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ALS: Hereditary & Familial Spinal muscular atrophy (SMA): Types Recessive SMA SMA: SMN 5q13 Congenital with arthrogryposis Werdnig-Hoffmann Kugelberg-Welander Spinal muscular atrophy 2 (SMA2) Spinal motor neuropathy: RBM7; 11q232 SMA + Congenital fractures TRIP4; 15q22 ASCC1: 10q22 SMA + Encephalopathy: TBCD; 17q25 SMA + Myoclonus Epilepsy: ASAH1; 8q22 SMA + Pontocerebellar hypoplasia (PCH) PCH1A: VRK1; 14q32 PCH1B: EXOSC3; 9p11 Other: Motor + Cerebellar EXOSC8; 3q13 EXOSC9; 4q27 Mitochondrial DGUOK: 2p13 SCO2: 22q13 SLC25A21: 14q13 TK2: 16q22 Congenital contractures Dominant, Proximal Adult: VAPB; 20q13 Adult + Cramps (SMAJ): CHCHD10; 22q11 Bulbar Congenital + Legs weak: TRPV4; 12q24 HMSN-P (Okinawa type): TFG; 3q12 Respiratory & Proximal arms: MAPT; 17q21 Scapuloperoneal syndromes SMALED 1: Leg predominant; DYNC1H1; 14q32 2: Early-onset; Contractures; BICD2; 9q22 X-linked SMA (Recessive) Bulbospinal (Kennedy): AR; Xq12 SMAX 2: Infant + Arthrogryposis; UBE1; Xp11 3: Distal; ATP7A; Xq21 |
HMN 1: 7q34; Dominant 2 A: HSPB8 (HSP22); 12q24; Dominant B: HSPB1 (HSP27); 7q11; Dom or Rec C: HSPB3 (HSPL27); 5q11; Dominant D: FBXO38; 5p31; Dom or Rec 5: Upper limb predominance A: GARS; 7p15; Dominant B: REEP1; 2p11.2; Dominant C: BSCL2; 11q13; Dominant 6: IGHMBP2; 11q13; Recessive 7: + Vocal cord paralysis, Dominant A: SLC5A7; 2q12 B: Dynactin 1 (DCTN1); 2p13 8: Congenital, Legs: TRPV4; 12q24 9 (dHMN): WARS1; 14q32; Dominant + Upper motor neuron Senataxin; 9q34; Dominant 4q34: Dominant HMN J: 9p21; Recessive 2B: HSPB1; 7q11; Dominant 5C: BSCL2; 11q13; Dominant 7B: Dynactin; 2p13; Dominant SPG + Motor neuropathy HMN: 11p; Recessive HMN: 16p HMN: KCC3; 15q14; Dominant HMN: SPTAN1; 9q34; Dominant HMN: MME; 3q25; Recessive CMT 2N: AARS; 16q22; Dominant CMT 2O: DYNC1H1; 14q32; Dominant Neuromyotonia: HINT1; 5q31; Recessive Childhood: BICD2; 9q22 Intellectual Disability: TBCK; 4q24 Protein mechanisms |
Motor Neuropathy Differential diagnosis General, Distal Lower motor neuron Motor syndromes Also: NMJ disorders Distal SMA (DSMA; dHMN) Recessive 1 (SMARD1): IGHMBP2; 11q13 2 (HMN J): 9p21 3: 11q13 4: PLEKHG5; 1p36 5: DNAJB2 (HSJ1); 2q35 dHMN: SIGMAR1: 9p13 dHMN: SYT2; 1q32 + Ataxia telangectasia: ATM; 11q22 + Encephalopathy: TBCE; 1q42 Lethal congenital contractures MND, Distal: VRK1; 14q32 SORD: 15q21 Dominant Calf predominant: FBXO38; 5p31 Leg predominant Distal Ulnar-Median Childhood: BICD2; 9q22 + Macular Δ: FBLN5; 14q32 + Hearing loss: MYH14; 19q13 Scapuloperoneal: TRPV4; 12q24 SMAJ1: GARS1; 7p14 HMN: HARS; 5q31 HMN: GBF1; 10q24 X-linked dHMN: AIFM1; Xq26 SMAX 3: ATP7A; Xq21 SMARD2: LAS1L; Xq12 Mitochondrial mtATP6 ± Episodic weakness mtATP8 Sporadic: Hirayama Distal Motor Neuropathy or Myopathy |
Multisystem disorders Recessive AAA syndrome: Aladin; 12q13 ANE: RBM28; 7q31 Chediak-Higashi: LYST; 1q42 CONDCA: AGTPBP1; 9q21 Hexosaminidase A: HEXA; 15q23 Leukoencephalopathy: SCP2; 1p32 MND + Dementia & Ophthalmoplegia MPAN: c19orf12; 9q12 STAT5B: 17q21 TBX5: 12q24 Motor PN + Myopathy: VWA1; 1p36 Dominant Cataracts & Skeletal abnormalities DDPAC: MAPT; 17q21 HMN: EMELIN-1; 2p23 Machado-Joseph: Ataxin-3; 14q32 Myopathy + Paget: HNRNPA2B1; 7p15 X-linked Cabezas: CUL4B; Xq23 Neuroaxonal dystrophy 2 Polyglucosan body: GBE1; 3p12 Mitochondrial: SCO2 Sporadic: Camera-Marugo-Cohen Spastic paraparesis Spastic paraparesis + Motor neuropathy Bulbar syndromes AAA syndrome: Aladin; 12q13; Recessive Brown-Vialetto-van Laere: SLC52A2/A3 BSMA: Androgen Receptor; Xq12 BSMA: Dominant Bulbar ALS Fazio-Londe: Recessive or Dominant FOSMN PLS, Juvenile: Alsin; 2q33; Recessive Worster-Drought |
