Zhou Yan and Jie Shenghua Department of Infection, Wuhan Union Hospital Jie Shenghua Carbohydrate metabolism disorder Glycogen Storage Disease (GSD), also known as VonGierke’s disease, is the most common type of glycogen accumulation disease I. It is caused by congenital deficiency of glucose-6-phosphatase (G6P) in the liver, resulting in impaired glycogen catabolism or synthesis, and the liver cannot form glucose from glycogen. The liver cannot form glucose from glycogen, lactic acid and amino acids, causing fasting hypoglycemia. The disease is autosomal recessive, and the mechanism of its occurrence is that the gene encoding G6P is located on chromosome 17, and there are various mutations, with R83C and Q347X being the most common. The detection rate of R83H and R83C is high in our population. The 727G→T mutation adds a new shear site to the site, resulting in a 91 base pair (bp) deletion in exon 5 and a stop codon at 713-715 bp, leading to a shortening of the G6P protein from 357 amino acids to 211 amino acids and a decrease in enzyme activity. Other mutation sites are V338F, D38V, G68R, IVS3-58T>A, IVS4+10G>A, etc. Molecular biology assays such as PCR, DNA sequencing, PCR-restriction fragment length polymorphism and PCR-allele-specific oligonucleotide hybridization (PCR-ASO) can be used to analyze the G6P gene, among which, PCR-ASO can effectively identify the mutant alleles carried by most patients with hepatic glycogen accumulation disease. Galactosemia Galactosemia is an inborn metabolic disorder caused by the deficiency of galactose-1-phosphate uridyltransferase (Gal-1-PUT) in the process of galactose metabolism and is autosomal recessive. It is prevalent in infants, with a gene frequency of 32 per 100,000 and a population incidence of 1 per 100,000. The mechanism is that Gal-1-PUT deficiency leads to the accumulation of galactose-1-phosphate (Gal-1-p) and galactitol in the body and an increase in galactose in blood and urine. Gal-1-PUT deficiency is due to a mutation in the gene encoding chromosome 9p13. Patients are pure congeners with absent or very low enzyme activity; heterozygotes generally do not develop the disease. The parents of patients can be pure or heterozygous, and the parents of heterozygotes are carriers of the disease-causing gene and have only 50% of the normal Gal-1-PUT activity. In recent years, through the study of the characteristics of the enzyme defect, the known variants include Duarte, Black variant, Indiana, Rennes, Bern, Chicago, Los Angel and Negro. The Duarte type is the most common, with pure Duarte type having 50% of normal enzyme activity and heterozygous Duarte type having 75%, which can only be detected by population screening because they are not clinically symptomatic. There are regional variants of PUT, commonly Q188R, G1391A, K285N, IVS5-24G>A, S135L and N314D loci mutations, with Q188R predominant in Europe and S135L mostly in African-Americans. Prenatal diagnosis can be made by analyzing the enzyme activity of cultured amniotic fluid cells, if reduced Gal-1-PUT activity is found. In addition, galactokinase and uridine diphosphate galactose-4-differentiase deficiency can also cause galactosemia. Both are due to genetic defects. (1) The gene for galactokinase is located on chromosome 17q21-22, and foreign studies have shown that the frequency of heterozygotes is 1/107 in newborns and 1/40,000 in pure heterozygotes. deficiency of this enzyme directly causes an increase in galactose in the body, leading to enhanced galactose bypass metabolism and increased production of galactitol. ②The gene for uridine diphosphate-galactose-4-differentiase is located on chromosome 1p35-36 and causes an increase in galactose and galactitol in the body mainly by affecting the metabolism of galactose-1-phosphate. Once this disease is diagnosed, galactose should be excluded from the diet and replaced with soy milk. With the development of enzyme technology and cell engineering, exogenous purified enzyme therapy with long half-life, low antigenicity and good orientation can be administered to children with genetic disorders and can soon be used in clinical practice. Abnormalities in amino acid, protein and enzyme metabolism Alpha 1 Anti-trypsin Deficiency-associated Liver Disease Alpha 1-AT deficiency can lead to accumulation of trypsin in the liver, resulting in inherited metabolic liver disease, which is an autosomal commensal genetic disorder. It is an autosomal co-dominant disease. 