Paedriatic Genetics 2 Flashcards
What are the embryological stages
Dorsal induction
Ventral induction
Migration and cell specialisation - neuronal migration from germinal matrix to the cortex
Myelination - starts inferior to superior, posterior to anterior
Describe the early neural tube
Early embryo there is a flat ‘neural plate’ which folds up to form the neural tube
Overlying that is the epidermis which becomes the cell
Overlying are the neural crest cells which migrates to innervate all the different parts of the body
Describe neural tube closure
Closure of the neural tube - closes at specific points along the tube
The somites represent the developing vertebral bodies - spine and ribs
Defects can occur at specific points across the cords
Anterior neural pore - brain
Posterior neural pore - bottom of the spinal cord
Describe the three parts of the neural tube folding
Prosencephalon - forms the cerebral hemispheres and thalamus
Mesencephalon forms the mid-brain
Rhombencephalon forms the pons, cerebellum, and medulla
Types of CNS malformation
Abnormalities of neural tube development
Affecting formation of cerebral hemispheres
Affecting formation of midbrain/brainstem
Neuronal migration
Myelination
What can you see in normal brain imaging - sagittal view
Sagittal view
Corpus callosum - bundle of white matter Posterior fossa - cerebellum, bulky Pons - oval shape ball Medulla - brain stem leading down into spinal cord Gyri - bumps, sulci - grooves
What can you see in normal brain imaging - coronal view
Lateral ventricles below the corpus callosum
What is neural tube anencephaly
No formation of the cerebral spheres - only has brain stem
Genetics uncertain - increased in Irish/Scottish and if family history
Teratogens – e.g. carbamazepine - increase risk
Folic acid lowers risk and inositol under trial
What is neural tube encephalocele
Can occur at point of any suture in skull
Image shows an occipital encephalocele, can also be very small
If small it may be okay, if its only fluid but if there is brain tissue then more care is taken
Syndromic or isolated
What is neural spina bidifa
This is when the spinal cord is fixed at the bottom so it becomes stretched when the child grows, affecting the nerve supply to the legs and bladder (spinal tethering)
Myelomeningocele - spinal cord material, most severe
Most serious spina bifida can be detected antenatally - affects appearances in the brain
Meningocele - outpouching of the defect
Spina bifida occulta - sign is a patch of hair
What is holoprosencephaly
Failure of brain to separate into cerebral hemispheres:
Alobar - complete failure
Semilobar
Lobar
Midline interhemispheric variant
Isolated or syndromic e.g. could occur in trisomy 13 (Patau’s syndrome)
Sign = single middle tooth , eyes slightly close together, cleft lip
What are the causes of holoprosencephaly
Chromosomal - trisomy 13
Teratogens - maternal diabetes
Single gene - 14 genes known: SHH (30-40%) (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF1 (18p11)
What are the three posterior fossa malformations
Dandy-Walker malformation
Chiari malformation
Cerebellar abnormalities
What are the Dandy-Walker malformation
Cystic dilatation of fourth ventricle (back of brain)
Complete or partial agenesis of the corpus callosum
Enlarged posterior fossa
Isolated or syndromic (chromosomal in ~50% antenatally diagnosed)
What are the Chiari malformation
Type 1 (Arnold) – downward displacement of the cerebellum, asymptomatic usually Incidental but could go down enough to plug the spinal cord causing pressure and headaches
Type 2 – with myelomeningocele = exerts a pull on the top of spinal cord causing the downpull
Type 3 – posterior encephalocele
Type 4 – cerebellar hypoplasia (small)
What are the cerebellar abnormality subtypes
Hemispheres or vermis (centre)
Isolated or syndromic
Congenital or progressive
What are syndromes with cerebellar abnormalities
Joubert
COACH syndrome (Joubert + hepatic fibrois)
Oro-facial digital syndrome
Walker-Warburg syndrome
Metabolic e.g. Smith – Lemli –Opitz syndrome
