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Table 1 Different subtypes of familial ALS and their genotype–phenotype correlations

From: Genotype-phenotype correlations of amyotrophic lateral sclerosis

ALS type Gene Inheritance ALS features FTD Other features/disorders
(chromosome)
ALS 1 SOD1 AD; AR; AAO: adult > juvenile; Onset: LL > UL > bulbar; Rare PMA, PBP, BFA, cerebellar ataxia, autonomic dysfunction
(21q22.1) De novo Progression: rapid > slow; UMN + LMN > LMN dominant
ALS 2 ALSIN AR AAO: juvenile; Onset: LL, UL; None PLS, IAHSP
(2q33.2) Progression: slow; UMN dominant > UMN + LMN
ALS 3 UN AD N/A N/A N/A
(18q21)
ALS 4 SETX AD AAO: juvenile > adult; Onset: LL > UL; None AOA2, cerebellar ataxia, motor neuropathy
(9q34) Progression: slow; UMN + LMN > LMN dominant
ALS 5 SPG11 AR AAO: juvenile > adult; Onset: bulbar, limb; Rare HSP, autonomic dysfunction, mental retardation
(15q21.1) Progression: slow; UMN dominant > UMN + LMN
ALS 6 FUS AD; AR; AAO: adult > juvenile; Onset: UL, bulbar > LL; Rare PMA, Parkinsonism, essential tremor, mental retardation
(16q11.2) De novo Progression: rapid > slow; UMN + LMN > LMN dominant
ALS 7 UN AD N/A N/A N/A
(20p13)
ALS 8 VAPB AD AAO: adult > juvenile; Onset: limb; None SMA, motor neuropathy, autonomic dysfunction
(20q13.3) Progression: slow; LMN dominant
ALS 9 ANG AD AAO: adult > juvenile; Onset: limb, bulbar; Yes PBP, PD
(14q11.2)
Progression: N/A; UMN + LMN
ALS 10 TARDBP AD; AR AAO: adult; Onset: limb, bulbar; Yes PSP, FTD with Parkinsonism, PD, chorea
(1p36.22) Progression: variable; UMN + LMN
ALS 11 FIG4 AD AAO: adult; Onset: bulbar > limb; None CMT4J, HSP, PLS, Yunis–Varon syndrome, epilepsy with polymicrogyria
(6q21) Progression: variable; UMN + LMN > UMN dominant
ALS 12 OPTN AD; AR AAO: adult; Onset: bulbar, limb; Yes POAG, Parkinsonism, aphasia
(10p13) Progression: slow; UMN + LMN
ALS 13 ATXN2 AD AAO: adult > juvenile; Onset: UL, LL; None SCA2, Parkinsonism
(12q24) Progression: variable; UMN + LMN
ALS 14 VCP AD AAO: adult > juvenile; Onset: limb > bulbar; Yes IBMPFD
(9p13) Progression: variable; UMN + LMN
ALS 15 UBQLN2 XD AAO: adult > juvenile; Onset: limb, bulbar; Yes PLS
(Xp11.21) Progression: variable; UMN + LMN > UMN dominant
ALS 16 SIGMAR1 AD AAO: juvenile; Onset: LL > UL; Rare motor neuropathy
(9p13.3) Progression: N/A; UMN + LMN
ALS 17 CHMP2B AD AAO: adult; Onset: bulbar, limb; Yes PMA; Parkinsonism
(3p12.1) Progression: N/A; UMN + LMN > LMN dominant
ALS 18 PFN1 AD AAO: adult; Onset: limb; None N/A
(17p13.2) Progression: N/A; UMN + LMN
ALS 19 ERBB4 AD AAO: adult; Onset: UL, bulbar; None N/A
(2q33.3-q34) Progression: slow; UMN + LMN
ALS 20 hnRNPA1 AD AAO: adult; Onset: N/A; Yes multisystem proteinopathy
(12q13.1) Progression: N/A; UMN + LMN > LMN dominant
ALS 21 MATR3 AD AAO: adult; Onset: bulbar, limb; Yes distal myopathy
(5q31.3) Progression: slow; UMN + LMN > LMN dominant
ALS-FTD C9ORF72 AD AAO: adult; Onset: bulbar, limb; Yes Parkinsonism, cerebellar ataxia
(9p21.2) Progression: rapid > slow; UMN + LMN
  1. Abbreviations: AAO age at onset, AD autosomal dominant, ALS amyotrophic lateral sclerosis, AOA2 ataxia and oculomotor apraxia type 2, AR autosomal recessive, BFA benign focal amyotrophy, CMT4J Charcot-Marie-Tooth disease, FTD frontotemporal dementia, HSP hereditary spastic paraplegia, IAHSP infantile-onset ascending hereditary spastic paralysis, IBMPFD inclusion body myopathy with Paget’s disease and frontotemporal dementia, LL lower limb, LMN lower motor neuron, N/A not available, PBP progressive bulbar palsy, PD Parkinson’s disease, PLS primary lateral sclerosis, PMA progressive muscular atrophy, POAG primary open angle glaucoma, PSP progressive supranuclear palsy, SCA2 spinocerebellar ataxia 2, UL upper limb, UMN upper motor neuron; UN unknown, XD X-linked dominant