The pedigree chart shows the inheritance of phenylketonuria. Genetic hereditary diseases
The law of cleavage also explains the inheritance of phenylketonuria (PKU), a disease that develops as a result of an excess of the important amino acid phenylalanine (Phe) in the human body. Excess phenylalanine leads to the development of mental retardation. The incidence of PKU is relatively low (approximately 1 in 10,000 births), however, about 1% of mentally retarded individuals suffer from PKU, thus constituting a relatively large group of patients whose mental retardation is explained by a homogeneous genetic mechanism.
As in the case of CG, researchers studied the incidence of PKU in the families of probands. It turned out that patients suffering from PKU usually have healthy parents. In addition, it has been observed that FKU is more common in families in which the parents are blood relatives. An example of a family of a proband suffering from PKU is shown in Fig. 2.3: a sick child was born to phenotypically healthy parents who are blood relatives (cousins), but the sister of the child’s father suffers from PKU.
Rice. 2.3. An example of a pedigree of a family in which PKU is inherited (the proband's aunt suffers from this disease).
A double line between spouses denotes a consanguineous marriage.
The remaining symbols are the same as in Fig. 2.1.
PKU is transmitted by a recessive mode of inheritance, i.e. The patient's genotype contains two PKU alleles received from both parents. Descendants who have only one such allele do not suffer from the disease, but are carriers of the PKU allele" can pass it on to their children. In Fig. Figure 2.4 shows the ways of inheritance of PKU alleles from two phenotypically normal parents. Each parent has one PKU allele and one normal allele. The probability that each child can inherit the PKU allele from each parent is 50%. The probability that a child will inherit PKU alleles from both parents at the same time is 25\% (0.5 x 0.5 = 0.25; the probabilities are multiplied because the events of inheriting alleles from each parent are independent of each other).
The PKU gene and its structural variants, found in different populations, have been well studied. The knowledge at our disposal allows us to carry out timely prenatal diagnosis in order to determine whether the developing fetus has inherited two copies of the PKU allele from both parents (the fact of such inheritance sharply increases the likelihood of the disease). In some countries, for example in Italy, where the incidence of PKU is quite high, such diagnosis is mandatory for every pregnant woman.
Rice. 2.4. Crossing scheme: allelic mechanism of inheritance of PKU.
0 dominant allele (“healthy”); [f] recessive allele that causes the development of the disease. FF, FF are phenotypically normal children (75% of them): only 25% have a normal genotype (FF); another 50% are phenotypically healthy, but are carriers of the PKU (Pf) allele. The remaining 25% of descendants are sick ([f][f])
As noted, PKU is more common among those who marry blood relatives. Although the incidence of PKU is relatively low, approximately 1 in 50 people are carriers of the PKU allele. The probability that one carrier of the PKU allele will marry another carrier of such an allele is approximately 2\%. However, when marrying between blood relatives (i.e., if the spouses belong to the same pedigree in which the PKU allele is inherited), the likelihood that both spouses will be carriers of the PKU allele and simultaneously pass on two alleles to the unborn child will become significantly higher 2\ %.
The law of cleavage also explains the inheritance of phenylketonuria
(PKU) - a disease that develops as a result of an excess of an important
amino acids - phenylalanine (Phe) in the human body. Excess
phenylalanine leads to the development of mental retardation. Frequency
The incidence of PKU is relatively low (approximately 1 in 10,000 new
born), however, about 1% of mentally retarded individuals
mov suffer from PKU, thus making up a relatively more
largest group of patients whose mental retardation is explained
homogeneous genetic mechanism.
As in the case of CG, researchers studied the frequency of occurrence
PKU in families of probands. It turned out that patients suffering from PKU
usually have healthy parents. In addition, it was noticed that
PKU is more common in families in which parents are blood
other relatives. Example of a family of a proband suffering from PKU
rice. 2.3: sick
phenotypic
healthy
parents-
relatives
suffers
transmitted
inheritance,
sick
contains
received
parents.
