Galactosemia is an inherited defect of galactose metabolism caused by an enzyme deficiency that prevents proper metabolism and utilization of galactose, or milk sugar. The main dietary source of galactose is lactose, the principle carbohydrate found in all forms of milk.
Hartnup disease is a rare genetic disorder of amino acid transport, presenting intermittent and variable clinical abnormalities. Originally described in the Hartnup family in London in the late 50’s, this entity became increasingly more studied in the recent years. The original patients presented a pellagra-like rash but failed to provide any evidence of dietary tryptophan insufficiency. Upon chromatography of the urine from the original patients, more than 14 amino acids were found in excess, pointing out to the most likely pathogenic mechanism : failure of some amino acids transport system at the renal level.
Wilson's disease, also called hepatolenticular degeneration, is a rare autossomal recessive inherited disease. It is primarly caused by an acumulation of copper in tissues all over the body, mainly in the liver, brain, kidneys and cornea.
Homocystinuria is an inherited autosomal recessive defect in methionine metabolism that is caused by a deficiency in cystathionine synthase. This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life
Histidinemia is an autosomal recessive metabolic disorder characterized by increased levels of histidine in blood, urine, and cerebrospinal fluid, and decreased levels of the metabolite urocanic acid in blood, urine, and skin cells. Although histidinemia was originally associated with mental retardation and speech defects, it is generally considered to be a benign disorder (Levy et al., 2001). However, it is possible that histidinemia may be a risk factor for developmental disorders in certain individuals under specific circumstances, such as perinatal events

Leigh's disease is a rare inherited neurometabolic disorder characterized by degeneration of the central nervous system. Leigh's disease can be caused by mutations in mitochondrial DNA or by deficiencies of an enzyme called pyruvate dehydrogenase. Symptoms of Leigh's disease usually begin between the ages of 3 months to 2 years and progress rapidly. In most children, the first signs may be poor sucking ability and loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function. Heart problems may also occur. In rare cases, Leigh's disease can begin during late adolescence or early adulthood and progress more slowly.

The most common treatment for Leigh's disease is thiamine or Vitamin B1. In patients who have a deficiency of pyruvate dehydrogenase enzyme complex, a high-fat, low-carbohydrate diet may be recommended. Oral sodium bicarbonate or sodium citrate may also be prescribed to manage lactic acidosis. Experimental protocols are currently using dichloroacetate to treat patients with lactic acidosis.

Lesch-Nyhan syndrome (LNS) is a rare, inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).LNS is an X-linked recessive disease-- the gene is carried by the mother and passed on to her son. LNS is present at birth in baby boys. The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to symptoms such as severe gout, poor muscle control, and moderate retardation, which appear in the first year of life. A striking feature of LNS is self-mutilating behaviors – characterized by lip and finger biting – that begin in the second year of life. Abnormally high uric acid levels can cause sodium urate crystals to form in the joints, kidneys, central nervous system, and other tissues of the body, leading to gout-like swelling in the joints and severe kidney problems. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.
Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol

Fucosidosisis a very rare lysosomal storage disorder belonging to the group of oligosaccharidoses or glycoproteinoses. Less than 100 cases have been documented (20 of them in Southern Italy). Clinical signs include facial dysmorphism, dysostosis multiplex, moderate hepatomegaly, severe intellectual deficit , deafness, and according to age, angiokeratomas. Every intermediate form exists, ranging from severe (type 1: onset between 3 and 18 months of age) to moderate (type 2, with a slower progression). It is caused by an alpha-L-fucosidase deficiency, responsible for generalized accumulation of fucose-containing glycolipids and oligosaccharides in body tissues. Transmission is autosomal recessive.

Fabry disease is caused by the lack of or faulty enzyme needed to metabolize lipids, fat-like substances that include oils, waxes, and fatty acids. The enzyme is known as ceramide trihexosidase, also called alpha-galactosidase-A. A mutation in the gene that controls this enzyme causes insufficient breakdown of lipids, which build up to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system. Since the gene that is altered is carried on a mother’s X chromosome, her sons have a 50 percent chance of inheriting the disorder and her daughters have a 50 percent chance of being a carrier. Symptoms usually begin during childhood or adolescence and include burning sensations in the hands that gets worse with exercise and hot weather and small, raised reddish-purple blemishes on the skin. Some boys will also have eye manifestations, especially cloudiness of the cornea. Lipid storage may lead to impaired arterial circulation and increased risk of heart attack or stroke. The heart may also become enlarged and the kidneys may become progressively involved. Other symptoms include decreased sweating, fever, and gastrointestinal difficulties, particularly after eating. Some female carriers may also exhibit symptoms. Fabry disease is one of several lipid storage disorders.
Enzyme replacement may be effective in slowing the progression of the disease. The pain in the hands and feet usually responds to anticonvulsants such as phenytoin and carbamazepine. Gastrointestinal hyperactivity may be treated with metoclopramide. Some individuals may require dialysis or kidney transplantation.

