Creatine Kinase (CK)
CK is a diametric enzyme found as 3 isomers: MM(muscle), BB(brain), MB(hybrid) (Vial, 2006). The role of CK in muscle is to catalyse the reaction that rapidly regenerates Adenosine Triphosphate (ATP) during muscle contraction and reversibly forms creatine phosophase (CP) which is used as a high-energy store (Campbell and Farrell 2009). The enzymatic CK reaction is reversible: ADP + CP ↔ ATP + creatine (Vial, 2006).
It is highly likely that serum CK levels increased as a result of rhabdomyolysis, the breakdown and necrosis of muscle fibre and release of cell K+, caused by extended periods of intense contraction that depletes ATP, and a lack of oxygenated blood flow resulting in muscle cell hypoxia (Cervellin, 2010).
Serum Concentrations/pH Levels
Hopkins (2000) discusses the causative effects symptomatic of MH such as an increase in Ca2+, associated muscle contractions and consequential reduced muscle blood-flow, increase in K+, build-up of lactic acidosis and subsequent reduction in blood pH. Interestingly, Hopkins (2000) draws the conclusion that an increase in serum K+ concentrations is due to rhabdomyolysis, whereas the increase in Ca2+ is directly linked to the volatile anaesthetic in essence stimulating the hyper-metabolic state. Furthermore, Hopkins (2000) links the reduction in phosphates to the build-up in lactic acid.
Ketamine - Alternative Anaesthetic
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Unlike volatile anaesthetic ketamine is considered a safe anaesthetic for MH suffers (Barash et al., 2009). Ketamine inhibits the release of Ca2+ from the sitoplasmic reticulum thus preventing hyper-stimulation of skeletal muscle. Ketamine can be administered intravenously or intramuscularly. Furthermore, ketamine can increase heart rate and blood pressure, thus stimulating the rather than suppressing. It is unlikely that the patient would have experienced a similar episode had the anaesthetic been ketamine. (.
In vitro Muscle Contracture Test (IVCT)
IVCT is a diagnostic tool used to identify susceptibility to MH. The test uses muscle biopsies based in caffeine and in halothane.
Mechanism - RyR1 mutation - MH and lactic acidosis
MH is a relatively uncommon, potentially fatal, autosomal dominant, genetic disorder of the skeletal muscle, triggered almost exclusively by pharmacological agents (Barash et al., 2009). RyR1 gene, responsible for MH, is located on chromosome 19 and encodes the ryanodine receptor. The mutation causes excessive Ca2+ release on contact with volatile anaesthetics thus triggering excessive muscle spasm and long duration contractions causing, MH and lactic acidosis. (Korf, 2007)
Disorders most likely predispose a patient to MH.
1. Central Core Disease (Robinson et al., 2006)
2. Duchenne Muscular Dystrophy (Gurnanay et al., 2009)
3. King-Denborough Syndrome (Benca and Hogan, 2009)
4. Glycogen Storage Disease: McArdle disease (Benca and Hogan, 2009)
5. Mitochondrial Myopathies. (Driessen et al., 2007)
DNA Coding Strand 5'-CTCAAGAAGA-3'
DNA Template Strand 3'-GAGTTCTTCT-5'
Resultant mRNA 5'-CUCAAGAAGA-3'
Convert the fathers DNA sequence into protein sequence and label as P1. Compare P1 to wild-type RyR1 protein (labelled as P2). Identify difference between P1 and P2.
Gly (G) is substituted for Arg (R) at position 22 (see below); Arg is a basic amino acid, whereas Gly is a non-polar amino acid therefore the type of mutation is missense.
Figure : P1 protein sequence from known homozygous father and P2 protein sequence of the wild-type RyR1 are compared. At position 22 P1 and P2 differ; P1 homozygous father position 22 contains Arg, whereas P2 wild-type RyR1 contains Gly. Arg codes as either CGU, CGC, CGA, CGG, AGA, AGG and is a Basic amino acid, whereas Gly codes as either GGU, GGC, GGA, GGG and is a Non-polar amino acid.
In addition, when considering the condons of Gly and Arg: Arg=CGU, CGC, CGA, CGG, AGA, AGG: Gly= GGU, GGC, GGA, GGG; it is clear a point mutation (transition) has occurred in that the base guanine (purine) in the wild-type protein sequence has been substituted for the base arginine (purine) in the MH homozygous protein sequence.
Pedigree - Genotypes/Phenotypes
MH homozygous individuals are extremely rare, therefore the likelihood of 2 homozygous individuals meeting, and having offspring are exceptionally rare. Given that the Father is homozygous, and taking the above assumption into account, it has been assumed that the grandparents of the Father are most likely to be heterozygous (Gelehrter, 1998).
Always on Time
Marked to Standard
Figure : Pedigree showing genotypes/phenotypes of Ruth, her parents, grandparents and brothers. The gender of the older brother's child is irrelevant as MH is not linked to gender (Islander et al., 2007). The child is illustrated as male on the IV generation.Question-10:
Punnet Squares (R= mutant: r=normal)
Possibility-1: Father-Rr : Mother-rr: Probability mutation present in child = ½
Figure : Punnet square which identifies the genotypes/phenotypes for Ruth's older brother and an assumption that his wife could be not susceptible (rr). This punnet square predicts the possible genotypes/phenotypes for their offspring given the aforementioned assumption and concludes that the probability of mutation present in the child is ½.
Possibility-2: Father-Rr-: Mother-Rr: Probability mutation present in child = 3/4
Figure : Punnet square which identifies the genotypes/phenotypes for Ruth's older brother and an assumption that his wife could be heterozygous (Rr). This punnet square predicts the possible genotypes/phenotypes for their offspring given the aforementioned assumption and concludes that the probability of mutation present in the child is 3/4.
Possibility 3: Father-Rr: Mother-RR: Probability mutation present in child = 1/1
Figure : Punnet square which identifies the genotypes/phenotypes for Ruth's older brother and an assumption that his wife could be homozygous (RR). This punnet square predicts the possible genotypes/phenotypes for their offspring given the aforementioned assumption and concludes that the probability of mutation present in the child is 1/1.
It is conceivable that the older brother's wife could be either homozygous (RR) or heterozygous (Rr). However, given that MH is a relatively uncommon autosomal genetic disorder, it is more probable that the wife be (rr) (Barash et al., 2009). Given that assumption, the probability of their child having the mutation is ½. If that assumption is incorrect the probability increases from ½ (given rr) to ¾ (given Rr) and 1/1 (given RR).
Porcine, affected by porcine stress syndrome, were used to identify the early biochemical changes. The position of the porcine RyR1 gene on its chromosome is close to the location of the RyR1 gene on the human chromosome suggesting a link. In addtion, symptoms of PSS are similar as are the biochemical changes (Fujii et al., 1991)
Cherednichenko et al., (2008) suggest the most likely mode of action of dantrolene sodium is to reversibly bind to the RyR1 primary calcium ion release channel of the sarcoplasmic reticulum thus inhibiting release of Ca2+.
MH is characterised by a uncontrolled release of calcium ions from the sarcosplasmic reticulum. Dantrolene targets the RyR1 amino acid sequence, specifically 1-1400, in the N-terminal region of the gene, (Paul-Pletzer et al., 2002).
The occurrence of MH in the general population is rare i.e. approximately 1:15000 anesthetised children and 1:50000 anesthetised adults ; therefore you would need a potentially unmanageably large sample size (Fuji et al., 1991).
Inter domain inter actions
Cytidine triphosphate malignant hyperthermiaREFERENCES
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