Phenylketonuria: symptoms, causes, treatment, diagnosis
What is it - phenylketonuria is a hereditary disease, the pathological manifestations of which are caused by a violation of the metabolism of phenylalanine.
As a result, this amino acid and the products of its anomalous metabolism accumulate in the body and lead to persistent toxic CNS damage with a decrease in mental abilities.
How does the disease develop and what is it? Phenylketonuria( PKU) binds several forms of impaired phenylalanine metabolism, which are similar in their features.
It is known that phenylpyruvic, α-toluic, phenyl-lactic acid, phenylethylamine and orthophenyl acetate, which normally hardly ever form, appear in body fluids and have a toxic effect on the central nervous system. It is assumed that this circumstance leads to a decrease in intelligence, but much has not been fully elucidated in the mechanisms of development of brain dysfunction.
The defeat of the nervous system can be the result of a number of factors:
If the disease is not treated, the nonspecific signs of central nervous system destruction appear already in the first six months of the child's life.
Symptoms of phenylketonuria such as increased excitability, hyperreflexia, tremor, intense vomiting can be observed. Acquired skills disappear, the child begins to lag behind in psychomotor, psychoemotional and speech development. Microcephaly is often observed, and cramps develop.
Autism spectrum disorders and manifestations of hyperactivity are not excluded. Characteristic and other neurologic disorders - a disorder of coordination of movements, a tremor, involuntary movements. Especially pronounced lag in development is approximately between 4 and 9 months of life.
This is the result of the cessation of melanin formation or a decrease in its level. Sometimes a skin rash appears on the skin, which is associated with increased sensitivity to injuries and sun rays. Also, a specific "mouse odor" can emerge from the skin due to excretion of phenylacetic acid in the urine.
As the child grows without adequate therapy, the disease progresses, resulting in mental retardation and disability. This clinical picture is typical for classical PKU.
Atypical forms have similar symptoms, but the course of the disease is more severe, and the treatment is ineffective. In type II phenylketonuria, the symptomatology develops during the second year of life, is characterized by increased excitability, tendon hyperreflexia, muscular dystonia, and spastic tetraparesis. Death can begin at the age of three.
With PKU III type, the clinic has microcephaly, spastic tetraparesis and deep mental retardation. Symptoms are similar to manifestations of Parkinson's disease and include hypokinesia, hypersalivation, gait difficulties, and swallowing disorders.
Diagnosis is based on the clinical picture and the results of continuous neonatal screening, the essence of which is in the mass study of blood samples of newborns. On the 4th day of life in the maternity hospital, the baby takes blood from the heel in order to determine the amount of phenylalanine in the blood. Phenylketonuria is diagnosed at an amino acid concentration higher than 8.0 mg / dL( the norm is 0-2 mg / dL).
A value between 2.0 and 8.0 mg / dl is characteristic of mild, or benign, hyperphenylalanineemia that does not require specific treatment. But in this case, during the first year of life, it is recommended to monitor the doctor and control the level of phenylalanine in the blood.
In practice, various methodical approaches to the study are used: Guthrie test, chromatography, fluorometry, tandem mass spectrometry. Molecular genetic diagnosis makes it possible to determine gene mutations and to reveal heterozygous carriage of a genetic defect with the help of synthetic oligonucleotide probes. Electroencephalography and MRI are also used.
Early diagnosis makes a huge difference, as it prevents the development of clinical symptoms of PKU and severe disability.
The main treatment for any form of phenylketonuria is a diet that involves the exclusion of high-protein foods. Strict dietary treatment must begin no later than the first weeks of the child's life and adhere to it should at least to puberty.
It is necessary to sharply limit the amount of phenylalanine supplied with food. For this, meat, bread, fish, eggs are completely excluded from food. You can not eat cottage cheese, nuts, chocolate, fizzy drinks. The diet consists of fruits, vegetables, vegetable oils. Carbohydrates are allowed in the form of jam, sugar, honey and sweets that do not contain aspartame.
There are special products based on extrusion and amylopectin starches. These are semi-finished products for cooking bread and baking, pasta. It is very important to determine the safe daily content of phenylalanine in the baby's menu every day.
The protein requirement is compensated for by the regular administration of amino acid mixtures. The nature of the diet also allows you to dosed the use of mother's milk in the first year of life, although earlier breastfeeding was completely abolished.
Regarding how long it takes to adhere to the diet, the opinions of many authors differ. Strict treatment is usually performed until 18 years, and then the diet gradually expands. There is also an opinion that it is impossible to refuse specific nutrition, that is, diet therapy should be lifelong.
As a result, this amino acid and the products of its anomalous metabolism accumulate in the body and lead to persistent toxic CNS damage with a decrease in mental abilities.
Causes and pathogenesis of
How does the disease develop and what is it? Phenylketonuria( PKU) binds several forms of impaired phenylalanine metabolism, which are similar in their features.
- Type I phenylketonuria( classical).- a mutation of the phenylalanine hydroxylase gene located in the long arm of chromosome 12 in the 12q22q24.1 area.
