Hydroxy 3 Methylglutaryl CoA Lyase Deficiency (HMG)
3-Hydroxy-3-MethylGlutaryl-CoA (HMG-CoA) Lyase has a dual function in the breakdown of Leucine and in regulating production of ketone bodies. It is located predominantly in mitochondria, but is also found in peroxisomes. In the last step in Leucine metabolism, it cleaves 3-hydroxy-3-methylglutaryl-CoA, producing acetyl-CoA and acetoacetate, one of the ketone bodies. HMG-CoA Lyase Deficiency was first described in 1971 and more than 60 patients have subsequently been diagnosed.

The onset of symptoms is initiated by fasting, infection, dietary protein load, or simply the stress of birth. Symptoms progress from vomiting, lethargy, trachypnea and dehydration to coma and possibly death. Hepatomegaly and neurologic abnormalities are seen on physical exam.

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.


Glutaric Acidemia-Type I (GA I)
Glutaric Acidemia, Type I (GA I), was first described in 1975. The disease is caused by a genetic deficiency of the enzyme, Glutaryl-CoA Dehydrogenase (GCD), which leads to the buildup of Glutaric acid in the tissues and its excretion in the urine of affected patients. GCD is involved in the catabolism of the amino acids, Lysine, Hydroxylysine, and Tryptophan.

Early, aggressive treatment prior to onset of clinical symptoms may prevent development of neurological damage. At the onset of any sickness or metabolic decompensation, prompt, vigorous initiation of IV fluids, including glucose and carnitine, with monitored administration of insulin, is recommended. Restriction of protein, i.e. Lysine and Tryptophan restriction, has not produced clear clinical benefits.

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.

Isobutyryl-CoA Dehydrogenase Deficiency
Isobutyryl-CoA Dehydrogenase (IBDH) is an enzyme involved in the metabolism of Valine, a branched-chain amino acid. Deficiency of IBDH was recently described and only a few patients have been identified. The gene for IBDH (ACAD8), located on chromosome 9, has been cloned and mutations have been identified in several patients.

The clinical features of IBDH deficiency are poorly defined and may have a highly variable presentation. The first patient described with this disease had failure to thrive and developed dilated cardiomyopathy associated with anemia at 11 months of age. Plasma carnitine levels were profoundly decreased. Several other patients have been identified by newborn screening and appear “asymptomatic”. Long-term clinical follow-up, however, is lacking and the true clinical spectrum of the disease is yet to be determined.

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.

Isovaleric Acidemia
Isovaleric Acidemia results from a defect in the metabolism of the amino acid, Leucine. The first patient with Isovaleric Acidemia was described in 1966 and the deficiency of Isovaleryl-CoA Dehydrogenase activity was found a few years later. Isovaleryl-CoA Dehydrogenase functions in the inner mitochondrial matrix. The gene is located on chromosome 15.

Isovaleryl-CoA Dehydrogenase deficiency causes overwhelming illness with vomiting and ketoacidosis progressing to lethargy, coma and death in greater than 50% of the patients within weeks of acute conditions. The patient commonly has a distinctive odor of “sweaty feet” during an illness because of the volatile isovaleric acid that accumulates.

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-Methylbutyryl-CoA Dehydrogenase Deficiency
Deficiency of 2-Methylbutyryl-CoA Dehydrogenase (also called Short/Branched-Chain Acyl-CoA Dehydrogenase or SBCAD) results from a defect in the metabolism of the branched-chain amino acid Isoleucine. The disorder was described in 2000 and only a few patients have been identified. The gene (SBCAD), located on chromosome 10, has been cloned and mutations identified in several patients.

SBCAD Deficiency shows symptoms ranging from poor feeding, lethargy, hypoglycemia, and metabolic acidosis at a few days of age to completely “asymptomatic” individuals. Those patients with symptoms have tended to display developmental delay, seizure disorder, or progressive muscle weakness in infancy and 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.

3-Methylcrotonyl-CoA Carboxylase Deficiency (3MCC Deficiency)
3-MethylCrotonyl-CoA Carboxylase (3-MCC) Deficiency has been recognized since 1984. It is a defect in the degradation of the amino acid Leucine. As a carboxylase enzyme, 3-MCC requires biotin for activity. There are four carboxylases in man that utilize biotin and each can be deficient singly or together. If biotin metabolism is defective, activities of all four carboxylases will be low, resulting in Multiple Carboxylase Deficiency. Some of the biochemical findings in 3-MCC Deficiency overlap with those seen in Multiple Carboxylase Deficiency, necessitating careful testing to distinguish the two disorders.