Mitochondrial
How can you identify cerebellar abnormalities
In a brain scan you can see a leaf pattern
What is Joubert syndrome
Part of the group of ciliopathies - aka cerebellooculorenal syndrome
Autosomal recessive
Association of cerebellar vermis hypoplasia with distinctive facial features, eye anomalies (retinal dystrophy), cystic renal disease, dysregulation of breathing
Brain imaging shows molar tooth sign (image) - medulla gets pulled down
Is joubert syndrome AR or AD
AR
What is the different between hypoplasia vs atrophy
Born small V became small
What are the neuronal migration defects
Schizencephaly
Lissencephaly
Pachygyria
Polymicrogyria
Heterotopias
Focal cortical dysplasia
What are causes of neuronal migration defects
Environmental
Infection - CMV, toxoplasmosis, syphilis
Radiation
Genetic Metabolic e.g. Zellweger Chromosomal e.g. 22q11 deletion Syndromic e.g. TSC - tuberous sclerosis Non-syndromic
Describe neuronal migration
From 8th week of foetal life neuroblasts migrate from germinal zone on ventricular surface
Neurons migrate in ‘inside-out’ fashion – those destined for deepest layer migrate first
Gyri and sulci form during this process
Neurons migrate along radial glial fibres that span entire thickness of hemisphere
Also evidence of tangential migration of GABAergic neurons from ventral to dorsal telencephalon
Migration continues to week 25 - thus not always detected antenatally
Can you detect neuronal migration
It is not always detectable antenatally
What are the genetic causes of isolated lissencephaly
LIS1 - Chr17p13.1
XLIS (DCX) - Xq22.3-q23
What does LIS1 do
Encodes intracellular 1b isoform of platelet-activating factor acetylhydrolase
Protein expressed in adult and foetal brain
Participates in cell motility and somal translocation–Interacts with tubulin
Can also cause Miller Dieker Syndrome
What does XLIS (DCX) do
Expressed exclusively in foetal brain
Protein binds to tubulin and may interacts with LIS1
X-linked dominant inheritance
Males with lissencephaly, while females with double cortex (due to X mosaicism)
3 cases of males who were somatic mosaics for DCX mutations presenting with double cortex
What is schizencephaly
Cleft to the brain, thought to be environmental
What is lissencephaly
Smooth brain, could be missing corpus callosum
Early developmental delay, seizures, spastic quadriparesis, limited life expectancy
What are the grades of LIS
Grade 1 LIS
Miller Dieker Syndrome
Severe DCX mutation
Grade 2-4 LIS
LIS1 (posterior>anterior)
Grade 4-6
DCX (anterior>posterior)
What is cobblestone lissencephaly
Brain is comparatively smooth but has some ‘chunks’ of gyri
Underlying condition is due to polymicrogyria
Associated with fukuyama muscular dystrophy (FCMD)
What is polymicrogyria
Many small folds, some genetic if specific distribution, exclude CMV
What are the proteins involved in tublinopathies
Tubulin proteins form heterodimers that assemble into microtubules
Play key role in processes required for cortical development
Neuronal proliferation, migration and cortical laminar organisation
Alpha tubulin - TUBA1A
Beta tubulin - TUBB2A/B, TUBB3, TUBB4A
Gamma tubulin - TUBG1
What is bilateral perisylvian polymicrogyria
Bilateral opercular syndrome or Foix-Chavany-Marie syndrome
History of poor feeding in infancy, delayed speech, dysarthria, drooling, restriction of tongue movements, epilepsy, dev delay
What is the inheritance pattern of tubulinopathies
AD - mostly de novo
What is bilateral fronto-parietal polymicrogyria (front and side)
○ Developmental delay +/- ataxia
AR - linked to chromosome 16 - mutations identified in GPR56
What are the types of polymicrogyria
Bilateral fronto-parietal polymicrogyria
Bilateral perisylvian polymicrogyria
What are the three tubulin proteins and their genes
Alpha tubulin - TUBA1A
Beta tubulin - TUBB2A/B, TUBB3, TUBB4A
Gamma tubulin - TUBG1
What do the tubulin proteins do
Play key role in processes required for cortical development
Neuronal proliferation, migration and cortical laminar organisation
