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

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.)

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.

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.

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

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

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.)

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)

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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)

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

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

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

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

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)

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

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

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

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