Rice. 2.3. An example of a family pedigree, in
suffer
transmitted
illness,
are
inheritance (the proband's aunt suffers
allele holders PKU and can
this disease).
hand over
A double line between spouses means
rice. 2.4 shown
consanguineous
Rest
formation of PKU alleles from two
the designations are the same as in Fig. 2.1.
phenotypically
normal
parents.
leu has one PKU allele and one normal allele. Probability
that every child can inherit the PKU allele from every
of the parents is 50%. The probability that the child is
follows the PKU allele from both parents at the same time, is 25%
(0.5 x 0.5 = 0.25; probabilities are multiplied as events are inherited
the alleles from each parent are independent of each other).
The PKU gene and its structural variants found in different
populations have been well studied. The knowledge at our disposal is
Rice. 2.4. Crossing scheme: allelic mechanism of inheritance of PKU.
F - dominant allele (“healthy”); [f] - recessive allele causing
development of the disease. FF, FF - phenotypically normal children (75% of them); only
about 25% have a normal genotype (FF); another 50% are phenotypically healthy,
but are carriers of the PKU (FF) allele. The remaining 25% of descendants are sick
([f][f]).
marriage, allow for timely prenatal diagnosis
tics in order to determine whether the developing embryo has inherited
breathe two copies of the PKU allele from both parents (the fact of such inheritance
vaniya sharply increases the likelihood of disease). In some countries,
for example in Italy, where the incidence of PKU is quite high
juice, such diagnostics are carried out without fail for each
milk a pregnant woman.
As already noted, PKU is more common among those who enter
marries with blood relatives. Despite the fact that the meeting
The incidence of PKU is relatively low, approximately 1 in 50 people is
carrier of the PKU allele. The probability that one carrier of the allele
PKU will marry another carrier of such an allele, is
approximately 2%. However, when marrying between consanguineous
relatives (i.e. if the spouses belong to the same pedigree, in
which PKU allele is inherited) the probability that
both spouses will be carriers of the PKU allele and at the same time transfer
will give two alleles to the unborn child, it will become significantly higher than 2%.
The genealogical method of studying heredity is one of the oldest and most widely used methods of genetics. The essence of the method is to compile pedigrees that allow one to trace the characteristics of the inheritance of traits. The method is applicable if the direct relatives of the owner of the studied trait on the maternal and paternal lines in a number of generations are known.
Contents 1. 2. 3. 4. 5. Symbols Rules for drawing up a pedigree Stages of problem solving Types of inheritance of characteristics Problem solving
Rules for compiling pedigrees The person from whom they begin to compile a pedigree is called a proband. The proband's brothers and sisters are called sibs. 1. The pedigree is depicted so that each generation is on its own horizontal line. Generations are numbered with Roman numerals, and members of the family tree are numbered with Arabic numerals. 2. Drawing up a pedigree starts from the proband (depending on gender - a square or circle, indicated by an arrow) so that from him it is possible to draw a pedigree both down and up. 3. Next to the proband, place the symbols of his siblings in order of birth (from left to right), connecting them with a graphic rocker.
4. Above the proband line, indicate the parents, connecting them to each other with a marriage line. 5. On the parents’ line, draw the symbols of the closest relatives and their spouses, connecting their degrees of relationship accordingly. 6. On the proband’s line, indicate his cousins, etc., brothers and sisters, connecting them accordingly with the parents’ line. 7. Above the line of parents, draw the line of grandparents. 8. If the proband has children or nephews, place them on a line below the proband's line.
9. After depicting the pedigree (or simultaneously with it), appropriately show the owners or heterozygous carriers of the trait (most often, heterozygous carriers are determined after the compilation and analysis of the pedigree). 10. Indicate (if possible) the genotypes of all members of the pedigree. 11. If there are several hereditary diseases in the family that are not related to each other, create a pedigree for each disease separately.
Stages of problem solving 1. Determine the type of inheritance of the trait - dominant or recessive. To do this, find out: 1) whether the trait being studied is common (in all generations or not); 2) how many members of the pedigree have the trait; 3) whether there are cases of birth of children possessing the trait, if the parents do not exhibit this trait; 4) whether there are cases of birth of children without the studied trait, if both parents have it; 5) what part of the offspring carries the trait in families if one of the parents is its owner.
