基因疾病

genetic diseases：genetic and epigenetic changes、genetic disorders、Paediatric diseases、Aetiology of malformations……

genetic diseases

• genetic and epigenetic changes
  • 疾病的分类
    • development
      • genetic
        • Humans have about 30000 coding genes, whose alterations may lead to a genetic disease, Many, but not all of them, will manifest in infancy,Hereditary disorders are derived from parents and transmitted in the gametes through the generations, Familial disorders present often within the same family,
        • 遗传异常的性质
          • 突变指的是DNA的永久地改变，germ line mutations 可能会被传递到后代并且造成遗传疾病，体细胞突变不会被传递到子代但可能会造成cancer or congenital defects, genetic alterations 可能会发生在protein-coding genes or in non-coding sequences(i.e.miRNA, InRNAs)
        • Types of mutations
          • point mutations
            • Point mutations derive from the substitution of a single nucleotide and can result in different outcomes
              • missense mutations错义突变 cause the substitution of an amino acid(sickle cell anaemia)
              • Non-sense mutations无义突变 cause a premature stop codon and often result in premature RNA decay
              • silent mutaions
              • frameshift mutation移码突变
          • expansion mutations
            • trinucleotide repeat mutations(三核苷酸重复突变）result in the amplification of a sequence of three nucleotides(fragile X syndrome)
          • structural variations
            • copy number variations(CNVs, either deletions or amplifications)may affect an entire gene or a substantial part of it
            • translocations易位
              • t(9；22) in CML
            • inversions倒位
            • chromosome number
              • monosomies
              • trisomies
              • polyploidies
        • Single nucleotide variations: not always a mutation
          • Most single nucleotide variations are frequently present in a population (with a frequency >1%) and are called single nucleotide polymorphysms (SNPs),They are usually not associated with a disease but may determine susceptibility for a certain disease它们通常与疾病无关，但可能决定对某种疾病的易感性
      • congenital
    • inflammatory
      • trauma
      • infections
      • immune
    • neoplastic
      • tumours
      • cancers
    • degenerative
      • aging
  • Epigenetic changes表观遗传的改变
    • epigenetic abnormalities determine the modulation of gene expression(i.e.silencing) and are not due to mutations of the DNA sequence
    • They derive from addition of methyl groups whose consequence is to compact chromatin
    • may affect both DNA and histones
• genetic disorders 4
  • mendelian disorders, which are due to single genes inherited in a Mendelian fashion(比如cystic fibrosis）
    • caused by single gene defects
    • Mutations of the same gene can result in a variety of phenotypic abnormalities involving multiple organs (pleiotropy)多效性
    • An identical phenotypic presentation could be due to defects in more than one gene
    • transmission pattern 3
      • autosomal dominant(i.e. familial hypercholesterolaemia)
        • due to >900 mutations in the LDLR gene, encoding the LDL receptor
        • As a result of the mutation, both biosynthesis and catabolism of cholesterol are impaired
          • Patients with these genetic mutations present with higher levels of serum LDL (2-3 fold increase in heterozygotes, >5 in homozygotes) and require pharmacological treatment(statins)他汀类
          • cholesterol accumulates forming skin xanthomas皮肤黄瘤 and premature atherosclerosis, increasing the risk of coronary heart disease
      • autosomal recessive(i.e. sickle cell anaemia, cystic fibrosis, phenylketonuria)
        • Autosomal recessive disease with a frequency of 1:10000 live born infants
        • due to mutations of the PAH gene, encoding the phenylalanine hydrolase enzyme, which converts phenylalaninem into tyrosine
          • Affected infants are normal at birth but within a few weeks exhibit a rising plasma level of phenylalanine
          • Higher phenylalanine levels impair brain development, leading to mental retardation
            • 必须在出生后不久进行及时的筛选测试，以发现这种生化损伤，并开始适当的饮食方案(限制苯丙氨酸的摄入)
            • 限制饮食的人可以过相当正常的生活
            • Many female patients with PKU will give birth to babies with mental retardation and congenital heart disease because of the teratogenic effect of phenylalanine
              • maternal PKU 母源性的PKU
