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Clinical Applications of Genomics in Rare Disease and Cancer > Paedriatic Genetics 2 > Flashcards

Paedriatic Genetics 2 Flashcards

1
Q

What are the embryological stages

A

Dorsal induction

Ventral induction

Migration and cell specialisation - neuronal migration from germinal matrix to the cortex

Myelination - starts inferior to superior, posterior to anterior

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2
Q

Describe the early neural tube

A

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

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3
Q

Describe neural tube closure

A

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

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4
Q

Describe the three parts of the neural tube folding

A

Prosencephalon - forms the cerebral hemispheres and thalamus

Mesencephalon forms the mid-brain

Rhombencephalon forms the pons, cerebellum, and medulla

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5
Q

Types of CNS malformation

A

Abnormalities of neural tube development

Affecting formation of cerebral hemispheres

Affecting formation of midbrain/brainstem

Neuronal migration

Myelination

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6
Q

What can you see in normal brain imaging - sagittal view

A

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
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7
Q

What can you see in normal brain imaging - coronal view

A

Lateral ventricles below the corpus callosum

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8
Q

What is neural tube anencephaly

A

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

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9
Q

What is neural tube encephalocele

A

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

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10
Q

What is neural spina bidifa

A

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

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11
Q

What is holoprosencephaly

A

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

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12
Q

What are the causes of holoprosencephaly

A

Chromosomal - trisomy 13

Teratogens - maternal diabetes

Single gene - 14 genes known: SHH (30-40%) (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF1 (18p11)

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13
Q

What are the three posterior fossa malformations

A

Dandy-Walker malformation

Chiari malformation

Cerebellar abnormalities

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14
Q

What are the Dandy-Walker malformation

A

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)

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15
Q

What are the Chiari malformation

A 
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)

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16
Q

What are the cerebellar abnormality subtypes

A

Hemispheres or vermis (centre)

Isolated or syndromic

Congenital or progressive

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17
Q

What are syndromes with cerebellar abnormalities

A

Joubert
COACH syndrome (Joubert + hepatic fibrois)
Oro-facial digital syndrome
Walker-Warburg syndrome
Metabolic e.g. Smith – Lemli –Opitz syndrome
Mitochondrial

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18
Q

How can you identify cerebellar abnormalities

A

In a brain scan you can see a leaf pattern

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19
Q

What is Joubert syndrome

A

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

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20
Q

Is joubert syndrome AR or AD

A

AR

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21
Q

What is the different between hypoplasia vs atrophy

A

Born small V became small

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22
Q

What are the neuronal migration defects

A

Schizencephaly

Lissencephaly

Pachygyria

Polymicrogyria

Heterotopias

Focal cortical dysplasia

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23
Q

What are causes of neuronal migration defects

A

Environmental
Infection - CMV, toxoplasmosis, syphilis
Radiation

Genetic
Metabolic e.g. Zellweger
Chromosomal e.g. 22q11 deletion
Syndromic e.g. TSC - tuberous sclerosis
Non-syndromic
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24
Q

Describe neuronal migration

A

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

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25
Q

Can you detect neuronal migration

A

It is not always detectable antenatally

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26
Q

What are the genetic causes of isolated lissencephaly

A

LIS1 - Chr17p13.1

XLIS (DCX) - Xq22.3-q23

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27
Q

What does LIS1 do

A

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

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28
Q

What does XLIS (DCX) do

A

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

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29
Q

What is schizencephaly

A

Cleft to the brain, thought to be environmental

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30
Q

What is lissencephaly

A

Smooth brain, could be missing corpus callosum

Early developmental delay, seizures, spastic quadriparesis, limited life expectancy

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31
Q

What are the grades of LIS

A

Grade 1 LIS
Miller Dieker Syndrome
Severe DCX mutation

Grade 2-4 LIS
LIS1 (posterior>anterior)

Grade 4-6
DCX (anterior>posterior)

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32
Q

What is cobblestone lissencephaly

A

Brain is comparatively smooth but has some ‘chunks’ of gyri

Underlying condition is due to polymicrogyria

Associated with fukuyama muscular dystrophy (FCMD)

