E3: L22/23 Metabolic Diseases

Question 1

Why is it critical to diagnose & treat PKU in early childhood?

Answer 1

The neurotoxic effects of Phe accumulation results in degradation of myelin sheaths, resulting in less White Matter. Myelination primarily occurs during early childhood, so early diagnosis & treatment can prevent the neurological symptoms associated with PKU.

Question 2

Does the putative deficiency of tyrosine lead to neurotoxicity?

Answer 2

Probably not:

• Postnatal Tyr supplementation alone without reduction of phenylalanine intake does not prevent severe mental retardation in PKU
• Also, dietary restriction of Phe by itself prevents neurotoxicity.

Question 3

Can transport processes and abnormal metabolic distributions cause the PKU phenotype?

Answer 3

Potentially yes.

• Studies show that elevated concentrations of phenylalanine could impair uptake of some amino acids, such as tyrosine and tryptophan, through the blood brain barrier (BBB).
• Phenylalanine competitively inhibits the transport of these two amino acids, thereby reducing tyrosine availability for neurotransmitter synthesis in the brain

Question 4

Can the affected neurochemistry and metabolism cause the phenotype?

Answer 4

Long-term exposure to high levels of phenylalanine impairs brain architecture, with;

• Significant demyelination
• Width of the cortical plate
• Cell density & organization
• Dendritic arborization
• Number of synaptic spines.

Question 5

The carbohydrates (saccharides) are divided into what four chemical groups?

Answer 5

1. Monosaccharides
2. Disaccharides
3. Oligosaccharides
4. Polysaccharides

Question 6

What are the 2 most common disorders of carbohydrate metabolism?

Answer 6

Galactosemia & Diabetes (Type II)

Question 7

What are the 2 autosomal recessive defects in fructose metabolism?

Answer 7

Fructosuria:

• Most common
• Caused by Loss-of-Function mutations in the gene encoding [Hepatic Fructokinase]
  
  • Catalyzes the conversion of dietary fructose to Fructose-1-Phosphate

Hereditary fructose intolerance (HFI):

• Autosomal recessive
• Caused by mutations in the ALDOB gene (9q22.3)
  
  • Codes for [Fructose Aldolase] in the liver, kidney cortex, and small intestine
• Diagnosis is typically suspected based on dietary history, especially in infants who become symptomatic after breast feeding is supplemented by fructose containing foods.
  
  • This suspicion is typically confirmed by molecular analysis

Question 8

What is the difference between Type 1 & Type 2 diabetes?

Answer 8

Diabetes mellitus:

• General term referring to all states characterized by hyperglycemia

Type 1:

• Autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency

Type 2:

• Multifactoral syndrome with combined influence of genetic susceptibility & influence of e_nvironmental factors_, the best known being obesity, age, and physical inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption

Question 9

How is the galactosemia disease inherited?

What is the most common cause?

What are the results of this disease?

Answer 9

Galactosemia:

• Most common cause: Missense mutations in exon 6 of the [galactose-1-phosphate uridyl transferase] gene
• Inheritance: Autosomal recessive
• The accumulation of galactose becomes the substrate for enzymes that catalyze carbohydrate metabolism
  
  • Galactitol accumulates in body tissues, excreted in the urine, & attributed to many of the negative effects
• Symptoms of Galactosemia:
  
  • Individuals with galactosemia, acquire toxic levels of galactose 1-phosphate in various tissues resulting in;
    
    • Hepatomegaly, cirrhosis, renal failure, cataracts, brain damage, & ovarian failure

Infants affected by galactosemia

• Typically present with symptoms of lethargy, vomiting, diarrhea, failure to thrive, & jaundice
  
  • None are specific to galactosemia, often leading to diagnostic delays, & potentially death
• Without treatment, mortality in infants with galactosemia is about 75%
• Most infants are diagnosed on newborn screening (detects enzyme levels prior to ingestion of galactose-containing formula or breast milk)

Question 10

How do you treat Galactosemia?

Answer 10

Only treatment for classic galactosemia is eliminating lactose & galactose from the diet

• Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long-term complications such as
  
  • Speech difficulties
  • Learning disabilities
  • Neurological impairment (e.g. tremors, etc.)
  • Ovarian failure

Question 11

What are the two primary diseases associated with abnormalities in copper?

Answer 11

Menkes Disease:

• X-linked recessive
• Caused by mutations & deletions in the ATP7A gene (Xq21.1)
• Results in an inability to export copper from the GI epithelium into the blood stream; Leads to a overall deficiency of copper in the body
• Symptoms include; mental retardation, seizures, hypothermia, loose skin, brittle hair, arterial rupture and death in early childhood Treatment consists of; subcutaneous injections of copper into the body to restore proper levels

Wilson Disease:

• Autosomal recessive
• Due to mutations in the ATP7B gene which causes copper accumulation in tissues
• Symptoms: progressive liver disease and neurological abnormalities, along with joint inflammation, cardiomyopathy, kidney damage & deposition of copper in the eye (brown ring on the edge of the iris)

Treatment consists of; administering chelating agents to reduce copper levels