Most tests use a few drops of blood from pricking the baby's heel. A hearing test involves placing a tiny earphone in the baby's ear and measuring his or her response to sound.

If a screening test suggests a problem, the baby's doctor will follow up with further testing. If those tests confirm a problem, the doctor may refer the baby to a specialist for treatment. Following the doctor's treatment plan can save the baby from life long health and developmental problems.

Consideration for doing newborn screening
Common considerations in determining whether to screen for disorders:

A disease that can be missed clinically at birth
A high enough frequency in the population
A delay in diagnosis will induce irreversible damages to the baby
A simple and reasonably reliable test exists
A treatment or intervention that makes a difference if the disease is detected early

Tests included in the screening
Iindividual countries have their own regulation on newborn screening, so the diseases screened for vary considerably. Most countries now suggest for the most thorough screening panel checks for about 40 disorders including congenital hypothyroidism, galactosemia, and phenylketonuria (PKU) etc.

1. Acylcarnitin Profile: Fatty Acid Oxidation Disorders

• Carnitine/Acylcarnitine Translocase (CACT) Deficiency

Carnitine/Acylcarnitine Translocase (CACT) Deficiency is a disorder of fatty acid oxidation. Fatty acid oxidation generates ATP in the mitochondria and provides acetyl-CoA for gluconeogenesis. CACT normally acts to transport long-chain acylcarnitine across the inner mitochondrial membrane into the mitochondrial matrix where ß-oxidation occurs. CACT also facilitates the export of free carnitine out of the mitochondria where it can be utilized for formation of acylcarnitines. Deficiency of this transport protein results in impaired long-chain fatty acid oxidation and causes the accumulation of long-chain acylcarnitines outside the mitochondria and in plasma. Short- and medium-chain (C8 and less) fatty acids do not require CACT for entry into the mitochondria and are therefore available for energy metabolism.

The severe form has neonatal onset of acute cardiorespiratory symptoms in the first days of life. If the patients survive the initial illness, they suffer from chronic muscle weakness, cardiac hypertrophy, hypoglycemia and hyperammonemia. Plasma carnitine is low. Death may occur due to cardiomyopathy complications.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Hydroxy Long Chain Acyl-CoA Dehydrogenase Deficiency (LCHAD)

Long-chain-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. LCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), which acts on shorter-chain substrates. LCHAD activity resides on the Mitochondrial Trifunctional Protein, which acts to catalyze 3 sequential steps in ß-oxidation. LCHAD deficiency occurs as an isolated defect (described here) or together with deficiency of the other 2 enzymes in Mitochondrial Trifunctional Protein deficiency. LCHAD deficiency impairs oxidation of dietary and endogenous fatty acids of long-chain length (16 carbons and longer).

LCHAD deficiency patients presents with symptoms of cardiomyopathy, may lead to death. Several cardiac problems have been described, including cardiomegaly, left ventricular hypertrophy, and poor contractility. Onset may be acute or chronic. A second group of patients presents, usually following fasting, with non-ketotic hypoglycemia, vomiting, hypotonia, and hepatomegaly. Rhabdomyolysis may occur. Both presentations are highly variable and may have overlapping features. Symptoms may be initiated by a seemingly innocuous illness (a cold or otitis media), leading to prolonged fasting. Symptoms often precede onset of hypoglycemia.

This disorder follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Medium Chain Acyl-CoA Dehydrogenase Deficiency

Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is a disorder of fatty acid ß-oxidation, occurring in at least 1 in 20,000 live births. The enzyme deficiency is medium-chain acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation of fatty acids. MCAD deficiency results in an impaired ability to oxidize dietary and endogenous fatty acids of medium-chain length (6 – 12 carbons).

MCAD deficiency generally presents between the second month and the second year of life, although onset as early as two days and as late as adulthood has been reported. Clinical presentation is often triggered by a seemingly innocuous illness like otitis media or a viral syndrome. The initiating event is probably prolonged fasting, which increases lipolysis and the need for fatty acid oxidation. Symptoms include vomiting, lethargy, apnea, coma, cardiopulmonary arrest, or sudden unexplained death. Initial symptoms often precede the onset of profound hypoglycemia, and are probably related to high free fatty acid levels.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Multiple Acyl-CoA Dehydrogenase Deficiency

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is also known as Glutaric Acidemia Type II (GA-II). It is associated with deficiency of several mitochondrial dehydrogenase enzymes that utilize Flavin Adenine Dinucleotide (FAD) as cofactor, at least 9 of which are known. These include the acyl-CoA dehydrogenases of fatty acid ß-oxidation, and enzymes that degrade glutaric acid, isovaleric acid, and sarcosine (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contributes its electrons to the oxidized form of Electron Transfer Flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF- ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins.

Three clinical presentations are reported for MADD. Two newborn presentations are seen – one with congenital anomalies, and one without. Those with congenital anomalies are often premature, and develop symptoms in the first 24–48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low. Those patients with no congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat. The third cohort of patients has a mild and/or later onset with variable symptoms including lipid storage myopathy.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Neonatal Carnitine Palmitoyl Transferase Deficiency-Type II (CPT-II)

Carnitine Palmitoyl Transferase II (CPT II) Deficiency is a disorder of mitochondrial fatty acid oxidation. Fatty acid oxidation normally generates ATP inside the mitochondria and provides acetyl-CoA for gluconeogenesis. Long-chain fatty acids require carnitine for transport into the mitochondria as long-chain acyl-carnitine esters (i.e. carnitine esterified to a fatty acid). CPT II is located on the inner mitochondrial membrane and acts to convert long-chain acyl-carnitine substrates that are transported across the outer mitochondrial membrane to acyl-CoAs for subsequent ß-oxidation. Deficiency of CPT II results in the accumulation of long-chain acylcarnitines inside the mitochondria and in the plasma. Medium- and short-chain (C8 and shorter) fatty acids do not require CPT II and are metabolized normally. Muscle is particularly dependent on fatty acid oxidation for energy production.

