Browsing Pathways

Triosephosphate isomerase deficiency is a genetic disorder caused by a mutation in the TPI1 gene. The mutation of this gene causes the production of enzymes that are unstable or enzymes that have reduced activity. This means that cells have reduced energy supplies as glycolysis is compromised. This disorder causes anemia, movement problems and muscle weakness. As a result of the lack of red blood cells to carry oxygen through the body, patients may experience fatigue and shortness of breath. Movement problems appear in early infancy, typically before the age of 2 in patients with this disorder. Treatment includes blood transfusions.

Holocarboxylase synthetase deficiency also called Multiple Carboxylase Deficiency, Neonatal or Early Onset Form, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of either mutations in the BTD gene or the HLCS gene. The BTD gene encodes for biotinidase and the HLCS gene encodes for holocarboxylase synthetase. This disorder is classified as a multiple carboxylase deficiency, a group of disorders characterized by impaired activity of enzymes dependent on biotin. Symptoms of holocarboxylase synthetase deficiency typically appear within the first few months of life, and include difficulty feeding, breathing problems, a skin rash, hair loss, and lethargy. Treatment using biotin supplements if immediate and lifelong can be effective in preventing many complications and managing the disorder. However, if left untreated the disorder can lead to delayed development, seizures, and coma.

Aromatase deficiency is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of mutations in the CYP19A1 gene. The CYP19A1 gene encodes for the enzyme aromatase. Aromatase converts androgens to estrogens which is vital for bone growth and regulation of blood sugar levels. Symptoms of decrease in estrogen and increase androgens such as testosterone can cause impaired female sexual development, unusual bone growth, insulin resistance, and a variety of other symptoms. It presents with virilization of pregnant mothers during the antenatal period, and virilization of female fetuses at birth. Treatments include lifelong hormone therapy. There have been about 20 reported cases of Aromatase Deficiency worldwide.

17-alpha-hydroxylase deficiency, also known as congenital adrenal hyperplasia (CAH) due to 17-alpha-hydroxylase deficiency or congenital adrenal hyperplasia type 5, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the steroidogenesis pathway. It is caused by a mutation in the CYP17A1 gene which encodes the enzyme steroid 17-alpha-hydroxylase. This enzyme hydroxylates both progesterone and pregnenolone into 17-hydroxyprogesterone and 17a-hydroxypregnenolone respectively in the mitochondria, as well as hydroxylating 21-deoxycortisol to 11b-hydroxyprogesterone within the endoplasmic reticulum. When mutated, it leads to an accumulation of pregnenolone, progesterone, deoxycorticosterone and 11-dehydrocorticosterone throughout the cell. 17-alpha hydroxylase deficiency is characterized by a deficiency of sex steroids, as well as glucocorticoids. Symptoms include male undervirilization, as well as lack of development during puberty including amenorrhea for females. Low levels of potassium in the blood due to the increased levels of mineralocorticoids can occur, as well as hypertension. Treatment with dexamethasone has been able to normalize blood pressure and blood potassium levels. It is estimated that 17-alpha-hydroxylase deficiency affects 1 in 1,000,000 individuals.

Succinic Semialdehyde Dehydrogenase (SSADH) deficiency is a rare autosomal recessive inherited disorder affecting the metabolism of γ-aminobutyric acid (GABA). With reduced GABA activity, oxidation of succinic semialdehyde (SSA) to succinic acid is impaired causing a build up of SSA and ultimately it’s downstream metabolite γ-hydroxybutyric acid (GHB). Symptoms of SSADH deficiency are primarily neuropsychiatric including developmental delays, hypotonia, expressive language impairment, seizures, difficulty coordinating movements (ataxia), decreased reflexes (hyporeflexia), and other behavioral issues. Patients with SSADH deficiency have elevated levels of GHB in urine, however this method is not a definitive diagnosis due to the potential volatilization of acidified urine and the use of GHB as a drug. Instead SSADH can be confirmed suing enzyme analysis in leukocytes and molecular genetic analysis of the Aldh5a1 gene at chromosome 6p22.

