Table of Contents<\/b><\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_single_image image=”5576″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 1. Essential Amino Acids.<\/b> What are the metabolic fates of amino acids<\/b>? Most of the amino acids have two fates: (a)<\/b> incorporation into protein; and (b) <\/b>conversion to various biomolecules. There are three types of amino acids: (i)<\/b> essential<\/b>, (ii) nonessential<\/b>, and (iii) conditionally essential amino acids<\/b>. As shown, there are 9 essential amino acids<\/i><\/b> that human body cannot synthesize and consequently need to consume in our diet. These amino acids are phenylalanine, methionine, isoleucine, leucine, histidine, tryptophan, lysine, threonine,<\/i><\/b> and valine<\/i><\/b>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”introduction”][vc_column][vc_custom_heading text=”Introduction”][vc_single_image image=”5580″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Inborn errors of metabolisms (IEMs)<\/b> or inherited metabolic disorders (IMDs),<\/b> are a heterogeneous group of genetic conditions that manifest mostly in childhood<\/i><\/b>. Although individually rare, collectively they are numerous and cause substantial morbidity and mortality. Most having an incidence of less than 1 per 100,000 births<\/b>. However, when considered collectively, the incidence may approach 1 in 800 to 1 in 2500 birth<\/b> [1, 2].<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Some IMDs present acutely and lead to death in the neonatal period, whereas others are benign. Some may be diagnosed in infancy, and need complex, often dietary treatment requiring lifelong monitoring. Many cause significant health problems for affected individuals.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n A specific diagnosis enables genetic counselling to be offered to the family and subsequent antenatal diagnosis in future pregnancies. As girls with IMDs reach adulthood, care during pregnancy becomes an additional critical issue<\/i><\/b>, especially, to achieve optimum outcome for the baby without compromising the mother\u2019s overall health. The field of IMDs is vast and ever expanding<\/b>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-1″][vc_column][vc_custom_heading text=”Modes of Inheritance”][vc_column_text single_style=””]<\/p>\n Human beings have 23 pairs of chromosomes<\/b> (Greek: Khroma \u2018color<\/b>\u2019 + soma \u2018body<\/b>\u2019). For each pair of chromosome, one is inherited from the father and one from the mother. One pair is the sex chromosomes<\/b>: males have one X and one Y chromosome (i.e., XY<\/b>), whereas females have two X chromosomes (i.e., XX<\/b>). The nonsex chromosomes are called autosomes<\/b>. Inherited metabolic disorders are due to mutations in the gene (DNA sequence) on the chromosomes. Autosomal recessive, autosomal dominant, and X-linked recessive are forms of Mendelian inheritance<\/i><\/b>, as shown in Figure 2. (cf. previous blog entitled as \u2018Developmental Delays in Infancy and Early Childhood: Branched-Chain Amino Acid and Organic Acid Metabolism Disorders\u2019<\/a><\/i> )<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n (i) Autosomal Recessive Inheritance<\/b><\/p>\n This particular situation is shown in Figure 2A<\/b>. Both parents are heterozygous<\/b>, i.e., they carry an abnormal recessive gene. Carriers are usually asymptomatic<\/i><\/b>, and most families are unaware that they carry a disorder until they have an affected child. For each pregnancy there is a 1 in 4 risk<\/b> of the child inheriting one abnormal gene from each parent and thus being affected with the disorder. On average, 25% of offspring will be affected (abnormal homozygotes). 25% will be normal, and 50% will be carriers (heterozygotes). Significantly, most IMDs have an autosomal recessive mode of inheritance<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n (ii) Autosomal Dominant Inheritance<\/b><\/p>\n This particular situation is illustrated in Figure 2B<\/b>. An affected parent has one copy of an abnormal dominant gene (and is affected with the disorder<\/i><\/b>). On average, half of that parent\u2019s offspring will inherit the abnormal gene and will be affected with the same disorder as their parent. Half of the parent\u2019s offspring will not inherit the gene and so they will not be affected with the disorder, nor will they be a carrier. For example, some of the porphyrias are inherited in an autosomal dominant fashion<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n (iii) X-Linked Inheritance<\/b><\/p>\n X-linked disorders are due to mutations on the X chromosome<\/i><\/b>. Males inherit their one X chromosome from their mother. If it carries a mutation they will be affected with the corresponding disorder, i.e., they will be a hemizygote<\/b>. This particular situation is shown in Figure 2C<\/b>.