What is Perisylvian Polymicrogyria
De novo mutation in AKT3
Heterozygous mutation in PIK3R2.3 affected sibs had same mutation, neither parent carried mutation – gonadal mosaicism
Somatic mosaic mutation in PIK3CAAll lead to increased P13K signalling and activation of P13K-mTOR pathway which is involved in neuronal migration
What is periventricular nodular heterotopia
Collections of heterotopic neurons located along lateral ventricles
Heterotopia - cluster of nerves in the wrong place
Periventricular - across the lateral ventricles
What symptoms and inheritance patterns are associated with periventricular nodular heterotopia
Present with epilepsy, intellectually normal
More frequent in females
Some families show X-linked dominant inheritance with prenatal lethality in males
What are the causes of periventricular nodular heterotopia
Loss of function mutations in Filamin A (FLN1) at Xq28 identified
Expressed in human cortex at 21-22 weeks gestation in radially migrating neurons
‘Mild’ mutations (ie non-truncating’) recently identified in affected males (9%)
Mutations identified in 19% sporadic females, 83% familial cases
What are the effects of loss in function of filamin A
Loss in function = periventricular nodular heterotopia
What are the effects of gain of function of filamin A
Gain of function mutations in the gene cause:
Melnick-Needles syndrome
Otopalatodigital syndrome type I and II
Frontometaphyseal dysplasia
What may happen to a child of someone suffering from ventricular nodular heterotopia due to filamin A loss of function
Aneurysmal patent ductus arteriosus
This is dilation of the duct connecting the aorta and pulmonary artery under the aortic arch
Good evidence that LOF filamin A mutations related to wider connective tissue disorder and can be associated with dilation of blood vessels including aortic root
What is tuberous sclerosis complex
AD - 60% de novo
Multisystem condition - where you get focal cortical dysplasia
White patches in the brain
Can lead to epilepsy and learning difficulties
What genes may cause tuberous sclerosis
TSC1 chromosome 9
TSC1 more likely to be familial, and overall milder
TSC2 chromosome 16
TSC1/2 form a complex that inhibits mTOR
What type of genes are causes of sexual disorders
Genes encoding transcription factors
Disruption affects tempero-spatial expression (timing and dosage)
What can occur due to failure of sexual differentiation
Sex Reversal
Sexual Ambiguity
Maintenance of Sexual Differentiation
What can occur due to failure of germ cell production
Infertility
Disorders of sexual function
What are the prenatal diagnosis signs of sexual disorders
Discordant sex - between karyotype and ultrasound findings
Ambiguous genitalia
What are the features used for postnatal diagnosis of sexual disorders
Ambiguous genitalia
Hernia - due to failure of migration of the testes
Failure of puberty
What are disorders of the cloaca
You do not get the right number of orifices
Not really a disorder of sexual development
What are key features of male and female sexual development
Female
Mullerian duct
Wnt pathway and β-catenin
Males
Wolffian duct - requires testosterone and anti-Mullerian hormone
SRY and SOX9
Summarise development of the gonadal ridge in both males and females
Male
Growth of Wolffian ducts
Primordial germ cells reach gonadal ridge
Secretion of AMH and leydig cell differentiation
Leydig cells produce testosterone
Male Mullerian ducts disappear
Female
Differentiation of Mullerian ducts
Meiotic entry of oocytes in the medulla
Degeneration of the female Wolffian duct
Are germ cells needed for development of the testis
No
Is cell proliferation more important in males or females in the early developing gonad for sexual development
Males
Sex reversal is more frequent in XY embryos with abnormalities of cell proliferation due to less SRY
What is the SRY gene
Sex determining region Y (SRY) is a transcription factor, signalling development of the testis
In its absence an ovary is formed
What 3 cells invade the genital ridge