Distal SMA
![]() From: Spiller |
Epidemiology & History Genes Clinical - Genetic correlations SMN1 SMN2 Modifiers Neighboring & Related SMN Protein Clinical features Congenital Arthrogryoposis SMA 0 Types: 1; 2; 3; 4 Lower motor neuron Pathology Treatments |
![]() Hoffman ~1891 ![]() From: Andrew Kornberg MD |
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5q CHROMOSOMES Typical SMN mutations in SMA |
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SMN1 Normal gene
![]() SMN1 Mutation types Deletion ![]() Conversion to SMN2 gene ![]() SMN2 gene ![]() More copies: Correlate with milder SMA. SMN2 mutations alone: Don't produce SMA |
![]() From: A Kornberg MD |
![]() From: M Ryan MD |
![]() SMA Spinal cord
Anterior roots are atrophic |
Androgen receptor protein Clinical features Clinical-genetic correlations Epidemiology Laboratory features Onset Pathogenic mechanisms Pathology |
![]() ![]() Bulbo-Spinal Muscular Atrophy
Gynecomastia |
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Hereditary Motor Neuropathies: General features
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Feature | Hereditary ALS | Sporadic ALS |
Males:Females | 1:1 | 1.7:1 |
Disease Duration | Bimodal < 2 & > 5 years |
Unimodal 3 to 4 years |
% of ALS cases | 5% to 15% | ~90% |
Onset | ||
Age distribution | More younger | More older |
Mean age | 46 years | 56 to 63 years |
Juvenile | ALS 2, 4, 5, 6 | Rare |
Bulbar features | 25% c9orf72 40% ALS1 10% |
15% |
Legs | Common | Occasional |
LMN predominant | ALS 1, 6, 17 | PMA |
Clinical features General Specific syndromes Mutations Location Functional aspects Specific correlations Pathology Population statistics SOD1 other SOD1 protein Variants Canine disorder SOD1 deficiency |
![]() From: M Weiss ALS-SOD1 (A4V): Tongue atrophy
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ALS syndromes: Correlations with some SOD1 mutations | |
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Specific SOD1 mutations l Exon 1; Ala4Val Most common mutation Rapid onset & progression (1.0 yrs) Frequently only lower motor neuron signs l Exon 2; His46Arg @ Cu binding site of SOD Onset: Late; Legs Bulbar unusual Slow progression (17 yrs) l Exon 2; 6 bp deletion(ΔG27/P28) 65 Mutation reduces transcription Low levels of mutant SOD1 protein Philipino founder Low penetrance Disease duration: 4.3 years l Exon 4; Leu84Val Lower motor neuron only Rapid progression (1.5 yrs) ?Earlier onset in males l Exon 4; Asp90Ala Onset: 20 to 94 yrs; Legs; Preparetic phase Leg cramps; Myalgia; Painful paresthesia Bladder dysfunction Progression: Slow; Legs ® Arms Inheritance Recessive: Finnish (2.5% carriers) Dominant: Clinically variable Incomplete penetrance l Exon 4; Ile104Phe Variable intrafamilial clinical features Age of Onset: 6 yrs - asymptomatic Course: 2 to 14 yrs until bulbar signs Limb onset: arms or legs l Exon 4; Ile113Thr Reported in Sporadic ALS patients Relatively common; Low penetrance Late Onset: Mean 59 years Course: Variable; 2 to 20 years l Exon 5; Codon 126 2 base pair deletion Rapid Progression ![]() |
ALS clinical features
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![]() Hyaline conglomerate inclusion |
Brown-Vialetto-van Laere 1: SLC52A3; 20p13; Recessive 2: SLC52A2; 8q24; Recessive 3: UBQLN1; 9q21; Dominant Bulbar ALS Fazio-Londe: SLC52A3; 20p13; Recessive Kennedy's Syndrome: Androgen Receptor ; Xq12; Recessive Madras motor neuron disease: Sporadic Spino-bulbar muscular atrophy: Dominant Worster-Drought |
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