- Phenylketonuria type II.- mutation of the structural gene for cytosolic dihydropterin reductase, which is localized on the short arm of chromosome 4( locus 4p15.3).
- Phenylketonuria III type.- mutation of the structural gene for cytosolic 6-pyruvyltetrahydropterine synthase. The gene is located on the long arm of chromosome 11 in the region of q22.3-23.3.
It is known that phenylpyruvic, α-toluic, phenyl-lactic acid, phenylethylamine and orthophenyl acetate, which normally hardly ever form, appear in body fluids and have a toxic effect on the central nervous system. It is assumed that this circumstance leads to a decrease in intelligence, but much has not been fully elucidated in the mechanisms of development of brain dysfunction.
The defeat of the nervous system can be the result of a number of factors:
- deficiency of brain neurotransmitters( catecholamines and serotonin);
- direct toxic effect of phenylalanine on the central nervous system;
- disorder in protein metabolism;
- disorder of membrane movement of amino acids;
- a violation of the metabolism of hormones.
Symptoms of phenylketonuria
If the disease is not treated, the nonspecific signs of central nervous system destruction appear already in the first six months of the child's life.
Symptoms of phenylketonuria such as increased excitability, hyperreflexia, tremor, intense vomiting can be observed. Acquired skills disappear, the child begins to lag behind in psychomotor, psychoemotional and speech development. Microcephaly is often observed, and cramps develop.
Autism spectrum disorders and manifestations of hyperactivity are not excluded. Characteristic and other neurologic disorders - a disorder of coordination of movements, a tremor, involuntary movements. Especially pronounced lag in development is approximately between 4 and 9 months of life.
At birth, children with phenylketonuria have a healthy appearance. Although often phenotypically the disease is manifested by a decrease in the pigmentation of the skin, blond hair and blue iris.
This is the result of the cessation of melanin formation or a decrease in its level. Sometimes a skin rash appears on the skin, which is associated with increased sensitivity to injuries and sun rays. Also, a specific "mouse odor" can emerge from the skin due to excretion of phenylacetic acid in the urine.
As the child grows without adequate therapy, the disease progresses, resulting in mental retardation and disability. This clinical picture is typical for classical PKU.
Atypical forms have similar symptoms, but the course of the disease is more severe, and the treatment is ineffective. In type II phenylketonuria, the symptomatology develops during the second year of life, is characterized by increased excitability, tendon hyperreflexia, muscular dystonia, and spastic tetraparesis. Death can begin at the age of three.
With PKU III type, the clinic has microcephaly, spastic tetraparesis and deep mental retardation. Symptoms are similar to manifestations of Parkinson's disease and include hypokinesia, hypersalivation, gait difficulties, and swallowing disorders.
Diagnostics of phenylketonuria
Diagnosis is based on the clinical picture and the results of continuous neonatal screening, the essence of which is in the mass study of blood samples of newborns. On the 4th day of life in the maternity hospital, the baby takes blood from the heel in order to determine the amount of phenylalanine in the blood. Phenylketonuria is diagnosed at an amino acid concentration higher than 8.0 mg / dL( the norm is 0-2 mg / dL).
A value between 2.0 and 8.0 mg / dl is characteristic of mild, or benign, hyperphenylalanineemia that does not require specific treatment. But in this case, during the first year of life, it is recommended to monitor the doctor and control the level of phenylalanine in the blood.
In practice, various methodical approaches to the study are used: Guthrie test, chromatography, fluorometry, tandem mass spectrometry. Molecular genetic diagnosis makes it possible to determine gene mutations and to reveal heterozygous carriage of a genetic defect with the help of synthetic oligonucleotide probes. Electroencephalography and MRI are also used.
Early diagnosis makes a huge difference, as it prevents the development of clinical symptoms of PKU and severe disability.
Treatment of phenylketonuria
The main treatment for any form of phenylketonuria is a diet that involves the exclusion of high-protein foods. Strict dietary treatment must begin no later than the first weeks of the child's life and adhere to it should at least to puberty.
It is necessary to sharply limit the amount of phenylalanine supplied with food. For this, meat, bread, fish, eggs are completely excluded from food. You can not eat cottage cheese, nuts, chocolate, fizzy drinks. The diet consists of fruits, vegetables, vegetable oils. Carbohydrates are allowed in the form of jam, sugar, honey and sweets that do not contain aspartame.
There are special products based on extrusion and amylopectin starches. These are semi-finished products for cooking bread and baking, pasta. It is very important to determine the safe daily content of phenylalanine in the baby's menu every day.
The protein requirement is compensated for by the regular administration of amino acid mixtures. The nature of the diet also allows you to dosed the use of mother's milk in the first year of life, although earlier breastfeeding was completely abolished.
Regarding how long it takes to adhere to the diet, the opinions of many authors differ. Strict treatment is usually performed until 18 years, and then the diet gradually expands. There is also an opinion that it is impossible to refuse specific nutrition, that is, diet therapy should be lifelong.