1) SMAs

1
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 lt6 months (may be in utero)
• - death usually lt2 years (intercostal type
• respiratory failure)
• - severely weak, floppy, suck poorly,
• never sit
• SMA II (intermediate)
• - onset lt18 months
• - death gt2 years (can survive to adulthood)
• - can sit never stand or walk alone

2
1) SMAs

• SMA III (juvenile - Kugelberg-Wielander)
• - onset gt18 months
• - death - adult (can have normal lifespan)
• - walk alone
• - proximal distal weakness, legs gt arms
• All 3 have
• - symmetrical muscle weakness/wasting (proximal
  gt distal)
• - decreased or absent DTRs
• - fasciculations tongue, but not EOM, facial,
  diaphragmatic or myocardial involvement
• - tremor hands
• (These distinguish them from distal SMAs.)
• - normal SNAPS, and motor NCVs gt70 N
• (These distinguish them from CMT2.)

3
1) SMAs

• Genetic mechanism
• - In mice, SMN deletion is embryonic lethal
  (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 of SMN
  protein expression and phenotype.
• - SMNc produces an alternatively
  spliced protein, lacking exon 7. In SMA
  III, SMNt gene is converted to an SMNc gene,
  partially rescuing the phenotype.

4
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.

5
1) SMAs

• 1c) X-linked bulbo-spinal muscular
  atrophy (Kennedys syndrome)
• Tested for locally
• Clinically
• - onset of wasting typically 30-50 years slow
  progression (decades)
• - muscle cramps almost universal can precede
  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

6
1) SMAs

• - postural tremor 50-100
• - DTRs decreased or (usually) absent
• - may have mild distal sensory loss
  great majority (gt85) 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
  causes testicular feminisation
• - probably combination of gain of novel function
  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 correlat
  ions
• 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 (lt1)
  mutation (tested Sydney)
• CMT1b 1q22-23 P0 AD Point mutation (6)
  (tested Sydney)
• CMT1c 10q21.1-22.1 EGR2 AD Point mutations
• CMTX 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 and
• some specific P0 mutations may have a CMT2
  phenotype.

11
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 all
• CMT1

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3) Inherited Neuropathies

• b) CMT2 ( HMSN2)
• median motor NCV gt42 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

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3) Inherited Neuropathies

• c) Dejerine-Sottas Syndrome (HMSN3) (rare)
• (some require median motor NCV lt10 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 - 20s
• - 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-20s
• - usually with painless foot ulceration/neurop
  athic 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

20
Hereditary Spastic Paraplegia

• Clinically divided into pure and
• complicated
• Pure HSP
• History
• - onset usually teens - 30s, but can be
  infancy to 80s
• - 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, Wartenbergs 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, gt40, - 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 RRFs)
• - not tested for routinely

23
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
  (gt35 years)
• - associated signs (weakness, wasting,
  decreased vibration perception, sphincter
  disturbances) related to disease
• - not always pure - cognitive impairment and
  epilepsy seen rarely

24
Hereditary Spastic Paraplegia

• Genetics of Complicated HSP
• X-linked
• i) 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 manifest
• AD or AR
• (Only gene found to date is for ARSACS
  Charlevoix-Saguenay spastic ataxia - only
  identified in French-Canadians to date)

25
Hereditary Spastic Paraplegia

• Differential diagnosis of HSP
• - major problem is with isolated case
• - other genetic causes
• - AMN (isolated male)
• - SCAs
• - 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

26
Friedreichs 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 DTRs
• - extensor plantars
• - median motor NCV gt40 ms-1, with reduced
  or absent SNAPs
• - within 10 years of onset should have
• - dysarthria

27
Friedreichs Ataxia

• - most patients also have
• - scoliosis
• - abnormal ECG/ECHO (but cardiac
  symptoms rare until preterminal)
• - abnormal ocular pursuit (nystagmus
  lt50)
• - 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 - gt25 years and can
  be in 50s-60s. Often preserved reflexes, no
  cardiomyopathy, slow progression

28
Friedreichs Ataxia

• ii) FARR - FA with retained reflexes.
  Reflexes can be brisk. Most patients with
  Hardings 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

29
Friedreichs Ataxia

• - frataxin - mitochondrial protein - absence
  causes iron accumulation and excess oxidative
  stress
• - idebenone reported to reverse cardiomyopathy in
  part
• Prognosis
• - variable - gt95 of classic patients
  wheelchair-bound by age 45
• - typically wheelchair-bound about 15
  years after onset
• - mean age of death mid-30s, 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

30
Friedreichs Ataxia

• ii) Abetalipoproteinaemia and hypobetalipoprot
  einaemia (not the same) - AVED-like picture
• iii) 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 picture
• i) 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

32
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(714)
  translocations and radiosensitivity
• - MRI - early cerebellar atrophy

33
Ataxia - Telangiectasia

• Clinical variants
• - AT sine telangiectasia
• ( - AT sine immune compromise)
• - both together constitute some, and maybe all,
  of Aicardis Ataxia Ocular Motor Apraxia
• Genetic mechanism
• - ATM (mutation in AT) gene 11q
• - large (gt180 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

34
Spinocerebellar Ataxias (SCAs)

• - All AD mostly adult - onset
• - Named in order of discovery, not frequency
• - SCAs 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 (lt10) but saccades
  often hypermetric
• - may have optic atrophy (mild)
• - MRI shows moderate pontocerebellar
  atrophy

35
Spinocerebellar Ataxias (SCAs)

• 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)

36
Spinocerebellar Ataxias (SCAs)

• - 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

37
Spinocerebellar Ataxias (SCAs)

• 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 SCAs 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

38
Spinocerebellar Ataxias (SCAs)

• - 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

39
Spinocerebellar Ataxias (SCAs)

• SCA 7 - 3p (CAG)n expansion (?38) in
  ataxin 7 gene
• - rare everywhere (1-2 of SCAs)
• - characterised by tritanopia leading
  to visual failure (ADCA II)
• - early onset lt30
• - later if later onset