Browsing Pathways

CCarbamoyl Phosphate Synthetase Deficiency, also called hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the urea cycle caused by a defective CPS1 gene. The CPS1 gene codes for the protein carbamoyl phosphate synthetase I, which plays a role in the urea cycle. This disorder is characterized by a large accumulation of ammonia in the blood. Symptoms of the disorder include unusual movements, seizures, unusual sleeping or coma. Treatment with citrulline or arginine, which maintains a regular rate of protein creation. It is estimated that carbamoyl phosphate synthetase deficiency affects 1 in 800,000 individuals in Japan.

Congenital sucrase-isomaltase deficiency is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by mutatins in the SI gene which encodes for the enzyme sucrase-isomaltase. Sucrase-isomaltase catalyzes the breakdown of sucrose, maltose and larger carbohydrates. Sucrose and maltose are disaccharides, and are broken down into simple sugars during digestion. Sucrose is broken down into glucose and fructose, while maltose is broken down into two glucose molecules. This disorder is characterized by stomach cramps, bloating, excess gas production, and diarrhea after ingestion of sucrose and maltose. These digestive problems can lead to failure to thrive and malnutrition. There is no cure for Sucrase-Isomaltase Deficiency, however orally administrated Sacrosidase can help relieve symptoms. Similarly, restricting high sugar diets can also help. Most affected children are better able to tolerate sucrose and maltose as they get older. Frequency of Sucrase-Isomaltase Deficiency is about 1 in 5,000 with European descent. 

Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the steps of biosynthesis of cortisol from cholesterol in the adrenal glands, also known as steroidogenesis. 21-hydroxylase deficiency, also known as CYP21 deficiency or CAH1, is an autosomal recessive disorder that accounts for the vast majority of cases of CAH. This deficiency affects cells in the adrenal cortex of the adrenal glands, and due to the deficiency in an enzyme used in many pathways. This prevents the completion of several hormone biosynthesis pathways, including those producing aldosterone and cortisol, and leads to a buildup of their precursors, including 17a-hydroxypregnenolone, which are then processed by the pathways that produce androgen hormones including testosterone. This disorder can vary in severity, depending on the amount of functional enzyme present. The most severe form is known as the salt-wasting form of 21-hydroxylase, and is caused by a complete lack of functional enzyme. This form is called the salt-wasting form, as the lack of aldosterone produced leads to high levels of sodium excreted in the urine, causing infant blood volume to decrease. High potassium levels in blood are also often observed, but if properly diagnosed, saline solution and hydrocortisone can restore normal blood levels and sodium content. In addition, males are typically visually unaffected, but females often possess ambiguous genitalia due to the excess exposure to testosterone during development. The second most severe form is known as the simple virilising form, which does not involve the salt loss of the salt-wasting form, due to a partially functional 21-hydroxylase enzyme. However, the androgen hormones build up similarly, leading to females with some amount of virilisation, or some amount of male characteristics, including ambiguous genitalia. The third and least severe form, known as the non-classical or late onset form, has the highest function in 21-hydroxylase enzymes, and leads to the smallest buildup of androgen hormones. This means that females exhibit little to no virilisation at birth, but as they age can experience male-associated hair growth and baldness, as well as decreased fertility and menstruation irregularities. It can also lead to an early puberty in both males and females, though treatment can help prevent this if it is caught in time.

Adrenal hyperplasia type 3, also called Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, is caused by a defect in the CYP21A2 gene which codes for Steroid 21-hydroxylase (21-hydroxylase). Steroid 21-hydroxylase catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone. A defect in this enzyme results in accumulation of 17-Hydroxyprogesterone, progesterone and 17a-Hydroxypregnenolone, androstenedione, and testosterone; decreased levels of cortexolone, deoxycorticosterone, aldosterone and cortisol. Symptoms include salt-wasting crises in infancy due to the lack of aldosterone, like spitting, poor weight gain, vomiting, severe dehydration, and circulatory collapse. The high level of testosterone results in virilization and genital ambiguity of female infants.

Non Ketotic Hyperglycinemeia (Glycine encephalopathy; Glycine cleavage system deficiency; NKH) is caused by mutations in several genes in the mitochondrial glycine cleavage system. These include the genes encoding P protein (GLDC), T protein (GCST), and, in one case, the H protein (GCSH). Most patients with GCE (Glycine Encephalopathy, or NKH) have a defect in the GLDC gene.The enzyme system for cleavage of glycine (glycine cleavage system), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). NKH is characterized by accumulation of glycine in plasma, spinal fluid and urine. Symptoms include seizures, respiratory distress, mental retardation, chorea, visual impairment and hydrocephalus.

