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BIOM30002 > lecture 34 > Flashcards

lecture 34 Flashcards

1
Q

How do are muscular dystrophies classified?

A
  • age of onset
  • pattern of weakness
  • pattern of inheritence
  • involvement of other systems
  • specific abornmalities on muscle biopsy
  • causative gene where identified (but sometimes genes have more than one clinical phenotype?)
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2
Q

Why make a diagnosis?

A
  • to know what the disease course is likely to be
    → life expectancy, independence etc
  • to enable monitoring for disease complications
    → cardiac, respiratory, endocrine, ocular etc
  • to ensure treatment is appropritate
    → and to avoid inappropriate treatments
  • to enable genetic counselling (always of benefit)
    → recurrent risk in siblings
    → counselling of other family members
    → where carrier status carriers its own risk
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3
Q

What is age of onset?

A
  • infantile: congenital muscular dystropy
  • e.g. in poor tone in baby, normal response is flex
  • adult onset: limb girdle muscular dystrophy
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4
Q

What are patterns of weakness?

A
  • generalised, whole body
  • focal: rigid spine syndrome
  • very important in making a diagnosis
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5
Q

What are inheritence patterns?

A
  • autosomal
  • recessive
  • dominat
  • sex linked
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6
Q

How are other systems involved?

A

brain

  • abnormalities of brain development or maturation
  • cognitive abnormalities

musculoskeletal

  • spinal rigidity, scoliosis
  • joint contractures (Achilles, ITB, elbow and wrist)
  • weakness

endocrine systems

eye

  • stuctural or retinal abnormalities
  • cataracts
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7
Q

What is FKRP?

A
  • gene

- mutations cause congenital muscular dystrophy, mental retardation and cerebellar cysts

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8
Q

What abnormalities might be seen on a muscle biopsy?

A
  • marked variation in fibre size
  • increase in central nuclei
  • fatty infiltration
  • increase in connective tissue
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9
Q

How are muscle biopsies done?

A
  • in children put them under GA for 15 minutes
  • need to check which type of anaesthetic to use
  • take a small piece of muscle about the size of a dice
  • gets sent off in three different pieces: histology
    EM block
    diagnostic screen
    → biochemical analysis?
    → research?
    → mutation analysis
    → western blot
    → immunohistochemistry

not a major procedure

needle in adults

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10
Q

What is immunohistochemistry?

A
  • fluorescent antibody staining
  • looking for specific proteins
  • e.g. membrane protiens
  • always compare to a normal
  • might show up as absent or decreased/incomplete staining
  • look for specific patterns of change
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11
Q

What is absent alpha-dystroglycan staining in DMD and LGMD1C?

A

A) characterisation of the alpha-dystroglycan antibody. By western blotting, the antibdoy stains a 156 kDa band in muscle (M) and a 120 kDa band in brain

B) transverse sections of control mouse: alpha-dystroglycan shows homogenous staining around the muscle fibre surface. no signal detected on cyrosections of mdx mice.

B) on 6 µm cyrosections, near complete loss of alpha-dystroglycan expression observed in a LGMD 1C patient in contast to a normal expression of beta-dystroglycan and the laminin alpha-2-chain. Muscle tissue from a DMD patient serves as a negative control. Bar, 50µm

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12
Q

What is myotonic dystrophy (DM1)?

A
  • autosomal dominant inheritence (1/8,000)
  • chromosome 19
  • a multisystem disorder
    → proximal and distal weakness and wasting
    → smooth muscle involvment: constipation, uterine
    → cognitive deficits
    → excessive somnolence, personality changes
    → cataracts
    → endocrine dysfunction: diabetes, infertility
  • shows anticipation (worse in successive generations)
  • muscle biopsy findings very non-specific
  • most common seen in adults
  • lots of people have it and don’t know
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13
Q

What is pattern of weakness in DM1?

A
  • quite patchy
  • often distal muscles
  • some muscles in the face
  • foot drop
  • smooth muscle: bowel, uterus
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14
Q

What are clinical findings re: myotonic dystrophy?

