What Are Inherited Metabolic Disorders?

Genetic metabolic diseases are genetic defects in the biosynthesis of certain enzymes, receptors, vectors, and membrane pumps composed of polypeptides and / or proteins necessary to maintain normal metabolism of the body, that is, mutations in the genes encoding such polypeptides (proteins) And cause illness. Also known as genetic metabolism abnormality or inborn metabolic defect.

Genetic metabolic diseases are a class of genetic diseases with defective metabolic functions, mostly single-gene genetic diseases, including metabolic macromolecular diseases: including lysosomal storage disease (more than thirty diseases), mitochondrial disease, etc., and small metabolism. Molecular diseases: amino acids, organic acids, fatty acids, etc. Part of the cause of genetic metabolic disease is caused by genetic inheritance, and part of it is caused by acquired genetic mutation. The onset period is not only newborns, but also covers all ages.

Causes of genetic metabolic diseases

The cause of the genetic metabolic disease is located at 13q14.3. The pathogenesis is unknown so far. The basic metabolic defect is that the liver cannot normally synthesize plasma ceruloplasmin, and the binding force between copper and ceruloplasmin decreases, so that copper is excreted from the bile. The amount is reduced. The human ceruloplasmin gene is located at 3q23-25, and its gene mutations are related to the disease. At present, six frameshift mutations have been found to cause the dysfunction of the ceruloplasmin that encodes the protein to fail to bind to copper. Copper is one of the trace elements necessary for the human body. Many important enzymes required for human metabolism, such as peroxidase dismutase, cytochrome C oxidase, tyrosinase, lysine oxidase and aerocin, etc. Requires copper ions to participate in the synthesis. However, too much copper in the body and high concentrations of copper can cause cell damage and necrosis, leading to damage to organ function. Its cytotoxicity may be caused by the excessive combination of copper with proteins and nucleic acids, or oxidation of lipids of various membranes, or the generation of excessive oxygen free radicals, which damages mitochondria and lysosomes of cells.

Clinical manifestations of genetic metabolic disease

Nervous system abnormality, metabolic acidosis and ketosis, severe vomiting, liver enlargement or liver insufficiency, special smell, weird appearance, skin and hair abnormalities, eye abnormalities, deafness, etc. Most genetic metabolic diseases are accompanied by neurological abnormalities In the neonatal period, patients with acute encephalopathy may develop acute encephalopathy, causing severe complications such as dementia, cerebral palsy, and even coma and death.

Urine

Abnormal odor and repeated positive ketones suggest the possibility of metabolic defects; -keto acids in urine can be tested with 2,4-dinitrophenylhydrazine (DNPH) method to determine the possibility of organic aciduria.

2. Hypoglycemia

Hypoglycemia in neonates can be caused by ingestion of certain ingredients in human food, it can be due to inherent metabolic defects that cannot maintain blood glucose levels, or due to the combined effect of two factors. When neonatal hypoglycemia occurs after eating, the effect of glucose supplementation is not obvious; or accompanied by significant severe ketosis and other metabolic disorders; or frequent episodes, all suggest the possibility of hereditary metabolic defects, the following should be considered:

(1) Endocrine deficiency, such as glucagon deficiency, multiple pituitary hormone deficiency (hypophyseal hypoplasia), primary adrenal cortex or medulla dysfunction, etc., and excessive endocrine such as Beckwith-Wiedemann syndrome, islet cytosis;

(2) Hereditary carbohydrate metabolism defects such as type I glycogen accumulation disease, fructose intolerance, galactosemia, glycogen synthase deficiency, and fructose 1,6-bisphosphatase deficiency;

(3) Hereditary amino acid metabolism defects such as maple syrup, propionate; methylmalonate, tyrosine, etc. Patients with acute hypoglycemia, clinical symptoms such as high-pitched crying, cyanosis, decreased muscle tone, temperature rise, irregular breathing, vomiting, convulsions, coma and other symptoms; those with hidden onset are mainly poor response, lethargy, antifeeding .

