Maple Syrup Urine Disease, Phenylketonuria & Alkaptonuria

Maple Syrup Urine Disease, Phenylketonuria & Alkaptonuria

1. Course Code: GEB204 Course Title: Biochemistry & Molecular Biology of Disease Presentation on Maple Syrup Urine Disease, Phenylketonuria & Alkaptonuria Group Members Asma Hossain ID: 2015-2-77-004 Rahatul Kabir 2015-2-77-033 Syeda Kashfia K a bir 2015-2-77-008 Kaberi Mostafa Saathi 2015-2-77-017 Farhana Shikder Lamia 2015-2-77-025 http://www.skara.se/

2. Metabolic Disorder A metabolic disorder can happen when abnormal chemical reactions in the body alter the normal metabolic process. It can also be defined as inherited single gene anomaly, most of which are autosomal recessive. Inherited metabolic disorders are one cause of metabolic disorders, and occur when a defective gene causes an enzyme deficiency. Metabolic diseases can also occur when the liver or pancreas do not function properly. Some metabolic disorders are Maple syrup urine disease Phenylketonuria Alkaptonuria

3. Maple Syrup U rine D isease

4. Introduction Maple syrup urine disease (MSUD) is an inherited metabolic disorder. Metabolic disorder can happen when abnormal chemical reactions in the body alter the normal metabolic process Person who is affected by MSUD is unable to process certain amino acids properly. MSUD is a rare genetic disorder characterized by deficiency of certain enzymes. MSUD due to an enzyme defect in the catabolic pathway of the branched chain amino acids .

5. Inheritance Pattern of MSUD MSUD is an autosomal recessive metabolic disorder affecting branched chain amino acid. Develops from inheriting a mutated gene from each parent. Mutation in BCKDHA (19q13.1-q13.2), BC2DHB (6p22-p21, 6p14 for Ashkenazi Jews )

6. Molecular mechanism

7. Signs & Symptoms of MSUD Symptoms are:- Sweet smelling urine and sweat Poor feeding Loss of appetite Weight loss Irregular sleep pattern

8. Babies with MSUD may also have episodes known as a “metabolic crisis”. Symptoms of a metabolic crisis include:- Lack of energy Vomiting Irritability Breathing difficulties

9. Causes of MSUD Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease . This 3 genes make a protein complex which is essential for breaking down the branched chain amino acids leucine, isoleucine, and valine. Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of the amino acids. Accumulation of these amino acids and their toxic byproducts results in the serious health problems associated with MSUD.

10. Risk Factors It is reported by National Organization for Rare Disorders that MSUD occurs at the same rate in males and females. The risk for having any form of MSUD depends on whether parents are carriers of the disease. If both parents are carriers, their child has: 25% chance of receiving two mutated genes which causing MSUD. 50% chance for receiving only one defective gene and being a carrier. 25%chance of receiving one normal gene from each parent.

11. Diagnosis Physical exam with evaluation of family medical history of the newborn. Urine amino acid test. Plasma amino acid test: A blood sample drawn from the baby’s heel detects high leucine levels. Urine smell which is like maple syrup. Ear wax may be examined sometimes for smell; it is similar to maple syrup smell.

12. Treatment High-protein foods need to be limited in diet. Such as: milk, fish, meat, egg, nuts etc. Tracking BCAA levels. Thiamine supplement is beneficial for the children who have “thiamine-responsive MSUD”. Liver transplant surgery is an optional treatment for people with MSUD. In the past, dialysis was used to cleanse the body. This is no longer used.

13. Phenylketonuria

14. What is Phenylketonuria? PKU is an metabolic disorder (inborn error) inherited in autosomal recessive manner. Caused by a defect in the gene that helps create an enzyme that breaks down phenylalanine. Phenylalanine is an essential amino acid in the body. Unprocessed phenylalanine builds up toxic levels in the blood and brain without proper management. Very rare, only 1/15000 children in the U.S are born with it.

15. Clinical Features of PKU Mental retardation Seizures , shaking, or jerking movements Stunted or slow growth Skin rashes, like eczema Microcephaly M ousy odour in urine, breath Hypopigmentation or albinism Very low IQ

16. Etiology Caused by a mutation in PAH gene located on the 12 th chromosome. The mutated PAH gene can reduce the activity of phenylalanine hydroxylase enzyme. phenylalanine from the diet cannot be processed effectively. phenylalanine can build up to toxic levels in the blood and other tissues. The excessive amounts of this phenylalanine can cause brain damage and other developmental problems.

17. Diagnosis

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19. Treatment We can manage the PKU through the diet and regular blood testing. Foods that are high in protein must be avoided as all protein contains phenylalanine. Foods containing aspartame should not be consumed. A special metabolic formula that provides all other vitamins, minerals, proteins and energy the baby needs to grow is essential. The energy and varieties are provided by low-protein foods, including fruits, non-starchy vegetables.