There are three clinical presentations of CPT II Deficiency. The classic form has adult onset of exercise-induced muscle weakness, often with rhabdomyolysis and myoglobinuria that can be associated with acute renal failure. CK levels are found to be elevated only during a symptomatic period. Carnitine levels are normal.

A second phenotype is often fatal in the period from 3 to 18 months of age. Presentation can be onset of seizures with hepatomegaly, non-ketotic hypoglycemia, cardiomyopathy, hypotonia, and muscle weakness. Plasma free carnitine levels are low and acyl-carnitine high.

A severe form presents in the newborn period with non-ketotic hypoglycemia, cardiomyopathy, muscle weakness, and renal dysgenesis in some patients. All of these patients have expired within days of birth.

These different clinical presentations appear to be correlated with residual CPT II enzyme activity. Adult onset patients are found to have approximately 25% of normal activity while the other clinical groups have less than 15%.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

-Carnitine Palmitoyl Trtansferase Deficiency Type 1

Carnitine palmitoyltransferase I deficiency is a condition that prevents the body from converting certain fats called long-chain fatty acids into energy, particularly during periods without food (fasting). Carnitine, a natural substance acquired mostly through the diet, is required by cells to process fats and produce energy. People with this disorder have a faulty enzyme that disrupts carnitine's role in processing long-chain fatty acids.

One of the main signs of this disorder is a low level of ketones, which are products of fat breakdown that are used for energy. Low blood sugar (hypoglycemia) is another major feature. Together these signs are called hypoketotic hypoglycemia, which can result in a loss of consciousness or seizures. People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, nervous system damage, and elevated levels of carnitine in the blood.

This condition is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections

This condition is rare; there are fewer than 50 individuals identified with this disorder. This disorder may be more common in the Hutterite populations of the northern United States and Canada, and in the Inuit populations of northern Canada, Alaska, and Greenland.

• Short Chain Acyl-CoA Dehydronase Deficiency (SCAD)

Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency is a disorder of fatty acid ß-oxidation. The defect involves short-chain (butyryl) acyl-CoA dehydrogenase, one of four mitochondrial acyl-CoA dehydrogenases that carry out the initial dehydrogenation step in the ß-oxidation cycle. SCAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons).

SCAD deficiency usually has clinical onset between the second month and second year of life, although presentations as early as two days and as late as adulthood have been reported. Clinical presentation is highly variable with patients having constant symptoms marked by episodic deterioration. Patients have hypotonia, progressive muscle weakness, developmental delay and, possibly seizures. Failure to thrive, vomiting, and hypoglycemia may be seen. Symptoms may be worsened by a seemingly innocuous illness (a cold or otitis media) that is associated with prolonged fasting, which may lead to lethargy, coma, apnea, cardiopulmonary arrest, or sudden unexplained death. Physical examination of the acutely ill child may reveal mild to moderate hepatomegaly. Symptoms often precede the onset of hypoglycemia, which occurs from an inability to meet gluconeogenic requirements during fasting despite activation of an alternate pathway of substrate production - proteolysis. Cerebral edema and fatty liver and muscle are noted at autopsy, often leading to a misdiagnosis of Reye’s Syndrome or Sudden Infant Death Syndrome (SIDS). SCAD deficiency accounts for about one of every 100 SIDS deaths. Older patients who present chiefly with progressive muscle involvement may respond to riboflavin (Vitamin B2) supplementation and have a generalized multiple acyl-CoA dehydrogenase deficiency. SCAD enzyme is the most vulnerable dehydrogenase to low riboflavin levels.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Short Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (SCHAD)

Short-chain-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency is a disorder of mitochondrial fatty acid ß-oxidation. SCHAD is one of two enzymes that carry out the third step (of 4) in the ß-oxidation of fatty acids – the other enzyme being long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), which acts on longer-chain substrates. SCHAD deficiency impairs oxidation of fatty acids of short-chain length (4 carbons and shorter). The gene for SCHAD has been cloned and mutations identified in several patients.

SCHAD deficiency has been reported in only a few patients and the true spectrum of the disease remains to be defined. Most patients have hypoglycemia as the major symptom with seizures, neurologic sequela or even death as the outcome. Several patients have presented in the first days or months of life with hypoglycemic seizures secondary to hyperinsulinism. Other patients have presented after one year of age with acute onset of vomiting, lethargy and hyponatremic seizures. One patient has presented at 16 years of age with recurrent episodes of hypoketotic hypoglycemia, myoglobinuria, encephalopathy and cardiomyopathy.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Trifunctional Protein Deficiency

Mitochondrial Trifunctional Protein (TFP) Deficiency is a defect in mitochondrial fatty acid ß-oxidation. Three enzyme activities that act sequentially in the oxidation of fatty acids reside together on the TFP enzyme complex located on the inner mitochondrial membrane. The enzymes are Long-Chain-2-Enoyl-CoA Hydratase, Long-Chain HydroxyAcyl-CoA Dehydrogenase (LCHAD), and ß-KetoAcyl-CoA Thiolase. The TFP complex consists of two different protein subunits (a and ß) coded for by two nuclear genes. The TFP complex has specificity toward fatty acids of ten carbons (C10) or longer.

Diverse clinical presentations have been reported in patients having TFP Deficiency. The usual presentation is in infancy and follows a period of fasting associated with a minor illness. Patients develop non-ketotic hypoglycemia, hypotonia, and lactic acidemia. Areflexia and cardiomyopathy is often found on physical exam, and sudden death can occur. Patients may have elevated CK levels and even rhabdomyolysis, and a few have had hyperammonemia. Low carnitine levels have been measured in serum and muscle. Hepatic steatosis is found at biopsy. Many of these patients succumb to severe muscular hypotonia with respiratory distress.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)

Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) is a disorder of ß-oxidation of fatty acids. The enzymatic deficiency is one of four mitochondrial acyl-CoA dehydrogenases that carries out the initial dehydrogenation step in the ß-oxidation of fatty acids. VLCAD deficiency impairs oxidation of dietary and endogenous fatty acids of long chain length (16 carbons and longer). The buildup of the long chain fatty acid acyl-CoA intermediates results in toxic effects to normal metabolism. The gene is on chromosome 17 and encodes a protein that functions on the inner mitochondrial membrane.