Primordial Germ Cells - Sperm (male) or Oocytes (female)
Primitive Sex Cords - Sertoli cells (male) or Granulosa cells (female)
Mesonephric Cells - become blood vessels and Leydig cells (male) or Theca cells (female)
What general genes are required for the differentiation of the gonadal ridge
Differentiation of gonadal ridge from intermediate mesoderm requires sufficient levels of SF1 and WT1
What may occur as a result of WT1 KO
No kidneys or gonads, lethal
Associated with Denys Drash, WAGR, Fraiser
What may occur as a result of SF1 KO
Gonadal and adrenal primordia degenerate
XY sex Reversal +/- adrenal insufficiency
What is the SF1 gene
SF1 (steroidal factor) - forms transcriptional complex with SRY to upregulate SOX9
What is the WT1 gene
Wilms tumour gene - transcription factor
Associated with Wilms tumour which is associated with Beckwith-Wiedemann and Fraser syndrome
Nephroblastoma in Deny’s Drash, or gonadblastoma in Fraser’s syndrome (cancers) can occur
Nephrotic syndrome - proteins in urine
Poor response to steroids initiated further investigation
Summarise development of female germ cells
Primordial Germ cells originate from pluripotent cells of the epiblast, reach gonadal ridge in 5th week, continue to undergo mitosis until 6th week
Female germ cells continue to proliferate by mitosis until 10th week and then enter Meiosis
Retinoic acid (RA) produced in the ovary binds to retinoic acid receptor induces genes
Summarise development of male germ cells
Primordial Germ cells originate from pluripotent cells of the epiblast, reach gonadal ridge in 5th week, continue to undergo mitosis until 6th week
Male germ cells enclosed in seminiferous cords differentiate into spermatogonial lineage no MEIOSIS until puberty
Cells in seminiferous tubules protected from RA action CYP26B1 expressed from sertoli cells that catabolise RA
Are germ cells essential for development of the ovary
Yes
Turner syndrome = uterus but no ovaries
Where does the SRY gene lie
Lies near a pseudoautosomal region in the Y chromosome
Crossover can occur here from Y to the X
How does SRY relate to XX males
Translocation of SRY accounts for 80% XX males (gain SRY)
How does SRY relate to XY females
Small proportion of XY females (loss SRY)
15% deletions/mutations in SRY in 45XY females
What is SOX9 gene
2 copies required for male development
It increases FGF9 and upregulates AMH
Why does SOX9 not affect females when they also have 2 copies
X mosaicism
How does SOX9 overexpression consequences differ between the sexes
Overexpression = male
Thus 1X 2Y = no problem
2X 1X = XX with male gonads, female gametes = XX sex reversal
sex-limited, X-dominant inheritance
What may underexpression of SOX9 cause
Campomelic dysplasia
XY sex reversal (genotypically males present female)
Pierre Robin Syndrome - small chin, cleft palate
What is campomelic dysplasia
Bent Tibia
Cleft palate
Sex Reversal in 46XY (genotypically males present female)
Pulmonary Hypoplasia
Underexpression of SOX9
How might noncoding variation affect sexual development
Promoters and silencers are distant thus these can become interrupted affecting the dosage of product - increase/decrease SOX9, DAX1
There are epigenetic differences between male and female genome
What is DAX1
Xp21
Dominant negative regulator of SF1
Works antagonistically to SRY
What may deletion or loss of DAX1 cause
X-linked congenital adrenal hypoplasia
What may gain of DAX1 cause
XY females
Do male gonads need DAX1
Some level of it, yes
What does WNT4 and RSPO1 do
Induces β Catenin silences FGF9 and SOX9
WNT4 Increases DAX1 which antagonises SF1 and thus contributes to inhibition of steroidogenic enzymes
What might WNT4 duplication cause
Ambiguous genitalia in XY
What might RSPO1 LOF cause
XX male as upregulation of SOX9
What is BPES
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare developmental condition affecting the eyelids and ovary.
Typically, four major facial features are present at birth: narrow eyes, droopy eyelids, an upward fold of skin of the inner lower eyelids and widely set eyes.
