DISTAL SPINAL MUSCULAR ATROPHY and related disorders

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DISTAL SPINAL MUSCULARATROPHY and related
disorders

• Louis VIOLLET
• SUMMER SCHOOL MYOLOGY 2004

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SMA -DEFINITION

• Anterior horn cell degeneration
• leading to
• progressive
• muscular atrophy
• with
• trunk and limb
• paralysis

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Neuronal loss
Muscle atrophy
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SMA- DIAGNOSISPhysical examination
neurophysiology

• 1-Muscle weakness
• 2-No sensory impairment
• 3-Progressive pattern
• 4-Denervation (EMG and/or muscle biopsy)
• 5-No nerve demyelination (NCV)
• 6-Normal distal sensory potentials

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SMA CLASSIFICATION3 major criteria

• 1-Distribution of paralysis
• Proximal
• Distal
• 2-Mode of inheritance
• Autosomal dominant
• Autosomal recessive
• 3-Age at onset
• Ante or perinatal period
• Infancy/childhood
• Adulthood

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CLINICAL HETEROGENEITY


-Distribution of paralyses
-Mode of inheritance


-Age at onset


-CNS abnormalities
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Classical SMA and atypical SMA
AR Proximal SMA (Werdnig Hoffmann and Kugelberg
Welander) SMNdel 95
Distal SMA
Bulbospinal SMA
SMA with CNS involvement
Others
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DISTAL SMA-Distal HMN- Spinal CMT-
Clinical features (Harding, 1980)

• dHMN type I AD CMT-like 
  
• dHMN type II AD Belgian type
• dHMN type III AR  Chronic AR distal
  SMA 
• dHMN type IV AR,  Severe AR distal SMA 
• dHMN type V AD,  upper limb
  predominance 
• dHMN type VI AR,  SMARD 
• dHMN type VII AD,  vocal cord paralysis 
  
• dHMNj (jerash type)AR  with upper neuron
  involvement 
• X-linked dHMN XR, Brazilian type

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AUTOSOMAL DOMINANT DISTAL SMA(Distal HMN type I)

• Onset 2-20 years
• Lower limb predominance
• Pes cavus
• No proximal weakness
• Rare scoliosis
• Low progression
•  CMT-like  but normal SAPs

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AUTOSOMAL DOMINANT DISTAL SMA (distal HMN type I)
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AD Distal HMN type I GENETICS
No genetic linkage, no gene identified BUT,
recently in some in sporadic cases
identification of mutations in the
HSPB1gene,(or HSP27) encoding a Small 27 kDa
Heat Shock Protein B1 affecting the assembly of
neurofilaments NB These mutations have been
also found in sporadic cases of axonal CMT !
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AD distal SMA - Distal HMN type II(Belgian
family. Timmerman et al, 1996)

• Onset 20-40 years (big toe and feet extensor
  muscles)
• Lower limb predominance
• No pes cavus
• Proximal involvement

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AD Distal HMN type II GENETICS

• Genetic localization 12q24.3
• Mutations in the HSPB8 gene (or HSP22) encoding a
  
• Small 22 kDa Heat Shock Protein
• NB -HSPB8 and HSPB1 are interacting proteins
• -Mutations in HSPB8 leads to intracellular
  agregates
• -Heat Shock Proteins are implicated in
  neurodegenerative disorders

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AD distal SMA with upper limb predominance-Distal
HMN type V-
Age at onset 5-20 years Clinical and genetic
heterogeneity
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7p-linked Distal HMN type V
CLINICAL PICTURE -Upper limb weaknessgtgtlower
limb -Slow progression
GENETICS -Linkage to the 7p14 region -Mutations
in the gene Glycyl tRNA synthetase
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Non7p-linked Distal HMN type V
CLINICAL PICTURE -Intra-familial heterogeneity
-Lower limb paralysis /-
GENETICS -Linkage to the 11q13 region in one
family -Mutations in the gene BSCL2 (Berardinelli
-Seip Congenital Lipodystrophy gene)
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BSCL2 one gene, 3 disorders
1-Berardinelli-Seip Congenital lipodystrophy,
Autosomal Recessive 2-Distal HMN type V linked
to 11q13 Autosomal Dominant 3-SILVER syndrome
(Hereditary spastic paraplegia with hand muscles
atrophy) Autosomal Dominant
BSCL2 encodes the SEIPIN protein
-Integral protein of the endoplasmic
reticulum -Mutations of SEIPIN leads to agregate
formation and neurodegeneration
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AD distal SMA with vocal cord paralysis-dHMN
type VII-

• CLINICAL PICTURE
• onset 10-20 years (wasting of the small muscles
  of the hand and thenar eminence)
• Subsequently weakness of the distal muscles of
  the lower limbs
• Hoarse voice
• Slow progression

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AD Distal HMN type VII GENETICS

