lipodystrophic accumulations) may have diminished or disappeared.
Intellectual disability stabilizes in this phase. But for many affected adolescents, abnormalities involving the peripheral nervous system (peripheral neuropathy) may worsen. Impaired transmission of nerve impulses from the brain and spinal cord to muscle tissue, particularly in the legs, causes further weakening and wasting away (atrophy) of the muscles. In addition, atrophy, weakness, and shortening of muscle fibers may cause certain joints, particularly in the legs and feet, to become fixed in a permanently flexed position (joint contractures). In addition, all individuals with PMM2-CDG exhibit various skeletal abnormalities that may become apparent during this stage. Some abnormalities include short stature with long limbs and a compressed body. Others are reduced bone mass, a barrel-shaped rib cage, and abnormal curvature of the spine (kyphosis). Many of the spinal malformations occurring in PMM2-CDG may contribute to mobility impairment.
Because many hormones are glycoproteins, both males and females with PMM2-CDG exhibit certain hormonal abnormalities. However, the range of such symptoms may be greater and more apparent in affected females.
Affected females may not develop secondary sexual development (such as the growth of pubic hair and hair under the arms [axillary hair], breast enlargement, and an increase in body fat around the hips and other areas); in addition, they do not menstruate (amenorrhea) and are infertile. In such cases, it appears that the ovaries, the pair of female sex glands (gonads) in which eggs develop, fail to respond appropriately to hormones (gonadotropins such as follicle-stimulating hormone [FSH]) that normally stimulate their function. As a result, many affected females may exhibit abnormally high levels of such gonadotropic hormone (elevated serum FSH).
Although males with PMM2-CDG experience puberty and develop secondary sexual characteristics (e.g., enlargement of the penis and testes; growth of pubic, facial, and other body hair), they tend to exhibit low levels of an important hormone that helps to stimulate sexual development (testosterone). Levels of gonadotrophin hormones (e.g., FSH), which stimulate cellular activity in the male sex glands (testes), may be normal or slightly elevated (elevated serum FSH).
At this stage of development, individuals with PMM2-CDG exhibit stable (nonprogressive) cerebellar ataxia and varying degrees of peripheral neuropathy. Some individuals may continue to exhibit epileptic episodes; however, such episodes tend to occur randomly and are generally mild.
Some adults with PMM2-CDG continue to have difficulty with verbalization and communication. Some are able to read and/or write simple sentences; however, they generally continue to communicate through their own basic telegraphic language. Although affected adolescents and adults require ongoing assistance with daily functions and mobility, many are able to complete special educational classes, and some are able to maintain employment with special supervision and support.
In recent years, more and more adults have been diagnosed with a mild form of PMM2-CDG. Some of these individuals have normal intellectual development. Therefore, the complete clinical spectrum of PMM2-CDG is still being defined.
PMM2-CDG is caused by mutations of the PMM2 gene and is inherited as an autosomal recessive genetic trait. The malfunctioning PMM2 gene has been tracked to gene map locus chromosome 16p13.3-p13.2.
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 16p13.3-p13.2" refers to a region on the short arm of chromosome 16 between band 13.3 and band 13.2. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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% 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%. The risk is the same for males and females.
Congenital disorders of glycosylation can be further subdivided. PMM2-CDG is further classified as a disorder of N-glycosylation, which involves carbohydrates called N-linked oligosaccharides. These oligosaccharides are created in a specific order to create specific sugar chain patterns, which are then attached to proteins on various cells. Disorders of N-glycosylation develop due to an enzyme deficiency or malfunction somewhere along the N-glycosylation pathway. Researchers have determined that the PMM2 gene encodes for the enzyme phosphomannomutase-2 (PMM2), which is required for the proper synthesis of N-linked oligosaccharides. Mutations in the PMM2 gene lead to deficient levels of functional phosphomannomutase-2 in the body, which, in turn, prevents proper glycosylation. Improper glycosylation is the underlying defect in individuals with PMM2-CDG.
PMM2-CDG is the most common of a growing family of more than 50 extremely rare inherited metabolic disorders. More than 700 cases of this disorder have been reported worldwide. Two other disorders in this family are each represented by more than 20 cases. The remaining disorders in this family have fewer than 20 cases with several earning a place in the medical literature based on the report of one or two cases. The exact incidence and prevalence of these disorders in the general population is unknown. It is difficult to determine the true frequency of PMM2-CDG in the general population since the disorder may still be under-recognized and under-diagnosed in many parts of the world.
