1) smas 1a)smn gene on 5q11.2-13.3 ar carrier frequency 1 / 40 total incidence 1 / 6,000 births...
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1) SMAs
1a) SMN gene on 5q11.2-13.3 AR
carrier frequency 1/40
Total incidence 1/6,000 births
Tested for locally
SMA I (Werdnig-Hoffman)
~1/20,000 carrier rate ~1/80
- onset <6 months (may be in utero)- death usually <2 years (intercostal type
respiratory failure)- severely weak, floppy, suck poorly,
never sit
SMA II (intermediate)
- onset <18 months
- death >2 years (can survive to adulthood)
- can sit; never stand or walk alone
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1) SMAs
SMA III (juvenile - Kugelberg-Wielander)
- onset >18 months
- death - adult (can have normal lifespan)
- walk alone
- proximal » distal weakness, legs > arms
All 3 have:
- symmetrical muscle weakness/wasting(proximal > distal)
- decreased or absent DTRs
- fasciculations tongue, but not EOM,facial, diaphragmatic or myocardialinvolvement
- tremor hands
(These distinguish them from distalSMAs.)
- normal SNAPS, and motor NCVs >70% N
(These distinguish them from CMT2.)
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1) SMAs
Genetic mechanism
- In mice, SMN deletion is embryoniclethal (mice have only 1 copy of SMN).
- In SMA I, 95% have SMNt exon 7 (and 8) deletions; but SMA II and III can as well.
- Deletion of SMNc has no effect.
- Is a tight correlation between level ofSMN protein expression and phenotype.
- SMNc produces an alternatively splicedprotein, lacking exon 7. In SMA III,SMNt gene is converted to an SMNcgene, partially rescuing the phenotype.
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1) SMAs
1b) Other forms of SMA
- “SMA IV” (adult)
- much rarer. Can be AR or AD.
- distal SMA (childhood/adult)
- ~10% of all SMA; ~15% of “peroneal muscular atrophy”
- (many other rarer kinds described)
- adult onset GM2 gangliosidosis (Tay- Sachs) - + cerebellar disease;
Ashkenazim.
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1) SMAs
1c) X-linked bulbo-spinal muscular atrophy (Kennedy’s syndrome)
Tested for locally
Clinically
- onset of wasting typically 30-50 years;slow progression (decades)
- muscle cramps almost universal; canprecede wasting by 20 years
- limb girdle weakness/wasting, usually in lower limbs first; most develop milder
distal weakness later
- bulbar involvement - tongue, facial, jaw muscles
- prominent tongue fasciculations
- “myokymia” of chin (?fasciculation)
- may ultimately aspirate
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1) SMAs
- postural tremor 50-100%
- DTRs decreased or (usually) absent
- may have mild distal sensory loss; great majority (>85%) have abnormal SNAPs
- gynaecomastia in ~50%; sexual function usually normal, though testicular size may be reduced
Genetic mechanism:
- CAG triplet repeat expansion in exon 1 of androgen receptor gene
- not just loss of function: this causestesticular feminisation
- probably combination of gain of novelfunction plus partial loss of function
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2) ALS
Background
- about 5-10% of ALS is dominant (FALS)
- about 20% of FALS is due to SOD1 mutations (21q22.1)
about 2-7% of sporadic ALS is also due to SOD1 mutations
(SOD1 mutations testable in Perth (? and Sydney))
- 50% penetrance by age 46; 90% by age 70
Clinical features
- identical to sporadic ALS (see El Escorial criteria), but pathologically FALS may have more posterior
column damage
(Do not confuse with X-linked BSMA, or FTDP-17.)
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2) ALS
Genetic mechanism
Over 50 point mutations in Cu-Zn SOD
(SOD1) gene
- some characteristic genotype-phenotype correlations
e.g.
