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

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

- 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.

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

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

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

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) 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

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

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

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

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

- 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

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

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

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)

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

- 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

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

- 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

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

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

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

*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

- 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

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

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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