Newborn Screening ACT Sheet

Elevated C3 Acylcarnitine and

Differential Diagnosis: Propionic acidemia (PROP) or (PA); Methylmalonic acidemias (MMA), including defects in B12 synthesis and transport; maternal severe B12 deficiency.

Condition Description: Propionic acidemia (PA); is caused by a defect in propionyl-CoA carboxylase, which converts propionyl-CoA to methylmalonyl-CoA; MMA results from a defect in methylmalonyl-CoA mutase (MUT), which converts methylmalonyl-CoA to succinyl-CoA, or from lack of the required B12 for methylmalonyl-CoA mutase (cobalamin A, B, C, D, E, F, G, and J).

Conditions associated with this analyte have been identified by the Society of Inherited Metabolic Disorders (SIMD) as critical, and require immediate action.

MEDICAL EMERGENCY: Take the Following IMMEDIATE Action • Contact family to inform them of the result and ascertain clinical status (poor feeding, , lethargy, and tachypnea). • Immediate telephone consultation with pediatric metabolic specialist (See attached list). • Evaluate the newborn; check for , and if elevated or is ill, initiate emergency treatment as indicated by metabolic specialist and transport immediately to tertiary center with metabolic specialist. • Initiate timely confirmatory/diagnostic testing as recommended by specialist. • Initial labs: plasma acylcarnitine profile, plasma total , plasma methylmalonic acid, and urine organic acids. • Repeat newborn screen if second screen has not been done. • Educate family about signs, symptoms and need for urgent treatment of and metabolic (poor feeding, vomiting, lethargy, tachypnea). • Report findings to newborn screening program.

Diagnostic Evaluation: Plasma acylcarnitine confirms the increased C3. analysis may show increased . Urine organic acid analysis will demonstrate increased metabolites characteristic of propionic acidemia or increased methylmalonic acid characteristic of Methylmalonic acidemia. Plasma total homocysteine will be elevated in the cobalamin C, D, E, F, G and J deficiencies. Serum B12 may be elevated in the cobalamin disorders.

Clinical Considerations: Patients with PA and severe cases of MMA typically present in the neonate with metabolic ketoacidosis, , hyperammonemia, ketonuria, vomiting, hypoglycemia, and failure to thrive. Long-term complications are common; early treatment may be lifesaving, and continued treatment may be beneficial.

Additional Information: American College of Medical and Genomics https://www.acmg.net/StaticContent/ACT/C3.pdf

Genetics Home Reference PROP http://ghr.nlm.nih.gov/condition=propionicacidemia MMA http://ghr.nlm.nih.gov/condition=methylmalonicacidemia

STAR G FELSI http://www.newbornscreening.info/Pro/facts.html http://www.newbornscreening.info/Parents/facts.html

Disclaimer: This information is adapted from the American College of and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet Propionic Acidemia (PROP or PA)

What is PROP? What is the Treatment for PROP? Propionic acidemia (PROP) is an inherited The following treatments are often used for condition in which the body is unable to break children with PROP: down certain and fats. It is considered an 1. Low- diet, medical foods and medical - organic acid condition because it can lead to a formula – The best treatment for PROP is a diet harmful amount of organic acids and toxins in the low in protein. Most of the low-protein food will body. If left untreated, it can cause brain defects be carbohydrates (such as bread, cereal, noodles, or even death. However, if the condition is fruits, vegetables). High-protein foods that should identified early in life and proper treatment is be limited or not eaten at all include: begun, children with PROP can minimize some of • milk and milk products the early complications of the condition. • meat and poultry What Causes PROP? • fish help start chemical reactions in the body. • eggs PROP happens when an called “propionyl • dried beans and peas CoA carboxylase” (PCC) is missing or not working. • nuts and peanut butter This enzyme changes certain amino acids so the body can use them. Glycine and The doctor may prescribe a special medical build up in the blood and cause problems when formula with the right amount of protein. There PCC doesn’t work. are also medical foods available for people with PROP. What Symptoms or Problems Occur with – Some PROP? 2. Do not go a long time without food babies and young children can have a Metabolic [Symptoms are something out of the ordinary that Crisis if they don’t eat often enough. They a parent notices.] shouldn’t go without food for more than 4 to 6 PROP causes periods of illness called Metabolic hours. Some children may need to eat even more Crises. Early symptoms of a Metabolic Crisis are: often. Your dietitian can give ideas for suitable • poor appetite snacks and knows the right foods for your child to • low muscle tone (floppy muscles and eat. joints) • too much sleepiness or lack of energy 3. Medication – The doctor may prescribe L- • vomiting for your child. This is safe and natural and helps the body make energy. If a Metabolic Crisis isn’t treated, a child with