- A4 V/T - lower limb onset, rapid progression
- I 113T - often “sporadic” - ?low penetrance
- D90A - high prevalence
(~2%) northern Sweden
- behaves recessively (but dominantly elsewhere)
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2) ALS
Not due to loss of SOD1 activity
- transgenics vs. knockouts
- SOD1 mutants may result in decreased, normal or increased SOD1 activity
- no deletion or premature stop codon(nonsense) mutations recorded
- may be due to aggregation of abnormal protein, or increase of peroxidation capacity
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3) Inherited Neuropathies
1) CMTs (= HMSNs) 1/2,500
a) CMT1 (= HMSN1)
median motor NCV 38 m/sec.
(? 42) m/sec.
(females with CMTX may have normal NCVs)
Locus Gene Mechanism
CMT1a 17p11.2-12 PMP22 AD Duplication (80%) (tested locally - FISH)/point (<1%) mutation (tested
Sydney)
CMT1b 1q22-23 P0 AD Point mutation (6%) (tested Sydney)
CMT1c 10q21.1-22.1 EGR2 AD Point mutationsCMTX Xq13.1 CX32 XR/D Point mutations (12%)(may have NCV 43 m/sec. (tested Sydney)in males)
Others
*Note that occasional patients with CX32 mutations andsome specific P0 mutations may have a CMT2 phenotype.
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3) Inherited Neuropathies
Clinical
- distal weakness commencing peroneal muscles and progressing to remainder of distal leg and hand muscles
- sensory features very mild/inapparent clinically
- DTRs diminished/absent
- pes cavus/claw toes common
- enlarged nerves may be felt
- typically mild - most patients retain full mobility/independence (~20% have significant disability)
(- “recessive CMT1” (labelled CMT4) is typically earlier onset/much more severe)
Note:- PMP22 duplication causes ~70% of allCMT1
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3) Inherited Neuropathies
b) CMT2 (= HMSN2)
median motor NCV >42 m/sec.
(less common - ~ 30% of CMT)
Locus Gene Mechanism
CMT2a 1p36 ? ?
CMT2b 3q21 ? ?(unusually severe sensory features)
CMT2c ? ? ?
(+ respiratory failure)
CMT2d 7p14 ? ?
CMT2e ? ? ?
Clinical
- like CMT1 except tendency for
- later onset
- more severe weakness/atrophy legs (? less hands)
- relatively better preservation of DTRs
- no enlarged peripheral nerves
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3) Inherited Neuropathies
c) Dejerine-Sottas Syndrome (=HMSN3) (rare)
(some require median motor NCV <10 m/sec; most do not - overlaps with severe CMT1 clinically)
Clinical
- severe, infantile/childhood onset, hypertrophic dysmyelinating neuropathy (+ onion bulbs) with enlarged nerves
- may have raised CSF protein
Genetic
- previously considered recessive as most are sporadic, BUT
- most have dominant (new) mutations of PMP22 or P0 (about equal numbers); dominant EGR2 mutations have occurred
- can have homozygosity for PMP22 duplication or P0 mutation
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3) Inherited Neuropathies
2) HNPP (tomaculous neuropathy) - AD
Clinical
- painless mononeuropathy developing after minor trauma or compression; typically resolves in days-weeks
- may show signs of more generalised neuropathy, like CMT1
- usually find slowing of lower limb NCVs and median distal latencies, as well as symptomatic focal conduction block
Genetic
- great majority PMP22 deletion (tested locally - FISH)
- a few PMP22 mutations, or non PMP22
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3) Inherited Neuropathies
3) Hereditary neuralgic amyotrophy (familial brachial plexus palsy) - AD
- typical attacks of (painful) brachial neuritis, may begin in childhood;
usually teens - 20’s
- axonal damage; no evidence of generalised neuropathy. Recovers
over months
- may have hypotelorism/short stature
- also Ch17, but 17q23-25, not 17p11.2-12
Note:- distinction of HNA from HNPP which may affect plexus (10%), but
- is painless
- has mild NCV decrease in legs
- does not have dysmorphic features
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3) Inherited Neuropathies
4) Sensory Neuropathies (=HSANs)
HSAN I (= AD hereditary sensory neuropathy) 9q22.1-22.3
- onset teens-20’s
- usually with painless foot ulceration/neuropathic joints; may be with burning feet or lancinating pain
- unmyelinated/small myelinated fibres affected first
- minimal autonomic/motor involvement
- DRGs and distal axonal
HSAN II (= AR sensory neuropathy) ?locus
- onset infancy/childhood
- all forms of sensation affected - severe ulceration, and loss of DTRs
- minimal autonomic involvement
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3) Inherited Neuropathies
HSAN III (= Riley-Day syndrome) 9q31-33
- overriding feature loss of unmyelinated C-fibres with severe autonomic dysfunction
- most have pain/temperature loss, and some lose larger fibre function.