Stages of problem solving 2. Determine whether the trait is inherited in a sex-linked manner. To do this, find out: 1) how often the symptom occurs in people of both sexes; if it is rare, then which gender carries it more often; 2) persons of which gender inherit the trait from the father and mother who carry the trait.
Stages of problem solving 3. Based on the results of the analysis, try to determine the genotypes of all members of the pedigree. To determine genotypes, first of all, find out the formula for the splitting of descendants in one generation.
Types of inheritance of a trait. 1. Autosomal dominant inheritance: 1) the trait occurs frequently in the pedigree, in almost all generations, equally often in both boys and girls; 2) if one of the parents is a carrier of a trait, then this trait will appear either in all of the offspring or in half.
Glaucoma is an eye disease characterized by increased intraocular pressure and decreased visual acuity. Risk factors for the development of glaucoma are: heredity, diabetes mellitus, atherosclerosis, eye trauma, inflammatory and degenerative eye diseases. With constantly elevated intraocular pressure, atrophy of the optic nerve gradually develops, and the person loses vision. Brachydactyly (brachydactylia; brachy- + Greek daktylos finger; synonym short-fingered) is a developmental anomaly: shortening of the fingers or toes. inherited in an autosomal dominant manner.
Types of inheritance of a trait. 2. Autosomal recessive inheritance: 1) the trait is rare, not in all generations, equally common in both boys and girls; 2) the trait can appear in children, even if the parents do not have this trait; 3) if one of the parents is a carrier of the trait, then it will not appear in children or will appear in half of the offspring.
What is phenylketonuria? Phenylketonuria (PKU) is an inherited disorder that increases the amount of the amino acid phenylalanine in the blood to harmful levels. (Amino acids are the building blocks of proteins). If PKU is not treated, excess phenylalanine can cause mental retardation and other serious health problems. How do people inherit PKU? PKU is inherited in an autosomal recessive manner, which means two copies of the gene must be changed for a person to be affected by the disease. Most often, the parents of a child with an autosomal recessive disorder are not affected, but are carriers of one copy of the altered gene.
Types of inheritance of a trait. 3. Sex-linked inheritance: 1) X - dominant inheritance: ü the trait is more common in females; ü if the mother is sick and the father is healthy, then the trait is transmitted to the offspring regardless of gender; it can manifest itself in both girls and boys; ü if the mother is healthy and the father is sick, then all daughters will exhibit the symptom, but sons will not.
3. Sex-linked inheritance: 2) X - recessive inheritance: the trait is more often found in males; More often the symptom manifests itself after a generation; If both parents are healthy, but the mother is heterozygous, then the trait often appears in 50% of sons; If the father is sick and the mother is heterozygous, then female persons can also have the trait.
3. Sex-linked inheritance: 3) Y-linked inheritance: ütrait occurs only in males; If the father carries a trait, then, as a rule, all sons also possess this trait.
An example of solving the problem The proband is a right-handed woman. Her two sisters are right-handed, her two brothers are left-handed. Mother is right-handed. She has two brothers and a sister, all right-handed. Grandmother and grandfather are right-handed. The proband's father is left-handed, his sister and brother are left-handed, the other two brothers and sister are right-handed. Solution: 1. Draw the symbol of the proband. We show the presence of the sign in the proband.
2. We place the symbols of her siblings next to the proband symbol. We connect them with a graphic rocker.
7. Determine the genotypes of the pedigree members. The sign of right-handedness appears in every generation in both females and males. This indicates an autosomal dominant type of inheritance of the trait. I A- A- II A- A- A- Aa aa A- III aa Aa Aa A- aa
Task 2. Based on the pedigree shown in the figure, determine the nature of the manifestation of the trait indicated in black (dominant, recessive, sex-linked or not). Determine the genotype of parents and children in the first generation.