Symptoms of the following disorders can be similar to those of PMM2-CDG. Comparisons may be useful for a differential diagnosis.
Numerous different metabolic disorders share similar signs and symptoms to PMM2-CDG. Such disorders include congenital muscle disorders (myopathies), urea cycle disorders, inborn errors of bile metabolism, fatty acid oxidation disorders, organic acidurias, and peroxisome biogenesis disorders. Additional disorders that have similar signs and symptoms include cerebral palsy, congenital coagulation disorders, and ataxia-telangiectasia and other hereditary ataxias. (For more information on these disorders, choose the specific disorder or umbrella group name as your search term in the Rare Disease Database.).
Prader-Willi syndrome is a genetic disorder characterized in infancy by diminished muscle tone (hypotonia), feeding difficulties, and failure to grow and gain weight. In childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity results because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. Without appropriate treatment, individuals with severe obesity may have an increased risk of cardiac insufficiency, diabetes or other serious conditions that can lead to potentially life-threatening complications. All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from learning disabilities to mild mental retardation. Behavior problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose "Prader-Willi" as your search term in the Rare Disease Database.)
A diagnosis of PMM2-CDG may be suspected based upon the identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests may be necessary to confirm a diagnosis of PMM2-CDG.
According to the medical literature, a diagnosis of PMM2-CDG should be considered if infants or young children exhibit intellectual disability and severe psychomotor developmental delay in association with prominent fat pads on the buttocks, inverted nipples, squinting, cerebellar hypoplasia (as indicated by special imaging tests such as computed tomography (CT) scanning or magnetic resonance imaging (MRI), feeding difficulties and poor weight gain, hypotonia, liver abnormalities, pericardial effusion, stroke-like episodes, and/or eye abnormalities such as strabismus or retinal pigmentary degeneration. In general, CDG should be ruled out in any unexplained syndrome.
Clinical Testing and Work-Up
A simple blood test to analyze the glycosylation status of tranferrin can diagnose CDG due to N-glycosylation such as PMM2-CDG. Transferrin is a glycoprotein found in the blood plasma and that is essential for the proper transport of iron within the body. Abnormal transferrin patterns can be detected through a test known as isoelectric focusing (IEF). IEF allows physicians to separate molecules such as proteins or enzymes based upon their electrical charge. This allows physicians to detect abnormal serum transferrin. IEF is the standard test for diagnosing CDG due to N-glycosylation. In some cases, a different test known as electrospray ionization-mass spectrometry may be used to detect abnormal transferrin.
Once a defect of N-linked glycosylation is diagnosed, further testing is required to determine the specific subtype. PMM2-CDG can be diagnosed by an enzyme assay, a tests that measures the activity of a specific type of enzyme (e.g., phosphomannomutase-2) in certain cells or tissues of the body.
Molecular genetic testing can confirm a diagnosis of PMM2-CDG. Molecular genetic testing can detect mutations of the PMM2 gene that cause the disorder. However, it is only available on a clinical basis.
In many cases, advanced imaging techniques may be used to confirm specific clinical features that may be associated with PMM2-CDG. For example, a complete neurological evaluation may be conducted including MRI, CT scanning, and electroencephalography (EEG). MRI and CT scanning may reveal underdevelopment (hypoplasia) of certain parts of the brain (e.g., the cerebellum).
Nerve conduction velocity (NCV) testing may be performed to evaluate the peripheral neuropathy associated with PMM2-CDG. In NCV testing, an electric stimulator placed in the skin over a peripheral nerve evaluates the time that it takes for a nerve impulse to travel over a certain, measured portion of the nerve. In most cases, in individuals with PMM2-CDG who exhibit peripheral neuropathy, such nerve conduction time is only moderately decreased; however, such a reduction may become more pronounced with age.
In many individuals with PMM2-CDG, x-ray studies may be used to reveal abnormally reduced bone mass (osteopenia) and to confirm certain skeletal malformations (e.g., scoliosis and/or kyphosis) often associated with the disorder.
Visual abnormalities associated with progressive retinal pigmentary degeneration may be detected and measured through electroretinography (ERG). Through the use of a special instrument, ERG measures the retina’s electrical response to light stimulation.
Liver abnormalities associated with PMM2-CDG may be detected through a number of specialized tests. Abnormally high levels of certain liver enzymes (i.e., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) may be confirmed through laboratory tests conducted on the fluid portion of the blood (serum assays). Imaging studies, including ultrasound, may reveal hepatomegaly or hepatosplenomegaly. In ultrasonography, reflected sound waves create an image of the organs in question. In addition, in some cases, examination of samples of liver tissue (biopsy) under a microscope (light microscopy) may reveal fatty infiltration (steatosis) and/or abnormal accumulations of scar tissue (fibrosis) within the liver.
