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 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.
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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
- 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
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