              • Maternal dietary restrictions are imperative必要的 before conception and throughout pregnancy
          • symptoms and clinical presentation
            • Depending on the mutation (>500 different mutations of the PAH gene) clinical presentation may be more or less severe, depending on the residual enzymatic activity
            • Usually mental retardation, seizures, decreased pigmentation of hair and skin are observed，在较轻的病例中，仅观察到血浆中苯丙酮尿水平的适度升高，没有任何相关的神经障碍，Biochemical screening tests have to be run shortly after birth to identify increased levels of phenylalanine，Genetic tests will have to be performed after that to identify the specific mutation先生化测试再基因测试
      • X-linked(i.e.glucose-6-phosphate deficiency)
        • Glucose-6-phosphate deficiency (G6PD) is an example of a genetic disease following Mendelian inheritance pattern，X-linked recessive disease， affecting mostly males
  • multifactorial disorders,which depend on multiple genes and the environment(比如hypertension）
    • Complex multigenetic disorders
      • are caused by more than one gene
      • 这是基因与环境相互作用的结果
      • In many disorders some SNPs may confer susceptibility to develop a certain disease when exposed to some environmental factors比如diabetes and obesity
  • disorders deriving from chromosomal aberrations(比如Down syndrome)
    • Cytogenetic disorders
      • Structural variations are genetic alterations affecting the number of the structure of one or more chromosomes
        • Numeric abnormalities
          • A numeric change of chromosomes may affect one or more chromosomes or all of them
          • Aneuploidy 非整倍性results from a numeric variation affecting only some chromosomes (i.e.monosomy, trisomy)
          • Polyploidy results when all chromosomes are affected (i.e. 3n)
        • Structural abnormalities
          • Translocations implies transfer of a part of a chromosome to another one (i.e. t(8;14) and are usually reciprocal
            • robertsonian translocation derive grom fusion of two acrocentric近端着丝的 chromosomes这种易位是不平衡的
              • In these translocations there is no substantial loss of genetic material but the carrier has 45 chromosomes
          • isochromosomes等染色体result from the duplication of an entire arm of a chromosome
            • The resulting chromosome will either have 2 short arms (p) or 2 long arms (q)
          • Deletions imply the loss of part of a chromosome
            • A ring chromosome may be formed after a deletion, when the two arms join and circularise
          • Inversions derive from a section of the chromosome is upside down
      • If the alteration is >5-6 Mb it is usually detected by cytogenetic analysis (karyotype), A smaller alteration will need more sensitive techniques (aCGH)
        • Karyotyping is the technique that allows the visualisation of metaphasic chromosomes after staining (usually the Giemsa staining)
      • Cytogenetic disorders involving autosomes
        • Chromosomal abnormalities involving autosomes are usually more severe than those affecting sex chromosomes
          • Only three autosomal trisomies are compatible with life (13, 18 and 21) although 13 (Patau syndrome) and 18 (Edwards syndrome) patients usually do not reach 1 year of life
            • Down syndrome (Trisomy 21)
              • 95% of the affected people have 47 chromosomes and syndrome derives from non-disjunction不分离 of sister chromatides of chromosome 21
              • 4% of the patients carry a Robertsonian translocation between chromosome 21 and 14 or 22, and an additional copy of chromosome 21, resulting in 46 chromosomes
              • 1% of the patients are a mosaic of normal and trisomic cells
              • Down patients present with mental retardation, congenital heart defects, congenital malformations of the GI (i.e. Hirschprung) and immunological problems，They have increased risk of developing leukaemia，Patients older than age 40 develop neuropathological conditions (i.e. Alzheimer)
              • 发病率与产妇年龄的增加有关
                • The exact pathogenesis of the syndrome is still unknown, though the alteration of the DYRK1A and RCAN1 genes has been described as a possible cause
          • Several abnormalities do not affect the entire chromosome, but part of it (i.e. 22q11.2 deletion syndrome)
            • Their clinical effect may depend on the size of the deletion
      • Cytogenetic disorders involving sex chromosomes