PROP can develop: Things to Remember • breathing problems Even minor illness such as a cold or flu can cause a • Metabolic Crisis. Call your doctor right away when • swelling of the brain your child has any of the following: • • loss of appetite • coma, sometimes leading to death • vomiting Later problems can include: • diarrhea • intellectual disabilities • infection or illness • low ability to fight illnesses • fever • (weak bones) • inflamed pancreas gland Many children with PROP must be treated in the • skin rashes hospital during illness to avoid serious health • poor growth problems.

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet Methylmalonic Acidemia (MMA)

What is MMA? What is the Treatment for MMA? Methylmalonic acidemia (MMA) is a condition with 1. Medication – shots are the main many different forms, all of which have different treatment for Vitamin B12 -responsive MMA, caused causes and treatments. Methylmalonic acidemia by not enough cobalamin A & B. Vitamin B12 helps caused by methylmalonyl-CoA mutase deficiency is most children with the first form (A). It helps close to just one type of MMA. In addition methylmalonic half of children with the second form (B). Your child’s acidemia can be caused by cobalamin disorders A and doctor may prescribe L-carnitine. This is safe and B, or methylmalonic acidemia with , natural and helps body cells make energy. Antibiotics which is caused by cobalamin disorders C, D, E, F, G may help. and J. 2. Low-protein diet, medical foods and medical What Causes MMA? formula – Foods high in protein should be limited or Enzymes help start chemical reactions in the body. not eaten at all. They include: Special enzymes break down certain amino acids and • milk and milk products fatty acids from the protein in food so that the body • can use them. MMA happens when one of these meat and poultry • special enzymes is missing or not working. There are fish a number of different kinds of MMA. Some improve • eggs with Vitamin B12 injections (Vitamin B12-responsive), • dried beans and peas and some do not (Vitamin B12 non-responsive). • nuts and peanut butter

What Symptoms or Problems Occur with MMA? The doctor may give your child a special medical [Symptoms are something out of the ordinary that a formula. A dietitian will tell you what kind of formula parent notices.] is best and how much to use. A nutritionist or dietician can help you plan a healthy diet for your MMA causes periods of illness called Metabolic child. Crises. Some of the first symptoms of a Metabolic Crisis are: Things to Remember • poor appetite Even minor illness can lead to a Metabolic Crisis in • low muscle tone (floppy arms and legs) children with MMA. Call your doctor right away when • vomiting your child has any of the following: • too much sleepiness or lack of energy • loss of appetite • If a Metabolic Crisis is not treated, a child with MMA vomiting can develop: • diarrhea • breathing problems • infection or illness • seizures • fever • stroke • coma, sometimes leading to death Children need extra fluids and starchy food (such as bread, rice, cereal, noodles) when they’re sick in Later problems can include: order to prevent a Metabolic Crisis. During illness, • intellectual disabilities you should limit protein and give your child starchy • low ability to fight illnesses foods and fluids. Sick children with MMA may need • poor growth to be treated in the hospital to avoid serious health • muscle spasms problems. • problems • skin rashes

• tight muscles • brittle bones

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet

Methylmalonic Acidemia (MMA) Cobalamin A, B Type (Cbl A, B)

What is Methylmalonic Acidemia Cobalamin A, B What Symptoms or Problems Occur with MMA Cbl Type (Cbl A, B)? A, B Type? Methylmalonic acidemia (MMA) is a condition with [Symptoms are something out of the ordinary that a many different forms, which all have different causes parent notices.] and treatments. Methylmalonic acidemia caused by cobalamin disorders A and B (Cbl A, B) is just one type Early Signs of MMA. The signs of MMA Cbl A, B can begin at any time from birth to adulthood. In most cases, signs first appear MMA is a condition in which the body is unable to during infancy (as early as the first few days after break down certain fats and proteins. It is considered birth). For babies, signs of Cbl A, B can include: an organic acid condition because it can lead to a • sleeping longer or more often harmful amount of organic acids and toxins in the • vomiting body. MMA caused by cobalamin A or cobalamin B • weak muscle tone (also called ) deficiencies is one type of MMA. Children with this • fever form of the condition have trouble producing • breathing trouble cobalamin enzymes A and B. Cobalamin enzymes are • frequent illnesses and infections necessary for the body to break down certain foods. • increased bleeding and bruising

