Use of Formulas For Infants with Metabolic Disease1
The following section provides information on several metabolic disorders along with typical treatment plans. This is an extensive, all-inclusive list. Care of children with any confirmed metabolic disorder should proceed under the guidance of the Maine Children’s Genetic and Metabolic Disorders Clinics and Dr. Wendy Smith and Dr. Tom Brewster.
Type of Condition
I. Amino Acid Disorders
Metabolic disorders involving an inability to break down specific amino acids (components of protein).
The term “homocystinuria” designates a biochemical abnormality, not a specific disease entity. There are many causes of homocystinuria. All result in the inability to break down the amino acid homocystine and affect one of the transsulfation pathways that convert the sulfur atom of methionine into the sulfur atom of cysteine. This pathway is the chief route of disposal of methionine. Clinical problems include multiple, recurrent thromboemboli. Death has been reported within the first year of life. Approximately 50 percent of untreated individuals die by 25 years of age; death is frequently a result of thromboembolic events. Developmental delay is reported in 65 to 80 percent of untreated individuals.
The survival rate may improve with early, effective treatment. Treatment seems to reduce the risk of thromboembolic episodes and the incidence of mental retardation or developmental delay may be prevented or reduced. For patients with classic (homozygous) homocystinuria, early treatment with good biochemical control (lifetime plasma-free homocystine <11 mol/L) seems to prevent mental retardation, ectopia lentis seems to be delayed, and the incidence of seizures is reduced.
Treatment consists of protein restricted diet, methionine-free formula (with added cysteine), betaine, and vitamins B6, folate, and vitamin B12 (in responsive individuals). Outcome: without treatment, developmental delay, intellectual disability, lens dislocation, cardiovascular disease. With treatment, there is a variable risk for above chronic conditions.
- Treatment depends on the underlying cause of homocystinuria. As a first step, pyridoxine (vitamin B6) responsiveness should be ascertained, because approximately 50 percent of patients respond to large doses of this vitamin.
- Nonresponsive patients with CBS (cystathionine beta-synthase) deficiency should be treated with a methionine-restricted, cysteine supplemented diet. Folic acid and betaine therapy may also be helpful with all patients.
- Specialized care is required that includes the ability to monitor amino acids and provide nutritional assessment and planning. Care should proceed under the guidance of the Maine Children’s Genetic and Metabolic Disorders Clinics and Dr. Wendy Smith and Dr. Tom Brewster.
Phenylketonuria (PKU) is the inability to break down the amino acid phenylalanine. Disease severity is based on the inherited ability to metabolize phenylalanine. Treatment consists of phenylalanine restricted medical formula. Outcome: without treatment, classic PKU results in mental retardation. With treatment and good dietary compliance most individuals do well. There remains an increased risk of learning disabilities and behavior problems, most often related to dietary compliance.
PKU is rarely diagnosed before 6 months of age without newborn screening, because the most common manifestation without treatment is developmental delay followed by mental retardation. Untreated individuals may also develop microcephaly, delayed or absent speech, seizures, eczema, and behavioral abnormalities.
Early treatment of PKU is associated with improved intellectual outcome. Therefore, an infant with a positive newborn screening result should receive the benefit of rapid diagnostic testing. Diagnostic testing includes quantitative determination of plasma Phe and tyrosine concentrations. If the Phe concentration is increased, additional studies are indicated to determine if the infant has an abnormality in synthesis or recycling of cofactor tetrahydrobiopterin BH4.
- Once the diagnosis of hyperphenylalaninemia is confirmed, metabolic control should be achieved as rapidly as possible. This is achieved through the use of medical foods, including medical protein sources that are low in Phe; small amounts of Phe must also be provided, which is achieved through the use of small amounts of natural protein.
- The infant with PKU can be given breast milk along with Phe-free formula under the direction of a metabolic dietitian.
- The response to dietary treatment is monitored through periodic measurement of blood Phe concentrations, assessment of growth parameters, and review of nutritional intake.
- Most US centers recommend lifelong dietary treatment. This is particularly important for women, because fetuses exposed to increased concentrations of Phe are at significant risk of microcephaly, congenital heart disease, and reduced IQ.
- Recent evidence suggests that some individuals with hyperphenylalaninemia and classic PKU may benefit from BH4 treatment in addition to dietary Phe restriction.
- As noted previously, there is no national or international consensus regarding the optimal concentration of Phe across the life span. Similarly, there is no consensus regarding discontinuation of dietary therapy.