Scheme for solving the problem: 1) The recessive trait is not sex-linked; 2) Genotypes of the parents: mother - aa, father - AA or Aa 3) Genotypes of the children: heterozygous son and daughter - Aa.
Task 3 Using the pedigree shown in the diagram, establish the type and nature of manifestation of the trait highlighted in black (dominant, recessive, sex-linked or not). Determine the genotypes of children in the first generation.
Scheme for solving the problem: 1) The trait is recessive, linked to the X chromosome; 2) Genotypes of the parents: mother – XHA, father – XAU; 3) Genotypes of children in F 1: son - Ha. Uh, daughter - HAHA daughter - HAHA
Task 4 Using the person’s pedigree shown in the figure, establish the nature of inheritance of the “small eyes” trait, highlighted in black (dominant or recessive, sex-linked or not). Determine the genotypes of parents and offspring F 1 (1, 2, 3, 4, 5). 1 2 3 4 5
Scheme for solving the problem: 1) The trait is recessive, not sex-linked; 2) Genotypes of the parents: mother – Aa, father – Aa; 3) Genotypes of descendants in F 1: 1, 2 – Aa, 3, 5 – AA or Aa; 4 – aa.
Codifier of content elements in biology 3. 4 Genetics, its tasks. Heredity and variability are properties of organisms. Genetics methods. Basic genetic concepts and symbolism. Chromosomal theory of heredity. Modern ideas about the gene and genome. 3. 5 Patterns of heredity, their cytological basis. Patterns of inheritance established by G. Mendel, their cytological basis (mono- and dihybrid crossing). Morgan's laws: linked inheritance of traits, disruption of gene linkage. Genetics of sex. Inheritance of sex-linked traits. Gene interaction. Genotype as an integral system. Human genetics. Methods for studying human genetics. Solving genetic problems. Drawing up crossing schemes.
SPECIFICATION of examination paper in biology A 7. Genetics, its tasks, basic genetic concepts. A 8. Patterns of heredity. Human genetics. A 9. Patterns of variability. A 30. Genetic patterns. The influence of mutagens on the genetic apparatus of cells and organisms. C 6. Solving problems in genetics to apply knowledge in a new situation.
Part A 1. Genetics is of great importance for medicine, since it 1) fights epidemics 2) creates medicines to treat patients 3) establishes the causes of hereditary diseases 4) protects the environment from pollution by mutagens
2. The method used to study the nature of the manifestation of characteristics in sisters or brothers who developed from one fertilized egg is called 1. 2. 3. 4. Hybridological Genealogical Cytogenetic Twin
3. The genealogical method is used for 1) Obtaining gene and genomic mutations 2) Studying the influence of education on human ontogenesis 3) Researching hereditary human diseases 4) Studying the stages of evolution of the organic world
4. What is the function of medical genetic consultations for parental couples? 1. Identifies the predisposition of parents to infectious diseases 2. Determines the possibility of having twins 3. Determines the likelihood of hereditary diseases in children 4. Identifies the predisposition of parents to metabolic disorders
Determine genotype by phenotype Eye color in a person is determined by an autosomal gene; color blindness is a recessive gene linked to sex. Determine the genotype of a brown-eyed woman with normal color vision, whose father is color-blind (brown-eyedness dominates blue-eyedness) 1) AAXDXD 3) Aa. Xd 2) Aa. XDXd 4) aa. XDXd
Part C Solution of genetic problems on the application of knowledge in a new situation: dihybrid crossing, inheritance of sex-linked traits, linked inheritance of traits (with crossing over, without crossing over), determination of blood groups, pedigree analysis
Part C In humans, the inheritance of albinism is not sex-linked (A - the presence of melanin in skin cells, and - the absence of melanin in skin cells - albinism), and hemophilia is sex-linked (XH - normal blood clotting, Xh - hemophilia). Determine the genotypes of the parents, as well as the possible genotypes, sex and phenotypes of children from the marriage of a dihomozygous woman, normal for both alleles, and an albino man with hemophilia. Make a diagram for solving the problem.