Symptoms often have onset with an infection, illness, or prolonged fasting. Patients with 3-MCC deficiency can lapse into catabolic stress leading to vomiting, lethargy, apnea, hypotonia, or hyperreflexia and seizures. Patients may have profound hypoglycemia, mild metabolic acidosis, hyperammonemia, elevated liver transaminases, and ketonuria. Plasma free carnitine levels may be very low. Other patients may present with failure to thrive beginning in the neonatal period or developmental delay.

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.

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.

Mitochondrial Acetoacetyl-CoA Thiolase Deficiency
Mitochondrial Acetoacetyl-CoA Thiolase (commonly called ß-Ketothiolase) is an enzyme with a dual function in metabolism. It acts in the breakdown of acetoacetyl-CoA generated from fatty acid oxidation and regulates production of ketone bodies. It also catalyzes a late step in the breakdown of the amino acid Isoleucine. ß-Ketothiolase Deficiency was first described in 1971 and more than 40 cases have been reported.

Most affected patients present between 5 and 24 months of age with symptoms of severe ketoacidosis. Symptoms can be initiated by a dietary protein load, infection or fever. Symptoms progress from vomiting to dehydration and ketoacidosis. Neutropenia and thrombocytopenia may be present, as can moderate hyperammonemia. Blood glucose is typically normal, but can be low or high in acute episodes. Developmental delay may occur, even before the first acute episode, and bilateral striatal necrosis of the basal ganglia has been seen on brain MRI.

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.

Propionic Acidemia (PA)
Propionic Acidemia (PA) is characterized by the accumulation of propionic acid due to a deficiency in Propionyl CoA Carboxylase, a biotin dependent enzyme involved in amino acid catabolism. Propionic acid may also accumulate in Multiple Carboxylase deficiency and Methylmalonic Acidemia. Multiple mutations for PA have been identified.

Patients with PA typically present in the first days of life with dehydration, lethargy, hypotonia, vomiting, ketoacidosis, and hyperammonemia. Seizures, neutropenia, thrombocytopenia, and hepatomegaly may be present. Untreated patients can progress to coma and die. Most patients who survive the neonatal period have episodes of metabolic acidosis precipitated by infection, fasting, or a high protein diet. In some cases, episodic hyperammonemia seems to predominate over the metabolic acidosis. Psychomotor retardation is a life-long complication. Some patients have first presented later in infancy with encephalopathy and associated ketoacidosis, or developmental delay.

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-CoA Carboxylase Deficiency
There are four carboxylase enzymes in man that require biotin for activity. These enzymes are propionyl-CoA carboxylase, 3-methylcrotonoyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. If biotin metabolism is defective, all four carboxylases will be deficient. Biotin is covalently linked to a key lysine residue in each carboxylase by action of holocarboxylase synthetase. When the carboxylase proteins are degraded, biotinoyl-lysine is subsequently cleaved by biotinidase releasing free biotin that can be reutilized. The two defects in biotin metabolism associated with Multiple Carboxylase Deficiency are caused by deficient activity of holocarboxylase synthetase and biotinidase. The disorders tend to present clinically at different ages, with holocarboxylase synthetase deficiency being known as early-onset (neonatal) multiple carboxylase deficiency and biotinidase deficiency referred to as late-onset multiple carboxylase deficiency. Both respond to biotin supplementation.

Patients affected with deficient holocarboxylase synthetase usually present in the first days or weeks of life with poor feeding, lethargy, hypotonia, and seizures, sometimes progressing to coma. Generalized rash and alopecia may be present. Affected patients exhibit metabolic acidosis and mild to moderate hyperammonemia. In contrast, Biotinidase deficiency, which constitutes the vast majority of patients with Multiple Carboxylase Deficiency, typically presents after several months of life with neurocutaneous symptoms including developmental delay, hypotonia, seizures, ataxia, hearing loss, alopecia, and skin rash. In some patients, the disease can be life-threatening.

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.