• Genetic localization 2q14
• Mutations in the gene encoding
• the DYNACTIN2 protein (also called
  DYNAMITIN)
• Mutations affect the microtubule binding
  domain
• Dysfunction of dynactin-mediated transport
  is
• responsible for human motor neuron
  disease

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Autosomal Recessive Distal Spinal Muscular
Atrophy in Childhood
-Spinal Muscular Atrophy with Respiratory
Distress -Chronic Autosomal Recessive Distal
SMA -Jerash-type Autosomal Recessive Distal SMA
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SMARD
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SMARD
Synonyms -Distal SMA with Neonatal
Respiratory Distress -Diaphragmatic
distal SMA -dHMN type VI

• 1 of early onset SMAs
• Very severe phenotype
• Autosomal recessive transmission

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SMARD

• Low weight at birth
• Normal alert
• Hypotonia at birth
• Bilateral clubfeet
• Grasping fingers
• -Rapidly progressive course
• -EMG denervation
• -No sensory defect
• - Nerve conduction velocities

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• -Acute respiratory distress
• -Due to bilateral diaphragmatic paralysis
  occurring in the first weeks of life
• No chest deformity
• Masking the neurological symptoms
• Leading to permanent assisted ventilation

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SMARD
PROXIMAL SMA type I
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SMARD-GENETICS

• Linkage to 11q13 IGHMBP2 gene mutations
• (Grohmann et al. 2001)
• IGHMBP2- unknown function
• -RNA helicase domains
• -Ubiquitous expression
• -Homologous to the neuromuscular
  degeneration mouse (nmd) gene.
• Genetic heterogeneity

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SMARD 1 OUR EXPERIENCE AT NECKER ENFANTS MALADES
HOSPITAL
-SMA Diaphragmatic paralysis -No homozygous SMN
gene deletion -No SMA carrier status
28 cases collected since 1990
9 novel IGHMBP2 mutations detected in 5 SMARD1
children
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IGHMBP2 gene mutations
  Q196R L251P
D565B
R603C
P216L
C496X L577P R637C
R790X
DEAD/DEAH Box Helicase
AAA ATPase
Znf
Putative DNA Helicase
R3H
Q41X H213
A320X E514K
V580I A43X L236X
L361P C496X
DelA661
DelAA983/984 DelT1463
(Grohmann K, 2001 Pitt M, 2003)
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CHRONIC DSMA
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Lower limb paralysis
AR CHRONIC DSMA - DIAGNOSIS

• First symptom (6 months to 24 months)
• Bilateral feet paralysis
• peroneal muscles
• intrinsic foot muscles
• floppy feet attitude
• foot drop contracture
• Walking disability and frequent falls

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Upper limb paralysis
AR CHRONIC DSMA - DIAGNOSIS

• Occurring later and less severe than feet
  paralysis
• bilateral hands paralysis
• wrist and fingers extensor muscles
• intrinsic muscles
• falling hand attitude
• grasping fingers

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Proximal muscles involvement
AR CHRONIC DSMA - DIAGNOSIS

• Always present
• Less severe than distal
• Limb girdle weakness
• hyperlordosis
• kyphoscoliosis
• No chest deformity

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AR CHRONIC DSMA

• - Normal intelligence
• - No pyramidal sign
• - Abolished or decreased
• osteotendinous reflexes
• - No sensory trouble
• - No fasciculation
• - No facial weakness

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Neurological Investigations

• Neurophysiology
• diffuse and progressive denervation on EMG
• normal or slightly reduced motor NCV
• normal sensory potentials and normal sensory NCV
• Muscular biopsy
• neurogenic atrophy
• Sural nerve biopsy
• strictly normal

Chronic AR Distal SMA
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AR CHRONIC DSMA -EVOLUTION
-Progressive course during childhood -Relative
stabilization at adult stage -Walking loss 60
of adult cases -Severe scoliosis
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AR CHRONIC DSMA -EVOLUTION
-Bilateral diaphragmatic paralysis -Often
misdiagnosed -Sometimes revealed by an acute
respiratory distress
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Pedigree 1
Whole genome scan (GENESCAN)
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Lod score at locus D11S4136
4.59 4,11 3,62
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19 pedigrees collected since 1999
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REFINEMENT OF THE GENETIC INTERVAL
D11S1889 D11S913 D11S4113 D11S1337 D11S4136
D11S1314 D11S4184 D11S1369 D11S916

• Haplotype analysis at the 11q13 locus
• in the collected pedigrees

• Evidence of homozygosity
• in the 11q13.3 region
• in 2 inbred families

• Generation of 5 microsatellite markers in this
  locus
• DSM2, DSM3, DSM4, DSMX, DSMY

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Fine chromosomal localization of Chronic DSMA
at11q13.3
DSM4
DSMX
D11S1369 D11S4184
DSMY