<\/p>\n [\/vc_column_text][vc_single_image image=”5578″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 2. Modes of Inheritance.<\/strong> The modes of inheritance illustrated are: (A)<\/strong> autosomal recessive; (B)<\/strong> autosomal dominant; and (C)<\/strong> X-linked recessive. The chromosomes carrying a mutation is indicated with an asterisk (*<\/strong>). A blue<\/strong> individual is normal, a purple<\/strong> individual is carrier, and a green<\/strong> individual is affected with the disorder. {A, dominant gene on autosome; a, recessive gene on autosome; *, disease causing gene.}<\/strong><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n In females, a process called \u2018lyonization\u2019 randomly inactivates one of the X chromosomes in each cell of the body<\/em><\/strong>. Consequently, in some female heterozygotes there is a chance that more abnormal than normal X chromosomes will be active. This can result in a female having symptoms of the disorder. If affected, females generally have a milder form the disorder, but nevertheless they may have significant clinical problems. Examples of X-linked disorders are adrenoleukodystrophy<\/strong> and the urea cycle disorder ornithine transcarbamylase deficiency<\/strong>.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-2″][vc_column][vc_custom_heading text=”Phenylketonuria (PKU)”][vc_single_image image=”5574″ img_size=”full”][vc_column_text single_style=””]<\/p>\n PKU is a disorder of amino acid metabolism<\/em><\/strong> that causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities<\/strong> caused by elevated serum phenylalanine<\/strong>. The primary cause is deficient phenylalanine activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The majority of PKU cases are referred to as \u2018classic<\/em><\/strong> \u2019 and involve a deficiency of the phenylalanine hydroxylase enzyme<\/em><\/strong> (PAH<\/strong>), a small number have an elevated phenylalanine level due to a defect in dihydrobiopterin reductase enzyme<\/em><\/strong> (DHPR<\/strong>) activity (nonclassical PKU<\/strong>) that regenerates tetrahydrobiopterin (BH4<\/sub><\/strong>) cofactor for PAH enzyme activity (see Figure 3, 4<\/strong>).<\/p>\n [\/vc_column_text][vc_single_image image=”5577″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 3. Metabolism of Tyrosine and Associated Disorders. <\/strong>Tyrosine is an amino acid that is a precursor of several neurotransmitters<\/em><\/strong> (e.g., dopamine, norepinephrine, epinephrine), hormones (e.g., thyroxine), and melanin; deficiencies of enzymes involved in its metabolism lead to a variety of syndromes, (e.g., tyrosinemia I, tyrosinemia II, alkaptonuria, albinism). [PKU<\/strong>, classical phenylketonuria; PKU (BH4<\/sub> variant),<\/strong> nonclassical phenylketonuria]<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The newborn with PKU may appear functionally normal, early detection through newborn screening<\/strong> identifies PKU at a time when early treatment can prevent development of the cardinal manifestation, viz., intellectual impairment. Should this escape detection or not be performed, then the affected individual develops a peculiar \u2018mousy odor\u2019 particularly in the urine, very fair complexion, hair, and pale eye color<\/u>.<\/em> This is in fact related to impairment of melanin synthesis. Additionally, child may exhibit missed developmental milestones such as walking and talking and later on will manifest severe intellectual impairment, eczema, seizure activity, and self-abusive behavior<\/u><\/em> unless treatment is initiated promptly [2, 4, 5].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-3″][vc_column][vc_custom_heading text=”Pathophysiology of PKU”][vc_column_text single_style=””]<\/p>\n When an excessive amount of phenylalanine crosses the blood-brain barrier<\/em><\/strong> (BBB<\/strong>), is toxic to the myelin sheath. Moreover, a decrease in the biosynthesis of dopamine, epinephrine, and norepinephrine<\/em><\/strong> explains the neurologic dysfunctions. Unless this is aggressively approached with dietary manipulation, irreversible damage occurs before 6 months of age. Besides, the low tyrosine level, due to the inability to convert phenylalanine to tyrosine, results in failure of pigment formation (pseudoalbinism) and consequently, would explain the light-colored eyes and skin<\/em><\/strong> (see Figure 3<\/strong>).