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33
Q

What is polymicrogyria

A

Many small folds, some genetic if specific distribution, exclude CMV

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34
Q

What are the proteins involved in tublinopathies

A

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

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35
Q

What is bilateral perisylvian polymicrogyria

A

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

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36
Q

What is the inheritance pattern of tubulinopathies

A

AD - mostly de novo

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37
Q

What is bilateral fronto-parietal polymicrogyria (front and side)

A

○ Developmental delay +/- ataxia

AR - linked to chromosome 16 - mutations identified in GPR56

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38
Q

What are the types of polymicrogyria

A

Bilateral fronto-parietal polymicrogyria

Bilateral perisylvian polymicrogyria

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39
Q

What are the three tubulin proteins and their genes

A

Alpha tubulin - TUBA1A
Beta tubulin - TUBB2A/B, TUBB3, TUBB4A
Gamma tubulin - TUBG1

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40
Q

What do the tubulin proteins do

A

Play key role in processes required for cortical development

Neuronal proliferation, migration and cortical laminar organisation

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41
Q

What is Perisylvian Polymicrogyria

A

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

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42
Q

What is periventricular nodular heterotopia

A

Collections of heterotopic neurons located along lateral ventricles

Heterotopia - cluster of nerves in the wrong place

Periventricular - across the lateral ventricles

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43
Q

What symptoms and inheritance patterns are associated with periventricular nodular heterotopia

A

Present with epilepsy, intellectually normal

More frequent in females

Some families show X-linked dominant inheritance with prenatal lethality in males

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44
Q

What are the causes of periventricular nodular heterotopia

A

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

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45
Q

What are the effects of loss in function of filamin A

A

Loss in function = periventricular nodular heterotopia

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46
Q

What are the effects of gain of function of filamin A

A

Gain of function mutations in the gene cause:
Melnick-Needles syndrome
Otopalatodigital syndrome type I and II
Frontometaphyseal dysplasia

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47
Q

What may happen to a child of someone suffering from ventricular nodular heterotopia due to filamin A loss of function

A

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

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48
Q

What is tuberous sclerosis complex

A

AD - 60% de novo

Multisystem condition - where you get focal cortical dysplasia
White patches in the brain
Can lead to epilepsy and learning difficulties

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49
Q

What genes may cause tuberous sclerosis

A

TSC1 chromosome 9
TSC1 more likely to be familial, and overall milder

TSC2 chromosome 16

TSC1/2 form a complex that inhibits mTOR

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50
Q

What type of genes are causes of sexual disorders

A

Genes encoding transcription factors

Disruption affects tempero-spatial expression (timing and dosage)

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51
Q

What can occur due to failure of sexual differentiation

A

Sex Reversal

Sexual Ambiguity

Maintenance of Sexual Differentiation

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52
Q

What can occur due to failure of germ cell production

A

Infertility

Disorders of sexual function

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53
Q

What are the prenatal diagnosis signs of sexual disorders

A

Discordant sex - between karyotype and ultrasound findings

Ambiguous genitalia

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54
Q

What are the features used for postnatal diagnosis of sexual disorders

A

Ambiguous genitalia

Hernia - due to failure of migration of the testes

Failure of puberty

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55
Q

What are disorders of the cloaca

A

You do not get the right number of orifices

Not really a disorder of sexual development

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56
Q

What are key features of male and female sexual development

A

Female
Mullerian duct
Wnt pathway and β-catenin

Males
Wolffian duct - requires testosterone and anti-Mullerian hormone
SRY and SOX9

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57
Q

Summarise development of the gonadal ridge in both males and females

A

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

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58
Q

Are germ cells needed for development of the testis

A

No

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59
Q

Is cell proliferation more important in males or females in the early developing gonad for sexual development

A

Males

Sex reversal is more frequent in XY embryos with abnormalities of cell proliferation due to less SRY