What does DMRT1 do
Maintains ‘maleness’
What causes BPES
Mutation in FOXL2 - maintenance of femaleness - lose eggs quickly postnatally
The maternal genome in the eggs helps stimulate egg to divide during fertilisation
What genes involved in sexual development are subject to gene dosage effects
Essential for SRY,SF1,SOX9.DAX1. DMRT1 and FOXL2
What are the roles of testosterone and dihydrogen testosterone
Maintenance of Wolffian ducts
Development of prostate and virilisation of the external genitalia
DHT needs to be produced close to end organ to cause effect
Steroidogenesis enzymes can be involved in sexual development
What is the role of 5α reductase
Essential for external genitalia in males by converting testosterone into DHT
At puberty however, the body responds to testosterone and the male gonads appear despite originally female genitalia
What is congenital adrenal hyperplasia caused by
21 hydroxylase inactivity
What are the symptoms of congenital adrenal hyperplasia in females
Ambiguous genitalia in females - prompts steroidogenesis enzyme investigation
17-hydroxyprogesterone (17-OHP) is used in the diagnosis and monitoring of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency
21-hydroxylase deficiency means that cortisol isn’t produced, thus 17-OHP builds up and is then converted into testosterone
What adrenal crises occur due to 21-hydroxylase deficiency
21-hydroxylase deficiency means that cortisol isn’t produced, thus 17-OHP builds up and is then converted into testosterone
What are the symptoms of congenital adrenal hyperplasia in females
No change in genitalia in males but have adrenal crises
How can you treat congenital hyperplasia
Treatment early in pregnancy with dexamethasone to prevent clitoromegaly
Treated all at risk pregnancy, and then tested those foetus to see if they were affected
Stopped doing this due to suggestion of brain defects
What is the cause of congenital hyperplasia Vs hypoplasia
ANS
What is Smith-Lemli-Opitz syndrome (SLOS)
• Deficiency of 7 dehydrocholesterol reductase which catalyses 7 dehydrocholesterol to cholesterol
What is the inheritance pattern of SLOS
AR
What are the symptoms of SLOS
46XY ambitious genitalia, cleft palates and 2-3 syndactyly
Bad behaviour and learning difficulties
Fed cholesterol to improve behaviour
What is antley bixler syndrome
Affects enzyme cytochrome p450 which can lead to 46XY AND XX sex reversal
Mother with XX foetus, ambiguous genitalia
Voice broke, and hair growth as foetus produced so much testosterone
Foetus grew up as female, but due to testosterone in brain, felt dysphoria
Why are androgen receptors important
If androgen receptors don’t work = androgens won’t function = external female genitalia, with internal male organs which form inguinal hernia’s
Why is LH receptor function important (sexual disorders)
LH receptor problems
XY = micropenis and cryptochidism
XX = amenorrhoea and infertility
What muscles and systems are affected by muscular dystrophies
Skeletal, cardiac, respiratory
CNS, musculoskeletal development, eye abnormalities, skin changes
What are some markers of muscular dystrophies
Elevated serum creatine kinase - measured in blood
Indicates muscle damage
Myopathic electrophysiology - myopathic changes
Muscle biopsy finding - fibres, connective tissue, fat infiltration, inflammation
Immunohistochemistry to distinguish subtypes
What may you see on muscular biopsies
Muscle biopsy finding
Dystrophic process affecting muscle fibres
Rounding up of fibre
Splitting of fibres
Regenerative fibres
Accumulation of connective tissue
Fat infiltration
Signs of inflammation
What can you see on a normal muscle biopsy H&E stain
Polygonal fibres, nuclei at periphery of fibre under sarcolemma, relatively little connective tissue
What can you see on a dystrophic muscle H&E stain
Rounding of muscle fibres, variation in fibre cells, build-up of connective tissue, nuclei are not under the sub-sarcolemma membrane