A
  • three phenotypes: classic, congenital and mild
  • congenital:
    → most severe, presents in first 4 weeks of life
    → respiratory failure, feeding difficulties and early death common
  • classic DM1:
    → most common
    → presents in adolescence or adulthood with muscle weakness
  • mild DM1
    → cataract and mild myotonia in adulthood, can be missed
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15
Q

What is congenital myotonic dystrophy?

A
  • presents at birth or in neonatal period
  • combination of:
    → hypotonia (‘floppy’ bay)
    → facial and proximal muscle weakness
    → delayed motor development
    → respiratory insufficiency
    – babies often die of respiratory failure <4 weeks of age
    → feeding difficulties
    → severe intellectual deficits
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16
Q

What do you see in adults with myotonic dystrophy?

A
  • characteristic pattern of facial weakness
  • immobility of facial expression
  • multisystem disorder
17
Q

What is myotonia?

A
  • = delayed relaxtion of muscles after contraction
  • seen in a number of muscle disorders
  • can be uncomfortable
  • not usually a big issue in myotonic dystrophy but useful for diagnosis
  • not seen in babies with DM1 but is present in affected parent
  • sometimes needs medical treatment if very uncomfortable
    → quinidine, mexilitine, carbamazepine
18
Q

What do you see in muscle biopsy of DM1?

A
  • lots of central nuclei
  • not particularly specific
  • ringbinden: aberrant myofibrils that wrap themselves around an existing muscle fibre in a tight spiral
  • occur most commonly in muscles affected by neurogenic atrophy
  • not specific
19
Q

What is the molecular pathogenesis os myotonic dystrophy?

A
  • expanded CTG trinucleotide repeat in the gene DMPK
  • normal alleles contain 5-35 CTG repeats
  • pre-mutation alleles: 35-49 repeats
    → individuals with pre-mutations: asymptomatic
    → offspring: risk of inheriting a larger repeat → symptoms
  • fully penetrant alleles: > 50 CTG repeats → DM1
  • genetic testing positive 100%
  • DM1 is inherited in an AD manner
20
Q

What is anticipation in DM1?

A
  • DMPK CTG alleles of >35 repeats are unstable and can expand in length during meisosis
  • offspring can inherit repeat lengths much long than those int he transmitting parent
  • anticipation = increasing disease severity and decreasing age of onset in successive generations
  • anticipation usually in maternal transmission of DM1
  • most often babies with severe congenital DM1 have inherited the expanded DMPK allele from the mother
21
Q

What is RNA gain of function in DM1?

A
  • mutant RNA transcribed from the expanded allele induce symptoms of the disease
  • RNA CUG expansions fold into hairpin-like secondary structures which sequester specific proteins, resulting in depletion below a functional threshold
  • two important proteins bind to CUG repeats: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1)
  • in DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in loss-of-function
  • CUGBP1 us up-regulated through a signalling pathway, causing downstream effects such as disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1
  • usually MBNL1 nuclear levels increase during development while CUGBP1 nuclear levels decrease: the level and localisation of these two proteins control a fetal to adult splicing tansition. This is reversed in DM1 tissues
  • embryonic stage: MBNL1 nuclear levels low, CUGBP1 levels high
  • during development MBNL1 nuclear levels increase while CUGBP1 levels decrease, inducing an embryonic-to-adult transition of downstream splice targets
    → IR exon 11, CIC-1 exons containing stop codons, and cTNT exon 5 etc
  • in DM1, MBNL1 is sequestered to CUG repeats, while CUGBP1 levels are increased due to phosphorylation and stablisation
  • this enhances expression of embryonic isoforms in adults, resulting in multople disease symptoms
22
Q

What are possible therapeutic strategies for DM1?

A

RNA-based mechanisms to inhibit the toxic CUG-expanded RNA species in DM1

  • small molecule inhibitors such as pentamidine-like compounds
  • RNA interference (RNAi)-mediated suppression of mutated DMPK transcripts
  • antisense oligonucleotide (AO)-mediated knowckdown of DMPK
23
Q

What are limb-girdle muscular dystrophies?

A
  • generally progressive muscle disorders
  • onset 2nd to 6th decade, M=F
  • present with muscle weakness and hypertrophy
    → usually pelvic girdle first, then shoulder
  • respiratory and cardiac involvement common
  • generally no central nervous system involvement
  • patholgy: generally cytoskeletal rather than contractile
  • i.e. generally associated with the sarcolemmal membrane
    some nuclear proteins or contractile apparatus
    DAPC
24
Q

What is the classification of LGMDS?

