I-cell disease is a lyosomal mucolipidosis. The storage disease is caused by a mutation of the GNPTA gene with gene locus q23.3 on chromosome 12. Symptomatic treatment is mainly by administration of bisphosphonates.
What is I-cell disease?
Storage diseases are characterized by the deposition of various substances in cells and organs of the human body. It is a heterogeneous group of diseases that can be divided into several subtypes. In addition to glycogenoses, mucopolysaccharidoses and lipidoses, medicine differentiates sphingolipidoses, hemosideroses and amyloidoses depending on the deposited substance. Lysosomal storage diseases affect the lysosomes. These are tiny, membrane-encased cell organelles in eukaryotes. Lysosomes are formed by the Golgi apparatus and are equipped with hydrolytic enzymes and phosphatases. With the help of their enzymes, their main function is to digest foreign substances and endogenous substances. I-cell disease is a lyosomal mucolipidosis with two distinct subtypes. Leroy and DeMars first documented the disease in the 1960s, noting its similarity to mucopolysaccharidosis type I, known as Hurler’s disease. The disease is named for the fibroblast inclusions, or inclusin-cells, in the skin of patients.
Causes
The cause of I-cell disease is deficient activity of N-acetylglucosaminyl-1-phosphotransferase. The impaired activity of this enzyme prevents a large proportion of lysosomal enzymes from entering the lysosome. The regulation of lysosomal enzymes is characterized by the activity of phosphotransferase. In a healthy organism, it enables the synthesis of a sorting signal. This process is disturbed in I-cell disease. Therefore, no labeling with mannose-6-phosphate takes place. For this reason, lysosomal enzymes are no longer adequately sorted and migrate uncontrollably across the plasma membrane into the extracellular matrix. This is caused by a mutation of the GNPTAB gene. It deprives N-acetylglucosaminyl-1-phosphotransferase of its functionality and thus the ability to catalyze mannose-6-phosphate synthesis. The transport of lysomal enzymes is thus impaired. N-acetyl-glucosamine-1-phosphotransferase consists of alpha, beta and gamma subunits. They are encoded on two genes. Hereditary I-cell disease affects the GNPTA gene on chromosome 12, with a mutation present in gene locus q23.3. An incidence of about 0.3 : 100,000 is reported for this rare disease. Inheritance is autosomal recessive. Thus, both parents must carry the defective gene to pass on the disease.
Symptoms, complaints, and signs
In most cases, the symptoms of I-cell disease can be observed immediately after birth or at the latest a few months later and are similar in characteristics to those of Hurler syndrome. Unlike patients of Hurler syndrome, those of I-cell disease do not show mucopolysaccharide excretion. The individual symptoms of the disease are subject to wide variation. Kornfeld and Sly summarize clinical features of the skeleton, internal organs, eyes, skin, central nervous system, and face. The skeleton is so commonly affected by kyphoscoliosis and hip dislocations. Club feet, joint contractures and deformities of the vertebrae may also be present. The same is true for short stature and dysostosis multiplex. In the internal organs, the disease may manifest itself in the form of hepatosplenomegaly and cardiomegaly or cardiac vitiation. The face of the patients shows coarsened facial features. Exophthalmos, hyperplastic gums, or scaphocephaly are also typical symptoms. Equally characteristic are an open mouth and a deeply sunken nasal bridge. The eyes of affected individuals often show corneal opacities or swollen eyelids. The skin is thick and coarse, with central nervous severe psychomotor or mental retardation.
Diagnosis and course of the disease
The initial tentative diagnosis of I-cell disease can be made by eye examination based on the history. To confirm the diagnosis, a biochemical determination of lysosomal enzyme activity in serum can be performed. This determination yields an aberrant ratio of intracellular and extracellular activity.The activity of phosphotransferase in fibroblasts can also be determined to confirm the diagnosis. The inclusions correspond to either mucopolysaccharides, lipids or oligosaccharides. If necessary, molecular genetic diagnostics can dispel final doubts. In case of an appropriate history, the disease can also be diagnosed in the course of prenatal diagnostics. However, because of the low prevalence, prenatal diagnosis is actually recommended only in cases of familial predisposition. The course of the disease depends on the symptoms in the individual case and is not directly predictable. However, most patients hardly survive the tenth year of life. However, milder courses are not completely excluded in individual cases.
Complications
I-cell disease can cause various complications and symptoms. However, these are not recognized until late, so I-cell disease can only be diagnosed at a late stage. Symptoms are relatively inconsistent, which often complicates treatment. There are usually complaints and malformations of the skin, the eyes and also of the internal organs. In the worst case, the affected person can go blind or die directly from organ failure. Furthermore, there is a pronounced short stature and also complaints of the heart. The eyelids are often swollen and there is reduced intelligence and mental retardation. It is not uncommon for the affected person to be dependent on the help of other people in everyday life due to the retardation in order to be able to cope with it. The patient’s quality of life is greatly reduced by the I-cell disease. Usually, there are no particular complications in the treatment of the disease. Medications and psychological treatments are used, which can alleviate the symptoms. However, complete and causal treatment of this disease is not possible. Life expectancy is decreased by the disease.