DSM3
Cen
Tel
IGHMBP2 gene exclusion
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Alleles at the D11S1369, DSM4 and D11S4184 loci
D11S1314 1 D11S1369 2 DSM4
3 D11S4184 4 DSM2 1
6 2 1 3 1
6 2 1 3 1
8 1 2 4 10
5 1 4 3 9
4 2 3 4 2
4 2 3 4 2
4 2 3 4 2
4 1 1 3 2
5 1 4 3 9
5 1 4 3 9
5 1 4 3 9
5 3 4 3 13
D11S1314 1 D11S1369 2 DSM4
3 D11S4184 4 DSM2 11
1 2 3 4 11
10 4 2 4 7
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Family A
Childhood onset DSMA
Adult onset DSMA
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Adult onset AR DSMA

• 19 -23 years
• pretibial muscles weakness
• intrinsic feet muscles atrophy
• intrinsic hand muscles atrophy
• normal osteotendinous reflexes
• Progressive pelvic girdle weakness
• Normal respiratory function

Onset
Evolution
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(No Transcript)
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dHMNj (jerash type)

• AR, onset 6-10 years
• Pyramidal signs
• Pes cavus
• Lower limb predominance
• Secondary upper limb
• involvement
• Linkage to 9p21

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DISTAL SMA-Distal HMN- Spinal CMT-

• Clinical features(Harding)
  Loci Gènes
• dHMN type I AD, onset 2-20 years ?
  ?(HSPB8)
• dHMN type II AD, onset 20-40 years 12q24
  HSPB1
• dHMN type III AR, onset 2-10 years
• dHMN type IV AR, onset 4 months-10 years
  ? ?
• dHMN type V AD, onset 5-20 years
  7p15 Glycyl tRNA Sase
• 11q13 BSCL2
• dHMN type VI AR, onset before 2 years
  11q13 IGHMBP2
• dHMN type VII AD, onset 10-20 years
  2q14 Dynactin
• dHMNj (jerash type) AR, onset 6-10 years
  9p21 ?
• Xlinked dHMN(Brazil) 1-10 years
  Xq13-q21 ?

11q13.3 ?
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Scapuloperoneal SMA

• Type I (Kaiser family)
• Onset 4-70 years
• Autosomal dominant
• Linked to 12q24.1-24.31
• Type II
• Onset 2-5 years
• -Autosomal recessive
• No linkage

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BULBO-SPINAL MUSCULAR ATROPHY

• Adult onset
• X-linked BSMA with gynecomastia
• located on chromosome X
• Androgen receptor gene mutation (unstable
  repeats)
• Autosomal recessive BSMA with rigid spine and
  nasal voice
• Autosomal dominant BSMA in adult

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BULBO-SPINAL MUSCULAR ATROPHY-CHILDHOOD ONSET

• Fazio-Londe disease
• First symptoms 2-12 years
• Progressive voice change and swallowing
  difficulties
• Ophtalmoplegia
• Atrophy of the tongue with fasciculations
• Spreading paralysis to shoulder girdle
• Normal intelligence
• Autosomal recessive inheritance
• No genetic localization

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BULBO-SPINAL MUSCULAR ATROPHY-CHILDHOOD ONSET

• Brown-Vialetto-Van Laere disease
• First symptoms 2-5 years
• Bilateral sensorineural deafness
• 7th, and 9th to 12th cranial nerves involved
• Spreading paralysis to shoulder girdle, arms and
  chest with diaphragmatic weakness
• Autosomal recessive inheritance

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SMA CNS INVOLVEMENT

• SMA OLIVO-PONTO-CEREBELLAR HYPOPLASIA (Norman
  syndrom)
• -Autosomal recessive
• -2 types
• PCH1 -congenital onset
• -death before 1 year of life
• -global cerebellar hypoplasia
• PCH2 -progressive microcephaly
• -extra pyramidal dyskinesia
• -epilepsia and mental retardation
• -No genetic localization

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INTERESTS OF ATYPICAL SMA GENETIC STUDIES
-Diagnosis of rare disoders and genetic
counselling -Understanding the motor neuron
degeneration mecanisms -by the identification of
novel proteins -by the identification of
neuronal metabolic pathways -apoptosis,
-axonal transport, -mRNA processing,
-axonal growth and maintenance, -etc
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CONCLUSION-ATYPICAL SMA

• Rare phenotypes
• Clinical heterogeneity
• Diagnosis usually easy
• physical examination
• pictures/video records
• EMG , NCV studies (motor sensory NCV)
• Large multiplex pedigrees are necessary to
  initiate genetic mapping
• International collaborative studies

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Distal SMA-Recruitment of additional
pedigrees(viollet_at_necker.fr)

• Distal predominance of motor weakness (but
  proximal weakness could be present )
• Adulthood or childhood
• Diaphragmatic insufficiency if severe form
• Neurogenic EMG pattern, with analysis of nerve
  condution velocities and distal sensory action
  potentials (SAP)
• No SMN gene deletion