What is Urea Cycle Disorder?
Urea cycle disorder (UCD), also known as hyperammonemia or hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is caused by a deficiency of Ornithine translocase. This occurs when ammonia gets accumulated in the blood because of an absence of the enzyme ornithine translocase.
Pregnancies in Urea Cycle Disorders
Women with UCD are especially at risk for metabolic decompensation during the first trimester when poor energy intake is common, during any intercurrent illness, with prolonged delivery, and in the postpartum period.
Nutrition management necessitates:
Maintaining normal maternal weight gain
Weight gain goals are the same for pregnant women with inborn errors of metabolism as for the general population. Weight loss should be avoided since this can cause protein catabolism and elevated amino acid concentrations. Energy needs increase as the pregnancy progresses, especially in the latter part of pregnancy when fetal growth is the greatest.
Maintaining adequate energy and protein nutriture throughout
As the pregnancy progresses an adequate amount of energy is needed for maternal and fetal growth. To prevent protein deficiency, any woman prescribed for a medical diet prior to pregnancy will need to continue this throughout her pregnancy. If the medical diet has been stopped for some reason, reintroduction of the diet is required, even if a woman has a milder form of the disorder.
Maintaining plasma amino acid concentrations within the normal range and anticipating a higher intact protein tolerance as pregnancy progresses
As with total protein, the needs for individual amino acids increase as pregnancy progresses, especially in the late second and third trimesters when fetal growth is the greatest. Frequent monitoring of the plasma amino acids levels is necessary, and, if low, an increase in the amount of intact protein is prescribed to maintain the restricted amino acids in the normal range.
Planning for intercurrent illness and complications affecting dietary intake
As with any pregnancy, persistent nausea, vomiting and intercurrent illness can occur. For women with intoxication disorders, these catabolic events need to be addressed to prevent increasing concentrations of amino acids and toxic metabolites. A plan for any needed admission should be established ahead of time and emergency protocols updated.
Constant contact with a specialist obstetric clinic
Given the risk of metabolic decompensation during pregnancy and postpartum period, women with amino acidopathies or urea cycle defects should be followed by an obstetric clinic specializing in high-risk pregnancies. Frequent assessment of fetal growth is also needed. For successful maternal and fetal outcomes, a multidisciplinary approach is required with input from both obstetric and metabolic teams.
Anticipating postpartum catabolism
Delivery and postpartum period are catabolic processes. The risk for decompensation increases in women with UCD if the delivery is prolonged or a sufficient source of calories and protein equivalents not provided during delivery and the postpartum period.
Good nutrition management during a pregnancy is essential to avoid dysmorphology, microcephaly, cardiac defects, or developmental delays.
Tyrosinemia is caused when the body cannot effectively break down the tyrosine. If untreated, tyrosine and its byproducts build up in tissues and organs, leading to serious liver and kidney disturbances.
Mutation in the Fumarylacetoacetate-hydroxylase (FAH) gene, Aminotransferase (TAT) gene and Hydroxyphenylpyruvate-dioxygenase (HPD) gene are all responsible for tyrosine degradation pathway.
- Type I tyrosinemia: can be caused by mutationsin the FAH gene.
- Type II tyrosinemia: can be confirmed by detection of a mutation in TAT gene in cultured fibroblasts.
- Type III tyrosinemia: mutation in the HPDgene in cultured fibroblasts.
- Intellectual disability
- Periodic loss of balance and coordination (intermittent ataxia)
- Increased tendon reflexes
Metabolic Pathway for Phenylalanine and Tyrosine
Dysfunction of various genes in the phenylalanine and tyrosine catabolic pathway results in all the types of tyrosinemias and are inherited in an autosomal-recessive pattern.
Methylmalonic acidemia or propionic acidemia is an autosomal recessive inherited disorder in which the body cannot break down valine, isoleucine, threonine, and methionine.
Lack of functional copies of the enzymes methylmalonyl CoA mutase, methylmalonyl CoA epimerase and propionyl-CoA carboxylase in an adequate level causes methylmalonic acidemia or propionic acidemia.
What is autosomal recessive inheritance?
In an autosomal recessive inheritance, both parents carry the mutated gene and each cell presents the mutation in both copies of their genes. Signs and symptoms of the conditions are not necessarily manifested in the parent. Every generation of an affected family does not show autosomal recessive disorders.
Autosomal recessive inheritance pattern
Autosomal recessive condition is rare, because chances that both parents are carriers for the same recessive genetic condition are low. Even if both the parents are carriers for the same condition, there is only a 25% chance of passing the non-working gene copy to the baby. These odds remain the same with each pregnancy, despite the number of children they have with or without the condition.
The above figure illustrates an autosomal recessive inheritance. The example below shows what happens when both father and mother are carriers of the abnormal gene. As mentioned earlier, chances of passing the abnormal gene, and causing a genetic condition remains 25%.
Let us take an example of parents who are carriers for the abnormal gene. Either they pass on their normal gene or abnormal gene to their child randomly.
The child is affected by the condition: When both the parents carry the same abnormal gene, there is a 25% (1 in 4) chances of inheriting an abnormal gene and child being affected by the condition.
The child is a healthy carrier: There is a 50% (2 in 4) chance of the child inheriting just one copy of the abnormal gene from a parent. Thus the child remains a healthy carrier, like the parents and is not affected by the condition.