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60
Q

What is the SRY gene

A

Sex determining region Y (SRY) is a transcription factor, signalling development of the testis

In its absence an ovary is formed

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61
Q

What 3 cells invade the genital ridge

A

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)

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62
Q

What general genes are required for the differentiation of the gonadal ridge

A

Differentiation of gonadal ridge from intermediate mesoderm requires sufficient levels of SF1 and WT1

63
Q

What may occur as a result of WT1 KO

A

No kidneys or gonads, lethal

Associated with Denys Drash, WAGR, Fraiser

64
Q

What may occur as a result of SF1 KO

A

Gonadal and adrenal primordia degenerate

XY sex Reversal +/- adrenal insufficiency

65
Q

What is the SF1 gene

A

SF1 (steroidal factor) - forms transcriptional complex with SRY to upregulate SOX9

66
Q

What is the WT1 gene

A

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

67
Q

Summarise development of female germ cells

A

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

68
Q

Summarise development of male germ cells

A

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

69
Q

Are germ cells essential for development of the ovary

A

Yes

Turner syndrome = uterus but no ovaries

70
Q

Where does the SRY gene lie

A

Lies near a pseudoautosomal region in the Y chromosome

Crossover can occur here from Y to the X

71
Q

How does SRY relate to XX males

A

Translocation of SRY accounts for 80% XX males (gain SRY)

72
Q

How does SRY relate to XY females

A

Small proportion of XY females (loss SRY)

15% deletions/mutations in SRY in 45XY females

73
Q

What is SOX9 gene

A

2 copies required for male development

It increases FGF9 and upregulates AMH

74
Q

Why does SOX9 not affect females when they also have 2 copies

A

X mosaicism

75
Q

How does SOX9 overexpression consequences differ between the sexes

A

Overexpression = male

Thus 1X 2Y = no problem

2X 1X = XX with male gonads, female gametes = XX sex reversal

sex-limited, X-dominant inheritance

76
Q

What may underexpression of SOX9 cause

A

Campomelic dysplasia

XY sex reversal (genotypically males present female)

Pierre Robin Syndrome - small chin, cleft palate

77
Q

What is campomelic dysplasia

A

Bent Tibia

Cleft palate

Sex Reversal in 46XY (genotypically males present female)

Pulmonary Hypoplasia

Underexpression of SOX9

78
Q

How might noncoding variation affect sexual development

A

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

79
Q

What is DAX1

A

Xp21

Dominant negative regulator of SF1

Works antagonistically to SRY

80
Q

What may deletion or loss of DAX1 cause

A

X-linked congenital adrenal hypoplasia

81
Q

What may gain of DAX1 cause

A

XY females

82
Q

Do male gonads need DAX1

A

Some level of it, yes

83
Q

What does WNT4 and RSPO1 do

A

Induces β Catenin silences FGF9 and SOX9

WNT4 Increases DAX1 which antagonises SF1 and thus contributes to inhibition of steroidogenic enzymes

84
Q

What might WNT4 duplication cause

A

Ambiguous genitalia in XY

85
Q

What might RSPO1 LOF cause

A

XX male as upregulation of SOX9

86
Q

What is BPES

A

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.

87
Q

What does DMRT1 do

A

Maintains ‘maleness’

88
Q

What causes BPES

A

Mutation in FOXL2 - maintenance of femaleness - lose eggs quickly postnatally

The maternal genome in the eggs helps stimulate egg to divide during fertilisation

89
Q

What genes involved in sexual development are subject to gene dosage effects

A

Essential for SRY,SF1,SOX9.DAX1. DMRT1 and FOXL2

90
Q

What are the roles of testosterone and dihydrogen testosterone

A

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

91
Q

What is the role of 5α reductase

A

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

92
Q

What is congenital adrenal hyperplasia caused by

A

21 hydroxylase inactivity

93
Q

What are the symptoms of congenital adrenal hyperplasia in females

A

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

94
Q

What adrenal crises occur due to 21-hydroxylase deficiency

A

21-hydroxylase deficiency means that cortisol isn’t produced, thus 17-OHP builds up and is then converted into testosterone