Tyrosinemia Type 1 Inability to break down the amino acid tyrosine. Treatment consists of phenylalanine and tyrosine restricted medical formula, NTBC medication, and liver transplant (in unresponsive individuals). Outcome: without treatment, failure to thrive, cirrhosis of the liver, clotting disorders, kidney disease, and cancer. With recently available NTBC drug treatment affected individuals are doing remarkably well. Long-term follow-up studies are in progress.
Tyrosinemia Type 2 Inability to break down the amino acid tyrosine (different pathway than type 1).Treatment consists of dietary restriction. Outcome without treatment, results in mental retardation and corneal ulcers. With dietary treatment most individuals do well.
An increased tyrosine concentration on newborn screening requires confirmation and additional testing, because it may be caused by other metabolic disorders (eg, fructose and galactose enzyme deficiencies), giant cell hepatitis, neonatal hemochromatosis, and neonatal infections. The optimal approach is complex and requires determination of the concentrations of tyrosine and other amino acids and metabolites in the blood and urine.
- Type 1- Treatment options for tyrosinemia include dietary therapy, liver transplantation, and use of the pharmacologic agent NTBC. Clinical signs and symptoms improve with NBTC therapy and diet.
- Type II- Therapy with a diet low in tyrosine and phenylalanine is curative in type II tyrosinemia. Early diagnosis can help avoid the risk of mental retardation in these patients.
- Neonatal- Most cases of neonatal tyrosinemia, especially those seen in small preterm infants, may be transient and controlled by reducing the protein intake to 2 to 3 g/kg per day or by breastfeeding. Some patients respond to ascorbic acid supplementation.
II. Carbohydrate Disorders
Lactose, or milk sugar, is broken down into its constituent simple sugars, glucose and galactose, before absorption in the intestine. Galactosemia: the inability to break down lactose (present in human and cow milk products) to sugars. Treatment consists of dietary restriction of milk products. Outcome: without treatment, infants present in the first few days of life with vomiting, poor feeding, liver disease, and life-threatening infection. With treatment, individuals do well in early childhood but frequently develop neuropsychological and ovarian problems during teenage years.
The genetic disorders that cause galactosemia vary in severity from a benign condition to a life-threatening disorder of early infancy. Early diagnosis and treatment of the latter condition can be life saving; hence, newborn screening for this disease has been instituted in many states. Exclusion of galactose from the diet results in marked improvement of the life-threatening complications of classic galactosemia. However, this treatment has only limited efficacy in the prevention of long-term complications. All newborn infants with positive screening results should be evaluated rapidly by an experienced physician for feeding difficulty, signs of sepsis, jaundice, and hepatomegaly. Untreated classic galactosemia may progress very rapidly to hepatic toxicity, with death resulting from sepsis or bleeding. Immediate restriction of dietary galactose is critical and should not await diagnostic testing.
Galactose is a reducing substance, and the presence of reducing substances in the urine is sometimes suggested as a test for galactosemia. However, this test is neither sensitive nor specific, and it should not be used as a screening or diagnostic test for galactosemia.
Diagnostic studies for classic galactosemia include quantitative analysis of GALT and red blood cell galactose 1-phosphate. In states where the screening test measures GALT activity, these studies will establish or rule out classic galactosemia. When the screening results, including estimates of galactose and galactose 1-phosphate and quantitative GALT activity, are normal, quantitative analysis of GALK and GALE are required to identify these forms of galactosemia. Infants suspected of having galactosemia should be fed with a galactose-free formula until diagnostic testing confirms a specific diagnosis.
- After dietary galactose has been eliminated, most infants improve rapidly. Milk and milk products are excluded from the diet indefinitely, because significant ingestion of galactose at any age can be toxic. WIC contract soy formula is lactose free and should be prescribed for these children.
- Because medications may contain galactose, the pediatrician should instruct parents to ask the pharmacist if a medication is galactose free before administering it to the child.
- Regular nutritional evaluation is necessary to ensure adequate calcium intake.
- Regular developmental evaluation and early speech assessment are also required. Girls should be monitored frequently in late childhood and adolescence for pubertal development.
- Regular measurement of galactose 1-phosphate in red cells is the most common method used to assess dietary compliance.
III. Fatty Acid Disorders
These disorders affect the body’s ability to breakdown fat as an energy source. The clinical findings are similar among these disorders including life-threatening coma and hypoglycemia (low blood sugar) due to prolonged fasting, such as with viral illnesses. Treatment consists of preventing prolonged fasting through feeding and IV fluids as needed.
Medium-chain acyl-CoA dehydrogenase (MCAD)
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a disorder of fatty acid oxidation (FAO) first described in 19821983. All together, 10 disorders affecting mitochondrial FAO and ketogenesis have been identified. Among these, MCAD deficiency seems to be the most important because it is the most common and it has been implicated in some cases of sudden infant death syndrome (SIDS) and Reye syndrome.