What Causes MMA Cbl A, B? Many of these signs may occur when your baby eats When we eat food, enzymes help to break it down. foods that his or her body cannot break down. They Some enzymes break down proteins into their can be triggered by long periods of time without building blocks, amino acids. Other enzymes break eating, illnesses, and infections. down these amino acids. In Cbl A, B, the enzymes “cobalamin A” and “cobalamin B” are not working If your baby shows any of these signs, be sure to correctly. Cbl A, B enzymes help break down amino contact your baby’s doctor immediately. acids. Children with Cbl A, B either do not make enough or make non-working Cbl A, B enzymes. What is the Treatment for MMA Cbl A, B Type? When these enzymes do not work, their bodies Supplements and Medications - There are two types cannot break down the amino acids , of MMA: cobalamin disorders and MUT deficiencies. , , and . This causes a One of the ways these two types of MMA differ is build-up of harmful substances in the body. their response to vitamin B12. MUT deficiencies are considered non-vitamin B12 responsive. Cbl A, B is an autosomal recessive genetic condition. This means that a child must inherit two copies of the Cobalamin deficiencies are vitamin B12 responsive. In non-working for Cbl A, B, one from each parent, these cases, vitamin B12 injections can prevent in order to have the condition. The parents of a child symptoms. This type of treatment is more successful with an autosomal recessive condition each carry one for cobalamin A disorders than for cobalamin B copy of the non-working gene, but they typically do disorders, but it is helpful for both. not show of the condition. While having a child with Cbl A, B is rare, when both Your baby’s doctor might also recommend L-carnitine parents are carriers, they can have more than one supplements. These supplements help the body child with the condition. break down fats and they can remove harmful substances from the body. Your baby’s doctor will need to write a prescription for these supplements.

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet (Page 2)

Methylmalonic Acidemia (MMA) Cobalamin A, B Type (Cbl A, B)

Dietary Treatment – Some forms of Cobalamin A and B During illness, you should limit protein and give your may not require dietary management. Other children child starchy foods and fluids. Sick children with may need a very carefully monitored diet. Children MMA Cbl A, B may need to be treated in the hospital with MMA need to avoid certain fats and proteins to avoid serious health problems. because their bodies cannot break down these substances. Your baby’s doctor can recommend Work with your baby’s doctor to determine the next special formulas made for babies with organic acid steps for your baby’s care. Your baby’s doctor will conditions. These formulas will likely need to be help you coordinate care with a physician who continued through adulthood specializes in , a dietician who can help plan your child’s specialized diet, or other medical It is also important for your baby to eat frequently. resources in your community. Long periods without food, illnesses, and infection may trigger many of the signs mentioned in the Early Some children with MMA have developmental Signs section. delays. If you think that your baby is not meeting his or her developmental milestones, ask your baby’s Things to Remember doctor about the next steps in requesting a Even minor illness can lead to a Metabolic Crisis in developmental evaluation and care. children with MMA Cbl A, B Type. Call your doctor right away when your child has any of the following: • loss of appetite • vomiting • diarrhea • infection or illness • fever

Children need extra fluids and starchy food (such as bread, rice, cereal, noodles) when they’re sick in order to prevent a Metabolic Crisis.

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet Methylmalonic Acidemia (MMA) with Homocystinuria (Cbl C, D, E, F, G, and J)

What is Methylmalonic Acidemia (MMA) with Children with Cbl D deficiency do not show signs until homocystinuria (Cbl C, D, E, F, G, and J)? later in childhood. If your baby has Cbl C, D, E, F, G, or MMA is a condition in which the body is unable to J you might notice signs including: process certain fats and proteins. It is considered an • delayed growth organic acid condition because it can lead to a • small head size harmful excess of certain toxins and organic acids. • skin rash MMA with homocystinuria (Cbl C, D, E, F, G, and J) is • vomiting one type of MMA. Individuals with this form of MMA • poor appetite have trouble producing certain cobalamin enzymes, • diarrhea which causes harmful levels of homocysteine and • fever methylmalonic acid to build up in their bodies. • sleeping longer or more often