What is the phenotypic classification of muscular dystrophies
Distribution muscle involvement
Proximal e.g. Limb girdle MD
Distal e.g. Tibial MD
Generalised e.g. Congenital MD
What is the genotypic classification of muscular dystrophies
According to gene involved - HOWEVER allelic disorders can cause different phenotype
What are examples of muscular dystrophies
Duchenne/Becker MD
Limb Girdle MD
Congenital MD
Distal MD
MD with contractures
Facio-scapulo-humeral MD
Myotonic MD
What are the genes involving limb girdle MD
LGMD1A,B,C… = autosomal dominant
LGMD2A,B,C… = autosomal recessive
What are the causes of congenital MD
MDC1A,B,C
What are the types of MD with contractures
Emery-Dreifuss XLR (X-linked), AD
Bethlem myopathy
What is the sarcolemma
The cell membrane
What is the overall structure of a msucle fibre
Outside = Connective tissue
Sarcolemma - membrane
Sarcomere - contractile unit
Nuclear membrane
What is the role of dystrophin
Dystrophin is a link between the proteins inserted into the sarcolemma membrane, dystroglycans and sarcoglycans and the contractile sarcomere
How is the sarcomere connected to the nuclear membrane
By the nuclear desmin
What does the nuclear desmin do
Connects the sarcomere to the nuclear membrane
What is the connective tissue outside the muscle fibre connected to
Dystroglycans
What is the cause of DMD/BMD
Dystrophin gene loss
What are the molecular classifications of MD
Dystrophinopathies DMD/BMD cardiomyopathy
Laminopathies EDMD, LGMD, Cardiomyopathy
Dystroglycanopathies CMD and LGMD
Sarcoglycanopathies LGMD2
Dysferlinopathies LGMD and distal MD
Collagenopathies LGMD and CMD
What are the featured of DMD
Pseudohypertrophy
Tip toe gait
Lumbar lordosis - hyper-curvature of lower spine
Gower’s manouver (Image of child on right)
Standing up using force from arms, due to proximal muscle weakness
What muscles are involved in DMD
Cardiomyopathy
Respiratory impairment
Scoliosis
Joint contractures
Behavioural problems (some)
Shortened lifespan
Loss of ambulation 12 years
What does immunohistochemistry show when testing DMD Vs normal tissue
Normal = control, polygonal, less connective tissue in between
DMD = DMD, variation, rounded, lots of connective tissue
No fluorescence of dystrophin
What are limb girdle MD types
Sarcoglycanopathies
Dystroglycanopathies
Dysferlinopathy
Dominant and recessive
What are distal myopathies
Adult onset - late, early, often dominant
What are three types of distal myopathies
Myofibrillar myopathies
Welander
Nonakka
What genes are involved in distal myopathies
GNE, Dysferlin, Myotilin, ZASP, Desmin, Beta crystallin
What are the types of congenital MD
Classical CMD (Merosin deficient/laminin α2)
Fukuyama CMD
Muscle-eye-brain MD
Walker-Warburg MD
What are the symptoms of classical CMD
Hypotonia +/- contractures (shortened muscle)
White matter changes MRI brain
Intellect normal
What are the symptoms of fukuyama CMD
Mental retardation
Structural brain abnormalities
What are the symptoms of muscle-eye-brain MD
Mental retardation
Hydrocephalus
Ocular abnormalities e.g. myopia, glaucoma, retinal or optic atrophy
What are the symptoms of Walker-Warburg MD
Mental retardation
Lissencephaly II “smooth brain”
Ocular malformations
How are beta and alpha dystrglycans involved in CMD
Beta and alpha dystroglycans
Alpha = glycan molecules added post-translationally, essential for connection with lamin α2
Lamin α2 links the integrins and to the collagens in the connective tissue
Added on in golgi and ER - depfects in these genes can cause CMD
Which ER genes affecting dystroglycans are involved in CMD
POMT1/2 (WWS)
Which Golgi genes affecting dystroglycans are involved in CMD
LARGE (MDC1D)
FKRP (MDC1C)
Fukutin (FCMD)
POMGnT1 (MEB)
What are examples of nuclear envelope protein neuromuscular disease genes
XLR (X-linked recessive) and AD Emery-Dreifuss MD
XL Emerin gene
AD Lamin A/C gene
What are features of nuclear envelope protein neuromuscular diseases