The scheme for solving the problem includes: 1) genotypes of the parents: ♀AAXHXH (AXH gametes); ♂aa. Xh. Y (gametes a. Xh, a. Y); 2) genotypes and gender of children: ♀Aa. XHXh; ♂Aa. XHY; 3) phenotypes of children: a girl who is outwardly normal for both alleles, but is a carrier of the genes for albinism and hemophilia; A boy who is outwardly normal for both alleles, but is a carrier of the albinism gene.
Anomalies leading to increased levels phenylalanine blood, most often phenylalanine hydroxylase (PAH) deficiency or phenylketonuria (PKU), illustrate almost all the principles of biochemical genetics related to enzyme defects. All genetic abnormalities of phenylalanine metabolism are the result of loss-of-function mutations in the gene encoding PAH or in the genes required for the synthesis or restoration of its cofactor, BH4.
Classic phenylketonuria(PKU) is rightfully considered an exemplary representative of inborn errors of metabolism. It is an autosomal recessive phenylalanine breakdown disorder caused by mutations in the gene encoding PAH, the enzyme that converts phenylalanine to tyrosine. Fehling's discovery of phenylketonuria (PKU) in 1934 was the first to demonstrate a genetic defect as a cause of mental retardation.
Due to inability to recycle phenylalanine patients with phenylketonuria (PKU) accumulate this amino acid in body fluids. Hyperphenylalaninemia damages the developing central nervous system in early childhood and interferes with the functioning of the mature brain. A small portion of phenylalanine is metabolized via alternative pathways, producing increased amounts of phenylpyruvic acid (the ketoacid for which the disease is named) and other metabolites excreted in the urine.
It's interesting that although enzyme defect has been known for decades, the exact pathogenetic mechanism of how increased phenylalanine damages the brain is still unknown. Importantly, the development of neurological damage caused by the metabolic block in classical PKU can largely be prevented by dietary changes that prevent phenylalanine accumulation. Treatment of phenylketonuria (PKU) has become a model for the treatment of many metabolic diseases, the outcomes of which may be improved by preventing the accumulation of enzyme substrate and its derivatives.
Newborn screening for phenylketonuria (PKU)
Population is widely used screening newborns for phenylketonuria (PKU). Phenylketonuria (PKU) is an example of genetic diseases for which mass neonatal screening is warranted; the disease is relatively common in a number of populations (up to 1 in 2900 live newborns). Treatment started early in life is very effective; without treatment, severe mental retardation inevitably develops. Screening tests are performed a few days after birth.
A drop of blood obtained from a puncture heels, applied to filter paper, dried and sent to a centralized laboratory to assess blood phenylalanine levels and the phenylalanine/tyrosine ratio. In the past, samples were collected before the baby was discharged from the hospital. The trend towards early discharge of mother and newborn after delivery has changed this practice. It is preferable not to test before 24 hours of age because phenylalanine levels in phenylketonuria (PKU) do not rise until after birth. Positive test results should be quickly confirmed, since delaying the initiation of treatment more than 4 weeks after delivery does not avoid the impact on the intellectual status of patients with phenylketonuria (PKU).
Various forms of phenylketonuria and hyperphenylalaninemia
Since (PKU) is associated with a severe deficiency of phenylalanine hydroxylase (PAH) activity (less than 1% compared with controls), mutant PAH with residual activity causes less severe phenotypic manifestations, so-called hyperphenylalaninemia and atypical phenylketonuria (PKU).
Hyperphenylalaninemia phenylketonuria (PKU), other than phenylketonuria (PKU), is diagnosed if the plasma phenylalanine concentration is below 1 mmol/L in the presence of a normal diet. This degree of hyperphenylalaninemia is only 10 times higher than normal and significantly lower than the concentrations found in classical phenylketonuria (PKU) (>1 mmol/L). A moderate increase in phenylalanine in hyperphenylalaninemia is not likely to harm brain function and may even be beneficial if the increase is small (<0,4 ммоль), такие дети обращают на себя внимание врачей только благодаря скринингу. Их нормальный фенотип оказался наилучшим показателем безопасного уровня фенилаланина плазмы, который не следует превышать при лечении пациентов с классической фенилкетонурии (ФКУ).