15%-20% of neonatal liver diseases may be caused by α1-AT deficiency. The disease tends to develop in infancy or exhibit features of chronic liver disease in adulthood. Some children develop intrahepatic cholestasis in the neonatal period, which manifests as hyperbilirubinemia, increased serum alkaline phosphatase activity, and hypertransaminaseemia. In most children, intrahepatic biliary siltation persists for six months before subsiding, and if it does not improve, progressive liver damage may develop, progressing to cirrhosis. The onset in adulthood is mostly seen in heterozygous α1-AT deficiency liver disease, where patients progress relatively slowly and can also develop liver failure clinically. Studies have confirmed that the gene encoding α1-AT is located at 14q24.3-32.1, and 75 different alleles have been distinguished by isoelectric focusing electrophoresis, with abnormalities in the Z and S alleles being the most common. The alleles are iso-dominantly expressed protease inhibitor genes (Pi genes), which are polymorphic and differentially expressed in the population. PiM is a gene with normal function and the majority of normal individuals are PiMM, with normal serum α1-AT levels and function; ②PiZ is purely congenic (PiZZ). Individuals carrying PiZZ have a severe deficiency of α1-AT in serum, only about 15% of normal individuals, and E342K and F51L are mutated loci, which can clinically lead to obstructive lung disease and juvenile cirrhosis; ③PiS pure congeners (PiSS). These patients have a moderate deficiency of α1-AT in serum, about 60% of normal, and patients have a tendency to develop emphysema and cirrhosis; ④ Heterozygotes (e.g. PiMZ, PiSZ, etc.). These individuals also have a tendency to develop emphysema and cirrhosis. The detection of α1-AT variants by PCR has the advantages of convenient sampling, low sample requirement, rapidity and high sensitivity, and has been used in some hospitals in China for the diagnosis of genetic defect diseases. Hepatolenticular Degeneration (HLD), also known as Wilson Disease (WD), was first reported by Wilson and is an autosomal recessive disorder in which the mutant protein binds copper and causes hepatitis, cirrhosis, and infantile hepatitis syndrome. Hepatitis syndrome and other diseases. The cDNA sequence is 4398 bp long and contains 21 exons and 20 introns, with exon lengths ranging from 77 to 1234 bp, mostly around 200 bp, and encodes a copper transport protein with ATPase activity consisting of 1465 amino acid residues. ATP7B has a wide variety of variant sites with racial differences. For example, H1069Q is most common in Caucasians of European origin and rare in Chinese populations, where R778L is a high-frequency mutation site compared to 4193d in India. 225 mutation types have been identified so far, including 144 missense, synonymous or nonsense mutations, 49 small deletions, 12 small insertions, 3 regulatory mutations, 1 insertion and deletion co-existing There were 144 missense, synonymous or nonsense mutations, 49 small deletions, 12 small insertions, 3 regulatory mutations, 1 insertion and deletion, 2 complex reassignment mutations, 11 splice mutations and 3 large fragment deletions. The hotspot mutation regions in the Chinese population were T1216G, S406A, G1366C, V456L, C2310G, L770L, G2333T, R778L, A2495G, K832R, C2975T, P992L, etc. In addition, there were missense mutations (S986F, I1348N, G1355D, M1392K, A1445P), gene deletions, and gene deletions. A1445P), gene deletions (2810delT), nucleic acid substitutions (-133A→Cand-215A→T), and N1270S, P1273L, A476T, L776L, etc. As there are more than 200 mutation sites, which make genetic screening very difficult, DNA microsatellite marker technology can be used to compare the genes of patients and their parents to determine whether their causative genes are pure or heterozygous. Siblings of patients have a 25% chance of having the disease, and genetic