95
Q

What are the symptoms of congenital adrenal hyperplasia in females

A

No change in genitalia in males but have adrenal crises

96
Q

How can you treat congenital hyperplasia

A

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

97
Q

What is the cause of congenital hyperplasia Vs hypoplasia

A

ANS

98
Q

What is Smith-Lemli-Opitz syndrome (SLOS)

A

• Deficiency of 7 dehydrocholesterol reductase which catalyses 7 dehydrocholesterol to cholesterol

99
Q

What is the inheritance pattern of SLOS

A

AR

100
Q

What are the symptoms of SLOS

A

46XY ambitious genitalia, cleft palates and 2-3 syndactyly

Bad behaviour and learning difficulties

Fed cholesterol to improve behaviour

101
Q

What is antley bixler syndrome

A

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

102
Q

Why are androgen receptors important

A

If androgen receptors don’t work = androgens won’t function = external female genitalia, with internal male organs which form inguinal hernia’s

103
Q

Why is LH receptor function important (sexual disorders)

A

LH receptor problems
XY = micropenis and cryptochidism
XX = amenorrhoea and infertility

104
Q

What muscles and systems are affected by muscular dystrophies

A

Skeletal, cardiac, respiratory

CNS, musculoskeletal development, eye abnormalities, skin changes

105
Q

What are some markers of muscular dystrophies

A

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

106
Q

What may you see on muscular biopsies

A

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

107
Q

What can you see on a normal muscle biopsy H&E stain

A

Polygonal fibres, nuclei at periphery of fibre under sarcolemma, relatively little connective tissue

108
Q

What can you see on a dystrophic muscle H&E stain

A

Rounding of muscle fibres, variation in fibre cells, build-up of connective tissue, nuclei are not under the sub-sarcolemma membrane

109
Q

What is the phenotypic classification of muscular dystrophies

A

Distribution muscle involvement

Proximal e.g. Limb girdle MD

Distal e.g. Tibial MD

Generalised e.g. Congenital MD

110
Q

What is the genotypic classification of muscular dystrophies

A

According to gene involved - HOWEVER allelic disorders can cause different phenotype

111
Q

What are examples of muscular dystrophies

A

Duchenne/Becker MD

Limb Girdle MD

Congenital MD

Distal MD

MD with contractures

Facio-scapulo-humeral MD

Myotonic MD

112
Q

What are the genes involving limb girdle MD

A

LGMD1A,B,C… = autosomal dominant

LGMD2A,B,C… = autosomal recessive

113
Q

What are the causes of congenital MD

A

MDC1A,B,C

114
Q

What are the types of MD with contractures

A

Emery-Dreifuss XLR (X-linked), AD

Bethlem myopathy

115
Q

What is the sarcolemma

A

The cell membrane

116
Q

What is the overall structure of a msucle fibre

A

Outside = Connective tissue

Sarcolemma - membrane
Sarcomere - contractile unit
Nuclear membrane

117
Q

What is the role of dystrophin

A

Dystrophin is a link between the proteins inserted into the sarcolemma membrane, dystroglycans and sarcoglycans and the contractile sarcomere

118
Q

How is the sarcomere connected to the nuclear membrane

A

By the nuclear desmin

119
Q

What does the nuclear desmin do

A

Connects the sarcomere to the nuclear membrane

120
Q

What is the connective tissue outside the muscle fibre connected to

A

Dystroglycans

121
Q

What is the cause of DMD/BMD

A

Dystrophin gene loss

122
Q

What are the molecular classifications of MD

A

Dystrophinopathies DMD/BMD cardiomyopathy

Laminopathies EDMD, LGMD, Cardiomyopathy

Dystroglycanopathies CMD and LGMD

Sarcoglycanopathies LGMD2

Dysferlinopathies LGMD and distal MD

Collagenopathies LGMD and CMD

123
Q

What are the featured of DMD

A

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

124
Q

What muscles are involved in DMD

A

Cardiomyopathy

Respiratory impairment

Scoliosis

Joint contractures

Behavioural problems (some)