<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n A normal nutritional diet contains an excess of phenylalanine necessary for normal metabolic requirements. Conversion to tyrosine occurs in the liver. Hundreds of mutations in the phenylalanine hydroxylase gene have been defined with impairment ranging from 50% activity to total enzyme inactivity<\/em><\/strong>. Only minor reduction in the enzyme activity may result in elevated levels of phenylalanine without neurological impairment (hyperphenylalaninemia<\/em><\/strong>). When the enzyme deficiency reaches critical levels, phenylalanine excess is \u2018shunted\u2019 into alternative metabolic pathways. It is these metabolic products, viz., phenylpyruvate<\/em><\/strong> and phenylacetate<\/em><\/strong> that are responsible for the odor in the urine of the infant. Strict dietary management of PKU can achieve a near normal phenylalanine level and, in turn, normal development.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n For this above reason, mandatory screening of all newborn infants has become the standard of care. Most importantly, PAH-deficient expectant mothers must be judicious in their dietary restriction of phenylalanine before and during pregnancy<\/em><\/strong>. Elevated levels of phenylalanine result in serious teratogenic damage in utero<\/em> <\/strong>i.e., toxic embryopathy<\/strong>, resulting in microcephaly<\/em> <\/strong>and cardiac abnormalities<\/em><\/strong> in this situation.<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-4″][vc_column][vc_custom_heading text=”Biochemical Basis of the Symptoms in PKU”][vc_column_text single_style=””]<\/p>\n PKU falls into the aminoacidopathies<\/strong> category of IEMs<\/strong>, due to the defective metabolism of amino acids (see Figure 1<\/strong>). Examples of various diseases that are associated with phenylalanine and tyrosine metabolism<\/strong> are illustrated in Figure 3 and 4<\/strong>. Accumulating molecules may be toxic giving rise to symptoms such as hyperactivity, intellectual disability, developmental delay, vomiting, and seizures<\/em><\/strong> [3, 4].<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-5″][vc_column][vc_custom_heading text=”Metabolic Fates of Amino Acids”][vc_column_text single_style=””]<\/p>\n Fundamentally, most of the amino acids have two metabolic fates: viz., (a) incorporation into protein<\/strong>; and (b) conversion to various biomolecules<\/strong>. There are 3 types of amino acids: i.e., (i) essential<\/em><\/strong>; (ii) nonessential<\/strong>, <\/em>and (iii) conditionally essential amino acids<\/em><\/strong> (see Table \u2013 1; Figure 1<\/strong>).<\/strong><\/p>\n [\/vc_column_text][vc_single_image image=”5573″ img_size=”full”][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-6″][vc_column][vc_custom_heading text=”Metabolic Fate of Tyrosine”][vc_column_text single_style=””]<\/p>\n Tyrosine is synthesized from phenylalanine by phenylalanine hydroxylase<\/em><\/strong> using tetrahydrobiopterin<\/em><\/strong> (BH4<\/sub><\/strong>) as a cofactor. In this context, tyrosine is the precursor of dopamine, norepinephrine, and epinephrine, also known as catecholamine neurotransmitters<\/em><\/strong>. It is also the precursor of the thyroid hormones<\/em><\/strong> and melanin<\/em><\/strong>. The cofactor tetrahydrobiopterin is essential not only for tyrosine synthesis but also for the synthesis of L-DOPA<\/strong>, the precursor for the catecholamines and for the synthesis of serotonin from tryptophan<\/em><\/strong>. These reactions are hydroxylations by monooxygenases using tetrahydrobiopterin as a cofactor. During this reaction, tetrahydrobiopterin is oxidized to dihydrobiopterin<\/strong> (BH2<\/sub><\/strong>) Recycling of dihydrobiopterin back to tetrahydrobiopterin by dihydropteridine reductase<\/em><\/strong> (DHPR<\/strong>) is required for the continued synthesis of tyrosine, L-DOPA, and serotonin (see Figure 4<\/strong>).<\/p>\n [\/vc_column_text][vc_single_image image=”5579″ img_size=”full”][vc_column_text single_style=””]<\/p>\n Figure 4. Phenylalanine and Tryptophan Metabolism.<\/strong> The role of dihydropteridine reductase in phenylalanine and tryptophan metabolism<\/em><\/strong> in the synthesis of neurotransmitters, such as dopamine, norepinephrine, serotonin, as well as hormones such as epinephrine and melatonin.