Sandhoff diseaseis a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease

Tay-Sachs disease lack a vital enzyme, hexosaminidase A (Hex-A). Hex-A is needed for the body to break down a fatty waste substance found in brain cells. Without Hex-A, this substance accumulates abnormally and causes progressive damage until the nervous system can no longer sustain life.

A baby with Tay-Sachs disease appears healthy at birth, and seems to be developing normally for a few months. Symptoms generally appear by six months of age. While symptoms vary from one child to the next, there is always a slowing down of development. Gradually, Tay-Sachs children lose motor skills and mental functions. Over time, the child becomes blind, deaf, mentally retarded, paralyzed and non responsive to the environment. Tay-Sachs children usually die by age five.

Tay-Sachs is an inherited disease that only occurs when both parents carry a Tay-Sachs gene and each parent transmits the defective gene to their child. A child who inherits two Tay-Sachs genes (one from each parent) produces no functional Hex-A enzyme and is certain to develop Tay-Sachs disease

Niemann-Pick disease (NP) refers to a group of inherited metabolic disorders known as the leukodystrophies or lipid storage diseases in which harmful quantities of a fatty substance (lipids) accumulate in the spleen, liver, lungs, bone marrow, and the brain. Symptoms may include lack of muscle coordination, brain degeneration, learning problems, loss of muscle tone, increased sensitivity to touch, spasticity, feeding and swallowing difficulties, slurred speech, and an enlarged liver and spleen. There may be clouding of the cornea and a characteristic cherry-red halo develops around the center of the retina. The disease has 4 related types. Type A, the most common type, occurs in infants. It is characterized by jaundice, an enlarged liver, and profound brain damage. Children with this type rarely live beyond 18 months. Type B involves an enlarged liver and spleen, which usually occurs in the pre-teen years. The brain is not affected. In types A and B, insufficient activity of an enzyme called sphingomyelinase causes the build up of toxic amounts of sphingomyelin, a fatty substance present in every cell of the body. Types C and D may appear early in life or develop in the teen or adult years. Affected individuals have only moderate enlargement of the spleen and liver, but brain damage may be extensive and cause an inability to look up and down, difficulty in walking and swallowing, and progressive loss of vision and hearing. Types C and D are characterized by a defect that disrupts the transport of cholesterol between brain cells. Type D usually occurs in people with an ancestral background in Nova Scotia.
There is currently no effective treatment for persons with type A. Bone marrow transplantation has been attempted in a few patients with type B, and encouraging results have been reported. The development of enzyme replacement and gene therapies might also be helpful for those with type B. Individuals with types C and D are frequently placed on a low-cholesterol diet, but its clinical benefit is not convincing
Maple syrup urine disease (MSUD) is an aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration in the infant who is not treated for MSUD. Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development. Consequently, MSUD has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with MSUD have a better outcome compared with infants who are diagnosed after they become symptomatic.
MELAS syndrome is one of a group of rare muscular disorders that are called mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material arises from a part of the cell structure that releases energy (mitochondria) resulting in disease of the brain and muscles (encephalomyopathies). This mitochondrial defect and a condition known as "ragged red fibers" (an abnormality of muscle tissue when viewed under a microscope) are typically present. The most characteristic symptom of MELAS syndrome is recurring, stroke-like episodes in which sudden headaches are followed by vomiting and seizures. Short stature, an accumulation of lactic acid in the blood (lactic acidosis), and muscular weakness on one side of the body (hemiparesis) are typically present. Visual symptoms may include impaired vision or blindness in one half of the visual field (hemianopsia) and/or blindness due to lesions in the area of the brain concerned with vision (cortical blindness). Although the exact cause of MELAS syndrome is not fully understood, it has been found to run in families (familial).
Wernicke encephalopathy is a serious disorder caused by thiamine (vitamin B-1) deficiency. Dr Carl Wernicke, a Polish neurologist, described it in 1881 as a triad of acute mental confusion, ataxia, and ophthalmoplegia. Korsakoff amnestic syndrome is a late neuropsychiatric manifestation of Wernicke encephalopathy with memory loss and confabulation; hence, the condition is referred to as Wernicke-Korsakoff syndrome or psychosis. It is most often seen in alcoholics, but it can be seen in disorders associated with malnutrition and also in patients on long-term hemodialysis or with AIDS. The disease is frequently unrecognized and is likely more prevalent than commonly supposed.

