Glycerol kinase deficiency, also known by the synonyms GK deficiency, glycerol kinase deficiency, hyperglycerinemia, or ATP-glycerol-3-phosphotransferase deficiency, is a metabolic disorder that can be treated in the Department of Human Genetics. A distinction is made between isolated, infantile, juvenile, and adult glycerol kinase deficiency.
What is glycerol kinase deficiency?
Glycerol kinase deficiency is a rare metabolic disorder in four different forms that can be treated by human genetics and belongs to the category of inherited diseases. The metabolism is affected because glycerol is not converted into glycerol-3-phosphate in the liver. Instead, oxidation or phosphorylation occurs, resulting in glycerol aldehyde-3-phosphate or glycerol 2-phosphate. Signs range from absence of symptoms to physical complaints and laboratory indications. Diagnosis can be made pretanally and postnatally by differential and molecular diagnostic methods. Mental retardation and musculoskeletal and vertebral disorders may present. Therapeutically, substitution with glucocorticoids and low-fat diet is indicated. Preventive measures are not known to date.
Causes
First and foremost is an X-linked recessive genetic defect. This is related to chromosome Xp21.3, and mutations in the GK gene at lacation Xp21.2 underlie the disease. The clinical criteria refer to growth retardation, mental retardation, osteoporosis with present fracture tendency. During fat digestion, glycerol is released in the intestine, absorbed by the tissues and transported to the liver. In the liver, glycerol kinase converts glycerol into glycerol-3-phosphate. To do this, the enzyme requires not only the substrate but also adenosine triphosphate, or ATP for short. During the cleavage of this phosphate, energy is released. Glycerol kinase uses this energy to catalyze the biochemical reaction with glycerol-3-phosphate. If this conversion does not take place, oxidation or phosphorylation (reversible attachment of a phosphate group to an organic molecule in biochemistry) can occur. Glyceraldehyde-3-phosphate or glyceric acid-2-phosphate is formed. This not only attacks the metabolism. Rather, there is dangerous interference with the metabolism with regard to the processing of fats and carbohydrates. In rarer cases, there is a combination of the clinical criteria with muscular dystrophy (hereditary muscle atrophy with increasing muscle weakness) and congenital adrenal hypoplasia (genetically caused underdevelopment of the kidney with insufficient cell formation). Another cause of glycerol kinase deficiency is in apolipoprotein C2, a component of lipoproteins that help transport lipids through the blood.
Symptoms, complaints, and signs
The symptoms are very versatile but can be reproduced very well by those affected, so that a medical history can be taken very well and extensively on the basis of the patient presentation. Thus, starting from an absence of symptoms to vomiting, recurrent sweating is also evident, especially during exertion and before eating. In laboratory terms, not only hypoglycemia (too low blood glucose level) is detectable. Rather, laboratory parameters in the blood and urine (hyperglycerinemia and hyperglycerinuria) are elevated. Enzyme deficiency and pseudohypertriglyceridemia (feigned elevation of triglycerides in the blood) can also be detected. Ketoacidosis (dangerous metabolic derailment due to insulin deficiency) and mental motor retardation, as measured by the average of the relevant age group, may add to the possible symptomatology.
Diagnosis
Diagnosis is made postnatally during molecular genetic testing using, among other methods, DNA sequence analysis of the GK gene. This requires three to five ml of EDTA blood. The result is available after two to three weeks. Free glycerol with elevated values can be detected in the urine as well as in the blood serum. If there is a medical indication, the laboratory examination is performed by means of a referral slip. Differential diagnosis includes the very rare Snyder-Robinson syndrome.This is a congenital disorder that can present mainly with mental retardation, muscular atrophy, osteoporosis or kyphoscoliosis (non-physiological, dorsally directed spinal curvature), but also facial asymmetry and gait instability. Diagnosis is also possible in the prenatal stage. All laboratory diagnostics can be based on biochemical and molecular diagnostics as well as heterozygote screening by NGS. “Diagnosis of intellectual disability” as postnatal diagnostics applies to mutation search, mutation screening as well as sequencing.
Complications
Glycerol kinase deficiency results in a wide variety of symptoms. However, in most cases, vomiting occurs, which is accompanied by profuse sweating in patients. The quality of life is considerably reduced by the symptoms, which in most cases occur directly after the consumption of food. Motor complaints also occur, so that ordinary activities in everyday life can no longer be performed. Most of those affected also suffer from increased retardation and are dependent on the help of other people to cope with their daily lives. It is not uncommon for movement disorders and gait instability to occur, so that patients suffer from an increased risk of falls and accidents. It is not possible to treat glycerol kinase deficiency directly, so treatment only takes the form of a suitable diet. This diet must be relatively low in fat to eliminate the deficiency. If diagnosed early, many symptoms can be limited and secondary damage can be avoided. Life expectancy is not reduced by the disease, but the patients’ everyday life is considerably restricted. The parents and relatives of patients also suffer greatly from psychological discomfort and possibly depression as a result of glycerol kinase deficiency.