Early contractures - Achilles, elbows, spine
Muscle wasting humeral and peroneal
Cardiac conduction defect/cardiomyopathy
Usually present by 30y
Onset usually in childhood - rare after 20 years
CK usually elevated but may be normal
Where are emerin and lamin found
• The emerin’s and Lamin A/C are in the inner nuclear membrane
What are collagen VI related muscle disorders
Bethlem myopathy AD myopathy
Ullrich congenital MD - AR and de novo AD
What genes are involve in collagen VI related muscle disorders
COL6A1, COL6A2, COL6A3
What are the features of bethlem myopathy AD
Mild proximal myopathy
Contractures long finger flexors, wrists, elbows, ankles long finger flexors, wrists, elbows, ankles
Skin features e.g. follicular hyperkeratosis, keloid formation, e.g. follicular hyperkeratosis, keloid formation, cigarette paper scars
What are the features of ullrich congenital MD
Early onset muscle weakness
Proximal joint contractures, later spine, achilles and finger flexorslater spine, achilles and finger flexors, distal joint laxity
Normal intelligence
May never walk independently
Respiratory failure second decade
Skin changes as per Bethlem myopathy
What is facio-scapula-humeral MD
Weakness of the facial muscles, stabilizers of the scapula, dorsiflexors of the foot
Severity is highly variable, but it is lowly progressive
~ 20% eventually wheelchair
Life expectancy normal
Autosomal dominant-FSHD1, >90%
Rarely Digenic – FSHD2
What gene causes facio-scapula-humeral MD
Autosomal dominant-FSHD1, >90%
Rarely Digenic – FSHD2
What chromosome is FSHD found in
Chr 4q = FSHD, with D4Z4 macrosatellite repeats (11-100)
SMCHD1 - binds the repeats to repress expression of DUX4
DUX4 should not be expressed post-natally
What are the genetic variants that make FSHD a cause of facial-scapulo-humeral MD
FSHD1
Loss of some of the D4Z4 macrosatellite repeat (repeat contraction) = 1-10 repeats
10-30% FSHD de novo contraction of D4Z4 repeat
Permissive haplotype required - contractions on specific 4q haplotypes pathogenic
Thus contraction itself not sufficient to cause the disease
FSHD2
SMCHD1 (Chr 18p) - mutant cannot bind to macrosatellite repeats
Also need permissive haplotype (thus inheriting permissive Chr4 and Chr18p genes)
What is myotonic dystrophy
Multisystem disorder
Muscle weakness distal +
Myotonia - obvious in hands, where the muscle stays contracted e.g. during handshake
What systems does myotonic dystrophy target
Respiratory failure Cardiac arrhythmias Cataracts - young onset Diabetes mellitus Hypogonadism
Anaesthetic risks - hypersensitive, meaning they could become paralysed and remain in ICU
What are the two types of myotonic dystrophy
CTF expansion with 50+ repeats, >800 = childhood, >1000 = congenital
DM1 (most common) CTG expansion 3’UTR DMPK gene ch 19
DM2 untranslated CTG expansion intron 1 ZNF9 ch 3
What are the features of congenital myotonic dystrophy
Myopathic faces - open mouth, narrow face, speech difficult to understand
Learning difficulties
What are the pathogenic mechanisms of myotonic dystrophy
Hypothesis that RNA pathogenesis causes multisystem clinical features
Normally CUG Binding protein and muscle blind NL
CUG BP hyperphosphorylated and MBNL sequestered thus cannot regulate splicing
RNA gain of function
Splicing alterations
Cardiac troponin T (cTNT)
Insulin Receptor (IR)
Muscle specific Chloride Channel (Clc-1)Muscle specific Chloride Channel (Clc-1)
Tau CNS
Myotubularin MTMR1 in congenital DM1 muscle
What are the treatments of MD
No cure but supportive with physiotherapy and occupational therapy
Steroids in DMD
Monitoring respiratory infections - ventilation at night time
Gene therapy with viral vectors - insert minigene
Antisense oligomers to convert out-of-frame to in-frame i.e. DMD to BMD phenotype “molecular -frame
PTC124 - small organic molecule that can force the translation machinery to ignore premature translation