Atypical(PKU) - a category that includes patients with phenylalanine levels intermediate between classic PKU and hyperphenylalaninemia; such patients require some restriction of phenylalanine in the diet, but less than for patients with classical phenylketonuria (PKU). The complex of these three clinical phenotypes with mutations in the PAH gene is an example of clinical heterogeneity.
Hyperphenylalaninemia: allelic and locus heterogeneity in phenylketonuria (PKU)
Molecular defects in the phenylalanine hydroxylase gene. Patients with hyperphenylalaninemia, including classical phenylketonuria (PKU), atypical phenylketonuria (PKU), and benign hyperphenylalaninemia, display a striking degree of allelic heterogeneity at the phenylalanine hydroxylase (PAH) locus (more than 400 different mutations worldwide).
The vast majority of alleles phenylalanine hydroxylase(PAH) are fairly rare mutations that disrupt the enzymatic properties of phenylalanine hydroxylase (PAH) and lead to hyperphenylalaninemia, although benign polymorphisms or less common benign variants have also been found.
In populations European descent about two-thirds of known mutant chromosomes are represented by six mutations. Six other mutations are responsible for just over 80% of phenylalanine hydroxylase (PAH) mutations in Asian populations. Other pathogenic mutations are less common. To make this information widely available, an international consortium has developed a database of mutations in the phenylalanine hydroxylase (PAH) gene.
In all populations There is marked genetic heterogeneity of phenylalanine hydroxylase (PAH). Due to the high degree of allelic heterogeneity at the locus, the majority of patients with phenylketonuria (PKU) in many populations are compound heterozygotes (i.e., they have two different pathogenic alleles), which is fully consistent with the observed enzymatic and phenotypic heterogeneity in phenylalanine hydroxylase (PAH) disorders.
At first it seemed that knowledge of the genotype phenylalanine hydroxylase(FA) reliably predicts phenotype details; this expectation was not fully justified, although a certain correlation was found between the PAH genotype and the biochemical phenotype.
In general terms, mutations that completely suppress or dramatically reduce activity phenylalanine hydroxylase(PAH) cause classical phenylketonuria (PKU), while mutations resulting in sufficiently large residual enzyme activity are associated with mild phenotypes.
However, some mutations phenylalanine hydroxylase(FA) in homozygous patients determine the entire spectrum of phenotypes, from classical phenylketonuria (PKU) to benign hyperphenylalaninemia.
Thus, it became obvious that in the formation phenotype observed in a specific genotype, other unidentified biological factors are involved, undoubtedly including modifier genes. This observation, now recognized as a common characteristic of many monogenic diseases, indicates that even monogenic diseases like phenylketonuria (PKU) are not genetically simple diseases.
Defects in tetrahydrobiopterin metabolism in phenylketonuria (PKU)
Initially it was believed that all children with hereditary hyperphenylalaninemia have primary phenylalanine hydroxylase (PAH) deficiency. It is now clear that approximately 1-3% of patients have a normal PAH gene and their hyperphenylalaninemia is the result of a genetic defect in one of several other genes involved in the synthesis or regeneration of the PAH cofactor, BH4. The association of one phenotype, such as hyperphenylalaninemia, with mutations in different genes is an example of locus heterogeneity.
As shown by mutations in protein-coding genes phenylalanine hydroxylase(PAH) and the metabolism of its cofactor biopterin, proteins encoded by genes exhibiting locus heterogeneity, usually participate in the same chain of biochemical reactions. Patients with BH4 deficiency were first identified because, despite successfully maintaining low phenylalanine concentrations in the diet, they developed early onset profound neurological problems.
The poor results are partly explained the need for cofactor BH4 for the activity of two other enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Both of these hydroxylases are critical for the synthesis of monoamine neurotransmitters such as dehydroxyphenylalanine, norepinephrine, epinephrine and serotonin. Patients with BH4 deficiency have an impairment in either its biosynthesis from GTP or the regeneration of BH4. Like classic phenylketonuria (PKU), the disorder is inherited in an autosomal recessive manner.
