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Flashcards in Non-mendelian Diseases Deck (24):

What is the pattern of inheritance in Cystic Fibrosis?

It is an autosomal recessive disorder with a heterozygote avantage provided by resistance to cholera induced chloride-losing diarrhea
It affects 1 in 2000 live births, is more common in Caucasians and patients have a life expectancy of 28 years


What are the clinical features of cystic fibrosis?

There is dysfunction of exocrine glands which produce viscous, dehydrated secretions
They have salty sweat, pancreatic insufficiency leading to malabsorption and failure to thrive
Electrophysiological profile of the affected tissues shows abnormalities in the transport of chloride and sodium ions across the membrane


What are the affected genes in Cystic fibrosis?

There have been over 750 mutations identified with 70% of these mutant alleles being a three base pair deletion in exon 10 which removes phenylalanine 508
Others include G542X, G551D, N1303K, W128K
The majority of mutations associated with this condition are very rare which can cause a practical challenge to the clinical geneticist with respect to molecular diagnosis


What s Duchenne muscular dystrophy?

This affects 1/3500 males and is the most severe and common form of muscular dystrophy
It results in progressive wasting of the muscles and is diagnosed between 6 months and 6 years of the patients life with death being common around age 30


What is Becker muscular dystrophy?

This is a milder form of muscular dystrophy than Duchenne with a later age of onset of over 10 years
The symptoms include muscle cramps, struggling at sport, difficulty walking and climbing stairs
These patients have normal lifespan but may require a wheelchair by the age of 40-50 years with cardiomyopathy being a rare feature


What is the difference between the causes of duchenne and Becker muscular dystrophy?

There is X linked cardiomyopathy due the promoter mutations which block transcription in cardiac muscle
In duchennes there are deletiosn or other mutations in this region which results in either a truncated or no protein while in Becker there are deletions or other mutations which result in only a partially functional protein


What is the difference between locus heterogeneity and allelic heterogeneity?

Locus heterogeneity is where the same clinical phenotype can result from mutations at any one several different loci
Allelic heterogeneity is where many different mutations within a given gene can be seen in different patients with the same genetic condition


What are dynamic mutations?

These result from instability of repeated DNA sequences of 3 nucelotides, above a threshold number (typically 40) these repeats will become unstable causing the repeat number to change between generations, they often tend to result in neurological or neuromuscular disorders
They may result in anticipation where there is an earlier age of onset and increased severity with successive generations


What is an example of a condition that has dynamic mutations?

Myotonic dystrophy


How does myotonic dystrophy affect vision?

this can impact vision by leading to cataracts and retinal damage


How does myotonic dystrophy affect the respiratory system?

it affects the respiratory system by leading to breathing difficulties, aspiration and sleep apnea


How does myotonic dystrophy affect the endocrine system?

There are low testosterone levels, testicular failure and gonadal atrophy in men
In women there is weakened uterine muscle, pregnancy related complications and gynecological related problems in women


How does myotonic dystrophy affect cognitive function?

There is intellectual impairment, behavioural and psychological disorders and excessive daytime sleepiness


How does myotonic dystrophy affect the cardiovascular system?

There are heart condition abnormailites, arrhythmias and cardiomyopathy


How does myotonic dystrophy affect the gastrointestinal tract?

There are swallowing issues, abdominal pain, irritable bowel syndrome, constipation/diarrhoea, poor nutrition and weight loss, chronic infections


How does myotonic dystrophy affect muscle?

There is weakness, wasting, myotonia and pain


How does myotonic dystrophy affect bone?

causing bone abnormalities, hypogammaglobulinemia, pilomatrixomas (skin condition)


What two things may result in anticipation?

There may be progressive worsening of the clinical phenotype in successive generations or this could be an artefact resulting from better observation and clinical diagnosis in recent times


What is the cause of myotonic dystrophy?

A large number of CUG repeats in the untranslated region of the DMPK gene


What is huntington’s disease?

This is an adult onset disease characterized by progressive mental and physical deterioration
It occurs in 7/100000 individuals and is autosomal dominant mutation of an expanded polyglutamine tract


What are the symptoms of Huntington’s disease?

The early clinical features are incoordination, involuntary movements, planning difficulites, depression and irritability
Later this will progress to Chorea, oculomotor disturbance, overactive reflexes, progressive dementia, speech disorders as well as psychiatric problems like personality change, affective disorders, schizophrenic psychosis, suicide and behavioural disturbance
In the end stage of the disease there is severe motor disability, mute, swallowing difficulites, incontinence, weight loss and sleep disturbance


What is imprinting?

Some genes retain a ‘memory’ of what parent they were inherited from causing a parent of origin effect which can cause monoallelic gene expression so the gene behave differently depending on whether they are inherited from the mother or father
There are about 200 imprinted genes with methylation appearing to be the principle mechanism
If there is disturbance in this mechanism there is typically abnormal embryonic development


What is an example of genetic imprinting?

Beckwith-Wiedemann syndrome
This is an autosomal dominant condition which only manifests when the gene is inherited from the mother


How do SNRPN (small nuclear ribonucleoprotein polypeptide N) and UBE3A (ubiquitin) show genetic imprinting?

Normally the maternal copy of SNRPN is methylated and inactivated while the Paternal copy of UBE3A is inactivated
This means if the paternal SNRPN is lost then the offspring will lose all ability to use the gene product and will develop Prader-Willi Syndrome
Alternatively if there is a deletion of the maternal UBE3A then the individual will develop angelman syndrome