When should you go to the doctor?
I-cell disease is usually diagnosed immediately after the child is born. Whether further treatment is needed depends on the nature and severity of the symptoms. Mild deformities do not necessarily require treatment. Clubfeet and deformities of the vertebrae, on the other hand, are serious malformations that must be treated surgically and with medication. Parents should consult a specialist immediately if the doctor in charge at the maternity hospital has not already done so. If an accident or fall occurs as a result of the symptoms, the child must be taken to the hospital or the parents should immediately call the emergency medical services. In the case of severe malformations, which may also affect the child’s psyche later in life, a therapist should be called in to accompany the medical treatment. I-cell disease therefore requires medical clarification in every case. The right contact person is the pediatrician or a specialist for hereditary diseases. In case of visual disturbances, an ophthalmologist should be consulted concomitantly.
Treatment and therapy
I-cell disease is considered incurable. Therefore, a causative therapy does not exist. Treatment is exclusively symptomatic and supportive. Psychotherapeutic care for affected families makes up a large part of supportive therapy. Symptomatic therapy depends on the individual case. Bone symptoms are often treated by the administration of bisphosphonates. These drugs are known from osteoporosis treatment and have a high affinity to the bone surface. They bind to the bone especially in the region of the resorption lacunae. They thus inhibit the osteoclasts that break down bone and in this way reduce bone resorption. The drugs are among the pyrophosphate analogs with a carbonaceous P-O-P bond. Thus, enzymatic hydrolysis does not occur on them. The most current of these substances are the aminobisphosphonates. In addition, alendronates, clodronates, etidronates, ibandronates, pamidronates and risendronates from the same group of drugs are approved in Germany. The same applies to Tiludronate and Zoledronate. In addition to these drugs, bone marrow transplants are available for the treatment of I-cell disease. However, the success of this treatment has been limited in previous cases. Gene therapies are now being investigated as a new therapeutic approach for gene defects. Gene therapies have shown initial success in animal models. However, they have not yet been applied in practice in humans.In the future, however, this relationship is likely to change.
Outlook and prognosis
I-cell disease is a hereditary disorder that, to date, cannot be treated symptomatically. Accordingly, the prognosis is negative. Although symptoms can be significantly reduced by early therapy, I-cell disease almost always takes a severe course. The short stature and the damage to the internal organs as well as to the head already reduce the life expectancy considerably. Furthermore, malformations of the face, skin and eyes may reduce the life expectancy, but primarily the quality of life of the affected person. Some affected persons reach the age of 40 or 50, but most of them die already in childhood or adolescence. If I-cell disease is not treated, sufferers often die in the first years of life. Accordingly, the prognosis is rather negative. Nevertheless, there is a prospect of a relatively symptom-free life if the patient is treated as part of a comprehensive therapy and, if necessary, placed in a facility for the physically disabled. Physiotherapy as well as therapeutic measures can significantly improve the well-being of the sufferer in the long term.
Prevention
I-cell disease can be prevented only by molecular genetic testing before family planning. In addition, as part of prenatal diagnostics, expectant parents may choose to terminate the pregnancy.
Follow-up
In most cases, those affected by I-cell disease have no or very few aftercare measures available to them. In this case, the disease must be detected by a physician as early as possible so that further worsening of the symptoms can be prevented. Since this is a genetic disease, genetic testing and counseling should always be performed first in the event that the patient wishes to have children in order to avoid passing on the I-cell disease to descendants. Most patients are dependent on taking various medications for this disease. Here, it is important to pay attention to a correct dosage and also to a regular intake of the drugs. If there are any uncertainties, side effects or questions, a doctor should always be consulted first. Likewise, many affected persons need psychological support with this disease, whereby loving conversations with parents or relatives can also have a positive effect on the course of the disease. One affected person needs the help and support in everyday life from his or her own family. In many cases, I-cell disease significantly limits or reduces the life expectancy of the affected person.
What you can do yourself
Patients suffering from I-cell disease can resort to various conservative and alternative treatments. Conservative therapy focuses on relieving symptoms and discomfort. The use of assistive devices such as crutches or orthopedic insoles can slow the progression of the respective deformities and thus reduce pain. Medications help relieve pain and can be supplemented with alternative measures such as massage or acupuncture. However, alternative therapies should be discussed with the responsible physician beforehand. The physician may be able to refer the patient directly to a homeopath or provide further tips for treating the symptom in question. Since I-cell disease is usually fatal despite all treatment options, therapeutic counseling should be sought. It is not only the affected person who should work through his or her fears. The relatives and friends usually also need support in dealing with the disease and a possibly negative course. For the patient and the relatives, participation in a self-help group is also a possibility. Contact with other sufferers helps to accept the disease, and often other sufferers can also name further treatment measures and strategies for daily life with I-cell disease.
