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Motor Syndromes

Motor   Differential diagnosis   Hereditary Amyotrophic lateral sclerosis   Hereditary   Sporadic   ALS variants     EOM & Extrapyramidal change     Primary lateral sclerosis (PLS)     Primary muscular atrophy (PMA)     Pseudobulbar paralysis (PBP)     Western Pacific ALS Disorders Amyotrophy   Lower extremity, benign   Monomelic Diabetic amyotrophy Hand weakness Hopkins Infections Insulinoma Mitochondrial: SCO2 Motor Neuron Disorders   Hereditary   Bulbar   Lower motor neuron   Upper motor neuron   Asymmetric   Symmetric   FOSMN Motor Neuropathy   Distal     Hereditary     Antibodies       IgG vs GM1       IgM vs GM1       IgM vs GalNAc-GD1a       IgM vs NS6S   Multifocal motor (MMN) Myopathies Painful Paraneoplastic   Lymphoma   Breast Poliomyelitis & Post-polio syndrome Rapid onset   Acute Axonal Motor Neuropathy   Acute flaccid myelitis   Poliomyelitis   Porphyria Spinal muscular atrophy: Hereditary   SMN (5q)   Androgen Receptor (Bulbar SMA)   Distal SMA (Distal HMN)   Hexosaminidase A (Tay-Sachs)   Scapuloperoneal   Spinal muscular atrophy 2   X-linked Infant & Arthrogryposis Spastic paraparesis Toxic

Motor Neuron Cell Bodies From: Quain

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Motor Neuron Disorders: Differential Diagnoses

Asymmetric Upper + Lower Motor Neuron Signs Amyotrophic Lateral Sclerosis (ALS) Sporadic ALS Hereditary ALS ALS variants Multi-system disorders ALS + Ophthalmoplegia & Extrapyramidal Δ Polyglucosan body disease Motor neuronopathy + Cataracts & Skeletal Δ Multiple system atrophy AAA syndrome FEWDON-MND Lower Motor Neuron Signs only (Asymmetric) Distal Lower Motor Neuron (LMN) Syndrome IgM vs GM1 ganglioside IgM vs GalNAc-GD1a ganglioside Also see: Multifocal motor neuropathy Proximal Lower Motor Neuron Syndromes Brachial amyotrophic diplegia (Flail arm) ? Associated with IgM vs asialo-GM1 Rare: Upper > Lower limbs + Hu antibodies Lower Motor Neuron Syndrome, No antibodies (PMA) ALS variants Hereditary Sporadic Focal motor neuron disease Monomelic Amyotrophy (Hirayama) Paraspinous muscle amyotrophy Cervical amyotrophy Paraneoplastic motor neuro(no)pathy Mild weakness: With lymphoma Severe weakness: With breast cancer Hopkins' syndrome: Acute post-asthmatic amyotrophy Infections Polio & Post-polio syndrome West Nile SMN2 (SMNC) deletions Neurofibromatosis, Type 2 5 Symmetric & Proximal: Hereditary Spinal Muscular Atrophy SMN: Chromosome 5q; Recessive BSMA (Androgen Receptor): X-linked; Recessive Hexosaminidase A (Tay-Sachs): Chromosome 15; Recessive Hand weakness Motor neuron disease Motor neuropathies Hirayama Hereditary motor neuropathies (HMN) & dSMA Myopathies Distal Myotonic Dystrophy Inclusion Body Myositis Myasthenia Gravis Peripheral nerve lesion Median: Recurrent motor branch; Anterior interosseus Ulnar: Guyon canal Radial: Posterior interosseus Brachial Plexopathy Distal SMA Bulbar involvement Bulbo-spinal Muscular Atrophy Androgen Receptor: X-linked Dominant Amyotrophic Lateral Sclerosis (ALS) Sporadic ALS Hereditary ALS ALS + Bulbar onset, Benign course & Bunina bodies Pseudobulbar paralysis Hereditary Bulbar syndromes Brown-Vialetto-van Laere Fazio-Londe Congenital Bulbar syndrome Worster-Drought: Congenital suprabulbar paralysis SCA 36 Painful: Diabetic amyotrophy Rapid Onset Acute Axonal Motor Neuropathy (with Campylobacter jejuni or serum IgG vs GM1) Poliomyelitis Porphyria 4 types cause neurologic attacks Acute intermittent Variegate Porphyria Coproporphyria δ-amino-levulinic acid dehydratase deficiency Urine: During attacks ↑ δ-amino-levulinic acid: All types Acquired Toxic: Lead; Dapsone; Botulism; Tick Paralysis Infections Polio West Nile Central European encephalitis HIV Creutzfeld-Jacob Amyotrophy Polyneuropathy (± Demyelinating) Other Distal SMA SMA & motor neuron syndromes: Other hereditary Multifocal Motor Neuropathy (MMN)

