Browsing Pathways

11-beta-Hydroxylase Deficiency, also called congenital adrenal hyperplasia (CAH), is an autosomal recessive disorder and caused by a defective 11-beta-hydroxylase. 11-beta-hydroxylase catalyzes the conversion of cortexolone into cortisol which is useful for maintaining blood sugar levels and suppressing inflammation. This disorder is characterized by a large accumulation of cortexolone in the endoplasmic reticulum (ER). Symptoms of the disorder include abnormality of hair growth rate and menstrual cycle. It is estimated that 11-beta-hydroxylase deficiency affects 1 in 100,000 to 200,000 newborns.

3-beta-hydroxysteroid dehydrogenase (HSD) deficiency is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the steroidogenesis pathway. It is caused by an defect in the HSD3B2 gene which encodes for the 3 beta-hydroxysteroid dehydrogenase enzyme, which is responsible for forming cortisol from 11b,17a,21-trihydroxypregnenolone. When the enzyme is not correctly produced, cortisol levels in the cell are lowered, and as cortisol is used in the production of other steroids, it may affect their levels as well. 3-beta-HSD deficiency is characterized by low levels of cortisol produced in the adrenal glands. Symptoms include abnormal genitalia for both males and females, as well as infertility. There is also a more severe salt-wasting form of this deficiency, characterized by dehydration. Treatment for 3-beta-HSD deficiency includes steroid replacement, as well as sex hormone replacement during puberty to allow proper development. Surgery can also be used to correct any genital abnormalities that may occur. It is estimated that 3-beta-HSD deficiency affects less than 1 in 1,000,000 individuals, with around 60 cases reported.

Dihydrolipoamide dehydrogenase deficiency, which is also known as DLDD, DLD, E3 deficiency, pyruvate dehydrogenase E3 deficiency, DLD deficiency, E3-deficient maple syrup urine disease, is a rare inherited inborn error of metabolism. DLD deficiency occurs in an estimated 1 in 35 000 to 48 000 individuals of Ashkenazi Jewish descent. DLDD is an autosomal recessive metabolic disorder characterized by mutations to the DLD gene, which codes for dihydrolipoamide dehydrogenase (DLD). DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide. The DLD homodimer functions as the E3 component of the pyruvate, alpha-ketoglutarate, and branched-chain amino acid-dehydrogenase complexes and the glycine cleavage system, all of which are located in the mitochondrial matrix. DLDD is a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). A common feature of dihydrolipoamide dehydrogenase deficiency is a potentially life-threatening buildup of lactic acid in tissues (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Neurological problems are also common in this condition; the first symptoms in affected infants are often decreased muscle tone (hypotonia) and extreme tiredness (lethargy). E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate. E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD) and is sometimes referred to as MSUD type III, although patients with E3 deficiency have additional biochemical defects.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle caused by a defective SLC25A15 gene. SLC25A15 codes for the mitochondrial ornithine carrier (ORC1) which transports ornithine between the cytoplasm and the mitochondrial matrix. This disease is characterized by a large accumulation of homocitrulline in the urine. Symptoms of the disease include mental retardation, spastic paraparesis, and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. Ornithine supplementation and restricted protein intake appear to be useful in the treatment of HHH syndrome.

Guanidinoacetate Methyltransferase Deficiency (Creatine-Deficiency-Syndrome) is a rare autosomal recessive disease caused by a mutation in the GAMT gene which codes for guanidinoacetate N-methyltransferase. A deficiency in this enzyme results in accumulation of 3-methylglutaconic acid in urine; guanidoacetic acid in urine and serum. Decreased concentrations of creatine are found in serum and urine; and creatinine in plasma, spinal fluid, and urine. Symptoms, which present at birth, include failure to thrive, mental and motor retardation, hyoptonia, and seizures. Treatment includes arginine-restricted diet, sodium benzoate, and L-ornithine hydrochlorate.

Prolidase deficiency is an autosomal recessive disorder. The enzyme prolidase cleaves iminodipeptides with N-terminal proline or hydroxyproline. Collagen has high levels of iminoacids therefore, these dipeptidases are important for collagen metabolism. A defect in this enzyme causes accumulation of imidodipeptides in urine. Symptoms include skin lesions, anemia, dysmorphism, mental retardation, and ptosis (drooping eyelid).

Metcaptolactate-cysteine disulfiduria (MCDU) is an autosomal disorder that leads to the loss of function of the enzyme mercaptopyruvate sulfurtransferase. The condition is characterized by the urinary excretion of large amounts of a sulfur-containing amino acid, which is beta-mercaptolactate-cysteine disulfide. Patients exhibit a low IQ, grand mal seizures, flattened nasal bridge, and an excessively arched palate.

Gamma-Glutamyltransferase Deficiency is an autosomal recessive disorder caused by a mutation in the GGT1 gene which codes for gamma-glutamyltranspeptidase 1. A deficiency in this enzyme results in accumulation of L-cysteine, gamma-glutamylcysteine, and glutathione in urine. Symptoms, which present at birth, include tall stature, psychosis, and mental retardation.

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

A transient defect in tyrosine metabolism is a common aminoacidopathy in the premature and full-term human infant. This disorder, termed neonatal tyrosinemia, was first described by Levine and Gordon in 1939. In the intervening years other workers have studied this disorder, and have noted the concurrence of tyrosinemia and tyrosyluria. In a current survey of 15,000 infants, 6 mild tyrosinemia occurred during the first week of life in 10% of full-term infants, and severe tyrosinemia occurred in approximately 30% of premature infants. The enzymatic basis of neonatal tyrosinemia is complex and involves the susceptibility of p-hydroxyphenylpyruvic acid oxidase to inhibition in the presence of its substrate, p-hydroxyphenylpyruvic acid and derivatives. The inhibition is reversible by removal of excess substrate and by reducing agents such as ascorbic acid, 2, 6-dichiorophenolindophenol, and a number of hydroquinone and phenylenediamine compounds.