Infants identified through newborn screening and prevented from prolonged fasting and hypoglycemia have normal growth and development without chronic illness. The classic presentation is an episode of vomiting and lethargy after a period of fasting in a child between 3 and 15 months of age. The child may have had a previous viral infection (gastrointestinal or upper respiratory) resulting in decreased oral intake that would have little consequence in an unaffected child. The episode may result in coma, and the child may remain obtunded even after hours of treatment with intravenous glucose. Undiagnosed disease has a mortality rate of 20% to 25%, many times with death occurring during the initial episode. Most deaths would be preventable if dietary therapy and measures to prevent fasting were begun before the onset of symptoms.
Any child with an octanoylcarnitine concentration of 1.0 mol/L or greater will require definitive diagnostic testing. Follow-up testing will consist of plasma acylcarnitine analysis, urinary organic acid analysis, and molecular testing. The plasma acylcarnitine analysis and urinary organic acid analysis will confirm the diagnosis.
- Treatment for MCAD deficiency consists of avoidance of fasting and mildly decreased intake of dietary fat coupled with L-carnitine supplementation.
- MCAD deficiency results in a secondary deficiency of carnitine, because carnitine couples with toxic intermediates, resulting in their excretion while depleting carnitine stores. Although it remains questionable how helpful supplemental carnitine is during periods when the patient with MCAD deficiency is healthy, there is no doubt that exogenous carnitine is recommended during times of illness.
- Care should proceed under the guidance of the Maine Children’s Genetic and Metabolic Disorders Clinics and Dr. Wendy Smith and Dr. Tom Brewster.
Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)
Infants diagnosed through newborn screening and prevented from having hypoglycemia are asymptomatic with normal growth and development. Infants diagnosed clinically prior to newborn screening exhibited failure to thrive, muscle weakness, and developmental delay.
Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD)
Features include chronic problems such as muscle weakness and heart muscle enlargement and dysfunction.
Long-Chain Hydoxyacyl-CoA Dehydrogenase Deficiency (LCHAD)
Many individuals have more severe disease with cardiomyopathy, progressive liver failure, and peripheral neuropathy.
Very-Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)
These children have a clinical presentation similar to LCHAD.
Glutaric Acidemia Type 2
Complete enzyme deficiencies result in severe illness in the newborn period with decreased muscle tone, low blood sugar, cardiomyopathy, and coma. Some infants are born with dysmorphic facial features and polycystic kidneys. Some mildly affected children benefit from riboflavin supplementation.
IV. Organic Acidemias
These disorders are due to errors in the break down of amino acids causing high levels of toxic acids in the blood. Fasting and illness can trigger serious complications. Common findings include refusal to feed, vomiting, acidosis, dehydration, and low blood sugar.
Glutaric Acidemia Type 1
Affected children may develop normally up to age 2. Hallmark of the disease is onset of a movement disorder similar to that seen in Huntington’s disease. Other findings include macrocephaly (large head) and stroke. Acute episodes may include vomiting, seizures, and coma. Treatment consists of a low-protein diet and supplemental riboflavin and carnitine. Long-term outcomes on treatment are currently not known.
Maple Syrup Urine Disease (MSUD)
The most severe form results in poor feeding and vomiting in the first week of life followed by lethargy and coma. There may be severe muscle rigidity. Acute treatment involves removal of branched-chain amino acids through peritoneal dialysis. Treatment after recovery of acute events involves synthetic formulas devoid of leucine, isoleucine, and valine. Long-term prognosis of affected children remains guarded.
Maple syrup urine disease (MSUD), also known as branched-chain ketoaciduria, is caused by a deficiency in activity of the branched-chain keto acid dehydrogenase (BCKD) complex. Deficiency of the BCKD complex results in accumulation of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine and the corresponding branched-chain ketoacids (BCKAs). Classic MSUD (residual enzyme activity <2%) is the most severe and most common form. Affected infants are normal at birth, with symptoms usually developing between 4 and 7 days of age; however, lower intake of protein, as in breastfeeding, can delay the onset of symptoms until the second week of life. Initial symptoms are lethargy and poor sucking with little interest in feeding. Weight loss follows with abnormal neurologic signs (alternating hypertonia and hypotonia; dystonic posturing of the arms) becoming more and more apparent. The characteristic odor of the urine, described as smelling like maple syrup, burnt sugar, or curry, is then noted. Finally, seizures and coma, leading to death (in untreated cases), occurs. Laboratory findings include increased concentrations of BCAAs, ketosis, acidosis, and occasionally hypoglycemia.
