03 - further disorders Flashcards
Name 3 group of Lysosomal storage disorders (LSDs)
1) Muccopolysaccharidosis (MPS) > MPSI - Hurlers > MPSII - Hunters > MPS III - Sanfilippo Syndrome > MPS IV - Morquio
2) Oligosaccharidosis
> I-cell disease
> Schlinder’s
3) Sphingolipidosis
> Tay Sach (HEXA)
> Fabry (GLA)
> Neiman Pick A/B
What are the genetic causes of a-thalassamia
> Haemoglobin (Hb) made up of alpha and beta chains in a tetamer
most common a2b2
2 genes encode a-globin - HBA1 and HBA2 (4 alleles in total)
carrier rates high in regions of malaria endemic
mutation type - mostly gene deletions:
> 1 del: Silent carrier
2 del: a-thal minor (asymptomatic)
3 del: a-thal = HbH disease (due to lack of a-globin, a tetramer of 4x b-globin chains formed)
4 del: Hb Barts hydrops fetalis syndrome
What are the genetic causes of b-thalassamia
> unlike a-globin, b-globin encoded by a single gene
mutation type also different = SNVs.
due to mutation type, can be either no expression of reduced activity of protein
3 types:
> B-thal Major: most severe type. Severe anemia & hepatosplenomegaly. Infant onset. Transfusions required
> B-thal intermediate: Later onset, milder anaemia
> B-thal minor: asymptomatic
What are the two main types of inherited cardiac disorders
1) Cardiomyopathy
2) Ion channelopathies (cardiac arrhythmias)
What are the types of Cardiomyopathy. what are the main genes
1 - Dilated Cardiomyopathy (DCM)
> 30% TTN
> MYH7
2 - Hypertrophic Cardiomyopathy (HCM)
> proteins involved in sarcomere
> MYBPC3
> MYH7
3 - Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
> PKP2
> DSP
> RYR2
What are the types of Ion channelopathies (cardiac arrhythmias). what are the main genes
1 - Long QT (LQT)
> potassium channel mutations result in delay after each heart beat
> KCNQ1
> KCNH2
2 - Brugada
> typical trace on ECG
> SCN5A
> CACNA1C
3 - Catecholaminergic polymorphic ventricular tachycardia (CPVT)
> exercise, stress and emotion induced cardiac instability
> Syncope (fainting) during exercise
> RYR2
What is sexual determination
Genetic sex. determine by transcription factors
What is sexual determination
Process in which internal and external genitalia form in response to hormones
Outline the process of sexual determination
> Embryo’s default is female. Need male factors to drive male sexual development
Initially the gonadal ridge forms a biopotential gonad, which can go down the male or female pathway:
MALE:
> SRY positive. SRY promotes SOX9 expressin
> This drives the development of testis
> Leydig cells form and express testosterone
> Sertoli cells form and express AMH (anti-mullerian hormone)
> Testosterone drives development of Wolffian ducts which become Vas deferens
> AHM drives regression of the Mullerian duct
FEMALE:
> SRY negative
> RSPO / WNT4 / B-catenin act to form ovary tissue
> in the absence of SRY, the Wolffian duct regress
> The Mullerian ducts develop which form the fallopian tubes, uterus and vagina
What can give rise to a FEMALE with 46,XY karyotype (e.g. 46,XY DSD)?
1) Disorders of testicular development (complete of partial gonadal dysgenesis):
> Swyer Syndrome (complete)
- appear normal female, normal external female genitalia and mullein ducts present. But do NOT have ovaries
- as no ovaries, they do not undergo puberty - so often detected from delayed puberty investigations
> instead of ovaries, they have streak gonads present - **risk of gonadoblastoma! **(often removed surgery)
> usually due to SRY deletion / LOF mutation
2) Disorder of Androgen synthesis
> androgens responsible for development of male ext genitalia.