In some individuals with PMM2-CDG, imaging tests such as ultrasonography may also reveal kidney (renal) abnormalities such as enlargement of the kidneys (nephromegaly) and/or the presence of numerous small cysts (renal microcysts). In addition, urine tests often reveal abnormally increased levels of protein in the urine (proteinuria).
In many cases of PMM2-CDG, routine blood tests may reveal periodically low levels of certain substances in the blood that interact to help the blood clot (coagulation factors, such as Factor XI) or to help prevent abnormal blood clotting (coagulation inhibitors, such as antithrombin III, protein C, protein S, and heparin cofactor II). In addition, laboratory tests (assays) conducted on the fluid portion of the blood (serum) may reveal abnormal levels of certain hormones. For example, in affected females, unusually elevated levels of follicle-stimulating hormone (FSH) may become apparent during early childhood or adolescence. Adolescent males tend to exhibit low levels of testosterone; in addition, their FSH levels may also be slightly elevated in some cases.
The treatment of PMM2-CDG is directed toward the specific symptoms that are apparent in each individual. Treatment requires the efforts of a team of specialists working together to agree on a comprehensive treatment plan. Such specialists may include pediatricians and/or internists; physicians who diagnose and treat disorders of the nervous system (neurologists), the eyes (ophthalmologists), the skeletal system (orthopedists), the gastrointestinal system (gastroenterologists), and the endocrine system (endocrinologists); physicians specializing in blood disorders (hematologists); those who specialize in abnormalities of speech and language development (speech-language pathologists); physical therapists; surgeons; dietitians; and/or other health care professionals.
The specific therapeutic procedures and interventions for individuals with PMM2-CDG will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual’s age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.
Some general therapies are common for infants and children with PMM2-CDG including nutritional supplements to ensure maximum caloric intake. In addition, in some cases, children may require the insertion of a tube through a small surgical opening in the stomach (gastrostomy) or a tube through the nose, down the esophagus and into the stomach (nasogastric tube). Many children develop persistent vomiting and dysfunction of oral motor skills, which involve the muscles of the face and throat. A variety of therapies may be necessary to ensure proper feeding including agents to thicken food, antacids, and maintaining an upright position when eating. Maintaining proper nutrition and caloric intake is critical for infants with chronic disorders and often a particular challenge for infants and children with PMM2-CDG.
Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well. Genetic counseling will also be of benefit for affected individuals and their families.
Other treatment is symptomatic and supportive. Additional therapies for PMM2-CDG depend upon the specific abnormalities present and generally follow standard guidelines.
Because infections and fevers may trigger stroke-like episodes, physicians may closely monitor affected infants and children, recommend preventive measures, and institute immediate antibiotic and/or other appropriate treatment should such infections and fevers occur. Stroke-like episodes may be treated intravenous (IV) hydration if necessary and physical therapy afterward.
Physicians may also monitor affected infants and children for other potentially serious findings often associated with the disorder (e.g., signs of hepatic dysfunction, pericardial and/or pleural effusion, ascites) to ensure that appropriate preventive and/or treatment measures are taken.
Regular ophthalmological exams may also be necessary to monitor and characterize the level of visual impairment and to ensure that affected children receive the benefit of early, appropriate supportive measures such as glasses, patching or surgery to correct strabismus.
In some cases, various orthopedic measures may be used to help treat skeletal and/or neuromuscular abnormalities associated with PMM2-CDG such as joint contractures, scoliosis and/or kyphosis, etc. Treatments may include a combination of various supportive techniques, splints, braces, casts, and/or other orthopedic measures. Few affected individuals can walk unsupported and therefore require wheelchairs or other mobility equipment.
In addition, for those affected individuals who have epilepsy, treatment with anti-seizure (anticonvulsant) drugs may help prevent, reduce, or control seizure activity. Hypothyroidism may be treated by hormone replacement therapy.
Blood clotting abnormalities (coagulopathies) require special attention if affected individuals need surgery, but rarely pose problems during normal daily activities.
Researchers are studying enzyme replacement therapy for the treatment of CDG such as PMM2-CDG. Enzyme replacement therapy involves replacing the missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with a certain forms of a related group of disorders known as the lysosomal storage diseases.