Shortened lifespan

Loss of ambulation 12 years

125
Q

What does immunohistochemistry show when testing DMD Vs normal tissue

A

Normal = control, polygonal, less connective tissue in between

DMD = DMD, variation, rounded, lots of connective tissue
No fluorescence of dystrophin

126
Q

What are limb girdle MD types

A

Sarcoglycanopathies
Dystroglycanopathies
Dysferlinopathy
Dominant and recessive

127
Q

What are distal myopathies

A

Adult onset - late, early, often dominant

128
Q

What are three types of distal myopathies

A

Myofibrillar myopathies

Welander

Nonakka

129
Q

What genes are involved in distal myopathies

A

GNE, Dysferlin, Myotilin, ZASP, Desmin, Beta crystallin

130
Q

What are the types of congenital MD

A

Classical CMD (Merosin deficient/laminin α2)
Fukuyama CMD
Muscle-eye-brain MD
Walker-Warburg MD

131
Q

What are the symptoms of classical CMD

A

Hypotonia +/- contractures (shortened muscle)

White matter changes MRI brain

Intellect normal

132
Q

What are the symptoms of fukuyama CMD

A

Mental retardation

Structural brain abnormalities

133
Q

What are the symptoms of muscle-eye-brain MD

A

Mental retardation

Hydrocephalus

Ocular abnormalities e.g. myopia, glaucoma, retinal or optic atrophy

134
Q

What are the symptoms of Walker-Warburg MD

A

Mental retardation

Lissencephaly II “smooth brain”

Ocular malformations

135
Q

How are beta and alpha dystrglycans involved in CMD

A

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

136
Q

Which ER genes affecting dystroglycans are involved in CMD

A

POMT1/2 (WWS)

137
Q

Which Golgi genes affecting dystroglycans are involved in CMD

A

LARGE (MDC1D)

FKRP (MDC1C)

Fukutin (FCMD)

POMGnT1 (MEB)

138
Q

What are examples of nuclear envelope protein neuromuscular disease genes

A

XLR (X-linked recessive) and AD Emery-Dreifuss MD

XL Emerin gene

AD Lamin A/C gene

139
Q

What are features of nuclear envelope protein neuromuscular diseases

A

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

140
Q

Where are emerin and lamin found

A

• The emerin’s and Lamin A/C are in the inner nuclear membrane

141
Q

What are collagen VI related muscle disorders

A

Bethlem myopathy AD myopathy

Ullrich congenital MD - AR and de novo AD

142
Q

What genes are involve in collagen VI related muscle disorders

A

COL6A1, COL6A2, COL6A3

143
Q

What are the features of bethlem myopathy AD

A

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

144
Q

What are the features of ullrich congenital MD

A

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

145
Q

What is facio-scapula-humeral MD

A

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

146
Q

What gene causes facio-scapula-humeral MD

A

Autosomal dominant-FSHD1, >90%

Rarely Digenic – FSHD2

147
Q

What chromosome is FSHD found in

A

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

148
Q

What are the genetic variants that make FSHD a cause of facial-scapulo-humeral MD

A

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)

149
Q

What is myotonic dystrophy

A

Multisystem disorder
Muscle weakness distal +
Myotonia - obvious in hands, where the muscle stays contracted e.g. during handshake

150
Q

What systems does myotonic dystrophy target

A 
Respiratory failure
Cardiac arrhythmias
Cataracts - young onset
Diabetes mellitus
Hypogonadism

Anaesthetic risks - hypersensitive, meaning they could become paralysed and remain in ICU

151
Q

What are the two types of myotonic dystrophy

A

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

152
Q

What are the features of congenital myotonic dystrophy

A

Myopathic faces - open mouth, narrow face, speech difficult to understand
Learning difficulties

153
Q

What are the pathogenic mechanisms of myotonic dystrophy

A

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

154
Q

What are the treatments of MD

A

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

Clinical Applications of Genomics in Rare Disease and Cancer (10 decks)

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