20241101_Aa_disorder

Amino acids are the primary components of proteins. They also act as intermediates in important metabolic cycles and function as neurotransmitters, which are essential for various life processes.

The disorders of the urea cycle share a common theme related to the metabolism of nitrogen and the removal of ammonia from the body, which is crucial for preventing toxic accumulation.

The clinical features associated with amino acid disorders differ markedly due to the biochemical heterogeneity of amino acids, affecting various metabolic pathways and functions.

Alkaptonuria is caused by the excretion of large amounts of homogentisic acid in the urine due to a metabolic defect.

As patients with alkaptonuria age, they develop:

1. Pigmentation of the sclerae and cartilage
2. Visible pigments in the ear by age 30
3. Pigmentation in the buccal mucosa and nails
4. Ochronotic arthritis, particularly affecting large joints like the hip and shoulder
5. High incidence of heart disease, with myocardial infarction being a common cause of death.

Homogentisic acid inhibits the growth of cultured human articular chondrocytes, leading to ochronotic arthritis and ultimately causing marked limitation of motion in patients.

Alkaptonuria is inherited as an autosomal recessive trait.

The gene for Alkaptonuria has been mapped to chromosome 3q2.

It is recommended to reduce the intake of phenylalanine and tyrosine in the diet.

One approach is to employ reducing agents, such as ascorbic acid, to prevent the oxidation of homogentisic acid to benzoquinone-acetic acid.

The metabolic pathway involves the conversion of Phenylalanine to Tyrosine through the action of the enzyme phenylalanine hydroxylase. In Phenylketonuria (PKU), this conversion is impaired due to a deficiency in the enzyme, leading to the accumulation of phenylalanine, which can cause neurological damage if not managed. Early detection and dietary management are crucial to prevent cognitive impairment.

In Alkaptonuria, the defect is in the enzyme homogentisic acid oxidase, which leads to the accumulation of Homogentisic Acid. This accumulation can result in darkening of urine and can cause joint and connective tissue damage due to the deposition of ochronotic pigment. Management includes dietary restrictions and monitoring for complications.

Albinism is characterized by a deficiency in the enzyme tyrosinase, which is crucial for the synthesis of melanin from Tyrosine. This results in reduced pigmentation in the skin, hair, and eyes, leading to clinical features such as increased sensitivity to sunlight, a higher risk of skin cancer, and vision problems due to lack of pigment in the retina.

The primary defect in PKU is the inability to convert phenylalanine (phe) to tyrosine (tyr) due to a deficiency in the enzyme phenylalanine hydroxylase.

Infants with PKU appear normal at birth. However, they may exhibit vomiting as a prominent early symptom. They are typically fair-haired and fair-skinned, with less pigment in the skin due to the inhibition of tyrosinase by elevated levels of phenylalanine.

If there is no dietary intervention in PKU, it can lead to severe mental retardation, with an I.Q. usually under 50.

Dietary treatment in PKU is effective in preventing mental retardation, making it a model for public health approaches to control inherited diseases.

Routine neonatal screening programs have been most effective in identifying PKU early, particularly in developed countries, allowing for timely dietary intervention to prevent severe outcomes.

PKU is transmitted by an autosomal recessive gene located on chromosome 12q.

At least 31 mutations have been defined for the gene responsible for PKU.

The incidence of classic PKU is approximately 1 in 10,000 births.

About 1 in 50 individuals is a carrier of the PKU gene.

The metabolites that accumulate in PKU lead to decreased levels of serotonin, epinephrine, norepinephrine, and dopamine.

The metabolites that accumulate in PKU inhibit glutamic acid decarboxylase, which decreases levels of 4-aminobutyric acid (GABA) in the brain.

Routine screening for an elevated concentration of phenylalanine in blood is the primary method for diagnosing PKU in infants. If the initial test is positive, a second quantitative assay of phenylalanine and tyrosine levels in the blood is performed.

The main treatment for PKU involves providing a diet that is sufficiently low in phenylalanine while still meeting the normal requirements for this essential amino acid to support growth. Additionally, frequent quantitative assessments of phenylalanine concentration in the blood are necessary.

Inputs:

• Dietary protein
• Turnover of endogenous (bound, polypeptide) pools

Outputs (Runouts):

1. Hydroxylation to tyrosine (catalyzed by phenylalanine hydroxylase)
2. Incorporation into bound (polypeptide) pools
3. Transamination and decarboxylation

Proportional Importance of Outputs:

• Hydroxylation to tyrosine: 3
• Incorporation into bound pools: 1
• Transamination and decarboxylation: trace

The site of the defect in PKU is in phenylalanine hydroxylase. As a consequence of this block, phenylalanine accumulates, leading to the production of various metabolites such as phenylpyruvate, phenylacetate, phenylacetylglutamine, o-Hydroxyphenylpyruvate, phenyllactate, and o-Hydroxyphenylacetate.

The two major types of melanin are:

1. Eumelanin: This type provides black and brown coloration.
2. Pheomelanin: This type provides red or yellow coloration.

Both types can be synthesized in a single melanocyte, and mixtures of the two types may occur.

The primary defect in oculocutaneous albinism may be restricted to the pigment cell (melanocyte) system or may involve many cell types, leading to hypopigmentation and associated optic abnormalities.

Common visual impairments associated with albinism include:

• Impaired vision
• Nystagmus: Involuntary rapid movement of the eyeball
• Abnormal decussation: Crossing over of the optic nerve fibers is commonly detected.

Melanin is synthesized in melanocytes through the metabolism of tyrosine within specialized organelles called melanosomes. The process of melanogenesis is stimulated by UV light and melanocyte-stimulating hormone.

The rate-limiting step is the hydroxylation of tyrosine.

The form of melanin responsible for the appearance of the black labrador retriever is eumelanin.

The initial compound is DOPA (dihydroxy-phenylalanine), and the two reactants involved in the process are cysteine and glutathione (GSH).

The molecule formed is called Cysteinyl DOPA. It has a benzene ring structure with two hydroxyl groups attached to carbons in the 1 and 2 positions, a S-CH2-CHCOOH group attached to carbon 3, and an NH2 group attached to carbon 4 of the CH2.

The final product of the conversion process is Pheomelanins, which are pigments responsible for the appearance of certain animals, such as the golden retriever.

Pheomelanin is significant as it is the pigment responsible for the golden coloration in golden retrievers, contributing to their distinctive appearance.

In a normal eye, the nerve fibers intersect normally at the Chiasm, while in an albino eye, the nerve fibers do not intersect at the Chiasm, leading to different pathways to the lateral geniculate nucleus.