1. Diseases Caused due to Malfunctions in the Metabolic Pathways
By: Swati Shetty & Shambhavi Verma

2. 1. Galactosemia
The inability of the body to metabolize the simple sugar galactose, causing the accumulation of galactose 1-phosphate in the body.
This causes damage to the liver, central nervous system, and other body systems.
Galactose is a breakdown product of lactose, which is most commonly found in milk products.
Since galactose cannot be broken down, it builds up in the cells and becomes toxic. 

3. Cause:
Due to lack of enough enzymes, or no enzymes, needed for the breakdown of galactose, leading to toxic levels of galactose to build up in the blood.
There are 3 forms of the disease:
1. Galactose-1 phosphate uridyl transferase deficiency : classic galactosemia, the most common and most severe form
2. Deficiency of galactose kinase
3. Deficiency of galactose-6-phosphate epimerase.

4. Diagnosis:
A galactosemia test is a blood or urine test that checks for the three enzymes that are needed to change galactose into glucose.
Due to the lack of the enzymes the build up galactose in the blood and urine can be tested.
Galactosemia usually causes no symptoms at birth, but jaundice, diarrhea, and vomiting soon develop and the baby fails to gain weight. 

5. Treatment:
The only treatment for classic galactosemia is eliminating lactose and 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.

7. 2. Wernicke-Korsakoff syndrome
A brain disorder involving loss of specific brain functions caused by a thiamine deficiency.
also called:
wet brain
Korsakoff psychosis
alcoholic encephalopathy
Wernicke's disease
encephalopathy – alcoholic
Beri beri

8. Cause:
The metabolically active form of thiamin is thiamin diphosphate which plays a major role as a cofactor Coenzyme in glucose metabolism.
The enzymes which are dependent on thiamin diphosphate are associated with the TCA Cycle and catalyse the oxidation of pyruvate, alpha-ketoglutarate and branched chain amino acids.
Thus, anything that encourages glucose metabolism will exacerbate an existing clinical or sub-clinical thiamine deficiency.

9. Symptoms: Vision changes Loss of muscle coordination
Double vision
Eye movement abnormalities
Eyelid drooping
Loss of muscle coordination
Unsteady, uncoordinated walking
Loss of memory, can be profound
Inability to form new memories
Confabulation (making up stories)
Hallucinations
Symptoms of alcohol withdrawal

10. Diagnosis:
Examination of the nervous/muscular system may show damage to multiple nerve systems. Reflexes may be decreased or abnormal. The person's walk and coordination will be tested. Muscles may be weak and may show atrophy (loss of tissue mass).
Examination of the eyes shows abnormalities of eye movement. Blood pressure and body temperature measurement may be low. Pulse may be rapid.
The person may appear malnourished. The following tests are used to check a person's nutrition level and may confirm malnourished state.
Serum B1 levels may be low.
Pyruvate is high.
Transketolase activity is decreased.
Blood or urine alcohol levels and liver enzymes may be high if the person has a history of chronic (long-term) alcohol abuse.

11. Treatment:
Treatment consists of reversing the thiamine deficiency by giving supplemental thiamine.
It is important to start the thiamine treatment before giving any glucose as the encephalopathy will be worsened by the glucose as glucose administration promotes dehydrogenation of pyruvate, a biochemical reaction which consumes thiamine
By the time amnesia and psychosis have occurred, complete recovery is unlikely.

13. 3. Refsum Disease:
Adult Refsum disease (ARD) is one of a group of genetic diseases called leukodystrophies, which damage the white matter of the brain and affect motor movements.
Due to a genetic abnormality, people with ARD disease lack the enzyme that breaks down phytanic acid, a substance commonly found in foods.
Consequently, this unusual, exogenous C20-branched-chain (3,7,11,15-tetramethylhexadecanoic acid) fatty acid accumulates in blood and tissues.
It is almost exclusively of exogenous origin and is delivered mainly from dietary plant chlorophyll and, to a lesser extent, from animal sources.

14. Cause:
This due to deficiencies of phytanoyl-CoA hydroxylase, a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation.
Phytanic acid replaces other fatty acids, including such essential ones as linoleic and arachidonic acids in lipid moieties of various tissues. This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis.
An infantile form of RD also exists that is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including raised plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids.

15. Symptoms
Patients with Refsum's Disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy.
Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation/remission occur.
Symptoms also include night blindness, ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including cataracts.

16. Treatment:
The primary treatment for ARD is to restrict or avoid foods that contain phytanic acid, including dairy products; beef and lamb; and fatty fish such as tuna, cod, and haddock.
Some individuals may also require plasma exchange (plasmapheresis) in which blood is drawn, filtered, and reinfused back into the body, to control the buildup of phytanic acid.

18. 4. Zellweger Syndrome:
Also called cerebrohepatorenal syndrome is a rare, congenital disorder (present at birth), characterized by the reduction or absence of peroxisomes (cell structures that rid the body of toxic substances) in the cells of the liver, kidneys, and brain.
One of a group of genetic disorders called the leukodystrophies that affect growth of the myelin sheath, the fatty covering--which acts as an insulator--on nerve fibers in the brain.

19. CAUSE:
The PXR1 gene has been mapped to chromosome 12; mutations in this gene cause Zellweger syndrome.
The PXR1 gene product is a receptor found on the surface of peroxisomes - microbodies found in animal cells, especially liver, kidney and brain cells.
The enzymes contained by peroxisomes carry out a number of metabolically important reactions.
The PXR1 receptor is vital for the import of these enzymes into the peroxisomes: without it functioning properly, the peroxisomes can not use the enzymes to carry out their important functions, such as cellular lipid metabolism and metabolic oxidations.

20. Symptoms:
The most common features include an enlarged liver, high levels of iron and copper in the blood stream, and vision disturbances.
Some affected infants may show prenatal growth failure.
At birth may include a lack of muscle tone, an inability to move and glaucoma.
May include unusual facial characteristics, mental retardation, seizures, and an inability to suck and/or swallow.

21. TREATMENT:
There is no cure for Zellweger syndrome, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive.
The prognosis for individuals with Zellweger syndrome is poor. Death usually occurs within 6 months after onset, and may be caused by respiratory distress, gastrointestinal bleeding, or liver failure.

22. 5. Ketoacidosis:
Ketoacidosis is a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the deamination of amino acids, and the breakdown of fatty acids.
The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate.

23. Causes:
Occurs when the body is producing high levels of ketone bodies via the metabolism of fatty acids (ketosis) and the body is producing insufficient insulin to slow this production.
The excess ketone bodies can significantly acidify the blood. The presence of high blood sugar levels (hyperglycemia) caused by the lack of insulin can lead to further acidity in the blood.
In healthy individuals this normally does not occur because the pancreas produces insulin in response to rising ketone/blood sugar levels.
Acidity results from the dissociation of the H+ ion at physiological pH of metabolic ketone bodies such as acetoacetate, and β-hydroxybutyrate.

24. Symptoms:
Ketoacidosis usually develops slowly. But when vomiting occurs, this life-threatening condition can develop in a few hours. The first symptoms are:
Thirst or a very dry mouth
Frequent urination
High blood glucose (sugar) levels
High levels of ketones in the urine
Next, other symptoms appear
Constantly feeling tired
Dry or flushed skin
Nausea, vomiting, or abdominal pain (Vomiting can be caused by many illnesses, not just ketoacidosis.  If vomiting continues for more than 2 hours, contact your health care provider.)
A hard time breathing (short, deep breaths)
Fruity odor on breath
A hard time paying attention, or confusion

26. Thank You