Two general presentations have been reported with VLCAD deficiency, although both can vary considerably. Infants can present with severe, sepsis-like symptoms resembling a Reye-like syndrome, which is often lethal. The patient may be hypoglycemic with fasting and have metabolic acidosis, elevated liver enzymes with hepatomegaly (due to steatosis), cholestasis, hypertrophic cardiomyopathy, proteinuria, and hematuria. A second presentation has later onset and exhibits lethargy and coma with fasting. These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

2. Acylcarnitin Profile: Organic Acid Disorders

• 3 Hydroxy 3 Methylglutaryl CoA Lyase Deficiency ( HMG )

3-hydroxy-3-methylglutaryl-coenzyme A (CoA) lyase deficiency (also referred to as HMG-CoA lyase deficiency) is an uncommon inherited disorder in which the body cannot properly process a particular amino acid (a building block of proteins). Additionally, the disorder prevents the body from making ketones, which are used for energy during fasting (periods without food). This disorder usually appears within the first year of life. The signs and symptoms of HMG-CoA lyase deficiency include vomiting, dehydration, extreme tiredness (lethargy), convulsions, and coma. When episodes occur in an infant or child, blood sugar becomes extremely low (hypoglycemia), and harmful compounds can build up and cause the blood to become too acidic (metabolic acidosis). These episodes are often triggered by an infection, fasting, strenuous exercise, or sometimes other types of stress.
This condition is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
This is a rare condition that has been reported in fewer than 100 individuals throughout the world.

• Glutaric Acidemia Type 1

Glutaric acidemia type I is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down the amino acids lysine, hydroxylysine, and tryptophan, which are building blocks of protein. Excessive levels of these amino acids and their intermediate breakdown products can accumulate and cause damage to the brain, particularly the basal ganglia, which are regions that help control movement. Mental retardation may also occur.
The severity of glutaric acidemia type I varies widely; some individuals are only mildly affected, while others have severe problems. In most cases, signs and symptoms first occur in infancy or early childhood, but in a small number of affected individuals, the disorder first becomes apparent in adolescence or adulthood.
Some babies with glutaric acidemia type I are born with unusually large heads (macrocephaly). Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity, or decreased muscle tone. Some individuals with glutaric acidemia have developed bleeding in the brain or eyes that could be mistaken for the effects of child abuse. Strict dietary control may help limit progression of the neurological damage. Stress caused by infection, fever or other demands on the body may lead to worsening of the signs and symptoms, with only partial recovery.
Glutaric acidemia type I occurs in approximately 1 of every 30,000 to 40,000 individuals. It is much more common in the Amish community and in the Ojibwa population of Canada, where up to 1 in 300 newborns may be affected.

• Isobutyryl CoA Dehydrogenase Deficiency

Isobutyryl-coenzyme A (CoA) dehydrogenase deficiency (IBD deficiency) is a rare disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down the amino acid valine, a building block of proteins.
Babies with this deficiency will likely be healthy at birth. The signs and symptoms of this disorder may not appear until later in infancy or childhood and can include poor feeding and growth (failure to thrive), a weakened and enlarged heart (dilated cardiomyopathy), seizures, and low numbers of red blood cells (anemia). Another feature of this disorder may be very low blood levels of carnitine (a natural substance that helps convert certain foods into energy). Isobutyryl-CoA dehydrogenase deficiency may be worsened by long periods without food (fasting) or infections that increase the body's demand for energy. Some individuals with gene mutations that can cause isobutyryl-CoA dehydrogenase deficiency may never experience any signs and symptoms of the disorder.
This disorder is very rare; fewer than 5 cases have been reported.

• Isovaleric Acidemia

Isovaleric acidemia is a rare disorder in which the body is unable to process certain proteins properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.
Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with isovaleric acidemia have inadequate levels of an enzyme that helps break down a particular amino acid called leucine.
Health problems related to isovaleric acidemia range from very mild to life-threatening. In severe cases, the features of isovaleric acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, seizures, and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death. A characteristic sign of isovaleric acidemia is a distinctive odor of sweaty feet during acute illness. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.
In other cases, the signs and symptoms of isovaleric acidemia appear during childhood and may come and go over time. Children with this condition may fail to gain weight and grow at the expected rate (failure to thrive) and often have delayed development. In these children, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), infections, or eating an increased amount of protein-rich foods.
Some people with gene mutations that cause isovaleric acidemia are asymptomatic, which means they never experience any signs and symptoms of the condition.
Isovaleric acidemia is estimated to affect at least 1 in 250,000 people in the United States.