Upper & Lower Motor neurons Concept of Synapses: Before & After establishment 18 1886 1899 Gowers: A manual of diseases of the nervous system Motor Neuron & Axon From: Quain 1912 Motor Unit Ramon y Cajal

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Paraneoplastic Motor Neuropathy ²⁵

Epidemiology: Majority male & > 50 years Clinical Onset: After diagnosis of neoplasm Weakness Asymmetric; Arms > Legs Mild Lower motor neuron only Normal bulbar Cramps: Painful Painless in some patients Course Most: Progressive then stabilizes or improves Few: Progressive to death Associated with Non-Hodgkin Lymphoma Also other lymphomas & myeloproliferative disorders 4 Laboratory CSF: No cells; Mildly increased protein MRI: Spinal cord normal ? Neuronopathy Pathology: Anterior horn cell loss; Gliosis Animal model: Similar disorder in mice 2° murine leukemic virus Also see: Paraneoplastic Lower Motor Neuron Syndrome

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Paraneoplastic Lower Motor Neuron Syndrome ^{8, 25}

• Epidemiology: Single patient, 72 year old female
• Onset: 4 months before diagnosis of tumor
• Clinical
  • Weakness
    • Asymmetric at onset
    • Arms & Legs
    • Severe
    • Lower motor neuron only
    • Bulbar: Hypophonia; Dysphagia; Unilateral facial paresis
  • Painless
  • Course
    • Progressive over months
    • Improvement after tumor removal
    • Long-term residual disability
  • Sensation: Normal
  • Tendon reflexes: Absent
  • CNS: Transient dizziness & Nystagmus
• Associated with
  • Ductal adenocarcinoma of breast
• Laboratory
  • Antibodies
    • Serum binding to βIV spectrin, isoform I (Bands at MW 250kD & 140kD)
    • Serm binding to axon initial segments & nodes of Ranvier in rat brain
  • Electrophysiology
    • EMG: Denervation
    • NCV: Small CMAPs; No conduction block
  • MRI: Spinal cord with high signal spots on T2
  • ? Neuronopathy
• Immunosuppressive treatment: No response
• Also see: Paraneoplastic Motor Neuropathy

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HOPKINS' SYNDROME: Acute post-asthmatic amyotrophy

• Clinical
  • Onset
    • Age: 1 to 13 years
    • After acute asthmatic attack: Latency 1 to 18 days
    • Mild pain: Limb, neck or meningismus
    • Rapid onset weakness
  • Weakness
    • Single limb; Asymmetric; May be Proximal > Distal
    • Severity: Mild to severe
    • Arm or leg
  • Wasting: Affected limb
  • Sensory: Normal
  • Tendon reflexes: Reduced
  • Prognosis: Permanent paralysis
• Laboratory
  • EMG: Denervation
  • CSF
    • Pleocytosis
    • Protein: ± Increased
  • MRI: May show signal (T2) in spinal cord