screening of families of confirmed patients is the most effective way to make an early diagnosis of other potential patients. The corneal K-F ring is also clinically valuable for diagnosis. Hereditary Hemochromatosis (HH) HH, also known as bronze diabetes or hyperpigmented cirrhosis, is a rare autosomal recessive disorder of iron metabolism, mainly seen in Caucasian Europeans, with a prevalence of 1.64% and rare in China. There are five different genotypes of the disease: type 1 is a human leukocyte antigen-associated hereditary disease, which is most common due to mutations in the HFE gene that cause cellular iron transfer dysfunction, resulting in increased iron loading and deposition in the organs, and the other four are rare types, which are associated with hemoglobin (HJV, type 2A) and HAMP (type 2B), transferrin receptor 2 (TfR2, type 3) and membrane transferrin ( FPN, type 4) dysfunction was associated with The HFE gene (or HLA-H) was identified and named in 1996 and is located on the short arm of chromosome 6, encoding the HLA-A*3 region. There are more than twenty mutations in this gene, with C282Y being the most common, followed by missense mutations H63D and S65C. studies have shown that two genotypes, A16V-SOD2 and -463G/A-MPO, are among the C282Y pure mutations, which are closely associated with cirrhosis or hepatocellular carcinoma. wallace et al. reported one case of primary hemochromatosis in which an intronic mutation was found. A T→C missense mutation at base 5 of the 5′ end of intron 3 of the HFE gene was reported in China (as a pure heterozygote, IVS 3+5 T-C), and it is speculated that the new shear site mutation IVS3+5T-C may be the molecular biological basis for the pathogenesis of HH. ②Type 2A. The hemocyanin protein consists of 426 amino acids, and its gene contains four exons and three introns. There are many types of mutations that can affect all regions of hemocyanin, the majority of which are termination determinants. The most common form of mutation is G320V, in addition to G320V/Q116X compound heterozygous mutations and Q6H, C80R, S85P, G99R, G99V, L101P, I222N, I281T, C321X, C32lW, R385XS105L E302K, N372D, R335Q and other mutations. (iii) Type 2B. This type is associated with mutations in the HAMP gene, the gene encoding chromosome 19 hepcidin, and contains three exons and two introns, which are mainly expressed in the liver. Numerous mutations have been identified, such as R56X, R59G, G71D, etc. The gene encoding TfR2 is located at 7q22 and is approximately 21 kb long. The types of mutations are: pure nonsense mutation Y250X, shift mutation E60X, base reversal M172K and R455Q and gene deletion AVA1294-297del. ⑤ Type 4. type 4 is an autosomal dominant disorder. fpn is encoded by the SLC40A1 gene and its mutations causes multiple abnormalities in transmembrane proteins, resulting in impaired iron release from intestinal epithelial cells and macrophages. Treatment of the disease by intravenous excision and bloodletting is both simple and effective, and the disease is now a good model for genetic screening for human disease. Before genetic screening of the population, a transfer iron saturation test can be done followed by HFE gene testing, and those presenting pure and heterozygous for the HFE gene mutation need further serum ferritin, liver function tests, and finally liver biopsy to confirm the diagnosis. As mentioned above, the development of many liver diseases is closely related to genetic factors. With the continuous advancement of molecular biology research, rapid development of genetic engineering and wide application in clinical practice, most of the genetic metabolic liver diseases have been successfully genetically analyzed and diagnosed. The effective use of these new methods and technologies can help prenatal diagnosis and is of great significance in understanding the genetic characteristics of related liver diseases, the relationship between genetic variants and the disease, and exploring new therapeutic approaches, and is expected to play a great role in the research and clinical treatment of hereditary liver diseases. (References available on request) http://www.ihepa.com/ArticleView_3911.html