• 2 Methylbutryl CoA Dehydrogenase Deficiency

2-methylbutyryl-coenzyme A dehydrogenase deficiency is a type of organic acid disorder in which the body is unable to process proteins properly. Organic acid disorders lead to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.
Normally, the body breaks down proteins from food into smaller parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with 2-methylbutyryl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme that helps process a particular amino acid called isoleucine.
Health problems related to 2-methylbutyryl-coenzyme A dehydrogenase deficiency vary widely from severe and life-threatening to mild or absent. Signs and symptoms of this disorder can begin a few days after birth or later in childhood. The initial symptoms often include poor feeding, lack of energy (lethargy), vomiting, and an irritable mood. These symptoms sometimes progress to serious medical problems such as difficulty breathing, seizures, and coma. Additional problems can include poor growth, vision problems, learning disabilities, muscle weakness, and delays in motor skills such as standing and walking.
Symptoms of 2-methylbutyryl-coenzyme A dehydrogenase deficiency may be triggered by prolonged periods without food (fasting), infections, or eating an increased amount of protein-rich foods. Some people with this disorder never have any signs or symptoms (asymptomatic). For example, individuals of Hmong ancestry identified with 2-methylbutyryl-coenzyme A dehydrogenase deficiency through newborn screening are usually asymptomatic.
2-methylbutyryl-coenzyme A dehydrogenase deficiency is a rare disorder; its actual incidence is unknown. This disorder is more common, however, among Hmong populations in southeast Asia and in Hmong Americans. 2-methylbutyryl-coenzyme A dehydrogenase deficiency occurs in 1 in 250 to 1 in 500 people of Hmong ancestry.

• 3 Methylcrotonyl CoA Carboxylase Deficiency

3-methylcrotonyl-coenzyme A (CoA) carboxylase deficiency is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down proteins containing a particular building block (amino acid) called leucine.
Infants with this disorder appear normal at birth but usually develop signs and symptoms during the first year of life or in early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Early detection and lifelong management (following a low-protein diet and using appropriate supplements) may prevent many of these complications. In some cases, people with gene mutations that cause 3-methylcrotonyl-CoA carboxylase deficiency never experience any signs or symptoms of the disorder.
The characteristic features of this condition are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
This condition affects an estimated 1 in 50,000 individuals worldwide.

• 3-Methylglutaconyl-CoA Hydratase Deficiency

• Methylmalomic Acidemia

Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants experience vomiting, dehydration, weak muscle tone (hypotonia), excessive tiredness (lethargy), and failure to gain weight and grow at the expected rate (failure to thrive). Long-term complications can include feeding problems, mental retardation, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases.
This condition occurs in an estimated 1 in 50,000 to 100,000 people.

• Mitochondrial Acetoacetyl CoA Thiolase Deficiency

Beta-ketothiolase deficiency is an inherited disorder in which the body cannot effectively process a protein building block (amino acid) called isoleucine. This disorder also impairs the body's ability to process ketones, which are molecules produced during the breakdown of fats.
The signs and symptoms of beta-ketothiolase deficiency typically appear between the ages of 6 months and 24 months. Affected children experience episodes of vomiting, dehydration, difficulty breathing, extreme tiredness (lethargy), and, occasionally, seizures. These episodes, which are called ketoacidotic attacks, sometimes lead to coma. Ketoacidotic attacks are frequently triggered by infections, periods without food (fasting), or increased intake of protein-rich foods.
Beta-ketothiolase deficiency appears to be very rare. It is estimated to affect fewer than 1 in 1 million newborns.

• Propionic Acidemia

Propionic acidemia is an inherited disorder in which the body is unable to process certain parts of proteins and lipids (fats) properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.
In most cases, the features of propionic acidemia become apparent within a few days after birth. The initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including heart abnormalities, seizures, coma, and possibly death.
Less commonly, the signs and symptoms of propionic acidemia appear during childhood and may come and go over time. Some affected children experience mental retardation or delayed development. In children with this later-onset form of the condition, episodes of more serious health problems can be triggered by prolonged periods without food (fasting), fever, or infections.
Propionic acidemia affects about 1 in 100,000 people in the United States. The condition appears to be more common in several populations worldwide, including the Inuit population of Greenland, some Amish communities, and Saudi Arabians.

• Multiple – CoA Carboxylase Deficiency

1. Biotinase deficiency

Biotinidase deficiency is an inherited disorder in which the body is unable to reuse and recycle the vitamin biotin. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of certain enzymes that depend on biotin.
The signs and symptoms of biotinidase deficiency typically appear within the first few months of life, but the age of onset varies. Children with profound biotinidase deficiency, the more severe form of the condition, often have seizures, weak muscle tone (hypotonia), breathing problems, and delayed development. If left untreated, the disorder can lead to hearing loss, eye abnormalities and loss of vision, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Immediate treatment and lifelong management with biotin supplements can prevent many of these complications.
Partial biotinidase deficiency is a milder form of this condition. Affected children experience hypotonia, skin rashes, and hair loss, but these problems may appear only during illness, infection, or other times of stress.
Profound or partial biotinidase deficiency occurs in approximately 1 in 60,000 newborns

2. Holocarboxylase synthetase deficiency

Holocarboxylase synthetase deficiency is an inherited disorder in which the body is unable to use the vitamin biotin effectively. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of certain enzymes that depend on biotin.
The signs and symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, but the age of onset varies. Affected infants often have difficulty feeding, breathing problems, a skin rash, hair loss (alopecia), and a lack of energy (lethargy). Immediate treatment and lifelong management with biotin supplements may prevent many of these complications. If left untreated, the disorder can lead to delayed development, seizures, and coma. These medical problems may be life-threatening in some cases.
The exact incidence of this condition is unknown, but it is estimated to affect 1 in 87,000 people.

• Malonic Aciduria

Malonic Aciduria is a rare disorder caused by deficiency of Malonyl-CoA Decarboxylase (MCD). MCD is an enzyme that catalyzes the degradation of malonyl-CoA. Malonyl-CoA is a substrate for fatty acid synthesis and it also regulates oxidation of fatty acids by controlling their uptake into mitochondria. MCD may therefore regulate fatty acid synthesis and oxidation by affecting intracellular malonyl-CoA levels, but its function is not completely known. The gene for MCD, located on chromosome 16, has been cloned and mutations identified in patients with MCD deficiency.