• What Causes Cbl C, D, E, F, G, or J? tiredness • weak muscle tone (called hypotonia) When we eat food, enzymes help break it down. Certain enzymes break down proteins into their Many of these signs may occur when your baby eats building blocks, amino acids. Other enzymes break foods that his or her body cannot break down. They down these amino acids. can be triggered by long periods of time without

eating, illnesses, and infections. Some enzymes need help from like vitamin B12 (also called cobalamin). The enzymes that break If your baby shows any of these signs, be sure to down the amino acids isoleucine, valine, methionine, contact your baby’s health care provider and threonine need vitamin B12 to work correctly. immediately.

If your baby has Cbl C, D, E, F, G, or J, his or her body What is the Treatment for Cbl Cbl C, D, E, F, G, or J? cannot use vitamin B12 correctly. Your baby’s body Dietary Treatment - Your baby will probably need to either does not make enough or makes non-working be on a restricted diet to avoid proteins that his or enzymes that are supposed to turn vitamin B12 from her body cannot break down. A dietician or food into a form that the body can use. nutritionist can help you plan a low-protein diet that Cbl C, D, E, F, G, and J is an autosomal recessive still gives your baby the right nutrients for healthy genetic condition. This means that a child must growth.

inherit two copies of the non-working gene for Cbl C, Your baby’s doctor might recommend special D, E, F, G, or J one from each parent, in order to have formulas or foods especially for children with Cbl C, the condition. The parents of a child with an D, E, F, G, or J. These formulas will likely need to autosomal recessive condition each carry one copy of continue through adulthood. the non-working gene, but they typically do not show signs and symptoms of the condition. While having a Eating often will also help prevent your baby from child with Cbl C, D, E, F, G, or J is rare, when both experiencing many of the signs mentioned in the parents are carriers, they can have more than one previous section. Illnesses and infections can also child with the condition. trigger these signs.

What Symptoms or Problems Occur with Cbl C, D, E, Supplements and Medications - Supplements can also F, G, or J [Symptoms are something out of the help treat Cbl C, D, E, F, G, or J. Vitamin B12 can help ordinary that a parent notices.] reduce the signs and symptoms of the condition in some children. Your baby’s doctor may need to try Signs of Cbl C, D, E, F, G, or J could begin anywhere this treatment for a short period of time in order to between the first few days of life and 14 years of age. determine if it is an effective treatment for your Children with Cbl C usually show symptoms between baby. Talk to your baby’s doctor before starting the first few days and the first month of life. vitamin B12 treatment.

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet (Page 2)

Methylmalonic Acidemia (MMA) with Homocystinuria (Cbl C, D, E, F, G, and J)

L-carnitine is another substance that helps get rid of Children need extra fluids and starchy food (such as harmful waste products in the body. Some babies do bread, rice, cereal, noodles) when they’re sick in not need this supplement, but your baby’s body order to prevent a Metabolic Crisis. During illness, might not be making enough carnitine naturally. Your you should limit protein and give your child starchy baby’s doctor can tell if your baby needs these foods and fluids. Sick children with Cbl C, D, E, F, G, or supplements and write an appropriate prescription. J may need to be treated in the hospital to avoid serious health problems. Betaine supplements can help lower homocysteine levels in your baby’s blood. Your baby’s doctor can Work with your baby’s doctor to determine the next write a prescription for these supplements. steps for your baby’s care. Your baby’s doctor may help you coordinate care with a physician who Things to Remember specializes in metabolism, a dietitian who can help Even minor illness can lead to a Metabolic Crisis in plan your child’s specialized diet, or other medical children with Cbl C, D, E, F, G, or J. Call your doctor resources in your community. Some children Cbl C, D, right away when your child has any of the following: E, F, G, or J have developmental delays. If you think • loss of appetite that your baby is not meeting his or her • vomiting developmental milestones, ask your baby’s doctor • diarrhea about the next steps in requesting a developmental • infection or illness evaluation and care. • fever

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet

Methylmalonic Acidemia Mutase Deficiency (methylmalonyl-CoA mutase deficiency) (MUT)