Absent histamine triple response
- AJs depressed/absent
- fungiform papillae absent from tongue
- often short stature, may have kyphoscoliosis
- (?nearly) all are Ashkenazim
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3) Inherited Neuropathies
HSAN IV
(= hereditary anhidrotic sensory neuropathy, = congenital insensitivity to pain with anhidiosis)
- AR, due to trkA receptor (for NGF) mutations (in some families, at least)
- all unmyelinated nerve fibres lost, myelinated fibres preserved
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3) Inherited Neuropathies
5) FAPs (Familial amyloidotic polyneuropathies)
Most are due to one of many point mutations in the transthyretin (TTR) gene.
Clinical
- neuropathy, usually lower limbs first, in nearly all, sensory before motor, small
before large fibre
- autonomic features common
- other features may be seen - CTS, cardiomyopathy, vitreous deposits
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Hereditary Spastic Paraplegia
Clinically divided into “pure” and
“complicated”
Pure HSP
History
- onset usually teens - 30’s, but can be infancy to 80’s
- typically slowly/relentlessly progressive
- bladder involvement may occur late
Examination features
- cranial nerves (JJ, rapid tongue movements) normal
- upper limb reflexes typically brisk with spread, ± Wartenberg’s thumb sign, but tone and power normal
- lower limb tone increased, ± clonus
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Hereditary Spastic Paraplegia
- lower limb power often decreased, especially hip flexors/ankle
dorsiflexors
- lower limb hyperreflexia + spread. Plantars usually extensor; abdominal
reflexes often preserved
- sensation usually normal: may have mild vibration perception loss
- may have pes cavus
Complicated HSP
- pure HSP + other features such as
- ataxia
- peripheral sensory loss/ mutilation
- amyotrophy
- retinitis pigmentosa
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Hereditary Spastic Paraplegia
Genetics of pure HSP
Most cases dominant (or just better ascertainment)
- AD - at least 7 defined loci
- only SPG4 (“spastin”) cloned to date (2p) (commonest AD HSP, >40%, - not tested for routinely)
- nuclear ATPase
- 39 point mutations found throughout 17 exons, so hard to test
- AR - at least 2 loci defined
- only SPG7 (“paraplegin”) cloned to date (16q)
- ATPase in mitochondria (have RRF’s)
- not tested for routinely
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Hereditary Spastic Paraplegia
Spastin mutation phenotype
- 25% non-penetrant or only detected on exam
- mean onset age 29, but range wide (infancy - 79!)
