Browsing Pathways

Maple syrup urine disease, also called BCKD deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective BCKDHA, BKCDHB or DBT gene. These genes code for a protein which is vital in the breakdown of amino acids, specifically the amino acids leucine, isoleucine and valine. This disorder is characterized by a large accumulation of these amino acids in the body. Symptoms of the disorder include a distinct maple syrup smell of the urine, vomiting, lethargy, abnormal movements and delayed development. Treatment includes long-term dietary management which aims to restrict the consumption of branched-chain amino acids. It is estimated that maple syrup urine disorder affects 1 in 185,000 infants globally. This number increases significantly when looking specifically at Old World Order Mennonites, where the prevalence is 1 in 380 infants.

The autosomal recessive disorder Smith-Lemli-Opitz Syndrome (SLOS; SLO Syndrome; RSH; Rutledge Lethal Multiple Congenital Anomaly, Syndrome; Polydactyly, Sex Reversal, Renal Hypoplasia, and Unilobar Lung; Lethal Acrodysgenital Syndrome) is characterized by disordered steroid biosynthesis. It results from a mutation in the DHCR7 gene coding for the enzyme sterol delta-7-reducatase. This enzyme catalyzes the production of cholesterol by reducing the C7-C8 double bond of 7-dehydrocholesterol (7-DHC). SLOS causes the accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol, and a decrease of cholesterol in plasma; and 3-methylglutaconic acid in urine. All patients with SLOS have mental retardation, and symptoms include ambiguous genitalia, hypotonia, microcephaly, syndactyly, limb abnormalities and deformities and polydactyly.

Fructose-1,6-bisphosphatase deficiency (FBP1D) is an autosomal recessive inborn error of metabolism (IEM) caused by a mutation in the FBP1 gene which encodes for fructose-1,6-bisphosphatase-1. This enzyme is responsible for catalyzing the conversion of fructose 1,6-bisophosphate into fructose 5-phosphate by removing a phosphate group from it as part of the gluconeogenesis pathway. FBP1D is characterized by hypoglycemia and acidosis after fasting, caused by the impairment of gluconeogenesis. Symptoms can also include hyperventilation. Treatment includes feeding more often with foods enriched with glucose, as well as avoiding foods high in fructose and sucrose, as well as avoiding fasting for longer than overnight. It is estimated that FBP1D affects between 1 in 350,000 and 1 in 900,000 individuals.

Glycogenosis, Type IA, also called Von Gierke Disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder and caused by a defective glucose-6-phosphatase. Glucose-6-phosphatase catalyzes the conversion of glucose 6-phosphate into D-glucose and conversion of D-glucose to glucose 6-phosphate. Symptoms of the disorder include hypoglycemic seizures, lactic acidosis, hyperuricemia, etc. Treatment with diet management is very effective.

Adenylosuccinate Lyase Deficiency. (Adenylosuccinase Deficiency ; Adenylosuccinate monophosphate lyase deficiency) is a rare autosomal recessive disease caused by a mutation in the ADSL gene which codes for adenylosuccinate lyase. A deficiency in this enzyme results in accumulation of succinyladenosine in plasma, spinal fluid, and urine. Symptoms, which present at birth, include hyptonia, seizures, mental retardation, and encephalopathy. Treatment includes allopurinol.

Glycine N-methyltransferase deficiency, also called GNMT deficiency, is an autosomal recessive disorder of methionine metabolism caused by a defective glycine N-methyltransferase (GNMT). GNMT catalyzes the conversion of glycine into N-methylglycine (sarcosine) using S-adenosylmethionine (SAM or AdoMet). This disorder is characterized by a large accumulation of methionine in the plasma and transaminases in the serum. Symptoms of the disorder include hepatomegaly.

Krabbe disease, also called globoid cell leukodystrophy, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. Krabbe disease is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). Krabbe disease is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for Krabbe disease: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile Krabbe disease usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.

2-Aminoadipic 2-oxoadipic aciduria is a disorder of lysine metabolism caused by a defective DHTKD1 gene. DHTKD1 is predicted to code for a component of a supercomplex similar to the 2-oxoglutarate dehydrogenase complex (OGDHc) which catalyzes the conversion of 2-oxoadipate into glutaryl-CoA. This disease is characterized by a large accumulation of 2-oxoadipate and 2-hydroxyadipate in the urine. Symptoms of the disease include mild to severe intellectual disability, developmental delay, ataxia, muscular hypotonia, and epilepsy. However, most cases are asymptomatic.

Leigh Syndrome, also called Leigh Disease or infantile subacute necrotizing encephalopathy, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder that is caused by a mutation of any one of 75 different genes. Disruptions of the complexes I or IV are the most common reasons for Leigh syndrome. Complex IV is crucial in the electron transfer steps of oxidative phosphorylation, which is needed to provide energy to the mitochondria. This disorder is characterized by a large accumulation of lactate in the body. Symptoms of the disorder include diarrhea, dysphagia and vomiting. There is no cure for Leigh syndrome and the loss motor skills degenerate rapidly. It is estimated that Leigh syndrome affects 1 in 40,000 individuals.

Argininosuccinic Aciduria, (Argininosuccinase Deficiency, Argininosuccinate Lyase Deficiency, ASL Deficiency) is an autosomal recessive disorder caused by a mutation in the ASL gene which codes for argininosuccinate lyase. It results in accumulation of citrulline, arginosuccinic acid, L-arginine, and L-glutamic acid in plasma as well as ammonia in blood. Infants are lethargic and unwilling to eat. They may develop seizures, coma, and failure to thrive as toxic ammonia accumulates.