Pyruvate Dehydrogenase (PDH) Deficiency is an X linked disease where individuals have a reduced number of functioning PDH complexes ultimately affecting the mitochondria’s energy metabolism. In a healthy individual, PDH complex catalyzes the conversion of pyruvate to acetyl coenzyme A, therefore PDH deficiency can cause the accumulation of excess pyruvate and lactic acid. PDH deficiency presents itself in a variety of ways, however since the brain obtains most of it’s energy from aerobic oxidation of glucose, all PDH deficient individuals have some degree of neurological impairment. Other symptoms range from fatal lactic acidosis in the newborns, chronic neurodegenerative conditions, brain lesions, cerebral atrophy and much more. Due to the fatal nature of the disease many with this condition do not live past childhood, however there are some that survive to adolescents and adulthood. Treatments have tried to minimize systemic lactic acid accumulation by feeding patients high fat/low carbohydrate diets. However, this does not reverse neurological structural damage already present and therefore does little to influence the end results.

Congenital lactic acidosis, also known as CLA, is an inherited inborn error of metabolism (IEM) characterized by the build-up of lactic acid in the body (lactic acidosis). The incidence of congenital lactic acidosis is unknown. One estimate places the incidence at 250-300 live births per year in the United States. CLA is typically caused by a mutation in the genes encoding the pyruvate dehydrogenase complex (PDC) leading to deficiencies in the function and efficiency of pyruvate dehydrogenase complex proteins, which are located in the mitochondria. Collectively the PDC converts pyruvate, NAD+, coenzyme A into acetyl-CoA, CO2, and NADH. While CLA-associated defects have been identified in all 3 enzymes of the PDC complex, the E1-alpha subunit is the most commonly mutated form. Defects in the citric acid cycle due to PDC deficiency deprives the body of energy and leads to an abnormal build-up of lactic acid in tissues and biofluids. CLA has either an autosomal recessive or X-linked mode of inheritance. There are two forms of CLA: severe and mild. Severe cases of CLA manifest in the neonatal period while milder cases may not manifest until early adulthood. Symptoms may be persistent or brought on by an event causing stress, such as an asthma attack, seizure, or infection. Symptoms in the neonatal form of CLA include hypotonia, lethargy, vomiting, and tachypnea. As the disease progresses, it can cause developmental delays, cognitive disabilities, abnormal development of the face and head, and organ failure. Treatments for CLA that are occasionally used include the ketogenic diet and dichloroacetate.

GM2 gangliosidosis varient B or Tay-Sachs disease(TSD) is a neurodegenerative disorder which causes death in infantiles by age 5. Symptoms of TSD are present within 6 months of birth and include lack of motor development, mental retardation, seizures, and ultimately death. TSD is caused by the accumulation of GM2 gangliosides. Hexosaminadase A is the enzyme responsible for the degradation of GM2 gangliosides. It is a heterodimer made an alpha and beta subunit. The deficiency of this enzyme leads to the accumulation of GM2 gangliosides in neuronal lysosomes, eventually leading to cell death

Ribose-5-phosphate isomerase (RPI) deficiency, is a genetic disorder caused by mutations in the RPIA gene that codes for RPI. RPI is an enzyme that is involved in the pentose phosphate pathway as part of carbohydrate degradation. It reversibly converts D-ribulose 5-phosphate into D-ribose 5-phosphate. In the case of this disorder, RPI functions partially in tissues, because if the gene was simply non-functional, it would likely be lethal. This means that a specific type of mutation needs to occur for this disorder to occur, leading to it being the rarest disease in the world, with only three confirmed cases. In the first known case, the patient had one allele containing a frameshift mutation, which led to a truncated protein, while the other allele contained a missense mutation. This combination meant that activity of RPI was found to vary across tissues and cell types. Characteristics of the RPI deficiency include higher ribitol and arabitol levels in a metabolic profile, as well as differences in polyol profiles. There are other symptoms, including leukoencephalopathy and neuropathy, which may be caused by a toxic accumulation of ribitol and arabitol, or a potential lack of ribose-5-phosphate in RNA synthesis.

3-Methylcrotonyl-Coenzyme A Carboxylase Deficiency Type I also called 3-MCC Deficiency is a rare inborn error of metabolism (IEM) and is the result of defective pair of genes. More specifically defects in genes MCCC1 and MCCC2 cause 3-MCC Deficiency. 3-MCC has a very important role in protein metabolism in the body. In particular, the said enzyme is pivotal in one of the many steps which constitute the breakdown of leucine. Mutations in the aforementioned genes leads to a reduction in the activity of 3-MCC. As would naturally be expected, this causes the body to be unable to uptake and breakdown leucine properly. Consequently, this leads to the build up of toxic byproducts which are not processed as the breakdown of leucine is left incomplete. If these toxic byproducts manifest themselves in sufficiently high levels they can be very harmful, damaging the brain and nervous system. Symptoms include recurring episodes of vomiting and diarrhea, lethargy, hypotonia, seizures, and coma.