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Hyperphenylalaninemia may arise due to a deficiency in either phenylalanine hydroxylase or DHPR<\/i><\/b> (see Figure 3 and 4<\/b>) Both of these deficiencies are considered as phenylketonuria. However, since tetrahydrobiopterin is a cofactor in several reactions, the effects of DHPR deficiency may cause even more severe neurological difficulties than those with phenylalanine hydroxylase deficiency. Patients with DHPR deficiency may also be less response to therapy<\/b>.<\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n Failure to convert phenylalanine to tyrosine results in the accumulation of phenylalanine, which becomes a major donor of amino groups in aminotransferase. As a result, phenylpyruvate is synthesized. The urinary phenylpyruvate accumulation is used as a diagnostic tool for PKU. Phenylpyruvate is further oxidized to phenylacetate, which imparts a \u2018mousy\u2019 odor to the urine.<\/i><\/b><\/p>\n [\/vc_column_text][vc_column_text single_style=””]<\/p>\n The progressive mental impairment<\/b> in untreated PKU is due to several reasons. For example:<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-7″][vc_column][vc_custom_heading text=”Treatment of PKU”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-scroll-point-8″][vc_column][vc_custom_heading text=”Take Home Messages”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row el_class=”blog-text-35795″ el_id=”conclusion”][vc_column][vc_custom_heading text=”Conclusion” el_class=”blog-text-35795″][vc_column_text single_style=””]<\/p>\n In this blog, we presented an overview of numerous disorders of phenylalanine and tyrosine metabolism. PKU, a rare, inherited defect in the metabolism of the amino acid phenylalanine, was first described in 1934. Consequently, the discovery of PKU was considered as a fundamentally important discovery for the fields of biochemistry, genetics, metabolism, and medicine. The creation and implementation of newborn screening programs for PKU and other rare inherited metabolic disorders, and the subsequent, successful treatment of affected infants, is a huge success story!<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row][vc_row][vc_column][vc_column_text single_style=”” el_class=”blog-banner-section”]<\/p>\n Folate (vitamin B9) is very important for your child\u2019s brain development!<\/p>\n During pregnancy, it helps prevent neural tube defects and plays a big role in forming a normal and healthy baby\u2019s brain and spinal cord. Folate also helps cells divide and assists in both DNA and RNA synthesis.<\/p>\n Emerging research suggests that the presence of FRAAs negatively impacts folate transport into the brain.<\/p>\n Yes, there is a test – The Folate Receptor Antibody Test (FRAT\u00ae<\/sup>) has emerged as a diagnostic tool for detecting the presence of FRAAs.<\/p>\n It is important to screen at an early age or as soon as possible as there may be corrective measures available. Please consult your physician for further information.<\/p>\n To request a test kit, click on the button below.<\/p>\n Request Now<\/a><\/div>\n<\/div>\n [\/vc_column_text][vc_column_text single_style=”” el_class=”text-gray-23″]For information on autism monitoring, screening and testing please read our blog<\/a>.[\/vc_column_text][\/vc_column][\/vc_row][vc_row el_id=”blog-references” el_class=”blog-text-35795″][vc_column][vc_custom_heading text=”References” use_theme_fonts=”yes”][vc_column_text single_style=””]<\/p>\n [\/vc_column_text][\/vc_column][\/vc_row]<\/p>\n","protected":false},"excerpt":{"rendered":" Discover the impact of inherited metabolic disorders on childhood development. Learn about modes of inheritance, phenylketonuria (PKU), and amino acid metabolism.<\/p>\n","protected":false},"author":3,"featured_media":5583,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[73,64],"tags":[],"yoast_head":"\n\n
\n<\/a><\/li>\n
\n(see Box \u2013 1<\/strong>) [1, 2].<\/p>\n\n
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\n6 mg\/dL (129 to 360 \u03bcmol\/L) for all children.<\/li>\nDid You Know? Folate Receptor Autoantibodies (FRAAs) may impede proper folate transport.<\/h4>\n
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Is there a test for identifying Folate Receptor Autoantibodies (FRAAs)?<\/h4>\n
![\"FRAT](\"https:\/\/autism.fratnow.com\/blog\/wp-content\/uploads\/2023\/12\/frat-mascot-image.webp\")
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\nhttps:\/\/doi.org\/10.1309\/LM62LVV5OSLUJOQF<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/30600976\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/16861488\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/18566668\/<\/a><\/li>\n
\nhttps:\/\/pubmed.ncbi.nlm.nih.gov\/24385074\/<\/a><\/li>\n<\/ol>\n