The presentation of malonic aciduria due to MCD deficiency is variable, ranging from an acute neonatal onset to later in childhood. Patients have symptoms of developmental delay, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, and ketosis. Hypertrophic cardiomyopathy can be seen.
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.
As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

3. Amino Acid Profiles: Amino Acid Disorders

• Carbamoylphosphate Synthetase Deficiency1

Metabolism of amino acids generates ammonia, a highly toxic nitrogen-containing molecule that is eliminated from the body by its incorporation into urea, a non-toxic end product excreted through the kidneys. Carbamyl Phosphate Synthetase (CPS) catalyzes the first step in the detoxification of ammonia through formation of carbamyl phosphate, which enters the urea cycle and ultimately contributes its nitrogen to urea. Deficiency of CPS results in hyperammonemia and life-threatening symptoms. CPS is localized to the mitochondrial matrix and is present in high amount in liver and intestine. The CPS gene has been cloned and mutations identified in patients.

Newborns with CPS deficiency appear normal for the first 24 hours. By 72 hours, symptoms of lethargy, vomiting, hypothermia, respiratory alkalosis and seizures progressing to coma appear. These patients are frequently thought to have sepsis. However, a key laboratory abnormality suggesting a urea cycle defect is low blood urea nitrogen, which should prompt measurement of ammonia. Patients who survive the newborn period often have recurrent episodes of hyperammonemia associated with viral infections or increased dietary protein intake. A neurologically damaged outcome is characteristic of CPS deficiency. Some patients have a later onset with a less severe course making diagnosis difficult.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Argininemia

Argininemia is a rare Urea Cycle defect caused by deficiency of Arginase in liver and erythrocytes. Arginase is the final enzyme in the Urea Cycle that catalyzes the breakdown of arginine to ornithine and urea, which is the major metabolite carrying waste nitrogen destined for urinary excretion. Patients with Arginase deficiency have elevated levels arginine in blood. The deficient Arginase gene is located on chromosome

Patients with Argininemia may present from two months to four years of age. Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly. Hepatomegaly may be present.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Argininosuccinic Aciduria

Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen.

Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the bloodstream only during periods of illness or other stress.

Argininosuccinic aciduria occurs in approximately 1 in 70,000 newborns.

• Citrullinemia

Citrullinemia is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. Two forms of citrullinemia have been described; they have different signs and symptoms and are caused by mutations in different genes.

Type I citrullinemia (also known as classic citrullinemia) usually becomes evident in the first few days of life. Affected infants typically appear normal at birth, but as ammonia builds up in the body they experience a progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. These medical problems are life-threatening in many cases. Less commonly, a milder form of type I citrullinemia can develop later in childhood or adulthood. This later-onset form is associated with intense headaches, partial loss of vision, problems with balance and muscle coordination (ataxia), and lethargy. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder.

Type II citrullinemia chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. In some cases, the signs and symptoms of this disorder appear during adulthood (adult-onset). These signs and symptoms can be life-threatening, and are known to be triggered by certain medications, infections, surgery, and alcohol intake in people with adult-onset type II citrullinemia.

The features of adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver condition is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. In many cases, the signs and symptoms of NICCD resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult-onset type II citrullinemia.

Type I citrullinemia is the most common form of the disorder, affecting about 1 in 57,000 people worldwide. Type II citrullinemia is found primarily in the Japanese population, where it occurs in an estimated 1 in 100,000 to 230,000 individuals. Type II also has been reported in other populations, including people from East Asia and the Middle East.

• Homocystinuria

Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. The most common form of the condition is caused by the lack of an enzyme called cystathionine beta-synthase. This form of homocystinuria is characterized by dislocation of the lens in the eye, an increased risk of abnormal blood clots, and skeletal abnormalities. Problems with development and learning are also evident in some cases.

Less common forms of homocystinuria are caused by a lack of other enzymes involved in processing amino acids. These disorders can cause mental retardation, seizures, problems with movement, and a blood disorder called megaloblastic anemia.

Homocystinuria caused by cystathionine beta-synthase deficiency affects at least 1 in 200,000 to 335,000 people worldwide. The disorder appears to be more common in some countries, such as Ireland (1 in 65,000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 3,000). Other forms of homocystinuria are much rarer, with a small number of cases reported in the scientific literature.

• Hypermethioninemia

Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body.

People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit learning disabilities, mental retardation, and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.

Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula.

Primary hypermethioninemia that is not caused by other disorders or excess methionine intake appears to be rare; only a small number of cases have been reported. The actual incidence is difficult to determine, however, since many individuals with hypermethioninemia have no symptoms.

• 2, 4-Dienoyl-CoA Reductase Deficiency

One patient has been reported with 2,4-Dienoyl-CoA Reductase Deficiency. This enzyme is necessary for the degradation of unsaturated fatty acids having even numbered double bonds.

The patient was born with a small body habitus, a short trunk, arms and fingers, and microcephaly. She was readmitted to the hospital on day 2 of life with symptoms of sepsis, hypotonia, decreased feeding and intermittent vomiting. A low carnitine level was found in her plasma. She responded poorly to treatment in the hospital, and later developed respiratory acidosis and died at 4 months of age.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders, affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Oxoprolinuria (Pyroglutamic Aciduria)

5-Oxoprolinemia is a rare clinical condition caused by a deficiency of any one of three enzymes in the ?-Glutamyl Cycle. The Cycle provides antioxidant for the body in the form of Glutathione. Three enzymes are involved in the sequential processing of 5-Oxoproline to form glutathione. A deficiency of any one of the enzymes causes 5-Oxoprolinemia, and two of the defects lead to low levels of glutathione. Patients with 5-Oxoprolinemia have been described in several ethnic groups around the world.

Clinical presentation of these deficiencies is variable, from severe to very mild. Glutathione Synthetase Deficiency is the most common defect, reported in over 40 cases worldwide. It usually presents in the newborn period with marked metabolic acidosis, hemolytic anemia, electrolyte imbalance, and jaundice. Patients who survive the initial onset may later have episodes of metabolic decompensation during intercurrent illnesses. They often develop progressive central nervous system symptoms. 5-Oxoproline can reach very high levels during illness.

