Inborn Errors of Metabolism Flashcards
Describe alkaptonuria.
- it’s an autosomal recessive condition
- it is a homogentisic acid oxidase deficiency
- the urine turns black on standing (and alkalinisation)
- present with black ochrontic pigmentation of cartilage & collagenous tissue
- also have arthritis
Describe cystinuria.
- it is an autosomal recessive condition
- occurs in 1:7,000 poeple
- there is defective transport of cystine and dibasic amino acids through epithelial cells of the renal tubule and intestinal tract
- cystine has low solubility, so we end up with formation of calculi in renal tract
- COLA or COAL
- mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19) cause this condition
Describe albinism.
You can be tyrosinase negative or positive.
TYROSINASE NEGATIVE:
- Type 1a - complete lack of enzyme activity due to production of inactive tyrosinase
- Type 1b - reduced activity of tyrosinase
TYROSINASE POSITIVE:
Type II
- AR, biosynthesis of melanin reduced in skin hair and eyes
- most individuals do acquire a small amount of pigment with age
Describe pentosuria.
A condition where you 1-4g pentose sugar L-xylulose daily (reducing sugar).
It is benign, and almost exclusively only found in Ashkenazi Jews of Polish-Russian extraction (1:2,500 births).
What are the features of the one gene - one enzyme concept?
- all biochemical processes in all organisms are under genetic control
- these biochemical processes are resolvable into a series of stepwise reactions
- each biochemical reaction is under the ultimate control of a different single gene
- mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction
What are the features of the molecular disease concept?
- brought about with the help of work on haemoglobin in sickle cell disease
- found direct evidence that human gene mutations actually produce an alteration in the primary structure of proteins
- inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered
List some different mechanims of inheritance.
- Autosomal recessive
- Autosomal dominant
- X-linked
- Codominant
- Mitochondrial
Expand on the autosomal recessive mechanism of inheritance.
- both parents carry a mutation affecting the same gene
- 1 in 4 risk each pregnancy
- consanguinity increases risk of autosomal recessive conditions
- examples: Cystic fibrosis, sickle cell disease
Expand on the autosomal dominant mechanism of inheritance.
- these are rare in IEMs
- examples: Huntingdon disease, Marfan’s, Familial hypercholesterolaemia
Expand on the x-linked mechanism of inheritance.
- it’s characterised by carrier females passing on condition to their affected sons
- there is no male to male transmission
- female carriers may manifest condition – lyonisation (random inactivation of one of the X chromosomes)
- X-linked dominant : fragile X
- X-linked recessive: haemophilia, Fabry’s disease
Expand on the codominant mechanism of inheritance.
- where two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein
- both alleles influence the genetic trait or determine the characteristics of the genetic condition
- example: ABO Blood group, α1AT
Expand on the mitochondrial mechanism of inheritance.
Mitochondrial DNA is inherited exclusively from the mother.
- only the egg contributes mitochondria to the developing embryo
- thus, only females can pass on mitochondrial mutations to their children; fathers do not pass these disorders to their daughters or sons
- however, it affects both male and female offspring
How is mitochondrial inheritance determined?
The distribution of affected mitochondria determines the presentation.
It’s also found that high energy-requiring organs are more frequently affected.
There’s a current debate on three parent babies to overcome this.
What are some features of inborn error of metabolism?
- inborn errors of metabolism are also known as inherited metabolic disease (IMD)
- they are individually rare (1:10,000 - 1:500,000)
- collectively, they present a sizeable problem but they’re cumulatively frequent and account for approximately 42% of deaths within the first year of life
- they make a significant contribution to the 1% of children of school age with physical handicap and the 0.3% with severe learning difficulties
- screening programmes are availabel, specifically for newborns
- there are signs that are important to recognise in a sick neonate
What are the WHO criteria for a good screening test?
- the condition screened for should be an important one
- there should be an acceptable treatment for patients with the disease
- facilities for diagnosis and treatment should be available
- there should be a recognised latent or early symptomatic stage
- there should be a suitable test or examination which has few false positives -specificity - and few false negatives - sensitivity
- test or examination should be acceptable to the population
- cost, including diagnosis and subsequent treatment, should be economically balanced in relation to expenditure on medical care as a whole