> lack of androgen can result in mild hypospadias to complete female ext. genitalia
3) disorders of androgen response
> AIS - due to mutations in the AR gene
> partial or complete
What can give rise to a MALE with 46,XX karyotype (e.g. 46,XX DSD)?
> Male external genitalia range from ambiguous to normal
XX males often short stature, small testis and maldescended testis
hypogonadism and gynaecomastia common
90% are SRY +ve
other mutations inc: SOX9 dup
CF is the most common AR disorder. What are the presenting signs of classical CF
> Elevated Cl in sweat > Breathing difficulties due to build up of mucus > frequenct pseudomonas infections > pancreatic insufficiency > Raised IRT on newborn blood spots
What are the 5 mutations classes seen in the CFTR gene. Give an example of each
1) No synthesis / protein expression
- truncating mutations such as G542X
2) Block in Processing
- protein misfolding and retained in ER = protein degraded
- F508del
3) Block in Regulation (Gating Defects)
- reduced capacity of CFTR protein to secrete Cl ion due to defects in channel ACTIVATION
- either defects in ATP binding domain or phosphorylation of R domain
- G551D
4) Altered conductance
- reduced capacity of Cl- conductance across membrane
- due to mutations within transmembrane domains
- often milder phenotype
- R117H
5) Regulation of other ion channel
- mutations in CFTR which affect function of other channel proteins such as ENaC sodium channel
- Deletion of Start Codon
What drugs are available to treat CF
> Ivcaftor - target gating defect mutations - G551D
> Lumacaftor - targets F508del
what 3 disorders are associated with FMR1 expansions
> Fragile X
FXTAS (FraX associated tremor ataxia syndrome)
POI
What is the proposed pathogenesis of DM1 RNA mediated GoF
- in DM1 the repeat is in the 3’UTR = non-coding, but is transcribed into mRNA
- proposed the expansion (CTG)n interferes with RNA processing
- CUG repeats in pathogenic rage, fold into hairpins which accumulate and trap essential RNA-binding proteins:
CUGBP1 + MBNL1 - these to proteins have function in regulating splicing and so impairment of these leads to a global impact upon RNA processing & splicing
What is unique to FSHD compared to other repeat disorders
> Repeats (D4Z4) are large (3kb each) & encode the DUX4 transcript on 4q35
Rather than expansion, repeat contraction causes FSHD
Tell me about FSHD
> FSHD - facioscapulohumeral muscular dystrophy
result from aberrant expression of DUX4 transcript
DUX4 is a gremline TF, normally repressed through silencing of the region
FSHD requires a ‘permissive genotype’
polymorphisms distal to D4Z4 on4q35 = 4qA and 4qB
only the 4qA polys create a polyadenylation signal required for DUX4 expression
What are the normal and pathogenic repeat ranges in FSHD
Normal = 11-100 rpts Pathogenic = <10 rpts
Contraction of D4Z4 repeats results is reduction of CpG islands, leads to reduction in methylation = relaxation of epigenetic silencing = expression of DUX4 (only on a 4qA background)
What is a lysosome
membrane bound organelle (vesicle) with acidic contents (maintained by a H+ proton pump)
Can you provide an example of a very severe and a very mild form of LSD
> SEVERE = neonatal Gaucher
> MILD = Heterozygous female carriers of Fabry
What are the presenting features of DCM, what genes are involved
- Reduced Ventricular wall thickness
- reduced force contraction
- 30% due to TTN
What are the presenting features of HCM, what genes are involved
- asymmetric thickening of ventricular walls
- obstruction of outflow
- present with angina, palpitations, presyncope
- common cause of SCD in young athletes
- typically AD
- most common cause is MYH7 mutations
What are the presenting features of ARVC, what genes are involved
- progressive loss of cardiomyocytes
- replacement of myocardium with fatty or fibre-fatty tissue
- presents with ventricular arrhythmias, heart palpitations and syncope
- PKP2, DSP, RYR2