It is important to distinguish patients with defects in BH4 metabolism from patients with mutations in phenylalanine hydroxylase(FA), since their treatment differs markedly. First, since the protein structure of phenylalanine hydroxylase (PAH) is normal in patients with BH4 disorders, its activity may be restored if these patients are given large doses of BH4, which leads to a decrease in plasma phenylalanine levels. Therefore, the degree of phenylalanine restriction in the diet of patients with defects in BH4 metabolism can be significantly reduced, and some patients can be switched to a normal diet (i.e., without phenylalanine restriction).
Secondly, you must also try normalize neurotransmitter levels in the brain of these patients by administering tyrosine hydroxylase and tryptophan hydroxylase products: L-dopa and 5-hydroxytryptophan, respectively. For these reasons, all newborns with hyperphenylalaninemia should be evaluated for abnormalities in BH4 metabolism.
Reaction to tetrahydrobiopterin with mutations in the PAH gene in phenylketonuria (PKU)
In most patients with mutations in the gene phenylalanine hydroxylase(PAH), and not in the metabolism of BH4, there was a clear decrease in the level of phenylalanine in the blood during oral administration of large doses of the cofactor phenylalanine hydroxylase (PAH) BH4. Patients with significant residual phenylalanine hydroxylase (PAH) activity (i.e., patients with atypical phenylketonuria (PKU) and hyperphenylalaninemia) respond best to such treatment, but a small number of patients even with classical phenylketonuria (PKU) also respond to this treatment. At the same time, the presence of residual PAH activity does not guarantee an effect on plasma phenylalanine levels when BH4 is prescribed.
It is most likely that the degree of response reactions on BH4 depends on the specific properties of each phenylalanine hydroxylase (PAH) mutant protein, reflecting the underlying allelic heterogeneity of PAH mutations. It has been shown that the introduction of BH4 into the diet has a therapeutic effect through several mechanisms caused by an increase in the amount of normal cofactor that comes into contact with the mutant one.
These mechanisms include stabilization of the mutant enzyme, protection of the enzyme from cell degradation, increased supply of a cofactor to the enzyme that has low affinity for BH4, and other beneficial effects in the kinetic and catalytic properties of the enzyme. Providing increased amounts of cofactor is a common strategy used in the treatment of many inborn errors of metabolism.
A number of gene mutations, in which the structure of only one gene is changed, leads to the development of mental retardation. According to some estimates, in 7-10% of patients with oligophrenia it is caused by mutations of this kind.
The set of biochemical reactions occurring in the body is called metabolism. Many genes encode proteins that participate as enzymes in certain metabolic reactions. A mutation in such a gene can lead to the body producing a less active or completely inactive enzyme, and sometimes to a complete cessation of enzyme synthesis. In this case, the reaction, normally carried out by this enzyme, either slows down or does not occur at all, which causes the corresponding hereditary disorder - one of the so-called inborn errors of metabolism. The most common genetic hereditary diseases include phenylketonuria, sickle cell anemia, Tay-Sachs disease, hemophilia, and diabetes mellitus. The extent to which they influence the phenotype depends on how important the affected enzyme is to the organism. We saw above that Tay-Sachs disease and cystic fibrosis lead to death. Some other genetic abnormalities cause various serious problems in the body, but are not fatal.
Phenylketonuria and albinism affect the same metabolic pathway.
Phenylketonuria is a disease in which, as a result of a mutation, the structure of the enzyme involved in the metabolism of the amino acid phenylalanine (phenylalanine hydroxylase) is disrupted. This enzyme is necessary for the conversion of phenylalanine to tyrosine. Diseases of this kind are called enzymopathies, i.e. caused by a defect in enzymes. With this disease, phenylalanine and products of its improper metabolism (phenylacetic acid) accumulate in the blood, which leads to damage to the developing nervous system. This is mainly the destruction of myelin and degeneration of the spongiform nervous system. Mental retardation, microcephaly, psychosis, tremor, convulsive activity, and spasticity occur.
