16. Metabolic Diseases 1

Metabolic Diseases – Amino Acids and PKU

• Historical Context

  • Variants in metabolism recognized by Sir Archibald Garrod in the early 1900s as 'inborn errors of metabolism'.

• Alkaptonuria (AKU)

  • Caused by deficiency in homogentisic acid oxidase leading to accumulation of homogentisic acid and associated complications (e.g., cartilage damage).

• Phenylalanine Metabolism Pathway

  • Variants leading to:

    1. Classic PKU

    2. Tyrosinase-negative oculocutaneous albinism

    3. AKU

    4. Tyrosinemia (associated with mental impairment).

Disorders in Metabolism

• Incidence: ~1/2500 births or 10% of all monogenic conditions in children.

• Most are inherited in an autosomal recessive pattern.

Amino Acid Disorders

• Prevalence

  • Phenylketonuria (PKU): 1/10,000

  • Tyrosinemia Type 1: 1/100,000

  • Maple Syrup Urine Disease: 1/180,000

  • Alkaptonuria: 1/250,000

  • Homocystinuria: 1/340,000

  • Cystinosis: 1/100,000

PKU

• an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.

• Enzymatic Effects

  • PAH nonfunctional → phenylalanine accumulates (can be detected in urine) → tyrosine is deficient

• Genetics

  • Amino acid insertions and substitutions often lead to translational frameshifts and premature stop codons.

  • 2/3 of PKU mutations are amino acid missense substitutions

• Clinical Effects

  • High plasma phenylalanine levels are associated with acute impairment of higher integrative brain functions

  • Less white matter, which is primarily responsible for myelination and cognitive effects

  • Epilepsy and severe mental impairment

• Treatment

  • Dietary Management: A strict low-phenylalanine diet is essential to prevent neurotoxicity.

    • Early intervention and continuous treatment necessary for good outcomes.

  • Enzyme replacement and gene therapy can be used as alternative treatment.

Lysosomal Storage Disorders

• Overview

  • Group of inherited metabolic disorders caused by lysosomal dysfunction, mainly inherited as autosomal recessive disorders.

  • Triggered when a particular enzyme exists in too small an amount or is missing altogether, causing substances to accumulate in the cell.

  • Mostly affect children who often die at young ages

• Symptoms

  • Developmental delay, movement disorders, seizures, dementia, deafness, blindness, hepatomegaly, splenomegaly.

• Treatment Approaches

  • Bone marrow transplantation

  • Enzyme replacement therapy

  • Substrate reduction therapy

  • Gene therapy under investigation.

Mucopolysaccharidoses

• Cause: do not produce enough of one of the 11 enzymes required to break down glycosaminoglycans, or they produce enzymes that do not work properly.

• Symptoms:

  • Deterioration in hearing, vision, joint, and cardiovascular and neurologic dysfunction.

  • Coarse/rough facial features, abnormal bone size/shape, dysostosis multiplex (bone changes), enlarged organs, heart disease

• Treatment: no cure, but symptoms can be treated

  • Limit dairy and sugar products

  • Surgery

  • Enzyme replacement therapy

  • Transplant of bone marrow, stem cells, or umbilical cord blood

Sphingolipidoses

• Overview

  • A class of lipid storage disorders relating to sphingolipid metabolism, generally inherited in an autosomal recessive pattern, besides Fabry disease which is x-linked recessive

  • More substantial in Ashkenazi Jew populations

• Tay-Sachs Disease

  • an autosomal recessive condition that causes a buildup of fatty acids (specifically gangliosides) in the brain and destroys nerve cells.

  • Caused by mutations in the HEXA (hexosaminidase A) gene

    • GM2 accumulates leading to dysfunction and death of neurons

    • Resulting in severe neurological impairment, progressive loss of motor skills, and early death, typically before the age of four.

Gaucher Disease

• Most common metabolic storage disorder

• Caused by a defect in the glucosylceramidase gene that catalyzes the breakdown of glucosylceramide.

• Gaucher cells (macrophages that become full of unprocessed glucocerebroside) accumulate primarily in the spleen, liver and bone marrow.

• Treatment

  • Enzyme replacement therapy: restoring low levels of glucocerebrosidase enzyme

  • Bone marrow transplant: transplanted cells are a source of lysosomal enzymes

  • Substrate reduction therapy: reduces the amount of mutated glucocerebroside produced by the body.

1. Type I (non-neuropathic type): most common form, affect mostly Ashkenazi Jews

   • Symptoms: splenomegaly, hepatomegaly, anemia, thrombocytopenia, leukopenia.

2. Type II (acute infantile neuropathic): rare, begins within 6 months, die by age 2

   • Symptoms: splenomegaly, hepatomegaly, extensive and progressive brain damage.

3. Type III (chronic neuropathic type): can begin in childhood or adulthood

   • Symptoms: splenomegaly, hepatomegaly, slowly progressive but milder neurologic symptoms