        • are usually more common and better tolerated
          • They may involve either chromosome or both
          • Disorders involving the X chomosome may range from monosomy of X to having multiple copies
            • These are usually not very severe because additional copies of X are inactivated (lyonisation)里昂化
            • Turner syndrome
              • Turner syndrome is diagnosed in female patients with a lower number of X chromosomes (usually the entire X chromosome but it may affect only the short arm)
              • Karyotype is usually 45, X (though mosaics do exist)
              • Patients present with short stature, amenorrhoea闭经, infertility, reduced secondary sex characteristics and other dismorphological changes
            • Klinefelter syndrome
              • Klinefelter syndrome is a male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes
              • Patients present with taller stature, feminine appearance, gynecomastia男子女子型乳房, very small testes and mental retardation in some cases
              • It is the most common cause of male hypogonadism，Patients have usually azoospermia无精子症
              • It may be related to increased maternal age and a history of irradiation of either parent
          • Up to three copies of the Y chromosome have also been described in phenotypically normal individuals
            • This depends on the low amount of genes on Y
  • disorders deriving from single genes, but not inherited in a Mendelian fashion (比如triplet expansion disorders, mitochondial genes, imprinting disorders) 3
    • diseases caused by triplet expansion mutations
      • Fragile X syndrome
        • Fragile X syndrome is the prototype of diseases caused by repetition of three nucleotides (Huntington disease as well)，Incidence is 1:1550 for males and 1:8000 for females，这是智力迟钝的第二大常见原因(仅次于唐氏综合症)
        • Fragile X syndrome derives from a mutation in the FMR1 gene, which maps to Xq27.3, which is silenced due to methylation of repeated triplets CGG序列扩增导致沉默
        • Normally there are 29 repeats of the sequence CGG in this gene正常的
        • In affected individuals the number of repetition varies between 200 and 4000，If there is a number ranging from 30 and 200 patients will be carriers (premutations)预突变，Anticipation预期 is observed in this disease, in which the number of triplets become bigger at each generation，Premutations will become mutations in the next generation as the number of repeated triplets increases due to anticipation
        • Phenotypic changes include a long face with a large mandible, large everted ears and large testicles in males(macroorchidism)，具有前突变的携带者(30至200次重复)通常无症状，尽管女性可能会出现premature ovarian failure和其他较轻的症状，但在以后的生活中可能会出现56
    • diseased caused by mutations in mitochondial genes
      • are rare and transmitted only by maternal inheritance
      • 它们通常影响编码参与氧化磷酸化的酶的基因，Skeletal muscles, heart and brain may be affected by such mutations
      • The prototype of these diseases is the Leber hereditary optic neuropathy, characterised by progressive bilateral visual impairment
    • diseases association with alteration of imprinted regions of the genome
      • For most genes no functional difference exists between paternally or maternally-derived genes，However, some paternally and maternally-derived genes may be functionally different because of genomic imprinting，Maternal imprinting refers to transcriptional silencing of maternally-derived genes, whereas paternal imprinting describes inactivation of paternal alleles
      • Prader-Willi and Angelman syndromes
        • 一个健康人有两个15号染色体拷贝，一个来自母亲，另一个来自父亲,然而，在15q11-13染色体区域，父系贡献和母系贡献表达某些基因有很大差异,This is due to sex-specific epigenetic imprinting, whose biochemical mechanism is DNA methylation （正常人的）
        • Both syndromes are examples of genomic imprinting diseases ,Both are associated with loss of the chromosomal region 15q11-13 (band 11 of the long arm of chromosome 15),This region contains the paternally expressed genes SNRPN and NDN and the maternally expressed gene UBE3A,临床表现将取决于是否丢失父源性或母源性染色体区域
        • In normal conditions, SNRPN and NDN genes are silenced on maternally-derived chromosome 15,whereas UBE3A is silenced on paternally-derived chromosome 15
          • Prader-Will syndrome
            • there is a microdeletionon the paternally-derived chromosome 15
            • About 70% of cases occur when part of the father's chromosome 15 is deleted (or part of it)