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Post-Polio Syndrome Diagnostic Criteria: Clinical History of polio Partial or complete neurological & functional recovery Stable function > 15 years Onset of Fatigue Muscle pain Functional loss Usually 2° Musculoskeletal disorder New weakness is rare Neurological examination Lower motor neuron syndrome (confirmed by EMG or MRI) Measurable loss of strength is rare Decreased or absent tendon reflexes No sensory loss Other No other explanation for symptoms Joint pain & cold intolerance may accompany the syndrome Laboratory features CK: Elevated Electrophysiology Very large motor units (up to 10 times normal) Some fibrillations & positive sharp waves even in stable patients Muscle pathology Near full recovery of strength & stable Type I muscle fiber predominance Persistent or new weakness 50% type I fibers Angular fibers; Atrophy + Hypertrophy New weakness & high CK More small angular fibers Muscle fiber necrosis Recommended exercise Mild paresis: Resistance training Moderate paresis: Submaximal endurance Severe paresis: None; Joint bracing

Old Polio Asymmetric atrophy & weakness   Atrophic right leg (arrow) in patient     with paralytic polio 70 years in past

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Monomelic Amyotrophy

• Nosology
  • Hirayama disease
    • Course: Progressive weakness over 1 to 4 years; Then plateau
    • More related to flexion myelopathy
  • O'Sullivan-McLeod syndrome
    • Course: Slow progression over decades
  • Juvenile muscular atrophy of distal upper extremities (JMADUE)
• Epidemiology
  • Male > Female: Up to 10:1
  • Family history
    • Usually sporadic
    • Occasional familial occurrence
      • Dominant ¹³ or Recessive
  • Geographic: Common in
    • Eastern India ⁷
    • Taiwan
    • Other: Japan, Sri Lanka, Indonesia, Korea, Hong Kong, Malaysia
  • Association: Heavy physical activity before onset
• Possible etiologies
  • Cervical myelopathy, central
    • Neck flexion induced
      • Forward displacement of posterior cervical dural sac
      • Increased segmental & range of motion in cervical spine
    • Cervical cord & vessel compression
      • Tightness within cervical dura
      • Due to: Differential elongation of spinal cord & dura during puberty
    • Anterior horn of spinal cord: Atropy & Ischemic changes
  • Motor neuron disease
  • Genetic associations
    • Koreans ¹⁶
      • KIAA1377 : G668S
      • C5ORF42 : P1794L
    • FLNA : XLPH-EDS (Ehlers-Danlos-like) ²¹
• Clinical ¹⁷
  • Onset
    • Age
      • Mean 15 to 20 years; Range 13 to 25 years
      • Up to 40 years in India
      • Females: 2 years younger than males ²⁶
    • Weakness: Distal; Single limb
  • Weakness
    • Asymmetric
      • Often predominant in one arm
      • Subclinical involvement of other arm: Common
    • Locations
      • Distal predominant (97%): Proximal (Up to C5) > Distal in 3% to 10%
      • Hand & Forearm
        • C8 & T1 ± C7, innervated muscles
    • Side: Right 1x to 3x > Left
    • Cold paresis: More weakness & stiffness in cold
  • Atrophy
    • Hands
    • "Oblique amyotrophy"
      • Wasted: C7 muscles
      • Preserved: Brachioradialis belly (C6)
  • Tremor or Minipolymyoclonus (80%)
    • On finger extension
    • Irregular & Coarse
  • Occasional other features
    • Weakness: Other
      • Ipsilateral shoulder
      • Progression to opposite limb
        • Frequency: 18% - 40%
        • Latency: Range 2 to 120 months; Mean 43 months
        • Usually milder weakness than 1st limb
      • Worsening on exposure to cold
    • Movements
      • Fasciculations
        • On affected side (47% to 66%)
        • May not be symptomatic
        • Contractile fasciculation
      • Minipolymyoclonus (85%)
    • Sensory loss
      • Mild or none in affected limb
      • Rarely prominent
      • Subjective numbness (20%)
      • Pin loss (C8 - T1)
    • Discomfort
      • Cramps & Spasms (30%)
      • Neck pain
    • Autonomic: Hyperhidrosis (18%)
  • Tendon reflexes: Usually normal or reduced; Occasionally increased
  • No cranial nerve, leg or pyramidal changes
  • Disease course
    • Typical monomelic amyotrophy ¹⁰
      • Progression: Over 1 month to 5 years; 7% as long as 8 years
      • Static after progression phase: May persist for decades
      • May be improvement after surgeery
      • Disability: Mild or none in 73%
    • O'Sullivan-McLeod syndrome ⁶: Progression over decades
  • Possible treatments
    • Neck bracing: Hard collar
    • Surgical ²³
      • Cervical spine stabilization
      • Better prognosis with
        • Younger age at surgery: Mean 19 years
        • Shorter disease duration: Mean 22 months
        • No: Babinski sign or Increased DTRs
        • Surgery type
          • Anterior only approach: Likely sufficient
          • Stabilization only: Better than decompression
• Laboratory
  • EMG
    • Location of pathology
      • Most common: C8-T1
      • Partial involvement: C7
      • Spared: C5-C6
      • Occasional: Legs
      • May be present in asymptomatic limbs
    • Acute & ongoing denervation in 45% to 70%: Fibrillations
    • Chronic denervation
      • In affected limb(s) (100%): Especially fasciculations
      • Opposite arm or lower extremities: 30% to 100%
  • NCV
    • CMAPs: Small in affected limbs; Especially ulnar nerve
    • Velocities: Normal
    • Sensory: Normal
  • Sympathetic skin response: May be abnormal
  • MRI ²⁷
    • Cervical pathology
      • Spinal cord atrophy
        • Frequency: 30% to 50%
        • Locations: C5 to C7
        • May be asymmetric
      • Anterior horns, gray matter: T2 signal at C5-C7
      • Cervical lordosis: Reduced
      • Neck flexion
        • Posterior epidural venous plexus: Engorgement
        • Posterior dura: Anterior shifting
        • Post-gadolinium T1 enhancement of posterior epidural plexus
        • Epidural flow voids
      • ? Some patients with inelastic dura
        • Spinal cord compression with neck flexion ¹
    • Other studies ³
      • No major spinal anomalies
      • Mild flexion-induced cord displacement
• Differential diagnosis: HMN & Distal SMA, especially HMN Type 5

