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Table 1 The genotype and phenotype associated with familial ALS-related genes

From: Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis

Type Gene Mode of inheritance Country Age at onset (range) Mean age at onset (years) Initial symptoms UMN Cognitive impairment Other features
ALS1 SOD1 AD, AR, de novo Japan, Italy, Spain, Korea, UK, USA, Turkey, Sweden, Iran, Porland, Bulgaria, China, France, Germany, Denmark, Pakistan, Canada, and so on 6–94 48 LL > UL > bulbar Positive (LMN dominant) Very rare Progressive muscular atrophy, progressive bulbar palsy, facial onset sensory motor neuronopathy (FOSMN) syndrome, vocal cord paralysis, cerebellar ataxia, sensory disturbance (vibration), autonomic dysfunction (incontinence, neurogenic bladder), lower back pain
ALS2 Alsin AR Tunisia, Saudi Arabia, Kuwait, Italy, Algeria, Hungary, Germany, The Netherlands, Pakistan, Bangladesh, Turkey, Japan, Portugal, France, Cyprus, China 1–11 2 LL, UL Positive None Juvenile ALS, juvenile primary lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia, generalized dystonia, cerebellar ataxia
ALS3 unknown AD        
ALS4 SETX AD USA, Austria, Belgium, Italy, Afghanistan, China 1–73 19 LL > UL Positive None Cerebellar ataxia, oculomotor apraxia (type 2), motor neuropathy, thin cervical spinal cord
ALS5 SPG11 AR Italy, Turkey, Japan, Canada, Brazil 7–23 16 Bulbar, LL, UL Positive Rare (mental retardation) Juvenile ALS, hereditary spastic paraparesis, autonomic dysfunction (incontinence)
ALS6 FUS AD, AR, de novo Belgium, Italy, Korea, UK, Japan, Turkey, Canada, France, USA, Germany 13–80 45 UL, bulbar > LL Positive (LMN dominant) Rare (mental retardation) Progressive muscular atrophy, Parkinsonism, essential tremor, schizofrenia, learning disabilities
ALS7 unknown AD        
ALS8 VAPB AD Brazil, UK, France (Japan), The Netherlands 18–73 44 UL, LL Negative None Progressive muscular atrophy, progressive bulbar palsy, motor neuropathy, postural tremor, autonomic dysfunction (chronic intestinal constipation, sexual dysfunction)
ALS9 ANG AD The Neitherland, Ireland, Scotland, UK, USA, Sweden, Italy, France, Germany, China, 21–86 55 UL, LL, bulbar Positive FTD Parkinsonism, progressive bulbar palsy
ALS10 TDP-43 AD, AR Italy, France, UK, China, Germany, Turkey, USA, Belgium, Japan, Porland, Afghaistan, Canada 20–77 54 UL, LL, bulbar Positive FTD (rare) Parkinsonism, chorea, progressive supranuclear palsy
ALS11 FIG4 AD USA 29–77 55 Bulbar > UL, LL Positive None Hereditary spastic paraparesis, primary lateral sclerosis, personality change
ALS12 OPTN AD, AR Japan, Italy, Turkey, The Netherlands, Denmark 24–83 51 Bulbar, UL, LL Positive FTD, AGD Primary open angle glaucoma, parkinsonism, finger deformity, personality change, depression
ALS13 ATXN2 AD USA, Belgium, the Netherlands, Canada, France, China, Germany, Switzerland, Italy, Turkey, Cuba 21–87 60 UL, LL Positive None Cerebellar ataxia, corticobasal syndrome, Parkinsonism
ALS14 VCP AD Italy, USA, The Netherlands, Japan 36–68 48 LL > UL > bulbar Positive FTD Paget’s Disease, inclusion body myopathy
ALS15 UBQLN2 SD USA, Australia, Canada, Italy, Turkey, Belgium, Germany, Bulgaria M: 14-72, F: 16-77 44 UL, LL, bulbar Positive FTD Primary lateral sclerosis, progressive bulbar palsy, relentlessly progressive choreoathetoid movements, spastic paralysis
ALS16 SIGMAR1 AD Saudi Arabia 1-68 1 LL > UL Positive FTD (rare) Juvenile ALS
ALS17 CHMP2B AD Denmark, the Netherlands 26-73 69 Bulbar, UL, LL, respiratory Positive (LMN dominant) FTD Progressive muscular atrophy, parkinsonism
ALS18 PFN1 AD Sephardic Jewish, Italy, USA, China, Belgium 33-63 53 Limb N/A N/A  
ALS19 ERBB4 AD Japan, Canada 45-70 61 UL, bulbar, respiration Positive None  
ALS20 HNRNPA1 AD N/A N/A N/A N/A N/A FTD Paget’s Disease, inclusion body myopathy
ALS21 MATR3 AD USA,UK, Italy, Taiwan 36-64 52 LL > UL, bulbar Positive FTD Distal myopathy (inclusion body myopathy)
ALS-FTD1 C9ORF72 AD Finland, Sardinia, Ireland, UK, Italy, USA,Canada, Germany, the Netherlands, Turkey, Israel, Australia, Japan 27–80 57 UL, LL, bulbar Positive FTD Parkinsonism, cerebellar ataxia, psychosis,
ALS-FTD2 CHCHD10 AD France, USA, Germany, Spain, Italy, Finland 35-73 56 Bulbar, UL, LL Positive (LMN dominant) FTD Cerebellar ataxia, mitochondrial myopathy, deafness, neurogenic bladder, facial paresis, Parkinsonism
  TBK1 AD, de novo Sweden, Denmark, Germany, France, Portugal 35-80 60 Bulbar, UL, LL, respiratory Positive FTD (50 %)  
  1. AD, autosomal dominant; AR, autosomal recessive; UL, upper limb; LL, lower limb; LMN, lower motor neuron; FTD, frontotemporal dementia