Modes Of Inheritance/ Disorders Flashcards
PWS - clinical features
1:10 000 - 30 000
15q11-q13
Early infancy severe hypotonia
Hyperphagia (excessive eating) > obesity > type 2 diabetes
Characteristic facial features
Mild-moderate mental retardation
Motor, language development delay
Distinctive behaviour - tantrums, obsessive compuls., skin picking
Hypogonadism - genital hypolasia, incomplete puberty, infertility
Short stature, small hands/feet
Narcolepsy/ day time sleepiness
Angelman Syndrome - clin features
1:12 000-20 000
15q11-q13
Severe dev del
Severe speech impairment
Learnin difficult
Epilepsy
Microcephaly
Phacial dysmorphism
Unique bahaviour - happy baby, laughing, hand clapping, fascination with water
Scoliosis
What is the UK carrier frequency of SMA?
1/50
What are the main clinical features of SMA?
Weakness and paralysis of the voluntary muscles, due to spinal cord and motor neuron degeneration. Muscular atrophy.
Progressive proximal weakness
Intercostal muscle weakness, leading to breathing difficulty.
Fine tremor
Fasciculations in the tongue make feeding difficult
Describe the 5 types of SMA
Prenatal - Arthrogryposis multiplex congenita and congenital axonal neuropathy. Death within 1 month. SMN2 copies: 1
Type I: Acute infant - diagnosed <6 months old. Floppy baby, weak intercostal muscles lead to respiratory failure. 60% of SMA. Death at early age (<2yrs old). Lack of motor development, tongue fasciculation. SMN2 copies: 2
Type II: Chronic infant - diagnosed 6-12months. 27% of SMA, hypotonia, 70% reach adulthood, sit unaided, no walking without support. Progressive muscle weakness. SMN2 copies 3-4
Type III: Juvenile - IIIa diagnosed at <3 years; IIIb diagnosed at >3 years. 12% of SMA. Some ambulation retained. Proximal muscle weakness develops, legs more severely affected than arms. SMN2 copies: 3-4
Type IV: adult - ~1% of patients, onset of muscle weakness in 2nd-3rd decade, legs more affected than arms. Normal life expectancy. SMN2 copies 4-8
How many individuals are thought to carry two copies of SMN1 on a single chromosome
4%
Describe the basic gene structure of SMN1/2.
5q13
SMN1 and SMN2 (pseudogene). Arranged in tandem.
SMN1 is functional, SMN2 is largely unfunctional and lacks exon 7 in most transcripts. Increased copies of SMN2 can compensate for loss of SMN1 in some cases.
SMN1 - >90% of transcripts are full length;
SMN2 90% of transcripts are missing exon 7, due to the c.840C>T silent variant present in an ESE.
How many bases so SMN1 and SMN2 differ by? What are the common variants that allow the two genes to be distinguished?
5.
c.840C>T and c.859G>C in SMN2
What is the SMN protein?
A ubiquitously expressed protein present in abundance in the motor neurons and spinal cord.
It functions to chaperone the assembly of the snRNAs used for splicing. Lack of the protein thought to disrupt mRNA processing in neuromuscular junctions.
What is the common mutation found in 95-98% of all SMA individuals?
A deletion encompassing at least exon 7 of SMN1 - deletion can occur by homozygous deletion, or by gene conversion to SMN2 exon 7 (contains the c.840G>C resulting in exon skipping)
What is the mutational spectrum of SMA?
95-98% deletion of exon 7
2-5% deletion + SNP
<1% homozygous SNP - majority located in exons 3 and 6. Some can be deep intronic
What is the rate of new mutation?
2% de novo.
Describe the genotype/phenotype correlations found in SMA
Type I: homozygous deletion of exon 7
Type II: SMN1 > SMN2 gene conversion plus a hemizygous gene deletion of the other allele.
Type III: 2 gene conversion event.
How can SMN2 copy number compensate, in part, for lack of SMN1?
Disease is caused by low levels of protein, rather than complete lack of protein.
SMA I: 9% normal active protein
SMA II: 14%
SMA III: 18%
Full length SMN levels of 23% are needed for normal function.
The presence of 3+ SMN2 copies can make the phenotype milder.
The c.859G>C variant creates an new ESE in exon 7 of SMN2, to enhance exon 7 inclusion.
List some modifier genes involved in the phenotypic severity of SMA
NAIP
SERF1
Plastin 3
ZPR1
PTEN