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Amyotrophy: Benign Lower Extremity (Crural) ¹¹

• Epidemiology
  • 70 cases
  • Male > Female: 5:1
• Onset age: Mean 20 to 41 years
• Clinical
  • Weakness: Posterior legs
    • Usual: Posterior calf; Peronei; Hamstrings
    • Rare: Quads
    • Often bilateral (50%)
      • Clinical or Subclinical
      • Asymmetry: Some
  • No sensory, bulbar or upper motor neuron signs
  • Tendon reflexes: Most often reduced
  • Course
    • Insidious onset
    • Slow progression: Few years
    • Stabilization
• Laboratory
  • MRI
    • Loss of muscle with fat replacement
    • Distribution: Lower extremities
      • Distal leg: Posterior compartment
      • Thigh: Long head of biceps
  • EMG: Denervation
  • Muscle biopsy: Denervation; Grouped atrophy

Benign lower limb amyotrophy: MRI
From: M Al-Lozi Legs: Involvement of posterior muscle groups	From: M Al-Lozi Thigh: Long head of biceps involved

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MND: Finger extension weakness + Downbeat nystagmus (FEWDON-MND) ²²

• Epidemiology: 6 patients; Sporadic
• Clinical
  • Onset age: 2nd to 4th decade
  • Motor Neuron Disease
    • Onset: Finger extension, unilateral
    • Progression: Distal & Proximal muscles
    • Legs: Weakness later in course
    • Fasciculations
  • Tendon reflexes: Often brisk
  • Upper motor neuron
    • Tone mildly increased in some
    • Plantar reflex: Normal
  • Eye
    • Nystagmus
      • Downbeat: Later in disease course
      • Gaze evoked
    • Osscillopsia
    • Diplopia
    • Skew Deviation
    • Esophoria: Comitant
    • Saccadic dysmetria
  • Sensation: Normal
• Laboratory
  • NCV: Motor axon loss
  • EMG: Denervation & Reinnervation
  • CSF: Normal
  • Brain MRI: Normal

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"Primary Muscular Atrophy" (PMA) ¹⁵