?-Glutamylcysteine Synthetase Deficiency is less severe than Glutathione Synthetase Deficiency, lacking the metabolic acidosis and having lower 5-Oxoproline levels in plasma and urine. Patients have mild compensated hemolytic anemia as the most consistent finding.

Only a few patients have been reported with 5-Oxoprolinase Deficiency. Their clinical symptoms vary tremendously and may not be due to the metabolic defect. They have normal glutathione levels in erythrocytes and no evidence of hemolytic anemia.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Hyperammonemia Hyperornithinemia Homocitrullinuria Syndrome (HHH)

Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome was first described in 1969. In affected patients, plasma Ornithine is found to be dramatically elevated. Hyperammonemia is chronically present, but worsens postprandially. The etiology is a deficiency of a mitochondrial carrier protein that normally functions to transport Ornithine into the mitochondria as part of the urea cycle. When transport is defective, Ornithine accumulates in the cytosol and the urea cycle is impaired, resulting in hyperammonemia. The ORNT 1 gene that codes for the transport protein is located on chromosome 13, and several mutations have been identified in affected patients.

HHH Syndrome may present at birth, during childhood or even adulthood. Newborns who are breast fed usually have an uneventful beginning with intermittent hyperammonemia. Infants on high protein formula or foods may vomit with feeding, refuse to eat, become lethargic or develop hyperammonemic coma. Most affected patients exhibit some symptoms, such as lethargy, vomiting, ataxia or chroeoathetosis, impaired growth and delayed development. Seizures are often reported. Mild to profound mental retardation is usually apparent by childhood. Over time, patients will gravitate to a diet low in milk and meat during childhood.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Hyperornithinemia with Gyrate Atrophy

The first description of a patient with gyrate atrophy of the choroid and retina, as defined by the characteristic appearance of the ocular fundus and a typical history of visual deterioration, was probably made in 1888. Since that time numerous other case reports have confirmed this condition as a distinct entity. Hyperornithinemia and ornithinuria were recognized as the biochemical marker for this disorder in 1973. Elevations in Ornithine, a non-protein amino acid, are associated with complete or partial deficiency of Ornithine Aminotransferase (OAT) activity.

The major clinical problem in these patients is a slowly progressive loss of vision leading to blindness, usually by the fifth decade of life. Myopia and decreased night vision are early symptoms, usually noted by the first or second decade. Reduced peripheral vision is typically present in the second decade, with nearly all patients ultimately developing cataracts. The combination of the cataracts and diminished visual fields results in progressive visual loss, which is frequently well established by the third decade of life in most patients. However, there is significant variability in vision and a few patients retain good visual function into their sixth or seventh decade.

Younger patients often come to the attention of the ophthalmologist in late childhood or around the time of puberty for evaluation of myopia or decreased night vision. Aside from visual impairment, patients with gyrate atrophy are for the most part asymptomatic. Some patients have mild muscle weakness with associated abnormalities on muscle biopsy and in electromyograms, although creatine phosphokinase activity is normal. Affected patients are developmentally normal.

Hyperornithinemia with Gyrate Atrophy is inherited as an autosomal recessive trait. Both parents are carriers of one normal gene and one abnormal Hyperornithinemia gene. An affected child is born when both parents pass along the Hyperornithinemia gene at conception, resulting in every cell of the body having the two abnormal genes. The risk for carrier parents having an affected pregnancy is one chance in four with every conception. If not screened at birth, all previous siblings should be tested to rule out Hyperornithinemia. This disease has been found in several ethnic groups around the world with a particularly high incidence in Finland.

• Maple Syrup Urine Disease

Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. Beginning in early infancy, this condition is characterized by poor feeding, vomiting, lack of energy (lethargy), seizures, and developmental delay. The urine of affected infants has a distinctive sweet odor, much like burned caramel, that gives the condition its name. Maple syrup urine disease can be life-threatening if untreated.

Maple syrup urine disease can be classified by its pattern of signs and symptoms or by its genetic cause. The most common and most severe form of the disease is the classic type, which appears soon after birth. Variant forms of the disorder appear later in infancy or childhood and are typically milder, but still involve mental and physical retardation if not treated.

Maple syrup urine disease affects an estimated 1 in 185,000 infants worldwide. The disorder occurs much more frequently in the Old Order Mennonite population, in which the incidence is about 1 in 358 newborns.

• Hyperargininemia due to Arginase

The urea cycle is a series of six reactions necessary to rid the body of the nitrogen generated by the metabolism, primarily of amino acids, from the diet or released as the result of endogenous protein catabolism. Arginase is the sixth and final enzyme of this cycle. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. Hyperargininemia due to arginase deficiency is inherited in an autosomal recessive manner and gene for arginase.

This condition rarely presents in the neonatal period and first symptoms typically present in children between 2 and 4 years of age. First symptoms are often neurologically based. If untreated, symptoms are progressive with a gradual loss of developmental milestones.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Ornithine Transcarbamylase Deficiency

Ornithine transcarbamylase deficiency (OTCD), the most common of the urea cycle disorders, is a rare metabolic disorder, occurring in one out of every 80,000 births. OTC is a genetic disorder resulting in a mutated and ineffective form of the enzyme ornithine transcarbamylase.

Like other urea cycle disorders, OTC affects the body's ability to get rid of ammonia, a toxic breakdown product of the body's use of protein. As a result, ammonia accumulates in the blood causing hyperammonemia. This ammonia travels to the various organs of the body including the brain, causing coma, brain damage and death.

Another symptom of OTC is a buildup of orotic acid in the blood. This is due to an anapleurosis that occurs with carbamoyl phosphate entering the pyrimidine synthesis pathway.