A blood leucine concentration greater than 4 mg/dL, or a concentration of 3 to 4 mg/dL (305 mmol) in the first 24 hours of life, requires immediate medical follow-up. Plasma amino acid analysis reveals findings diagnostic for MSUD: increased concentrations of BCAAs, low alanine concentrations, and the presence of alloisoleucine.
- Treatment consists of a carefully regulated diet that provides sufficient BCAAs for normal growth and development without exceeding the patient’s degradative enzyme capacity. Because natural protein must be limited, a medical food product (BCAA-free) supplement is necessary.
- The goal of long-term dietary management is normalization of blood BCAA concentrations while providing nutrition adequate to sustain growth and development in children. Dietary therapy should be continued for life.
- A metabolic team, including not only a metabolic specialist but also a metabolic nutritionist, is crucial. Care should proceed under the guidance of the Maine Children’s Genetic and Metabolic Disorders Clinics and Dr. Wendy Smith and Dr. Tom Brewster.
- MSUD has been treated since the early 1960s, and consequently, some neurologically intact MSUD-affected women have reached childbearing age and reproduced. As has been reported for other enzyme deficiencies, postpartum metabolic decompensation can be a problem.
3-Hydroxy-3 Methylglutaryl-CoA Lyase Deficiency
Clinical presentation includes vomiting, dehydration, seizures, and coma. Treatment of acute events includes hydration and IV glucose infusion. Long-term management includes dietary protein and fat restriction.
3-Methylcrotonyl-CoA Carboxylase Deficiency
This disorder has varied age of onset with difficulty feeding, breathing problems, skin rash, alopecia, delayed development, seizures, and coma. Long-term treatment consists of dietary leucine restriction and carnitine supplementation.
Clinical presentation is quite variable ranging from no symptoms into adulthood to severe acidosis in the first year of life leading to coma and death. Affected children may be asymptomatic in between episodes. Development is normal.
Newborns with the severe form of this metabolic disorder develop vomiting and acidosis in the first few days of life followed by lethargy, seizures, coma, and death if therapy is not initiated. Long-term management consists of a low-protein formula and carnitine supplementation. Milder forms of IVA have been identified through newborn screening and have an excellent prognosis.
Severely affected newborns have acidosis, elevated blood ammonia, low blood count, coma, and death. Children with later onset forms have failure to thrive, hypotonia, and developmental delay. Long-term treatment consists of low-protein diet and administration of carnitine and vitamin B12. Prognosis depends on the type of enzyme defect.
Acute symptoms usually begin in the early weeks of life with poor feeding, vomiting, lethargy, dehydration, progressing rapidly to coma and death. Long-term management consists of natural protein diet along with synthetic protein formula deficient in proprionate precursors. Long-term prognosis is guarded.
V. Urea Cycle Disorders
These inborn errors of metabolism prevent the detoxification of free ammonia released by the breakdown of amino acids to urea. The ammonia is highly toxic to the central nervous system. Affected newborns present with signs and symptoms of brain dysfunction. Affected babies are normal at birth but become symptomatic after protein feedings. They refused to eat, followed by vomiting, rapid respirations, lethargy, and coma. Seizures are common. Acute management consists of removal of ammonia from the body including the use of peritoneal dialysis or hemodialysis if needed and provision of adequate calories and essential amino acids.
Clinical presentation is different than the other urea cycle disorders. Symptoms may not develop for several months to years. Choreoathetotic movements and loss of developmental milestones suggest a degenerative disease of the central nervous system. Mental retardation is progressive. Treatment consists of a low-protein diet devoid of arginine. Administration of a synthetic protein made of essential amino acids usually results in a dramatic decrease in plasma arginine and improvement in neurologic abnormalities. Intellectual disabilities persist despite treatment.
The severity of the clinical features varies from high blood ammonia in the first few days of life with high mortality to later onset forms with mental retardation associated with vomiting, failure to thrive, and hepatosplenomegaly. Treatment is similar to other urea cycle disorders.
The clinical spectrum ranges from severe to asymptomatic forms. Mild forms may have a gradual onset with failure to thrive, frequent vomiting, and developmental delay. Some patients may remain asymptomatic into adulthood. Prognosis is poor for symptomatic newborns. Children with mild disease usually do well on a protein-restricted diet. Mild to moderate intellectual disabilities are common even in well-treated patients.
Ornithine translocase deficiency, also called Hyperonithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
Symptoms associated with elevated blood ammonia levels may develop shortly after birth or may be delayed into adulthood. Acute episodes may be associated with refusal to eat, vomiting, lethargy, and coma. Progressive neurologic findings include lower leg weakness, spasticity, seizures, and varying degrees of mental retardation if undiagnosed and untreated. Treatment consists of protein restriction.
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