What is Methylmalonic Acidemia Mutase What Symptoms or Problems Occur with MMA Deficiency? Mutase Deficiency? Methylmalonic acidemia (MMA) is a condition with [Symptoms are something out of the ordinary that a many different forms, all of which have different parent notices.] causes and treatments. MMA caused by methylmalonyl-CoA mutase deficiency is just one Early Signs -Signs of MMA mutase deficiency can start type of MMA. at any time from birth to adulthood. In most cases, the signs begin during infancy (either in the first few What Causes MMA Mutase Deficiency? days or in the first few months of life). For babies, When we eat food, enzymes help break it down. signs of MMA mutase deficiency can include: Some enzymes break down proteins into their • sleeping longer or more often building blocks, amino acids. Other enzymes break • tiredness down fats into their building blocks, fatty acids. More • vomiting enzymes break down these amino acids and fatty • weak muscle tone (also called hypotonia) acids. • fever • breathing trouble In MMA, the enzyme methylmalonyl-CoA mutase is • frequent illnesses and infections not working correctly. This enzyme helps break down • increased bleeding and bruising odd-chain fatty acids and the amino acids isoleucine, valine, methionine, and threonine. If your baby is Many of these signs may occur when your baby eats affected with MMA mutase deficiency, then his or foods that his or her body cannot break down. They her body is either not making enough or making non- can be triggered by long periods of time without working methylmalonyl-CoA mutase enzymes. eating, illnesses, and infections.

In “MMA mutase deficiency 0” forms of MMA mutase If your baby shows any of these signs, be sure to deficiency, this enzyme is completely deficient. That contact your baby’s doctor immediately. means that there are no working methylmalonyl-CoA mutase enzymes in the body. In the “MMA mutase What is the Treatment for MMA Mutase Deficiency? deficiency+” forms, some methylmalonyl-CoA mutase There are two types of MMA: cobalamin disorders enzymes work correctly, but there are not enough. and MMA mutase deficiency. Cobalamin disorders Without enough working enzymes, your baby’s body are considered vitamin B12 responsive. MMA mutase has trouble using fats and proteins for energy. deficiency deficiencies are non-vitamin B12 responsive. You may hear about other babies with MMA mutase deficiency is an autosomal recessive MMA receiving vitamin B12 injections. This treatment genetic condition. This means that a child must will not help a baby with MMA mutase deficiency. inherit two copies of the non-working gene for MMA mutase deficiency, one from each parent, in order to Supplements and Medication - Your baby’s doctor have the condition. The parents of a child with an might recommend L-carnitine supplements. These autosomal recessive condition each carry one copy of supplements help the body break down fats, and the non-working gene, but they typically do not show they can remove harmful substances from the body. signs and symptoms of the condition. While having a Your baby’s doctor will need to write a prescription child with MMA mutase deficiency is rare, when both for these supplements. parents are carriers, they can have more than one child with the condition.

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015

Newborn Screening FACT Sheet (Page 2)

Methylmalonic Acidemia Mutase Deficiency (methylmalonyl-CoA mutase deficiency) (MUT)

Dietary Treatments - Your baby will need a very Children need extra fluids and starchy food (such as carefully monitored diet. Children with MMA need to bread, rice, cereal, noodles) when they’re sick in avoid certain fats and proteins because their bodies order to prevent a Metabolic Crisis. During illness, cannot break down these substances, causing a you should limit protein and give your child starchy buildup of toxic substances. Your doctor can foods and fluids. Sick children with MMA mutase recommend special formulas and foods made for deficiency may need to be treated in the hospital to children with organic acid conditions. These formulas avoid serious health problems. will likely need to be continued through adulthood. Work with your baby’s doctor to determine the next It is also important for your baby to eat frequently. steps for your baby’s care. Your baby’s doctor may Long periods of time without food, illness, or help you coordinate care with a physician who infections may trigger many of the signs mentioned in specializes in metabolism, a dietician who can help the previous section. plan your child’s specialized diet, or other medical resources in your community. Some children with Things to Remember methylmalonic acidemia have developmental delays. Even minor illness can lead to a Metabolic Crisis in If you think that your baby is not meeting his or her children with MMA mutase deficiency. Call your developmental milestones, ask your baby's health doctor right away when your child has any of the care provider about the next steps in requesting a following: developmental evaluation and care. • loss of appetite • vomiting • diarrhea • infection or illness • fever

Disclaimer: This information is adapted from the American College of Medical Genetics and Genomics (ACMG) 01/2015