Nosology: Aran-Duchenne syndrome Epidemiology Frequency: 7% to 11% of ALS-like disorders Male in 74%: vs 55% in ALS Lower Motor Neuron Syndrome: Widespread Weakness: Distribution Distal & Proximal: Either may be more prominent Asymmetric Often involves paraspinous & respiratory muscles Often spares bulbar musculature Spontaneous motor activity Cramps: Common in legs, at night Fasciculations Upper motor neuron signs Not present at diagnosis After 5 years: 20% More with younger onset age 50% develop in 1st year after diagnosis Pain: Related to immobility Time course Progressive Survival Mean = 4 years: vs 3 years in ALS Range vs typical ALS: Similar, Faster, or Slower   Overall mortality: 68% Laboratory Muscle pathology Grouped atrophy > Fiber type grouping No serum antibodies No conduction block Treatment: No evidence for response Differential diagnosis Proximal lower motor neuron syndrome ALS Sporadic Hereditary SOD mutations: A4V, Leu84Val, D101N CHMP2B Lower Motor Neuron Syndromes & Motor neuropathies Radiculopathy: Cervical spine Pathology Loss of motor neurons in anterior horn of spinal cord Shrinkage of remaining motor neurons Inclusion bodies: Intracytoplasmic, Hyaline

Gowers Primary muscular atrophy Wasting: Includes   paraspinous muscles. Putnam

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Primary Lateral Sclerosis (PLS) ²

Dominant, Adult onset   4p16   c9orf72   FIG4: 6q21   SPG7 PLS + FTD   PSEN1: 14q24   TBK1: 12q14 Recessive, Childhood onset   ALS2   ERLIN2   SIGMAR1   SPG11 Sporadic, Adult onset   Mills (Asymmetric) syndrome From Bramwell: Diseases of the Spinal Cord PLS: "Sclerosis" of pyramidal tracts   (Upper thoracic cord)

"About the Case of primary systematic Degeneration of the Pyramidal tracts with Symptoms of a general spastic Paralysis" Deutsche Zeitschrift für Nervenheilkunde 1894;5:225–246