The child is neither a carrier nor affected by the condition: There is a 25% (1 in 4) chance of the child inhering both the normal copies of the genes from the parents. Thus the child will neither be a carrier nor affected by the condition.
All in all, there is a 75% (3 in 4) chance that the child will not be affected by the condition. The probability remains the same in every pregnancy whether the baby is male or female, and possible outcomes occur randomly.
MSUD is inherited disorder that ends up in progressive nervous system degeneration and for some, brain damage. The hereditary defect that produces MSUD comes from a defect within the enzyme called branched-chain alpha-keto acid dehydrogenase (BCKD), an important ingredient for the breakdown of certain amino acids (leucine, isoleucine, valine). In the absence of the BCKD enzyme, these amino acids build up to toxic levels within the body.
The name MSUD comes from the fact that when the blood amino acid levels are high, urine takes on the syrup’s distinctive odor. 1 out of every 185,000 babies born in the world are detected with MSUD.
The four types of maple syrup urine disorders are:
Other names for this condition
- BCKD deficiency
- Branched-chain alpha-keto acid dehydrogenase deficiency
- Branched chain ketoaciduria
MSUD is generated by the modification in the genes DBT, BCKDHB and BCKDHA. These genes provide instructions for making proteins that work together as part of a complex.
Mutations in any of these 3 genes prevent normal breakdown of leucine, isoleucine, and valine, reducing functions of the protein complex. As a result, these amino acids and their byproducts build up in the body leading to complications.
- Poor appetite
- Sleepiness or lack of energy
- Poor weight gain
- Fast and shallow breathing
- Maple sugar smell in the earwax, sweat, or urine
- Changes in muscle tone, muscle spasms, and seizures
- Delayed development
Screening for Maple Syrup Urine Disorder
Newborn screening for MSUD is done using a small amount of blood collected from your baby’s heel. It involves analyzing the blood of 1–2-day-old newborns through tandem mass spectrometry. The blood concentration of leucine, isoleucine and valine is measured relative to other amino acids to determine if the newborn has a high level of branched-chain amino acids.
Treatment and management
Diet low in protein:
Most natural foods contain some protein. Thus, any food intake must be closely monitored, and day-to-day protein intake calculated on a cumulative basis to ensure individual tolerance levels are not exceeded at any time.
As the MSUD diet is protein-restricted, and adequate protein is a requirement for all humans, tailored metabolic formula containing all the other essential amino acids, as well as any vitamins, minerals, omega-3 fatty acids and trace elements are an essential aspect of MSUD management.
Careful monitoring of the isoleucine, leucine and valine levels in the blood helps in maintaining MSUD under control. Nutritional analysis of the blood draws and regular metabolic consultations are recommended.
With two defective copies of the BCKD gene there are no methods for preventing the manifestation of the pathology of MSUD in infants. However, DNA testing can be done for screening of the disease with the consultation of genetic counselors. DNA testing also helps identify the disease in an unborn child.
The amino acid leucine is digested by the enzyme isovaleryl CoA dehydrogenase. Deficiency of the enzyme isovaleryl CoA dehydrogenase causes Isovaleric acidemia.
Newborn screening for isovaleric acidemia is done by blood spot screening, where a drop of blood from the baby’s heel is used. While screening, the amount of acylcarnitines in your baby’s blood is measured.
Newborn screening (NBS) has 3 parts:
- Blood spot screening, which determines if a baby might have one of several serious conditions
- Pulse oximetry screening, which determines if a newborn might have certain heart defects
- Hearing screening, which determines if a newborn might be deaf or hard of hearing
Blood Spot Screening:
The most important of these is blood spot screening, also known as “heel stick” or “24-hour test”.
- It is conducted 24 to 48 hours after the child is born
- To make the process easier, the health care provider will gently warm the baby’s foot to increase blood flow, then make a quick pinprick on the baby’s heel
- A few drops of blood are collected from the heel, and dropped onto small circles on a special card
- The circles on the card are made of filter paper, which absorbs the droplets.
- The part outside the circles will contain the name and information about the baby, and the baby’s health care provider
- Once the blood spots have dried, the card is sent to a laboratory for the GC-MS (Gas chromatography–mass spectrometry) and confirmatory or follow up tests, done by TMS (Tandem Mass Spectrometry), for signs of Isovaleric acidemia
Blood spot screening results:
The results of the baby’s newborn blood spot screening become available five to seven days after birth.
The 3 types of possible results:
- In-range (also called negative, normal, or low risk): An in-range result means that the baby probably does not have IVA detected by blood spot screening. Babies with in-range results do not need more testing.
- Out-of-range (also called positive, abnormal, or high risk): An out-of-range result means that the baby might have IVA detected by the screening test. Babies with out-of-range results need more testing.
- Borderline (also called inconclusive or medium risk): A borderline result means that the baby’s screening results fall somewhere between an in-range and out-of-range result. Babies with borderline results need more screening or testing, and another blood sample may be collected to repeat the original screening.
What happens after an IVA out-of-range screening result?
An out-of-range screening result for isovaleric acidemia does not mean that the baby has the condition, it simply means that these follow-up tests are required:
- Blood and/or urine tests
- Genetic testing using a blood sample
It is recommended that follow-up testing should be completed as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.