Once LEU is split off from food protein, it is absorbed, Think of the situation as a traffic light (Figure 3). A green within first few weeks of life. A “sweaty-feet” odor of the changed, and used to form many other useful substances traffic light (normal enzyme) allows LEU to be used normally. Mother’s Genes Father’s Genes blood and urine are noted. Some infants also exhibit severe in the body. In a DLC, the enzymes needed to rid the body A red light (no or too little enzyme) keeps LEU from being acidosis seizures, high ammonia levels (hyperammonemia), of the products of the breakdown of LEU are absent or not used. If the light is stuck on red, a traffic jam occurs—LEU low platelet count in the blood (thrombocytopenia), low working properly. People with a DLC, such as your child, and organic acids increase in the blood and tissues and cause number of white blood cells (neutropenia), low number of do not have any normally working enzyme or do not have symptoms of a DLC. red and white blood cells and platelets (pancytopenia), and enough to handle all the LEU that is in the protein foods they If a person is not treated, LEU and organic acid also spill into A B Normal Gene low calcium levels (hypocalcemia). eat. In either case, LEU cannot be used normally and LEU or the urine and perspiration (sweat). DLC Gene • “Chronic Intermittent” IVA children are normal at the products from its breakdown build up as organic acid and birth. During the first few years of life, they may develop other toxic (poisonous) substances. Enzyme not working. C D episodes of vomiting, metabolic acidosis, and excessive This excess keeps another important substance, coenzyme A LEU cannot be broken down. LEU tiredness (lethargy). The characteristic “sweaty-feet” odor (CoA), from working and causes the symptoms of a disorder and organic acids build up in the is typically present, and temporary hair loss (transient of leucine catabolism (Figure 2). blood and urine. Figure 4. Genetic inheritance of DLC. alopecia) is usually seen. Episodes may begin as early as 2 weeks of age, and the frequency of attacks seems to Enzyme not working well. decrease with age. Infections tend to trigger the episodes, Dietary protein L-Leucine Tissue protein LYS and TRP may not be You, as parents of a child with DLC, are carriers. Brothers as does illness and an excessive intake of protein. broken down efficiently. and sisters of your child with DLC may also be carriers. Additional Therapies. The goal of nutrition management GDH working. A child with gene set D has DLC caused by the two DLC genes of IVA is to avoid too much isovaleric acid in the blood LYS and TRP used normally. ( ), one from the mother and one from the father. Her body and urine while supplying energy, protein, vitamins, and Breakdown products do not will not be able to use the LEU in food normally. She will also minerals needed for normal growth and development. An 2-Keto-isocaproic acid build up. pass a DLC gene on to each of her offspring. Your child with a LEU-free medical food with the addition of a low-protein Figure 3. The disorders of leucine catabolism (DLC) traffic light. DLC has this gene set. diet (restricting LEU) is recommended. Your metabolic doctor may also recommend carnitine and/or glycine Isovaleryl-CoA DISORDERS OF LEUCINE CATABOLISM: TYPES OF DISORDERS OF LEUCINE supplementation. Carnitine and glycine help the body get rid AN INHERITED DISORDER CATABOLISM of toxic metabolites that build up in the body as well as help to IVA prevent possible deficiencies. DLCs are genetic disorders inherited from both mother There are four disorders of leucine catabolism considered to be and father, just like other features such as eye and skin branched-chain organic acidurias. The name of the deficiency 3-Methylcrotonyl-CoA Carboxylase Deficiency (meth- color. Genetic information, which determines each person’s generally refers to the enzyme affected. Dependent upon which ill-crot-o-nil Co-A car-box-ill-ase), or 3-MCC, is a deficiency 3-Methylcrotonyl-CoA characteristics, is carried on pairs of genes in every cell in the disorder of leucine catabolism your child has will determine in 3-methylcrotonyl CoA, blocking the body’s ability to break body. These genes serve as blueprints, or patterns. treatment methods. Your metabolic doctor and nutritionist will down LEU (Figure 2). Children typically have normal growth 3-MCC discuss which treatment method is best for your child. and development until they have an acute episode between Each parent of a child with a DLC has one normal ( ) and one 6 months and 3 years of age. Symptoms have also been 3-Methylglutaconyl-CoA altered DLC ( ) gene. Each one of their offspring will have Isovaleric Acidemia (I-so-val-air-ic a-cid-ee-mia), or IVA, is reported in the neonatal period and also as late as adulthood. one gene from each parent and could have one of four gene a deficiency of isovaleryl-CoA dehydrogenase (i-so-val-air-ill Symptoms typically occur after an infection and may include sets (Figure 4). Co-A dee-hi-drog-en-ase) (IVD), that prevents LEU from being poor muscle tone (hypotonia), or coordination, poor feeding, 3-Methylglutaconic used in the body. Because LEU cannot be used normally, LEU vomiting, excessive tiredness (lethargy), developmental Aciduria A child who receives gene set A inherits two normal genes ( or the products from its breakdown build up as isovaleric acid delay, or symptoms resembling Reye’s syndrome (low blood 3-Hydroxy-3-methylglutaryl-CoA ). Her body will make enough enzyme to use LEU normally. and other toxic (poisonous) substances. This excess keeps sugar [hypoglycemia], high ammonia levels in the blood HMG-CoA lyase She will pass a normal gene on to each of her offspring. another important substance, coenzyme A (CoA), from working [hyperammonemia], metabolic acidosis, elevated liver A child who receives gene set B or C inherits one normal ( ) and causes the symptoms of IVA. A characteristic feature of enzymes [transaminases], and seizures). and one DLC ( ) gene. His body will make enough enzyme IVA is a distinctive odor of sweaty feet. This odor is caused by Acetoacetic acid Acetyl-CoA Mevalonic acid to use LEU normally, but he can pass on the DLC gene to his the build-up of isovaleric acid in affected individuals. There are Additional Therapies. Nutrition management of 3-MCC Figure 2. Metabolic pathway for LEU. The black boxes show offspring. A person with this gene set—one normal and one two different types of IVA—acute and chronic. deficiency involves management of the initial infection that the site of where there could be an enzyme that doesn’t work, DLC—is called a carrier. Being a carrier does not affect the • “Acute” IVA infants appear normal at birth but develop triggered the 3-MCC symptoms, correction of carnitine causing the noted disorders. person’s health. poor feeding, vomiting, diarrhea, and drowsiness (lethargy) deficiency (if present), and possible LEU restriction. 4 5