Gene therapy is also been studied as another approach to therapy for individuals with CDG or related disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a "cure." However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.
While some individuals with PMM2-CDG have significantly deficient levels of the phosphomannomutase-2 enzyme, other individuals may have residual enzyme activity. This is often the case in individuals with milder disease expression. Researchers are seeking ways to boost or improve any residual enzyme activity in such individuals in the hope that it can further minimize symptom severity and progression.
Researchers are also studying whether simple pharmacological agents can be developed that would bypass the underlying genetic defect in CDG such as PMM2-CDG allowing proper glycosylation to occur. Such agents may increase the production (synthesis) or activity of alternative enzymes that could carry out the functions normally performed by the deficient enzyme in question.
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 website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
NORD and the European Organization for Rare Disorders (EURORDIS) have established Rare Disease Communities for several rare disorders. These disease-specific online patient communities allow patients to read information about their disease, share and read stories from other patients, and network with others in five different languages. To access the Congenital Disorders of Glycosylation (CDG) Rare Disease Community, please visit: www.rarediseasecommunities.org
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Patterson M. Congenital disorders of glycosylation syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:457-58.
Jaeken J, Matthijs G, Carchon H, et al. Defects of N-Glycan Synthesis, In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:1601-22.
Jaeken J. Congenital disorders of glycosylation. Ann NY Acad Sci. 2010;1214:190-198. http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05840.x/pdf
Freeze HH. Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients. Biochim Biophys Acta. 2009;1792:835-840. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783247/?tool=pubmed
Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta. 2009;1792:825-826. http://www.ncbi.nlm.nih.gov/pubmed/19765534
Haeuptle MA, Hennet T. Congenital disorders of glycosylation: an update on defects affecting biosynthesis of dolichol-linked oligosaccharides. Hum Mutat. 2009;30:1628-1641. http://www.ncbi.nlm.nih.gov/pubmed/19862844
Coman DJ. The congenital disorders of glycosylation are clinical chameleons. Eur J Hum Genet. 2008;16:2-4. http://www.nature.com/ejhg/journal/v16/n1/pdf/5201962a.pdf
Coman D, McGill J, MacDonald R, et al. Congenital disorder of glycosylation type 1a: three siblings with a mild neurological phenotype. J Clin Neurosci. 2007;14:668-672. http://www.ncbi.nlm.nih.gov/pubmed/17451957
Van de Kamp JM, Lefeber DJ, Ruijter GJG, et al. Congenital disorder of glycosylation type 1a presenting with hydrops fetalis. J Med Genet. 2007;44:270-280. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598051/?tool=pubmed
Freeze HH, Aebi M. Altered glycan structures: the molecular basis of congenital disorders of glycosylation. Curr Opin Struct Biol. 2005;15:490-98. http://www.ncbi.nlm.nih.gov/pubmed/16154350
Matthijs G. Research network: EUROGLYCANET: a European network focused on congenital disorders of glycosylation. Eur J Hum Genet. 2005;13:395-97. http://www.nature.com/ejhg/journal/v13/n4/full/5201359a.html
Dyer JA, Winters CJ, Chamlin SL. Cutaneous findings in congenital disorders of glycosylation: the hanging fat sign. Pediatr Dermatol. 2005;22:457-60. http://www.ncbi.nlm.nih.gov/pubmed/16191002
Giurgea I, Michel A, Le Merrer M, Seta N, de Lonlay P. Underdiagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol. 2005;32:121-23. http://www.ncbi.nlm.nih.gov/pubmed/15664773
Jaeken J, Carchon H. Congenital disorders of glycosylation: a booming chapter of pediatrics. Curr Opin Pediatr. 2004;16:434-39. http://www.ncbi.nlm.nih.gov/pubmed/15273506
Jaeken J. Congenital disorders of glycosylation (CDG): update and new developments. J Inherit Metab Dis. 2004;27:423-26. http://www.ncbi.nlm.nih.gov/pubmed/15272470
De Lonlay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet. 2001;38:14-19. http://www.ncbi.nlm.nih.gov/pubmed/11134235
FROM THE INTERNET
Sparks SE, Krasnewich DM. Updated:04/21/2011. PMM2-(CDG-Ia). In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.
Seta N. The CDG Syndrome. Orphanet encyclopedia, September 2004. Available at: http://www.orpha.net/data/patho/Pro/en/CDGSyndrome-FRenPro3553.pdf Accessed on: November 27, 2011.
Report last updated: 2012/07/30 00:00:00 GMT+0