The Evidence for ALS as a Multisystems Disorder of Limited Phenotypic Expression

Can. J. Neurol. Sci. 2001; 28: 293-308

Table 1: Familial ALS - known inheritance patterns

Inheritance Pattern

Chromosomal linkage

Unique features

Reference

Autosomal Dominant

ALS 1

21q22.1

Cu/Zn superoxide dismutase mutations

55

ALS X

Xp11 - q12

Adult onset

206

ALS 3

 

Adult onset; absence of linkage to Cu/Zn superoxide dismutase

207

ALS 4

9q34

Juvenile onset, complete penetrance; very slow progression; distal limb amyotrophy with pyramidal signs

208,209

ALS 6

9q21 - q22

Frontotemporal dementia associated

53

ALS with bulbar onset

unknown

Japanese family; juvenile onset with prominent early onset bulbar dysfunction; slow progression; dementia

210

NFH

22q12.1 - q22

Mutations in KSP repeats (not observed in fALS; only found in sporadic ALS)

115-118

Autosomal recessive

ALS 2

2q33 - q35

Spastic pseudobulbar syndrome with spastic paraplegia; childhood onset; slow progression,

2,211

ALS 5

15q15.1 - q21.1

Not pseudobulbar; distal amyotrophy; minor spasticity; long-term survival

212

Brown-Vialetto-van Laere syndrome

 

Progressive bulbar paralysis; childhood onset; progressive deafness; pyramidal signs;

213

X-linked

Kennedys syndrome

Xq12

Progressive muscle atrophy; gynecomastia; reduced fertility; Androgen receptor gene mutation (trinucleotide (CAG) repeat)

214-217

Miscellaneous

Hexosaminidase A and B

15q23 - q24

Late onset GM2 gangliosidosis

218-221

Disinhibition-dementia-parkinsonism-amyotrophy syndrome

Chr 17

Allelic with frontotemporal dementia and parkinsonism

54

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Table 2: Familial ALS 1 - general syndrome features associated with specific point mutations

Lower motor neuron predominant

A4V; L84V; D101N

Slow progression

G37R (18y); G41D (11y); G93C; L144S; L144F

Rapid progression

A4T (1.5y); N86S (homozygous, 5 months); L106V (1.2y); V148G (2y)

Late onset

G85R; H46R

Early onset

G37R; L38V

Female predominant

G41D

Bulbar onset

V148I

Low penetrance

D90A; I113T

(modified in part from Andersen PM, Morita M, Brown RH, Jr. Genetics of amyotrophic lateral sclerosis: an overview. In: Brown RH, Jr., Meininger V, Swash M, eds. Amyotrophic lateral sclerosis. London: Martin Dunitz Ltd., 2000: 223-250. )

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