            • 25% of cases the person has two copies of chromosome 15 from their mother and none from their father (uniparental disomy)
            • Patients present with mental retardation, short stature, hypotonia, obesity, small hands and hypogonadism,Symptoms arise when genes that normally should be expressed from paternal chromosome 15 are lost due to a deletion (affecting genes SNRPN and NDN)来自母亲的基因由于甲基化而失去了功能
          • Angelman syndrome
            • there is also a deletion of the same region of chromosome 15, but on the maternally-derived chromosome 15, where the UBE3A gene maps
            • Occasionally, Angelman syndrome is due to inheriting two copies of chromosome 15 from a person's father and none from their mother (no functional UBE3A gene)
            • On paternal chromosomes the UBE3A gene is inactivated by genomic imprinting, and no functional version of the gene remains
            • Symptoms are similar to those of Prader-Willi, but also ataxic gait, inappropriate laughter and seizures are present,due to loss of the UBE3A gene of maternal origin, involved in the ubiquitin pathway这种基因在大脑中缺乏表达是导致神经表现的原因
• Paediatric diseases
  • Many diseases of infancy are of genetic origin,其中一些并不一定是由于基因异常，但其他原因也存在,婴儿疾病造成的死亡风险最高
  • Congenital anomalies先天畸形
    • 先天性畸形是一出生就存在的结构缺陷，Some of these (i.e. heart and kidney diseases) will not manifest their consequences until later in life，Malformations畸形 are primary errors of morphogenesis，They derive from an intrinsic abnormal developmental process
    • Congenital anomalies are usually mutifactorial rather than deriving from a single gene alteration，在某些情况下，它们只影响一个器官(即先天性心脏病)，在其他一些病例中，它们涉及多个器官
  • disruptions 突发事件
    • Disruptions derive from secondary destructions of an organ or body region that was previously normal in development，They arise from extrinsic disturbance in morphogenesis，Rupture of amnion may form amniotic bands that encircle, compress or attach to part of the developing foetus, causing disruptions
    • Disruptions are not inheritable because they are not due to genetic defects
  • deformations变形
    • Deformations also represent extrinsic disturbances of the development,Deformations may occur due to localised or generalised compression of the foetus最常见的原因是 uterine constraint
    • Additional conditions (i.e. first pregnancy, small uterus, malformed uterus, leyomyomas子宫肌瘤)may also cause deformations
  • Sequence
    • Sequence refers to multiple congenital anomalies that result from secondary effects of a single localised aberration in organogenesis (i.e.oligohydramnios)羊水过少，Oligohydramnios (decreased amniotic fluid) may be caused by a variety of maternal, placental or foetal abnormalities,The reduced volume of amnion results in a classical phenotype of the foetus (i.e. flattened facies,positional abnormalities of hands and feet)
  • Malformation syndrome
    • 畸形综合征指的是存在几种缺陷，不能在形态发生的一个单一错误的基础上解释,Syndrome often arises from a single condition (i.e. viral infection,chromosomal abnormalities) that simultaneously affect several tissues
• Aetiology of malformations 3
  • Genetic causes
  • Environmental factors (i.e. viral infections, drugs and radiation)
  • Multifactorial (due to the interaction of genes and environment)
• Perinatal infections
  • may occur in utero or during delivery
    • They may be acquired transcervically (ascending infections) if the baby is infected through the cervicovaginal canal (i.e. herpes simplex infection)
  • Transplacental infections gain access to the foetal bloodstream by crossing placenta (i.e. HIV, Hepatitis B)
    • 表现
      • Early infections during gestation by TORCH pathogens cause growth restriction, mental retardation, cataracts白内障, congenital cardiac abnormalities
      • Later infections cause encephalitis, chorioretinitis, hepatomegaly, pneumonia and myocarditis
  • Prematurity and foetal growth restrictions
    • Prematurity is defined as gestational age less than 37 weeks，Premature newborns weight less than 2500 g and may have incomplete development of several organs, 婴儿的体重应该调整到胎龄，早产儿是小胎龄(SGA)small gestational age
      • Foetal growth restriction in SGA infants may be due to several reasons:
        • Foetal factors (i.e. chromosomal disorders, congenital anomalies or infections)
        • Placental factors
        • Maternal factors (i.e. drugs, alcohol, cigarette smoke, malnutrition)