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33 Cards in this Set
- Front
- Back
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What is SMA and what is its classification and how is it inherited? |
Spinal muscular atrophy common autosomal recessive disorder that is characterised by degeneration of anterior horn cells of spinal cord |
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What is the incidence of SMA? |
1/10,000 live births and a carrier frequency of approx 1/40 - 1/50 |
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What are the types and how are they classified? |
Types I, II, III, IV According to age of onset and achieved motor abilities |
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Age of onset, life span, motor milestones, other findings of SMA1 |
Before 6 months Most often two years or less - may live longer Sit without support only Mild joint contractures (shortening permanent) Normal or minimal facial weakness Variable such and swallow difficulties |
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Age of onset, life span, motor milestones, other findings of SMAII |
6-18 moths 70% alive at 25 years old Independent sitting when placed Postural tremor of fingers |
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Age of onset, life span, motor milestones, other findings of SMAIII |
After 12 moths Normal Independent ambulation (move about) |
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Age of onset, life span, motor milestones, other findings of SMAIV |
Adulthood Normal Normal
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What are the clinical features of SMAI? |
Marked proximal weakness Mobile expressive face - facial weakness late - tongue fasciculation (muscle twitch) Frog leg positioning Spontaneous movement decreased Bell shaped chest Reflexes lost Normal intelligence |
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What are the clinical features of SMAII and SMAIII? |
Slower progression Unique to individual Late development - feeding problems - aspiration pneumonia - scoliosis - contractures
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What is SMA caused by and what are the gene characteristics? |
Survival motor neuron gene (SMN1) Differs mildly to SMN2 by 5 bases SMN1 lost in SMA - 95% homozygous deletion 2% denovo 5-8% of the population carry SM1x2 on one chromosome (cis) which complicates carrier testing |
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What happens if the protein abundance is diminished in SMA? |
SMN1 is selectively necessary for motor neurone survival as diminished abundance for protein results in death of neuron cells at anterior horn of spinal cord and eventual muscle atrophy |
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What is the relationship between SMN1 and SMN2? |
SMN1 codes for survival of motor neuron protein (SMN) that plays a cruitial role in the survival of motor nurons SMN2 gene can have a variation in a single nucleotide that leads to alternative splicing at the exon 6-8 junction This produced only 10-20% of SMN2 transcripts coding a fully functional SMN protein while others lead to a tuncated protein compound (SMNdelta7) that is degraded in the cell
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If there is a mutation in the SMN1 gene what happens? |
SMN1 gene mutated in a way that is unable to correctly code the SMN protein All patients retain at least one copy of SMN2 gene which still encodes small amounts of SMN protein allowing some neurons to survive Reduced availability of SMN protein will result in gradual death of of motor neuron cells in anterior horn of spinal cord and the brain
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What does the variability of SMA depend on? |
Autosomal recessive 95-98% of individuals with SMA are homozygous for the absence of exons 7 and 8 of SMN1 or point mutations
Copy number of SMN2 correlates inversely with severity of disease |
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What is DMD? |
Duchenne muscular dystrophy is an X-linked recessive disorder that is caused by a mutation in the DMD gene that encodes the protein dystrophin
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What is the incidence of DMD? |
1/3500 live births 1/3 of mothers of isolated cases are not carriers - gonadal mosaicism (15-20%) - de novo mutation
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What is the role of dystrophin? |
Dystrophin is a cytoplasmic protein that is a vital part of a protein complex that connects the cytoskeleton of a muscle fibre to the surrounding extracellular matrix through the cell membrane
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What is the DMD gene and how is it varied? |
Largest known gene 2.4 megabases Large deletions account for approx 65% of DMD and 85% of BMD Duplication account for 6-10% cases Other mutations small insertions or point mutations |
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How is variability determined for DMD? |
Males DMD phenotypes are best correlated with the degree of expression of dystrophin Determined largely by the reading frame of the spliced message obtained from the deleted allele Complete absence of dystrophin causes most severe phenotype in DMD Amount of protein significantly influences BMD |
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When does DMD present and what are its features? |
Early childhood before 4 years old usually - symptoms persist before 5yo Features include: - Delayed motor milestones -Calf hypertrophy (enlargement of cells) -Waddling gait -Cardiomyopathy - Survival rarely past 3rd decade |
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What is the course of DMD? |
Variable Independent mobility lost between 6 and 14 years Gradual decline in upper limb function Death average formerly 21 years Death is usually respiratory Cardiac death in 10% |
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What is creatine kinase and what role does it have in DMD? |
CK is an enzyme that catalyses the conversion of ATP in skeletal muscles and is released into the blood due to muscle cell damage in 100% cases of DMD CK levels are >x10 normal Can indicate carrier of DMD
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What are some of the cognative issues in DMD? |
1/3 have significant learning difficulties Verbal working memory skills impaired increased learning difficulty Skewed to the left |
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What treatment is available for DMD? |
Steroid treatment Offered earlier if long term side effects were not an issue Offered at time of decline or frequent falls Risks may include weight gain, behaviour, short stature, fractures, delayed puberty, cataracts |
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What are anticipatory monitoring complications? |
Learning problems Scoliosis Respiratory muscle weakness Cardiomyopathy
Good to maintain ambulation - more independent and maintain the range of motion + bilateral symmetry |
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What are some adult issues with DMD? |
Delayed puberty Transferring to adult care Life expectancy Psychiatric issues Independent living Employment Cognitive issues may complicate transition |
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What is palliative care and what is it aimed at? |
Maximise quality of life for as long as possible Minimise stress and fear for families Giving young men choices and control over their death |
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What is neurofibromatosis and what is the incidence and penetrance? |
Causes a number of conditions that carry a high risk of tumour formation particularly in the brain 1:3000 100% penetrant by 5 years Severity cannot be predicted |
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What is BMD? |
Becker muscular dystrophy Progressive symmetrical muscle wekaness and atrophy, proximal greater than distal More mild and varied - onset can be in teens or early adulthood Progressive muscle weakness is much slower and less severe Preservation of neck flexor muscle strength |
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Neurofibromatosis type 1 genetics? |
Autosomal dominant mutations in NF1 Numerous mutations that affect the tumour suppressor gene |
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How do you diagnose neurofibromatosis type 1? |
Two or more of the following? 6 cafe au lait patches 2 neurofibromas axillary and/or inguinal Freckling Optic glioma 2 lisch modules
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Future problems for children with neurofibromatosis type 1? |
50% medical probelms 50% learning problems 5% problems in childhood resulting in lifelong morbility Malignant tumor risk 5% above background
Other problems - hyper tension |
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What things should be carried out during a genetic counselling session for neurofibromatosis type 1? |
Must examine parents - confirm diagnosis of child - provide recurrence risk - look complications in them
Prenatal diagnosis rarely requested - is becoming more common, PGD? Can use linakage analysis |