Ornithine transcarbamylase deficiency often becomes evident in the first few days of life. An infant with ornithine transcarbamylase deficiency may be lacking in energy (lethargic) or unwilling to eat, and have poorly-controlled breathing rate or body temperature. Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. Complications from ornithine transcarbamylase deficiency may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Other symptoms include irrational behavior (caused by encephalitis), mood swings, and poor performance in school.

In some affected individuals, signs and symptoms of ornithine transcarbamylase may be less severe, and may not appear until later in life. Some female carriers become symptomatic later in life. This can happen as a result of anorexia, starvation, malnutrition, or even (in at least one case) as a result of gastric bypass surgery. It is also possible for symptoms to be exacerbated by extreme trauma of many sorts, including, (at least in one case) adolescent pregnancy coupled with severe stomach flu.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Arginase deficiency

Argininemia is a rare Urea Cycle defect caused by deficiency of Arginase in liver and erythrocytes. Arginase is the final enzyme in the Urea Cycle that catalyzes the breakdown of arginine to ornithine and urea, which is the major metabolite carrying waste nitrogen destined for urinary excretion. Patients with Arginase deficiency have elevated levels arginine in blood. The deficient Arginase gene is located on chromosome 6.

Patients with Argininemia may present from two months to four years of age. Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly. Hepatomegaly may be present.

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

• Biotinaidase deficiency

Biotinidase deficiency is an inherited metabolic disorder of biotin (vitamin B) recycling that leads to multiple carboxylase deficiencies.

Symptoms of untreated biotinidase deficiency may appear at any time from 1 week to10 years of age. The most common early symptoms include seizure activity of various types (myoclonic, grand mal, and focal or infantile spasms) and hypotonia. Other early symptoms include breathing problems (tachypnea, hyperventilation, stridor, apnea), skin rashes and alopecia. Later developmental delays, speech problems, ataxia, and vision and hearing problems may occur. Less frequent findings include feeding difficulties, vomiting/diarrhea, fungal infections, hepatomegaly and splenomegaly.

This disorder is inherited in an autosomal recessive pattern. As an autosomal recessive disorder, the parents of a child with biotinidase deficiency are unaffected, healthy carriers of the condition and have one normal gene and one abnormal gene. With each pregnancy, carrier parents have a 25 percent chance of having a child with two copies of the abnormal gene, which results in biotinidase deficiency. Carrier parents have a 50 percent chance of having a child who is an unaffected carrier and a 25 percent chance of having an unaffected, non-carrier child. These risks hold true for each pregnancy. All siblings of infants diagnosed with biotinidase deficiency should be tested; genetic counseling services should be offered to the family.

• Cystic Fibrosis

Cystic fibrosis (CF), or mucoviscoidosis, is a hereditary disease that affects mainly the lungs and digestive system, causing progressive disability. Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply cystic fibrosis.

Difficulty breathing and insufficient enzyme production in the pancreas are the most common symptoms. Thick mucus production, as well as a less competent immune system, results in frequent lung infections, which are treated, though not always cured, by oral and intravenous antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and potential infertility (mostly in males, due to the condition Congenital bilateral absence of the vas deferens) result from the effects of CF on other parts of the body. Often, symptoms of CF appear in infancy and childhood; these include meconium ileus, failure to thrive, and recurrent lung infections.

CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTCR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally. Therefore, CF is considered an autosomal recessive disease. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) of the biliary tract ("cystic" being a generic term for all that is related to the biliary vesicle and/or the bladder), first recognized in the 1930s.

Gene therapy holds promise as a potential avenue to cure cystic fibrosis.

4. Other Amino Acid Profiles

Other amino acid profiles include:

- Hyperalimentation
- Medium Chain Triglyceride Oil Administration
- Liver Disease
- Treatment with Benzoate, Pyvalic Acid, or Valproic Acid
- Presence of EDTA coagulants in blood specimen
- Carnitine Uptake Deficiency

5. Disorders Detected by other Technologies:

• Galactosemia

Galactosemia is a disorder that affects how the body processes a simple sugar called galactose. A small amount of galactose is present in many foods. It is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas. The signs and symptoms of galactosemia result from an inability to use galactose to produce energy.

Researchers have identified several types of galactosemia. These conditions are each caused by mutations in a particular gene, and affect different enzymes involved in breaking down galactose. Classic galactosemia, also known as type I, is the most common and most severe form of the condition. Galactosemia type II (also called galactokinase deficiency) and type III (also called galactose epimerase deficiency) cause different patterns of signs and symptoms.

If infants with classic galactosemia are not treated promptly with a low-galactose diet, life-threatening complications appear within a few days after birth. Affected infants typically develop feeding difficulties, a lack of energy (lethargy), a failure to gain weight and grow as expected (failure to thrive), yellowing of the skin and whites of the eyes (jaundice), liver damage, and bleeding. Other serious complications of this condition can include overwhelming bacterial infections (sepsis) and shock. Affected children are also at increased risk of delayed development, clouding of the lens of the eye (cataract), speech difficulties, and mental retardation. Females with classic galactosemia may experience reproductive problems caused by ovarian failure.

Galactosemia type II causes fewer medical problems than the classic type. Affected infants develop cataracts, but otherwise experience few long-term complications. The signs and symptoms of galactosemia type III vary from mild to severe and can include cataracts, delayed growth and development, mental retardation, liver disease, and kidney problems.

Classic galactosemia occurs in 1 in 30,000 to 60,000 newborns. Galactosemia type II and type III are less common; type II probably affects fewer than 1 in 100,000 newborns and type.

• Congenital Hypothyroidism

Congenital hypothyroidism is a condition that affects infants from birth (congenital) and results from a partial or complete loss of thyroid function (hypothyroidism). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism).

Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, abnormally located, or severely reduced in size (hypoplastic). In the remaining cases, a normal-sized or enlarged thyroid gland is present, but production of thyroid hormones is decreased or absent. If untreated, congenital hypothyroidism can lead to mental retardation and abnormal growth. In the United States and many other countries, all newborns are tested for congenital hypothyroidism. If treatment begins in the first month after birth, infants usually develop normally.

