peroxisomal disorder

brief introduction about peroxisomes and one of its disorders

1. Rhizomelic Chondrodysplasia Punctata Type 1 Presented by: Fatma Adel Peroxisomal disorder

2. Peroxisomes (also called microbodies ) are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids , branched chain fatty acids , D-amino acids , and polyamines . They also contain approximately 10% of the total activity of two enzymes in the pentose phosphate pathway , which is important for energy metabolism. Peroxisomes

3. A major function of the peroxisome is the breakdown of very long chain fatty acids through beta-oxidation . In animal cells, the very long fatty acids are converted to medium chain fatty acids, which are subsequently shuttled to mitochondria where they are eventually broken down to carbon dioxide and water. In yeast and plant cells, this process is exclusive for the peroxisomes . Metabolic functions

4. Peroxisomes contain oxidative enzymes , such as catalase , D-amino acid oxidase . However the last enzyme is absent in humans, explaining the disease known as gout , caused by the accumulation of uric acid. Participates in the synthesis of bile acids . Participates in the synthesis of the lipids used to make myelin . Breakdown of excess purines (AMP, GMP) to uric acid .

5. Peroxisomal disorders are a group of congenital (existing from birth) diseases characterized by the absence of normal peroxisomes in the cells of the body. There are about 25 peroxisomal disorders known, although the number of diseases that are considered to be separate, distinct peroxisomal disorders varies among researchers and health care practitioners. Peroxisome Disorders

6. Peroxisomal disorders are subdivided into two major categories. The first are disorders resulting from a failure to form intact, normal peroxisomes , resulting in multiple metabolic abnormalities, which are referred to as peroxisome biogenesis disorders (PBD) or as generalized peroxisomal disorders. The second category includes those disorders resulting from the deficiency of a single peroxisomal enzyme.

7. A genetic disease that is characterized by systemic shortening of the proximal bones (i.e. rhizomelia), seizures, recurrent respiratory tract infections, and congential cataracts and has material basis in mutations of the alkyldihydroxyacetonephosphate synthase (alkyl- dhap synthase) gene. is a condition that impairs the normal development of many parts of the body. Rhizomelic Chondrodysplasia Punctata Type 1

8. Rhizomelic chondrodysplasia punctata affects fewer than 1 in 100,000 people worldwide. RCDP1 is more common than RCDP2 or RCDP3. Rhizomelic chondrodysplasia punctata results from mutations in one of three genes. Mutations in the PEX7 gene, which are most common, cause RCDP1. Changes in the GNPAT gene lead to RCDP2, while AGPS gene mutations result in RCDP3. Cause

9. The genes associated with rhizomelic chondrodysplasia punctata are involved in the formation and function of structures called peroxisomes . Peroxisomes are sac-like compartments within cells that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of fats (lipids) used in digestion and in the nervous system. Cause

10. Within peroxisomes , the proteins produced from the PEX7, GNPAT, and AGPS genes play roles in the formation (synthesis) of lipid molecules called plasmalogens. Plasmalogens are found in cell membranes throughout the body, although little is known about their function. Mutations in the PEX7, GNPAT, or AGPS genes prevent peroxisomes from making plasmalogens. Researchers are working to determine how problems with plasmalogen synthesis lead to the specific signs and symptoms of rhizomelic chondrodysplasia punctata. Cause

11. The major features of this disorder include skeletal abnormalities, distinctive facial features, intellectual disability, and respiratory problems. characterized by shortening of the bones in the upper arms and thighs (rhizomelia). Affected individuals also have a specific bone abnormality called chondrodysplasia punctata, which affects the growth of the long bones and can be seen on x-rays. People with rhizomelic chondrodysplasia punctata often develop joint deformities (contractures) that make the joints stiff and painful. Signs and symptoms

12. Distinctive facial features are also seen with rhizomelic chondrodysplasia punctata. These include a prominent forehead, widely set eyes (hypertelorism), a sunken appearance of the middle of the face (midface hypoplasia), a small nose with upturned nostrils, and full cheeks. Additionally, almost all affected individuals have clouding of the lenses of the eyes (cataracts). The cataracts are apparent at birth (congenital) or develop in early infancy. Signs and symptoms

13. Most children with this condition do not achieve developmental milestones such as sitting without support, feeding themselves, or speaking in phrases. Affected infants grow much more slowly than other children their age, and many also have seizures. Recurrent respiratory infections and life-threatening breathing problems are common. Because of their severe health problems, most people with rhizomelic chondrodysplasia punctata survive only into childhood. It is rare for affected children to live past age 10. Signs and symptoms

14. The presence of physical deformities at birth indicates RCDP, and x-rays and other imaging tests will show abnormalities in bones and cartilage development. While these symptoms further indicate RCDP, a definitive diagnosis is made through laboratory testing, specifically skin biopsies and blood tests which show biochemical imbalances due to abnormal proteins in the cells. Diagnosis

15. There are two other rare genetic disorders which have the same basic symptoms as RCDP, though they do not cause the same protein abnormalities as RCDP. While a diagnosis can be made without genetic testing, if all other signs, symptoms and test results point to RCDP, an absolute diagnosis can be confirmed with genetic testing. The genetic test will show abnormalities in the abnormal PEX7 gene, confirming beyond a doubt the diagnosis of Rhizomelic Chondrodysplasia Punctata, as no other disorder is known to be caused by that specific gene.

16. There is no cure for RCDP however research is being carried out in the United States into potential treatments. Doctors and therapists can help manage the symptoms of RCDP. It is important a child has the level of ‘ phytanic acid’ in their blood measured. If the result is unusually high the child should follow a low-fat diet. Phytanic acids are found in high-fat dairy products and oily fish. treatment