3. Hyperammonemia

In addition to liver failure caused by neonatal sepsis and hepatitis, hyperammonemia in the neonatal period is often caused by genetic metabolic diseases, and the onset is mostly rapid. The child was normal at birth and gradually developed drowsiness, antifeeding, vomiting, hypotonia, moaning breathing, convulsions and coma, and even death after feeding for several days. Sometimes alternate limb rigidity and abnormal movements can be seen. Many metabolic defects can lead to hyperammonemia. Those who are caused by a deficiency of urea cycle enzymes are often accompanied by mild acidosis; and those with branched-chain amino acid metabolism disorders are accompanied by moderate and severe metabolic acidosis.

Genetic metabolic disease test

1. Types of genetic metabolic diseases

There are many kinds of inborn defects related to the synthesis, metabolism, transport and storage of various biochemical substances in the body. According to the involved biochemical substances, they can be divided into the following categories:

(1) Macromolecules Lysosomal storage disease mainly includes: Gaucher disease, Fabry disease (Fabry disease), metachromatic leukodystrophy, spherical cell leukodystrophy, and GM1 ganglioside storage Edema, GM2 black dementia (Tay-Sachs disease), Sanhoff disease, Niemann-Pick disease, glycogen storage disease type II (pompe), fucoid storage disease, mannoside storage disease, - Mannosidemia, aspartyl glucosamine, MPS, MPS, MPSA, MPSB, MPSC, MPSD, MPSIVA, MPSB, MPS, MPS, MPSIX, ML and , NCL infant type, NCL advanced infant type, Farber Disease, sialic acid storage disease, Wolman disease, etc. Mitochondrial diseases Mainly include: Maternal genetic Leigh syndrome, mitochondrial myopathy, multisystem diseases: cardiomyopathy, progressive extraocular muscle paralysis, Leer hereditary optic neuropathy, mitochondrial myopathy, myopathy, diabetes and deafness, ataxia Dance disease, extracellular matrix chronic migratory erythema, progressive extraocular muscle palsy, mitochondrial anemia, MERRF-mitochondrial myopathy, myoclonus (epilepsy), mitochondrial encephalomyopathy, MERRF, mitochondrial myopathy, Ataxia complicated with pigmented retinitis, familial bilateral striatum necrosis, ataxia combined with pigmented retinitis, familial bilateral striatum necrosis, skeletal muscle lysis, sudden infant death syndrome.

(2) Small molecules Defects in glucose metabolism Galactosemia, fructose intolerance, glycogen accumulation disease, sucrose and isomalt intolerance, lactic acid and pyruvate poisoning, etc. Defects in amino acid metabolism Phenylketonuria, tyrosinemia, melanuria, albinism, maple syrup, isovalerate, homocysteineuria, congenital hyperammonemia, hyperglycemia Wait. Lipid metabolism defects such as adrenal white matter dystrophy, GML ganglioside disease, GM2 ganglioside disease, lack of medium chain fatty acid acyl-CoA dehydrogenase, Nieman Pick's disease, and Gaucher's disease. metal metabolism diseases such as hepatolenticular degeneration (wilton disease) and Menkes disease.

2. Metabolic disorders of genetic metabolic diseases

The metabolic disorder of this disease is manifested in the following aspects:

(1) Lack of end-products of metabolism, insufficient synthesis of products required by normal human body, or complete inability to synthesize, corresponding symptoms appear clinically, such as glycogen accumulation deficiency of glucose-6-phosphatase, insufficient glycogen breakdown of liver glycogen, Hypoglycemia when hungry or delayed eating.

(2) The accumulation of intermediate and / or bypass metabolites in the affected metabolic pathways causes the corresponding cells and organs to enlarge, toxic reactions and metabolic disorders, such as phenylketonuria and galactosemia.

(3) The metabolic pathway is blocked, and the energy supply and functional dysfunction of the material lead to insufficient energy supply, such as glucose metabolism deficiency, congenital hyperlactic acid, etc.

