Carbohydrate-deficient glycoprotein syndrome.

Q Our 3-year-old daughter was recently diagnosed with carbohydrate-deficient glycoprotein syndrome. I had a normal pregnancy and delivery, and there is no family history of any serious neurological disease that started in infancy. Our daughter seemed to have feeding difficulties and difficulty gaining weight almost from birth. She has low muscle tone (it is a little better now that she is in an early intervention program), and all her developmental milestones are delayed. She also has visual problems and will require surgery to correct crossed eyes.

The whole syndrome is very confusing to my husband and me. The more questions we ask, the more confused we get. I have found out that there are multiple forms of this disorder and that the prognosis varies. Are there any new forms of treatment? How can we best plan for our daughter's future in terms of her physical and mental development?

A Carbohydrate-deficient glycoprotein syndrome (CDGS) is relatively rare but probably significantly underdiagnosed. It is an inherited metabolic disorder that was only discovered in 1989. I had not heard about it until recently; so far only one of my patients has been diagnosed with CDGS. There are at least six types: IA, IB, II, III IV, and V. The most research to date has been done on Type I than on the others.

CDGS is inherited as an autosomal recessive trait, that is, each parent must have at least one copy of the gene, which is located on chromosome 16. This means, on average, that one child out of four born to these parents will inherit two defective genes and have CDGS; two children will be carriers of one copy of the gene, but will not have CDGS; and one child will not carry any copies of the gene. Therefore, the risk of a child being born with CDGS is 25 percent in each pregnancy.

What is CDGS?

Carbohydrate-deficient glycoprotein syndromes are very complex multisystem diseases (more than one organ of the body can be involved). It is worthwhile to briefly discuss the biochemical basis of CDGS to explain why so many organ systems are affected.

A metabolic disorder is an error in the process used by living cells in converting food and oxygen into the energy that the body requires to grow, repair itself, and carry out the basic processes of life. In CDGS, there are defects or errors involved in the process of attaching certain carbohydrates (also called saccharides or sugars) to proteins to form essential compounds. This process is called glycosylation, and the carbohydrate-protein combinations that it forms are called glycoproteins. Glycoproteins are important in many normal bodily functions, including: interactions between cells, especially in the central nervous system; transfer of nutrients from the blood into the cells; hormone function; regulation of growth; sexual development; coagulation of blood; and many others. Hence, multiple organs in the body may be involved.

CDGS I

The type of CDGS was not specifically mentioned in your letter. It sounds as if your daughter has Type IA based on the symptoms you mentioned and the lack of certain other symptoms, such as skin color abnormalities, seizures, and microcephaly, among others.

CDGS Type IA is the best described of the six known types. Typically, there are four age-related stages. The first two stages, "infantile" and "childhood," vary in severity but usually manifest with: feeding difficulties, failure to thrive, chronic diarrhea, and vomiting. Hypotonia (floppy muscle tone) and global developmental delays are very common. Underdevelopment of portions of the brain, particularly the cerebellum (the part of the brain that coordinates voluntary muscle activity and equilibrium), may also occur. In some cases, very serious complications related to liver dysfunction and coagulation (blood clotting) may occur. Other severe complications, including pericardial effusions (fluid buildup around the heart) and gastrointestinal bleeding are also possible.

Atypical physical appearances may include a prominent jaw and inward deviation of the eyes (also called internal strabismus, esotropia, or "crossed eyes"). Prominent pads of fat (lipodystrophic accumulations) above the buttocks, around the external genitalia, or on the lower limbs, are fairly common.

Approximately 50 percent of young children with CDGS have periods of stupor, lethargy, visual difficulties, paralysis, and seizures that often accompany fevers or infections. These episodes are described as "stroke-like," and their effects are generally temporary.

In the childhood stage, there may be demyelination (loss of the fatty coverings around nerve fibers). This leads to abnormal conduction of nerve impulses from the brain and spinal cord to the muscles in the extremities. This results in weakness in the muscles of the extremities.

Hearing impairment, mental retardation, developmental delays, and speech and communication dysfunction are common in this disorder. Please remember as you read all these symptoms, however, that the way that CDGS presents in different individuals is highly variable. You should not assume that your daughter will have all these symptoms.

The teenage stage does not present many new or significant problems. There may be more complications related to the demyelination of the peripheral nervous system (the nerves outside the brain and spinal cord). This is especially seen in the legs ("teenage leg atrophy"). Scoliosis (sideways curvature of the spine) and/or kyphosis (front-to-back curvature of the spine) may also occur.

The adult stage is usually fairly stable, manifested primarily by lack of secondary sexual development in females (resulting in infertility), cerebellar ataxia (incoordination due to the lack of development of the cerebellum), and symptoms of peripheral neuropathy (weakness and loss of sensation due to the demyelination of the peripheral nerves). Most adolescents and adults with CDGS are short in stature.

Diagnosis and treatment

When a child has a cluster of obscure clinical findings that seem to indicate the possibility of Type I CDGS, a blood test can be performed. This test measures the levels of a particular glycoprotein, carbohydrate-deficient transferrin, via a method called isoelectric focusing. There are other blood tests available that help to establish a diagnosis of the other types of CDGS. These blood tests can be done very early in life so that early intervention can then begin immediately. In addition, the genetic mutations that cause CDGS Types I and II can now be detected in carriers.

Treatment for CDGS is primarily supportive and focuses on the child's specific clinical findings and symptoms. Treatment should be aggressive and on-going. Institution of early intervention services is important to help infants and young children with CDGS reach their potential. Researchers have found that administration of mannose, a carbohydrate, may be helpful in some cases of Type IB CDGS. Other forms of therapy are being investigated in the United States and in Europe.

I realize that much of what I have written may not apply to your daughter. However, I feel that CDGS is largely underdiagnosed. While the majority of children and infants will not have CDGS, I hope that this column will serve as a source of information about this uncommon condition.

For more information, contact: CDGS Family Network c/o Donna Yunes 4 Wryan Rd Derry, NH 03038 Telephone: [phone] Web site: http://www.cdgs.com/ E-mail: [e-mail]