Phenylketonuria affects individuals who are homozygous for a recessive gene that deprives them of the ability to synthesize one of the enzymes necessary to convert the amino acid phenylalanine into another amino acid, tyrosine. Instead of being converted to tyrosine, phenylalanine is converted to phenylpyruvic acid, which accumulates in toxic quantities in the blood, affects the brain and (if not treated promptly) causes mental retardation. The urine of patients also contains phenylpyruvic acid, which gives it a characteristic odor. Currently, phenylketonuria is treated with a special diet. To do this, in the first years of a child’s life, phenylalanine is almost completely excluded from his diet. Once brain development is complete, a patient with phenylketonuria is placed on a normal diet, but a woman with this genetic disorder should follow a diet low in phenylalanine during pregnancy to prevent abnormal development of the fetal brain. In the United States, in many states, all newborns are required to undergo special tests for PKU and some other inborn errors of metabolism.
Individuals homozygous for the albinism gene lack the enzyme that normally catalyzes the conversion of tyrosine to melanin, i.e. pigment that determines the brown or black color of eyes, hair and skin. Albinos have white hair and very light skin and eyes. Naturally, the question may arise whether patients with phenylketonuria are also albinos, since their bodies do not produce tyrosine, from which melanin is ultimately produced. However, such patients are not albinos, because tyrosine is not only formed in the body itself from phenylalanine, but also enters the body with food. True, patients with phenylketonuria are usually light-eyed, fair-skinned and fair-haired. Of course, there may be albinos among them, but only if the individual is homozygous for both recessive genes.
Inheritance of phenylketonuria (PKU) explains the law of splitting. This mutation is recessive, i.e. can resist in phenotype only in the homozygous state. The highest incidence of phenylketonuria was observed in Ireland (16.4 cases per 100 thousand newborns); for comparison: in the USA - 5 cases per 100 thousand newborns.
The PKU gene and its structural variants, found in different populations, have been well studied. The knowledge at our disposal allows us to carry out timely pre-natal diagnosis in order to determine whether the developing embryo has inherited two copies of the PKU allele from both parents (the fact of such inheritance sharply increases the likelihood of the disease). In some countries, for example in Italy, where the incidence of PKU is quite high, such diagnosis is mandatory for every pregnant woman.
PKU is more common among those who marry blood relatives. Although the incidence of PKU is relatively low, approximately 1 in 50 people are carriers of the PKU allele. The probability that one carrier of the PKU allele will marry another carrier of such an allele is approximately 2%. However, when a marriage occurs between blood relatives (i.e., if the spouses belong to the same pedigree in which the PKU allele is inherited), the likelihood that both spouses will be carriers of the PKU allele and simultaneously pass on two alleles to the future child will become significantly higher 2 %.
In the case of phenylketonuria, we have a striking example of how the development of a disease that has a genetic nature can be prevented by selecting environmental influences. Currently, phenylketonuria is easily detected during routine examinations of newborns at 2-3 days of age (normally, the concentration of phenylalanine in the blood plasma should not exceed 4 mg/dL). Patients are placed on a diet low in phenylalanine, which helps avoid developmental damage to the nervous system. In this case, tyrosine becomes an essential amino acid and it is necessary to ensure its presence in the diet. The most critical period is the early stages of ontogenesis, therefore, in adulthood, many no longer adhere to dietary restrictions, although this is still desirable. Women with phenylketonuria, regardless of their own condition, must follow a special diet during pregnancy, otherwise the high levels of phenylalanine in their blood will have a damaging effect on the developing fetus.
Phenylketonuria is a good example of a genotype-environment interaction. The essence of this disease is the different sensitivity of individuals with different genotypes to environmental influences. The same environment (in this case, the environment is the nature of nutrition) causes a severe illness (phenylketonuria) in some genotypes, while in other genotypes absolutely no pathological changes are observed. Under other environmental conditions (subject to a special diet), the differences between genotypes for this trait (phenylketonuria) disappear.