When should one go to the doctor?
As a rule, glycerol kinase deficiency should always be examined by a physician. With this condition, there is no self-healing. The symptoms usually increase and have a very negative effect on the quality of life of the affected person. A doctor should be consulted if vomiting occurs very frequently and, above all, without cause. However, severe sweating may also indicate glycerol kinase deficiency and should be investigated. These can occur especially after ingestion of food. In many cases, glycerol kinase deficiency also leads to mental and motor retardation. This can be detected mainly by parents or relatives and should also be examined by a physician. First and foremost, a visit to a general practitioner or a pediatrician is suitable for this purpose. The treatment itself depends on the exact symptoms and also on the cause of the deficiency. Early diagnosis and treatment has a positive effect on the course of the disease.
Treatment and therapy
Treatment consists of a low-fat diet. If there is concomitant adrenal hypoplasia, glucocorticoid substitution may not only be important but even vital. For appropriate therapy to limit the possible sequelae, it is important to detect the disease as early as possible and treat it appropriately. In this respect, prenatal diagnostics is a milestone in differential and molecular diagnostic medicine. Glycerol is present in all fats and fatty acid esters (triglycerides = triple esters of glycerol). The level of concentration of these triglycerides in blood represents the indicator of human health. The following values can be used as a basis for a considered therapy:
If the value of triglycerides is above 150 milligrams per dl, it is considered too high and may indicate a lipid metabolism disorder (hypertriglyderidemia). One cause may be a genetic predisposition and the other may be a deficiency of lipoprotein lipase.
Outlook and prognosis
When medical guidance is sought, the prognosis of glycerol kinase deficiency is usually favorable. Patients are subjected to lifelong therapy for the hereditary disease because the genetic defect cannot be corrected for legal as well as scientific reasons.Depending on the severity of the disease, it is often sufficient to develop and adhere to a special low-fat diet. As a result, patients experience significant relief from existing symptoms and can enjoy their lifestyle in many other areas without complaints. In severe cases, the deficiency also leads to the regular administration of medications. This ensures the survival of the patient. The metabolism is stimulated by the medication and ultimately monitored so as not to trigger any complications or sequelae. Refusal of medical care can lead to severe disorders and discomfort. The average life expectancy also decreases. If patients suffer from mental retardation due to glycerol kinase deficiency, the prognosis is unfavorable. Despite support programs and timely medical care, this cannot be compensated or remedied in the necessary form. The patient is dependent on help and support in coping with everyday life for the rest of his life. Nevertheless, an improvement in the quality of life can also be achieved in this case with adherence to a diet as well as the administration of medication.
Prevention
Medical research has not yet succeeded in developing target-oriented measures in the context of prophylaxis. Thus, the best possibility for targeted treatment in the early stages is the earliest possible detection of glycerol kinase deficiency.
Follow-up
In glycerol kinase deficiency, there are usually no special follow-up measures available to the patient. In this case, the affected person is primarily dependent on medical treatment, although a complete cure is usually not possible. The symptoms can only be treated symptomatically and not causally. If the affected person wishes to have children, genetic counseling and testing can also be performed to prevent the recurrence of glycerol kinase deficiency in the offspring. This deficiency is usually treated by a special diet. In doing so, the affected person must pay attention to a low-fat diet in order to counteract the deficiency. In cases of doubt, the attending physician can also provide the affected person with a plan that can support the diet. Since glycerol kinase deficiency can also lead to other diseases and complications, regular examinations of the entire body are very useful. In some cases, the deficiency also reduces the life expectancy of the affected person. In general, a healthy lifestyle with a balanced diet has a positive effect on the course of the disease. Also, contact with other patients suffering from glycerol kinase deficiency can be useful, as it is not uncommon for this to result in an exchange of information.
Here’s what you can do yourself
It is not possible to treat glycerol kinase deficiency by self-help means. For this reason, those affected are always dependent on medical treatment. This usually involves the use of substitutes to compensate for the deficiency. Often, these drugs have to be taken throughout the patient’s life in order to permanently reduce the symptoms. Patients should therefore ensure that they take these drugs regularly. Furthermore, early diagnosis of glycerol kinase deficiency is very important, as this can prevent further diseases and consequential damage. Therefore, a doctor should be consulted at the first signs of glycerol kinase deficiency. If glycerol kinase deficiency is a genetic disease, those affected and their parents should undergo genetic counseling, as this can prevent the occurrence of the disease in further children. Furthermore, contact with other people affected by the disease often has a positive effect on the disease, as it can lead to an exchange of information. This can make everyday life easier and increase the quality of life of the person affected. Children should be fully informed about the disease and its possible consequences.