PLS : Sporadic, Adult onset ¹⁴

• Nosology
  • Pure upper motor neuron disease/dysfunction (PUMND)
  • ? Discrete syndrome vs ALS variant
  • Variant: Mills (Asymmetric) syndrome
• Definition
  • Progressive upper motor neuron dysfunction,
  • No: Lower motor neuron signs; Hereditary spastic paraplegia
  • Frequently involves: Limbs & bulbar regions
• History: Early description by Adolf von Strümpell (1853-1925) ¹⁹
• Epidemiology
  • 1% to 5% of sporadic motor neuron disease
  • Male = Female
• Genetics
  • Family history: Usually none
  • No mutations in Alsin gene in sporadic cases
  • c9orf72 mutations: 1% to 3%
  • Risk factor: ANTXR2 ¹⁰⁶
• Clinical
  • Onset
    • Spasticity
      • Legs before Arms
      • Slow progression
    • Age: Most common in 5th & 6th decade; Range 34 to 78 years
  • Motor dysfunction
    • Corticospinal ± Corticobulbar tract dysfunction
      • General patterns
        • Paraparetic: Legs > Arms
          • Uncommon
          • Earlier age onset
          • Rule out HSP
        • Bulbar
        • Asymmetric: Mills syndrome
        • Rule out
          • Extrapyramidal disease
          • Neurodegenerative disorder
      • Spasticity
        • Legs > Arms
        • Bulbar: Dysarthria; Dysphagia
          • Especially with disease onset > 45 years
          • May be selectively present
        • Pattern: Flexors in arms, Extensors in legs
      • Tendon reflexes: Brisk
      • Plantar reflex: Normal or upgoing
      • Pseudobulbar Affect: Emotional lability
      • Treatment
        • Spasticity & Stiffness: Baclofen; Levodopa
        • Pseudobulbar affect
          • Dextromethorphan & Quinidine
          • Tricyclic antidepressants
    • Symmetry
      • Symmetric: 20% to 50%
      • Asymmetric: 50% to 80%; May be classified as Mills syndrome
    • No lower motor neuron change
    • Respiratory
      • Vital capacity reduced with bulbar involvement
      • Rarely symptomatic
  • Sensory: Normal
  • Cortical
    • Frontal lobe dysfunction (10% to 20%): Mild
    • Cognition impaired (36%): Mild; Language & Verbal fluency
  • EOM disorders (25%): Saccadic pursuit or Up gaze reduced
  • Bladder dysfunction
    • Frequency: 30% to 50%
    • Urgency
    • Normal until later (Mean 4.5 years) in disease course
  • Progression
    • Gradual & Slow
    • May stabilize after several years
    • > 3 years; Up to 3 decades
    • Lower motor neuron signs
      • Frequency: 40%
      • Onset: 3 to 10 years after onset
    • Evolution to ALS after 4 years
      • Rarely
      • 20% develop denervation on EMG
  • Differences from ALS: PLS has less
    • Bulbar onset
    • Weakness
      • Focal
      • Limb
    • Fasciculations
    • Weight loss
    • Vital capacity reduction
    • Speed of progression
• Laboratory
  • Magnetic stimulation
    • Absent or prolonged cortical motor evoked latencies
  • MRI ²⁴
    • Motor cortex: Medial
    • Precentral gyrus, Focal atrophy
    • Corpus callosum
    • White matter: Corticospinasl tract
    • Cerebellum: White matter; Body; Splenium
    • Other: Insular, Inferior frontal; Left pars opercularis
  • PET & FDG-PET: "Stripe sign"
    • Reduced glucose consumption in pericentral region
    • Hypometabolism in primary motor cortex
    • Also occurs in ALS
  • fMRI: Cerebro-cerebellar connectivity increased
  • Central motor conduction times: Prolonged
  • EMG
    • Few fibrillations or fasciculations in 1 or 2 muscles
    • Motor units: Normal or Mildly reduced number
  • Normal: Serum; CSF; Spinal cord imaging; Serum CK
• Disease association: ? Breast cnacer
• Pathology
  • Corticospinal tract: Axon loss
  • Normal: Anterior horn cells ± Betz cells
• Differential diagnosis
  • Structural disorders
    • Spinal
    • Foramen magnum
    • Hydrocephalus
  • Hereditary spinal disorders
  • Systemic: Infections & Toxins
  • "Degenerative"
    • ALS
    • Progressive supranuclear palsy
• PLS variant: Mills syndrome (PLS + Hemiparesis, Progressive) ²⁰
  
  • Epidemiology: Subgroup of patients with PLS syndromes
  • Clinical
    • Onset
      • Age: 19 to 88 years
      • Regions: Arm, Leg or Bulbar
    • Spastic hemiparesis
      • May begin in leg or arm
      • Tone: Increased; Spastic
      • Distribution: More severe
        • Corticospinal pattern
        • Arm flexion
        • Leg extension
      • Tendon reflexes: Increased; Asymmetric
      • Plantar response: Extensor on hemiparetic side
      • Progressive: May plateau
    • Sensory: Normal
    • Course
      • Progressive over years
      • May develop
        • Bulbar signs (70%): Onset after or before hemiparesis
        • Contralateral signs (40%)
  • Laboratory
    • EMG: Normal
    • Brain MRI: Normal or Cortical atrophy, mild
    • Brain PET: Motor & Premotor areas
      • Hypometabolism: Contralateral > Ipsilateral to weakness

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Pseudobulbar Paralysis, Selective

Epidemiology Female predominant: 65% to 90% Onset age: 50 to 80 years Clinical Bulbar weakness: Mostly Upper motor neuron Tongue: Slow movements; Little atrophy Jaw jerk: Brisk De-differention of movements Movement of jaw along with tongue Orbicularis oris: Weak mouth closure Dysphagia Inability to swallow food or saliva May require G-tube for nutrition Dysarthria Speech quality: Slow; Indistinct Speech may be lost entirely Pseudobulbar affect Respiratory Reduced ability to voluntarily inhale or exhale Measured vital capacity: Often reduced Respiratory failure: Uncommmon Tendon reflexes May be normal in extremities Diffusely increased in some patients Course Slow progression over years Some patients: Develop more generalized ALS Treatment for Pseudobulbar affect Dysphagia Inability to swallow saliva Laboratory Bulbar EMG Often normal May show some denervation Variant: Bulbar onset evolving into general ALS More common with c9orf72 mutations (FTD-ALS1)

