Browsing Pathways

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. 

Mucopolysaccharidosis type VII (MPS VII), also called Sly syndrome, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by mutations in the GUSB gene. This gene encodes for the beta-glucuronidase enzyme, which normally breaks down glycosaminoglycans (GAGs). However, without beta-glucuronidase, accumulation of GAGs in cells specifically the lysosome increases. The increase in cell size causes tissues and organs to become enlarged as well. This disorder is characterized by macrocephaly, a buildup of fluid in the brain, characteristic facial features, and a large tongue. Other symptoms may include hepatosplenomegaly, heart valve abnormalities, and umbilical or inguinal hernias. MPS VII also causes various skeletal abnormalities, including joint issues and decreased growth. Treatments such as enzyme replacement therapy are still fairly new, however traditionally treatments for Mucopolysaccharidosis VII included symptom relief such as surgery. It is estimated that MPS VII affects 1 in 250,000 individuals.

Glycogen storage disease type VI, also called GSDVI or Hers disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective liver glycogen phosphorylase. Liver glycogen phosphorylase catalyzes the conversion of glycogen into amylose which is substrate of 1,4-alpha-glucan-branching enzyme and glycogen debranching enzyme. The disorder may show as enlarged liver in infancy to early childhood. Treatment may not required for some individuals. Glycogen storage disease type VI has been reported in approximately 11 people at least.

Glycogen storage disease type IV, also called GSD IV, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective 1,4-alpha-glucan-branching enzyme. 1,4-alpha-glucan-branching enzyme catalyzes the conversion of amylose into glycogen which is essential component for cells to build up bodies. Symptoms of the disorder happen mainly in infants, which include failure to thrive, loss weight, enlarged liver and spleen, etc. Treatment with strict dietary therapy is effective in some cases. It is estimated that GSD IV affects 1 in 600,000 to 800,000 individuals worldwide.

Glycogen storage disease type III, which is also known as GSD III or Cori disease, is a rare inherited inborn error of metabolism (IEM). GSD-III has an incidence of about 1 in 100 000. The incidence of GSD-III is higher in North African Jews (1 in 5 400), Faroese (1 in 3 100) and the Inuit population in Nunavik, Canada (1 in 2 500). GSDIII is an autosomal recessive metabolic disorder characterized a deficiency in glycogen debranching enzymes, specifically the enzyme amylo-1,6 glucosidase. GSD III causes a buildup of a complex sugar called glycogen in the body's cells. The accumulated glycogen is structurally abnormal and impairs the function of certain organs and tissues, especially the liver and muscles. GSD III typically presents during infancy with hypoglycemia and failure to thrive. Clinical examination usually reveals hepatomegaly. Muscular disease, including hypotonia and cardiomyopathy, usually occurs later in life. GSD III is divided into the types IIIa, IIIb, IIIc, and IIId, which are distinguished by their pattern of signs and symptoms. GSD types IIIa and IIIc affect primarily the liver and muscles. This is in direct contrast to GSD types IIIb and IIId which affect only the liver. Differentiating between the types of GSD III which affect the same tissue is extremely challenging. Out of all the GSD types, IIIa and IIIb are the condition's most common forms. Treatment for glycogen storage disease type III may involve a high-protein diet, in order to facilitate gluconeogenesis.

Glycogen storage disease, also called glycogenosis and dextrinosis, is a rare inborn error of metabolism (IEM) and recessive disorder, which is caused by a defective glycogen synthase. Glycogen synthase catalyzes the conversion of uridine diphosphate glucose into amylose and uridine 5'-diphosphate which amylose is the substrate of 1,4-alpha-glucan-branching enzyme and glycogen debranching enzyme. This disorder is characterized by a large accumulation of glycogen in the liver or muscles. Symptoms of the disorder depends on the type of glycogen storage disease (e.g. GSD I, GSD III, etc.). Treatments are also depend on the type of glycogen storage disease.

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.

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.

2-Ketoglutarate dehydrogenase complex deficiency, also known as alpha-ketoglutarate dehydrogenase deficiency or oxoglutaric aciduria, is an autosomal recessive disorder of the Krebs cycle caused by a defective oxoglutarate dehydrogenase complex (OGDC). OGDC catalyzes the conversion of 2-ketoglutarate into succinyl-CoA. This disorder is characterized by a large accumulation of 2-ketoglutarate in the urine. Symptoms of the disorder include opisthotonus, ataxia, developmental delay, and seizures.

Mitochondrial complex II deficiency, which is also known as CII deficiency, is a rare form of an inherited inborn error of metabolism (IEM). CII deficiency is an autosomal recessive disorder that arises from mutations in the succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD). These genes code for the mitochondrial enzyme known as succinate dehydrogenase, a multicomponent, membrane-bound enzyme, which is also known as SDH, succinate-coenzyme Q reductase (SQR), or respiratory complex II. SDH is found in the inner mitochondrial membrane and catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. SDH or complex II is assembled via the action of two assembly factors (SDHAF1 and SDHAF2). Mutations in SDHA and SDHAF1 are most commonly found in patients with CII deficiency. Because complex II is found in the mitochondria, CII deficiency is technically considered a mitochondrial disease. CII deficiency accounts for between 2%-23% of all respiratory chain deficiency diagnoses. The signs and symptoms of mitochondrial complex II deficiency can vary greatly from severe life-threatening symptoms in infancy to muscle disease beginning in adulthood. The symptoms are very much dependent on the mutations to the SDH components. SDHA gene mutations cause myoclonic seizures and Leigh’s syndrome, a severe neurological disorder that is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within 1-2 years. SDHB gene mutations can cause leukodystrophy which affects the myelin sheath, the material surrounding and protecting nerve cells. Damage to the myelin sheath slows down or blocks messages between the brain and the rest of the body, which leads to problems with movement, speech, vision, hearing, and mental and physical development. SDHAF1 gene mutations can cause severe progressive leukoencephalopathy, which is characterized by the degeneration of the white matter of the brain. Interestingly, complex II deficiency gene mutation carriers may be at an increased risk for certain cancers.