3-hydroxyacyl-CoA dehydrogenase deficiency, also known as HADH deficiency or formerly SCHAD deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the mitochondrial beta-oxidation of short chain saturated fatty acid pathway. It is caused by a mutation in the HADH gene which encodes the mitochondrial enzyme hydroxyacyl-coenzyme A dehydrogenase. This enzyme is responsible for the beta-oxidation of 3-hydroxyhexanoyl-CoA and 3-hydroxybutyryl-CoA into 3-oxohexanoyl-CoA and acetoacetyl-CoA respectively. Symptoms of HADH deficiency include hypoglycemia, as well as vomiting, diarrhea and seizures. Treatment with diazoxide, a potassium channel activator, has been effective. It is estimated that HADH deficiency affects less than 1 in 1,000,000 individuals.

Succinyl CoA: 3-Ketoacid CoA Transferase (SCOT) deficiency is a rare inherited metabolic disorder causing reduction of ketone body utilization. In normal functioning patients, ketone bodies such as Acetoacetate (AcAc) and 3‐hydroxybutyrate (3HB) are metabolized inside the liver from free fatty acids. Next, ketone bodies are transported to extrahepatic tissues via the blood stream. Once in extrahepatic tissues, SCOT converts AcAc to acetoacetyl‐CoA and T2 cleaves acetoacetyl‐CoA into acetyl‐CoA. This process is crucial for producing alternative energy sources to glucose in order to maintain blood glucose levels. Patients with SCOT deficiency have this process disturbed and ketoacidosis which is the acidification of the bloodstream due to excess ketone body accumulation, can occur. Current treatments include avoiding actions that could onset ketoacidosis such as fasting and early infusion of glucose. The severity of SCOT deficiency differs from patient to patient. Some exhibit severe genotypes where ketones are always in abundance in the body, while others could have mild genotypes with no preeminent ketosis however both could exhibit ketoacidotic episodes.

Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type, also known as methionine synthase deficiency or methylcobalamin deficiency, cblG type, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the methionine metabolim pathway. It is caused by a mutation in the MTR gene which encodes the enzyme methionine synthase. This enzyme is responsible for forming L-methionine and tetrahydrofolic acid from homocysteine and 5-methyltetrahydrofolic acid. When the enzyme is mutated, this leads to lower amounts of L-methionine in the cell, as well as increased levels of homocysteine. Methionine synthase deficiency is characterized by an increase in homocysteine levels in the body and excreted in the urine, as well as decreased levels of methionine in the blood. Symptoms include megaloblastic anemia, and can also include developmental delays, seisures and kidney failure. Treatment with vitamin B12, as well as folates and betaine is effective. It is estimated that methionine synthase deficiency affects less than 1 in 1,000,000 individuals.

The condition pyridoxine dependent-epilepsy is a condition that sees seizures beginning in infancy. In some cases, the seizures begin before birth. The seizures involve status epilepticus, which are seizures that last several minutes. The symptoms specific to pyridoxine dependent seizures can include hypothermia, dystonia and irritability right before an episode. They also include loss of consciousness, convulsions, and muscle rigidity. Rarely does this condition manifest between 1 to 3 years of age, although it has occured. Traditional anticonvulsant medication has proven ineffective in patients with this condition; patients are instead treated with pyridoxine daily in large doses. This compound is a b-vitamin found in food. Encephalopathy can occur if this condition is not treated, which can result in permanent brain damage. Although this condition is treated with pyridoxine, it can still cause neurological issues, such as learning disorders or developmental delay, regardless of treatment.

Fanconi-Bickel Syndrome is a syndrome first described in 1949, by Falconi and Bickel, where the body is missing a glucose transport, causing glycogen stores to accumulate and cause symptoms such as swelling of the liver and spleen, rickets, and failure to thrive. Hypoglycemia may occur in between meals for patients with this condition. This condition happens through a mutation on the SLC2A2 gene, which has the instructions on how to create a protein which is the glucose-transporter protein 2 (GLUT2). GLUT2 does not work properly when there is an SLC2A2 gene mutation, which makes glycogen build up in the liver and kidneys, causing the symptoms of this condition.