Korsakoff's syndrome is caused by lack of thiamine (vitamin B1), which affects the brain and nervous system. Excessive use of alcohol is often the cause of thiamine deficiency. This is because:
  • Many heavy drinkers have poor eating habits. Their nutrition is inadequate and will not contain essential vitamins.
  • Alcohol can inflame the stomach lining and impede the body's ability to absorb the key vitamins it receives.
Korsakoff's syndrome may also occur in other conditions where there is severe malnutrition, but this is extremely rare.
Korsakoff's is part of the Wernicke-Korsakoff syndrome, which consists of two separate but related stages: Wernicke's encephalopathy and Korsakoff's psychosis. However, not all cases of Korsakoff's are preceded by an episode of Wernicke's. Another term for Korsakoff's is 'alcohol amnestic syndrome', amnestic meaning loss of memory
Reye's (pronounced "rye") syndrome is a disease which is believed to be caused by the ingestion of medicines (such as aspirin) that contain salicylate (pronounced "sa(LISS(a(late") that affects all organs of the body, but affects the liver and brain most lethally. It occurs when abnormal accumulations of fat develop in the liver and other organs of the body, along with a severe increase of pressure in the brain. It affects mostly children and teenagers and appears soon after flu-like infection or chicken pox. Reye's syndrome occurs most frequently during the months of January, February and March when influenza is most common, although cases have been reported throughout the year
3-alpha-methylcrotonylglycinuria is an inborn error of leucine catabolism due to a deficiency of 3-methylcrotonyl-CoA carboxylase. As the enzyme requires biotin as a cofactor, the isolated enzymatic defect must be differentiated from other forms of methylcrotonylglycinuria caused by deficiencies in the biotin pathway (biotinidase and holocarboxylase synthetase deficiencies). The disease has a wide range of manifestations, from severe metabolic crisis with ketoacidosis and vomiting—leading, without appropriate treatment, to coma and death—to no symptoms throughout life. The key metabolites leading to diagnosis are 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in urine and 3-hydroxyisovalerylcarnitine in plasma.

tyrosinemia Blood tyrosine levels are elevated in several clinical entities was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was given at a time when specific enzymatic diagnosis was unavailable, and the world is left with a clinical description that has not been duplicated in the 50 years since its publication.
Transient tyrosinemiais believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and disappears spontaneously with no sequelae. Because it is not caused by a genetic mutation, transient tyrosinemia is not categorized as an inborn error of metabolism.
Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbage-like) odor, renal tubular dysfunction (Fanconi syndrome), and survival of <12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Occasional patients have a later onset, usually at <6 months, and a somewhat protracted course.
PKU (phenylketonuria) is an inherited disorder of body chemistry that, if untreated, causes mental retardation. Fortunately, through routine newborn screening, almost all affected newborns are now diagnosed and treated early, allowing them to grow up with normal intelligence.

About 1 baby in 14,000 is born with PKU in the United States. The disorder occurs in all ethnic groups, although it is more common in individuals of Northern European and Native American ancestry than in those of African-American, Hispanic and Asian ancestry.

Due to a missing or deficient enzyme, children with PKU cannot process a part of the protein called phenylalanine, which is present in nearly all foods. Without treatment, phenylalanine builds up in the bloodstream and causes brain damage and mental retardation.

Ornithine transcarbamylase (OTC) deficiency is the most common of the urea cycle disorders. The muted enzyme protein results in the impairment of the reaction that leads to condensation of carbamyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes symptomatic Hyperammonemia. The gene for this enzyme is normally expressed in the liver and is intramitochondrial.

Menkes Disease is caused by a defective gene that regulates the metabolism of copper in the body. Because it is an X-linked gene, the disease primarily affects male infants. Copper accumulates at abnormally low levels in the liver and brain, but at higher than normal levels in the kidney and intestinal lining. Affected infants may be born prematurely. Symptoms appear during infancy. Normal or slightly slowed development may proceed for 2 to 3 months, and then there will be severe developmental delay and a loss of early developmental skills. Menkes Disease is also characterized by seizures, failure to thrive, subnormal body temperature, and strikingly peculiar hair, which is kinky, colorless or steel-colored, and easily broken. There can be extensive neurodegeneration in the gray matter of the brain. Arteries in the brain can also be twisted with frayed and split inner walls. This can lead to rupture or blockage of the arteries. Weakened bones (osteoporosis) may result in fractures.
Early treatment with subcutaneous (under the skin) or intravenous (in a vein) injections of copper supplements may be of some benefit. Other treatment is symptomatic and supportive.

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