A
  • later onset (differences within this group)
  • pattern of weakness
  • inheritence:
    → autosomal recessive: LGMD type 2 (most common)
    → autosomal dominant: LGMD type 1, FSHD
    → x-linked: DMD/BMD, EDMD
25
Q

What are clinical cues to the LGMDs?

A

patient ? LGMD

clinical presentation
- pattern of muscles involved, additional clinical features? family history 
\+
creatine kinase levels
\+ 
muscle histology 
\+
muscle immunoanalyiss 
→→
genetic testing 
→ 
precise diagnosis ~75% 
→
genetic counselling 
recognition of risk of cardiac/respiratory complications 
surveillance 
proactive management
26
Q

What are main areas of muscle weakness in different types of dystrophy?

A
  • DMD/BMD: proximal
  • Emery-dreifuss type: proximal upper limb
  • limb-girdle type: proximal
  • FSHD: face, proximal upper limp
  • oculopharyngeal: ocular, proximal

specific patterns are indicative of specific dystrophies
distribution of weakness gives clues to diagnosis
- e.g. early contractures are universal in boys with Emery-Dreifuss MD

27
Q

What is muscle pathology in the LGMBs?

A
  • can be very variable
  • some helpful
  • vaculoses in LGMD1A
  • myotilin aggregates on myotilin staining in LGMB1A
28
Q

What are clinical clues to the LGMDs?

A
  • typical picture of LGMD caused by lamin A/C mutations with a prominent contractural phenotype involving the achilles tendons, elbows and spine predominantly, together with humeroperoneal muscle weakness
  • dominant forms are type 1
  • recessive are type 2: much more common, often associated with cardiomyopathy, respiratory involvment
29
Q

What is the presentation of FSHD?

A
  • dominantly inherited myopathy
  • affects 1/20,000 people
  • most symptomatic by age 20
  • facial weakness
  • scapular winging
  • proximal arm weakness
  • leg weakness usually less prominent
    → peroneal but not proximal, causes foot drop

don’t close their eyes when asleep

30
Q

What are signs of FSHD on examination?

A
  • weakness of eye closure
    → most never able to whistle
    → always sleep with eyes open
  • high riding scapulae
  • poorly developed pectoral and scapular muscles
  • pectus carinatum (‘pigeon chest’)
  • weakness of anterior compartment of leg
    → foot frop - weakness of peroneal muscles
31
Q

What is the muscle involvement in FSHD?

A
  • selective muscle involvement
  • weakness often patchy
  • often asymmetric
  • scapular and pectoral muscles affected early
  • lower 1/3 of abdomen affected → Beevor sign
  • heart unaffected
  • respiratory muscles usually unaffected
  • distributions poorly understood
    → ? why some muscles and not others
32
Q

What is the genetic basis of FSHD?

A
  • the gene for FSHD is not known
  • inheritance is autosomal dominant
    → 90% cases map to chromosome 4q35
    → 10-30% cases sporadic
  • penetrance incomplete
    → 30% all inherited cases are asymptomatic
    → symptoms more common in males than females
  • germline mosaicism is occasionally seen
33
Q

What is the D4Z4 repeat sequence?

A
  • Deletion of D4Z4 repeat sequence near telomere chr 4
    → most people: 12-96 copies of the repeat sequence
    → FSH patients have no more than 8 copies
    → smaller the fragment, the more severe the FSHD
    → smaller the fragment the earlier the age of presentation
    →→ infantile FHSD: 1- 3 repeats, very severe weakness
  • problem: the gene prove detects changes in homologous (very similar areas) on chromosomes 4 + 10 (some difficulties differentiating between the two)
  • about 5% of patients have a negative gene test
    → technical problems with the gene test
    → genetic heterogeneity: ? more than 1 gene causes FSHD
  • 4q repeat arrays can translocate to chromosome 10

more complex gene probes enable distinction between changes on 4q and 10q

34
Q

Can FSHD be due to new mutations?

A

yes
de novo mutation: one-off event
- germline mosaicism - possibly more than 1 event

BIOM30002 (36 decks)

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