20. ALKAPTONURIA

21. WHAT IS ALKAPTONURIA? Alkaptonuria (AKU, black urine disease, black bone disease) is an inborn error of amino acid metabolism: rare disorder of autosomal recessive inheritance in which the body cannot process the amino acids phenylalanine and tyrosine , which occur in protein due to a mutation in a gene. A ffected Populations: It affects males and females in equal numbers, although symptoms tend to develop sooner and become more severe in males. In the United States it is estimated to occur in 1 in 250,000-1,000,000 live births. Alkaptonuria has been reported in all ethnic groups. Areas with increased frequencies of the disorder have been identified in Slovakia, the Dominican Republic and Germany.

22. MOLECULAR MACHANISM It results from absence of homogentisate 1,2 dioxygenase (HGD) enzyme, predominantly produced by hepatocytes in the liver and within the kidney, is responsible for the breakdown of homogentisic acid (HGA); an intermediate in the degradation pathway of the amino acids (phenylalanine and tyrosine) to the Krebs cycle.

23. MOLECULAR MACHANISM It is caused by a mutation or defect in HGD gene. Cytogenetic Location: chromosome 3 in region 3q21-q23. Molecular Location: base pairs 120,628,168 to 120,682,571 on chromosome 3. HGD is split into 14 exons , ranging from 35 to 360 bp in lengths. AKU-causing mutations are distributed throughout the entire HGD gene with some prevalence in exons 8, 7, 6, 3 and 13. Missense mutations are the most numerous, followed by splicing, frameshift , nonsense, genomic deletions and finally, one change leading to expansion. More than 65 mutations in the  HGD  gene have been identified in people with alkaptonuria . Most of these mutations change single amino acids used to build the homogentisate oxidase enzyme. For example, a substitution of the amino acid valine for the amino acid methionine at protein position 368 is the most common  HGD  mutation in European populations. Due to this mutation or defect in HGD gene which causes lack of this enzyme and that results in the accumulation of HGA.

24. MOLECULAR MACHANISM HGD protein and effects of the mutations : The HGD gene codes for the protomer composed of 445 amino acids. The functional, wild-type HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers ) and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme. Some will affect the assembly of the hexamer , others will affect the stability of the protomer and some will interfere with the active site of the enzyme.  Without HGD, the build up of HGA occures in the bones, cartilage and urine. In contact with air, HGA reacts with oxygen and turns the urine black. This is caused by a black pigment called “ alkapton ”, and leads to the name alkapton-uria . This same black pigment, in a process called ochronosis , causes tissue and bone to darken and degenerate. This causes painful and disabling joint disease, known as osteoarthritis.

25. The risk factors of Alkaptonuria include : Family history of the condition: Alkaptonuria is a genetic disorder inherited in an autosomal recessive pattern. This means that the mutation must be inherited from both parents in order to inherit the disorder and manifest the signs and symptoms of Alkaptonuria . If the individual only inherits one copy of the mutated gene, they will be a carrier of AKU and will not manifest the disorder.

26. Some Symptoms of Alkaptonuria Dark stains on a baby’s diaper one of the earliest signs of Alkaptonuria . Symptoms become more noticeable after ages, such as: Dark spots in the sclera of eyes Thickened and darkened cartilage in ears Blue speckled discoloration of skin, particularly around sweat glands Dark-colored sweat or sweat stains Black earwax Kidney stones Osteoarthritis (especially hip and knee joints) Heart problems

27. Diagnosis The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by a test called gas chromatography. DNA testing also used to check for the mutated HGD gene. Family history is very useful in making a diagnosis of alkaptonuria . However, many people don’t know they carry the gene. Their parents might be carriers without realizing it.

28. Treatments There is no specific treatment for Alkaptonuria . Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Commonly recommended treatments include : Put on a low-protein diet . Large doses of Ascorbic acid or vitamin C Nitisinone  may be effective in the treatment of alkaptonuria . Nitisinone blocking the production and accumulation of HGA. Doctor may prescribe anti-inflammatory medications or narcotics for joint pain. Physical and occupational therapy may help to maintain flexibility and strength in muscles and joints. Avoid activities that put a lot of strain on joints. Other treatments for alkaptonuria are focused on preventing and relieving possible complications, such as: Arthritis Heart disease Kidney stones

29. CONCLUSION Although these conditions do not reduce life expectancy, they significantly affect quality of life. There is no proper treatments available to cure these diseases, we can just prevent and manage these diseases. Since, here discussed all diseases are inherited in a autosomal recessive manner, genetic counseling will help assess risks, before planning for a child.

30. Thank You! Any Questions?