Studies of populations from North America, Europe, Japan, and Australia, indicate that congenital hypothyroidism affects 1 in 3,000 to 4,000 newborns. For reasons that remain unclear, congenital hypothyroidism affects more than twice as many females as males.
Mutations in the DUOX2, PAX8, SLC5A5, TG, TPO, TSHB, and TSHR genes cause congenital hypothyroidism. Gene mutations cause the loss of thyroid function in one of two ways. Mutations in the PAX8 gene and some mutations in the TSHR gene prevent or disrupt the normal development of the thyroid gland before birth. Mutations in the DUOX2, SLC5A5, TG, TPO, and TSHB genes prevent or reduce the production of thyroid hormones, even though the thyroid gland is present. Mutations in other genes that have not been well characterized may also cause congenital hypothyroidism.

Most cases of congenital hypothyroidism are sporadic, which means they occur in people with no history of the disorder in their family.

An estimated 15 to 20 percent of cases are inherited. Many inherited cases are autosomal recessive, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Some inherited cases (those with a mutation in the PAX8 gene or certain TSHR mutations) have an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

• G6PD Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hereditary disease featuring abnormally low levels of the G6PD enzyme, which plays an important role in red blood cell function. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes. It is closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava). Sometimes the name, favism, is alternatively used to refer to the enzyme deficiency as a whole.
Patients are almost exclusively male, due to the X-linked pattern of inheritance, but female carriers can be clinically affected due to lyonization where random inactivation of an X-chromosome in certain cells creates a population of G6PD deficient red cells coexisting with normal red cells. G6PD manifests itself in a number of ways:

• Prolonged neonatal jaundice
• Hemolytic crises in response to:
• Certain drugs (see below)
• Certain foods, most notably broad beans
• Illness (severe infections)
• Diabetic ketoacidosis
• Very severe crises can cause acute renal failure

G6PDD is said to be the most common enzyme deficiency disease in the world, affecting approximately 400,000,000 people globally. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. An explanation is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PDD carriers an evolutionary advantage.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (most notably erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage. G6PD converts glucose-6-phosphate into 6-phosphoglucono-d-lactone and is the rate-limiting enzyme of the pentose phosphate pathway.

Patients with G6PD deficiency are at risk of hemolytic anemia in states of oxidative stress. This can be in severe infection, medication and certain foods. Broad beans contain high levels of vicine, divicine, convicine and isouramil — all are oxidants.
In states of oxidative stress, all remaining glutathione is consumed. Enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to electrolyte imbalance, membrane cross-bonding and phagocytosis and splenic sequestration of red blood cells. The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations) or excreted directly by the kidney (causing acute renal failure in severe cases).

Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also causes a reduction of NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to G6PD deficiency. Some other epidemiological reports have pointed out, however, that G6PD seems to decrease the susceptibility to cancer, cardiovascular disease and stroke.

Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).
Congenital Adrenal Hyperplasia

21-hydroxylase deficiency (also known as congenital adrenal hyperplasia) is an inherited disorder that affects the adrenal glands. These glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. Two of these hormones, cortisol and aldosterone, are produced from cholesterol through the activity of an enzyme called 21-hydroxylase. Cortisol has numerous functions such as maintaining blood sugar levels, protecting the body from stress, and suppressing inflammation. Aldosterone, sometimes called the salt-retaining hormone, acts on the kidneys to regulate the levels of salt and water in the body, which affects blood pressure. People with 21-hydroxylase deficiency have a shortage of the 21-hydroxylase enzyme, which impairs the conversion of cholesterol to cortisol and aldosterone. When the precursors of cortisol and aldosterone build up in the adrenal glands, they are converted to male sex hormones called androgens. Androgens are normally responsible for the appearance of secondary sex characteristics in males (virilization). Elevated levels of androgens can affect the growth and development of both males and females.

There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the simple virilizing and salt-loss types. Simple virilizing 21-hydroxylase deficiency causes a buildup of potent androgens that leads to the masculinization (development of male characteristics) of external genitalia in females at birth. The development of the internal reproductive organs (uterus and ovaries) in these patients is normal. Salt-loss 21-hydroxylase deficiency results from an almost complete loss of enzyme activity. In these cases, so little aldosterone is produced that the kidneys do not reabsorb sodium (a component of salt). In the third type of 21-hydroxylase deficiency, known as the nonclassic form, levels of functional 21-hydroxylase enzyme are moderate. Both males and females with the nonclassic type can display signs and symptoms of androgen excess after birth.

The classic form of 21-hydroxylase deficiency appears in 1 in 15,000 newborns. The prevalence of the nonclassic form of 21-hydroxylase deficiency is estimated to be 1 in 100 individuals. The prevalence of both classic and nonclassic forms may vary among different ethnic populations.

• Cystic Fibrosis

Cystic fibrosis (CF), or mucoviscoidosis, is a hereditary disease that affects mainly the lungs and digestive system, causing progressive disability. Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply cystic fibrosis.

Difficulty breathing and insufficient enzyme production in the pancreas are the most common symptoms. Thick mucus production, as well as a less competent immune system, results in frequent lung infections, which are treated, though not always cured, by oral and intravenous antibiotics and other medications. A multitude of other symptoms, including sinus infections, poor growth, diarrhea, and potential infertility (mostly in males, due to the condition Congenital bilateral absence of the vas deferens) result from the effects of CF on other parts of the body. Often, symptoms of CF appear in infancy and childhood; these include meconium ileus, failure to thrive, and recurrent lung infections.

CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTCR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works normally. Therefore, CF is considered an autosomal recessive disease. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) of the biliary tract ("cystic" being a generic term for all that is related to the biliary vesicle and/or the bladder), first recognized in the 1930s.

Gene therapy holds promise as a potential avenue to cure cystic fibrosis.