- progression highly variable, but significantly faster in those with late onset (>35 years)
- associated signs (weakness, wasting, decreased vibration perception,
sphincter disturbances) related to disease
- not always “pure” - cognitive impairment and epilepsy seen rarely
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Hereditary Spastic Paraplegia
Genetics of Complicated HSPX-linkedi) LI-CAM mutations (SPG1)
CRASH syndrome(corpus callosum agenesis,
retardation, adducted thumbs, spastic paraplegia, hydrocephalus) - includes MASA syndrome
ii) PLP mutations (SPG2)Pelizaeus-Merzbacher disease- widely variable severity, from
infantile hypotomia/nystagmus/pyramidal/ cerebellar/dystonia, to complicated HSP, to pure HSP
- female carriers may manifestAD or AR(Only gene found to date is for ARSACS Charlevoix-Saguenay spastic ataxia - only identified in French-Canadians to date)
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Hereditary Spastic Paraplegia
Differential diagnosis of HSP
- major problem is with isolated case
- other genetic causes
- AMN (isolated male)
- SCA’s
- DRD (therapeutic trial)
- structural causes (do not forget tethered cord, AVM)
- degenerative causes
- MS
- PLS variant of MND
- infectious causes
- TSP, HIV (subacute courses)
- metabolic causes
- B12, lathyrism
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Friedreich’s Ataxia
AR - equal commonest genetic ataxia of childhood (~1/40,000)
- carrier rate ~1/100
Classical Clinical Picture
- onset 8-15 years; can be as late as 25
- within 5 years of onset should have
- progressive limb and gait ataxia
- absent lower limb DTR’s
- extensor plantars
- median motor NCV >40 ms-1, with reduced or absent SNAP’s
- within 10 years of onset should have
- dysarthria
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Friedreich’s Ataxia- most patients also have
- scoliosis- abnormal ECG/ECHO (but cardiac symptoms rare until preterminal)- abnormal ocular pursuit (nystagmus <50%)- pyramidal weakness in legs
- a minority of patients also have- glucose intolerance (~20%; 10% diabetic)- optic atrophy (~30%)- sensorineural hearing loss (~20%)
(Note:- MRI typically does not show cerebellar atrophy)
BUT this is too restrictive! Since gene test,many non-classical presentations recognised
i) LOFA - late-onset FA - >25 years and can be in 50’s-60’s. Often preserved
reflexes, no cardiomyopathy, slow progression
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Friedreich’s Ataxia
ii) FARR - FA with retained reflexes. Reflexes can be brisk. Most patients
with Harding’s AR ataxia with preserved reflexes have this.iii) Acadian ataxia - a milder variant in
Acadians (ex French-Canadians)iv) Assorted others (rare) - e.g. spastic
paraplegia, pure sensory ataxia, chorea/myoclonus
Genetic Mechanism- GAA triplet repeat expansion in intron 1 of
frataxin gene (9q). ~95%- rarely point mutations (various)- severity inversely proportional to amount of
residual gene product (-/- mice are not viable)- longer GAA repeats decrease
product more, so severity depends on length of shorter repeat
- double point mutations probably lethal - do not occur
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Friedreich’s Ataxia
- frataxin - mitochondrial protein - absence causes iron accumulation and excess oxidative stress
- idebenone reported to reverse cardiomyopathy in part
Prognosis- variable; - >95% of classic patients
wheelchair-bound by age 45- typically wheelchair-bound about 15 years after onset- mean age of death mid-30’s, but normal survival possible if no cardiomyopathy or diabetes
Imitators (genetic)i) AVED (isolated Vitamin E
deficiency)- mutations in -tocopherol transferase (8qB)- FA-like, with fine retinal pigmentation
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Friedreich’s Ataxia
ii) Abetalipoproteinaemia and hypobetalipoproteinaemia (not the
same) - AVED-like pictureiii) NARP (neuropathy, ataxia, retinitis
pigmentosa) mitochondrial inheritance - ATP synthetase subunit 6 point mutations
(Note:- Roussy-Levy syndrome is really CMT1)
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Ataxia - Telangiectasia
AR - equal frequency to FA (1/40,000, so carrier rate ~1/100)
- commonest cause of inherited ataxia before age 5- typically wheelchair-bound by age 10-11
Clinical picturei) neurological