3. Common symptoms and signs of genetic metabolic disease

The clinical symptoms of this disease are diverse and vary with age, and all organs of the body can be affected. Most have symptoms of nervous system involvement and digestive system symptoms, in addition to metabolic disorders, abnormal appearance, changes in hair and skin pigmentation, and special smells of urine.

Diagnosis of genetic metabolic diseases

Depends on various laboratory inspections. According to the clinical characteristics and medical history, from simple to complex, from initial screening to accurate, the corresponding experimental examination was selected.

Urine test

(1) Color and odor of urine Some metabolites are excreted in large quantities from urine, which can make urine show special color and smell. Such as urinary blue mother make urine blue; urinary black acid is blue-brown; porphyrin is red.

(2) Test of reducing substances in urine Reducing substances such as galactose, fructose, glucose, oxalic acid, and 4-hydroxyphenylpyruvate in urine can be detected, which will help further selection and inspection.

(3) Urine screening test Commonly used are ferric chloride test, dinitrophenylhydrazine (DNPH) test, nitroprusside test, and toluidine blue test.

2. Blood biochemical test

Such as blood glucose, blood electrolytes, liver and kidney function, bilirubin, blood ammonia, blood gas analysis and other items.

3. Amino acid analysis

Blood and urine amino acid analysis can be performed, and the indications are:

(1) Patients in the family who have been diagnosed with hereditary metabolic disease or patients with similar symptoms;

(2) Those who are highly suspected of deficiencies in amino acid and organic acid metabolism (metabolic acidosis, ketonuria, hyperammonemia, hypoglycemia, decreased blood and urinary creatinine content, urinary stones, etc.)

(3) Unexplained encephalopathy (sleepiness, convulsions, mental retardation, etc.);

(4) Monitoring of disease diet treatment.

4. Organic acid analysis

Organic acids in the human body are derived from carbohydrates; fatty acid, amino acid metabolism, diet, drugs, etc. can be analyzed by urine, plasma, cerebrospinal fluid, etc. Urine is the most commonly used. Its indications are roughly the same as amino acid analysis:

(1) Unexplained metabolic abnormalities;

(2) Suspected diagnosis of organic acid or amino acid disease;

(3) Suspected of fatty acid metabolism and energy metabolism disorders;

(4) Hepatomegaly and jaundice of unknown cause;

(5) Unexplained neuromuscular diseases;

(6) Multi-system progressive damage.

Differential diagnosis of genetic metabolic disease

Antifeeding, vomiting, and diarrhea are quite common. These symptoms often occur shortly after eating. Those with persistent jaundice and growth retardation are common in crigler-Najjar syndrome, 1-antitrypsin deficiency, peroxisome disease, and bile acid metabolism disorders. , C type Niemann-Pick disease (chronic neurotype), Byler disease, etc .; fatty acid oxidation disorder and urea cycle enzyme deficiency can present Reye syndrome-like symptoms; hepatomegaly accompanied by hypoglycemia and convulsions, the author often suggests ( or ) Type) Glycogen accumulation disease and hyperinsulinemia, etc. When symptoms of liver failure (jaundice, bleeding symptoms, increased transaminase, ascites, etc.) appear, galactosemia, type I tyrosinemia, fructose intolerance should be considered And respiratory chain dysfunction, etc .; Diabetes, hypoglycemia, hyperammonemia, hyperlactic acidemia, hypertyrosinemia, hypermethionine can occur clinically in liver cell failure caused by various reasons. Conditions such as amino acidemia must be identified.

Genetic Metabolic Disease Treatment

The general principles of treatment are to reduce the accumulation of toxic substances caused by metabolic defects, to supplement normally needed substances, enzymes or to perform genetic medicine. Most genetic metabolic diseases are mainly treated with diet, and some diseases can be treated with vitamins and coenzymes. Many diseases can be effectively controlled through symptomatic treatment, and they can live, study and work normally.