- onset between infancy and 20; gait ataxia- may have titubation, myoclonus, chorea- dystonia in post-adolescent patients- dysarthria - slow, slurred- impassive facies; may drool- ocular motor “apraxia”, with
compensatory head thrust- may develop sensory loss/distal
weakness/areflexia, but plantars are flexor
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Ataxia - Telangiectasia
ii) non-neurological- telangiectases - bulbar conjunctivae
between ages 3-5, then- pinnae, palate, elbow and
knee flexures- recurrent sinusitis/pneumonia- lymphomia/leukaemia
(- solid organ malignancies when older)- marked radiosensitivity
Laboratory tests- elevated FP and CEA (may be normal in childhood)- 2/3 show impaired humoral and/or cellular immunity
- absent or low IgG2, IgA, IgE (IgG and M normal)- decreased DTH and T cells
- cytogenetic studies show t(7;14) translocations and radiosensitivity
- MRI - early cerebellar atrophy
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Ataxia - Telangiectasia
Clinical variants- AT sine telangiectasia
(- AT sine immune compromise)- both together constitute some, and maybe all, of Aicardi’s “Ataxia Ocular Motor Apraxia”
Genetic mechanism- ATM (“mutation in AT”) gene 11q- large (>180 kb, 3056 aas), many point
mutations, so not tested for routinely (Research - QIMR)
- most mutations nonsense (deletions, splice mutations, stop mutations)
- missense mutations produce milder phenotype in homozygotes/compound heterozygotes
Note: - Heterozygote carriers have increased sensitivity to DXRT
- Female heterozygote carriers may have increased risk of breast cancer
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Spinocerebellar Ataxias (SCA’s)
- All AD; mostly adult - onset
- Named in order of discovery, not frequency
- SCA’s 1, 2, 3, and 6 tested locally; SCA 7 in Sydney
SCA 1 - 6q; (CAG)n expansion (39) in ataxin 1 gene
- common(est) in Anglocelts
- pyramidal features common - slow MEPs
- nystagmus uncommon (<10%) but saccades often hypermetric
- may have optic atrophy (mild)
- MRI shows moderate pontocerebellar atrophy
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Spinocerebellar Ataxias (SCA’s)SCA 2 - 12q; (CAG)n expansion (34) in
ataxin 2 gene
- commonest +++ in Italians
- typically - slow/viscous eye movements
- depressed reflexes
- may have early dementia
- MRI typically shows severe pontocerebellar atrophy
SCA 3/MJD - 14q; (CAG)n expansion (66) in ataxin 3 gene
- commonest in Portuguese, Germans, Chinese
- very variable syndrome
± spasticity, ± amyotrophy,
± neuropathy (may be small fibre)
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Spinocerebellar Ataxias (SCA’s)- may have autonomic
dysfunction (confusion with sporadic OPCA)
- may present as extrapyramidal syndrome; parkinsonism/ dystonia common
- may be ophthalmoplegia, but typically horizontal gaze-
evoked nystagmus ± diplopia
- MRI shows enlargement of 4th ventricle only
SCA 4 - 16q; gene unknown
- ?frequency - may be rare
- sensory axonal neuropathy prominent (may be 1st); pyramidal signs
May also be a cause of pure ataxia (ADCA III)
SCA 5 - 11 cent; gene unknown
- ?frequency
- relatively slow course; pure or + pyramidal signs
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Spinocerebellar Ataxias (SCA’s)
*SCA 6 - 19 p; CACNL1 A4 gene (1A subunit of P-type voltage gated Ca2+ channels) CAG repeat (21-29)
- common (except in France) (equal with SCA 1 here)
- The exception in SCA’s because
- repeat number small (and stable)
- mutation disrupts function of Ca2+ channel
(not gain of novel function)
- topography of neuropathology matches distribution of gene product
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Spinocerebellar Ataxias (SCA’s)
- Clinically
- may cause later onset, slowly progressive pure ataxia (ADCA III) - ?shorter repeats
- may cause earlier, more rapid ataxia with pyramidal signs (ADCA
I) - ?longer repeats
- Allelic with (and phenotypic overlap with)
- EA2 - nonsense (truncating) CACNL1A mutations
- FHM1 - missense CACNL1A mutations
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Spinocerebellar Ataxias (SCA’s)
SCA 7 - 3p; (CAG)n expansion ++ (38) in ataxin 7 gene
- rare everywhere (~1-2% of SCA’s)
- characterised by tritanopia leading to visual failure (ADCA II)
- early onset <30
- later if later onset