From: Dejerine, J. Semiologie des affections du systeme nerveux. Paris: Masson et Cie (pub.) 1914

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PLS: Recessive, Juvenile onset ⁹
  ● Alsin (ALS2) ; Chromosome 2q33.1; Recessive

• Epidemiology: Cypriot family
• Genetics
  • Mutation
    • Deletion: In Exon 9
    • Homozygous c.2980-2A>G mutation at splice acceptor site of intron 17: Frameshift
  • Allelic with
    • ALS2: Mutations in another region of alsin gene
    • Familial spastic paraparesis, infantile onset (IAHSP)
• Clinical
  • Onset: Childhood
  • Spasticity: Bulbar; Extremities
  • Gaze paresis: Saccadic
  • Normal: Cognition; Sensation
  • Progression: Slow; Some remain ambulatory for decades
• Laboratory
  • Central motor conduction times: Delayed or Unrecordable
  • EMG: No denervation
  • Brain imaging: Normal

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PLS: Dominant, Adult onset (PLSA1)
  ● Chromosome 4p16; Dominant

• Epidemiology
  • Single French-Canadian family
  • Male:Female = 1:1
• Onset
  • Age: 30 to 60 years
  • Spasticity: Leg; Asymmetric
• Clinical
  • Spasticity: Arms & Legs; Asymmetric
  • Strength: Normal
  • Reflexes
    • Tendon: Diffusely increased
    • Plantar: Extensor
  • Dysphagia: 60%
  • Sensation: Normal
• Laboratory
  • EMG: Denervation, mild, distal, chronic
  • MRI: Normal or Spinal cord atrophy, mild

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PLS: Dominant, Adult onset ²⁸
  ● Presenilin 1 (PSEN1) Chromosome 14q24.2; Dominant

• Epidemiology: 1 family, 3 patients
• Genetics
  • Mutation: Pro284Leu
  • Allelic disorders
    • Acne inversa, familial
    • Alzheimer disease, type 3 ± Spastic paraparesis & Apraxia
    • Cardiomyopathy, dilated, 1U
    • Dementia, frontotemporal
    • Pick disease
• PSEN1 protein
  • Catalytic component of γ-secretase.
  • γ-secretase;: Proteolytic cleavage of APP & NOTCH receptor proteins
• Clinical
  • Onset age: 27 to 37 years
  • Pyramidal
    • Spastic paraparesis/quadriparesis: Asymmetric
    • Gait disorder
    • Dysarthria
    • Pseudobulbar affect
    • Tendon reflexes: Brisk
  • Face: Paresis
  • Cognitive disorders
  • Urinary incontinence
  • Course: Progressive
• Laboratory
  • CNS: Corticospinal tract microgliosis; Aβ pathology in motor cortex
  • EMG: Normal
  • Brain MRI: Atrophy, Global + Cervical spine

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PLS with Frontotemporal Dementia ¹²
  ● Sporadic

• Epidemiology: 2 patients
• Differential diagnosis
  • See ALS-FTD2
  • TBK1
  • UBQLN2
• Onset
  • Age: 6th to 8th decade
  • Dementia
  • Dysarthria
• Clinical
  • Cortical
    • Dementia
    • Aphasia
  • Motor
    • Spasticity
    • Bulbar dysfunction: 1 patient
    • Strength: Normal
    • Tendon reflexes: Brisk
    • Plantar responses: Extensor
  • Course
    • Slow progression
    • Death after 7 years
• Pathology
  • Neuronal loss: Frontotemporal & Motor cortex
  • Inclusions: Ubiquitin & TDP-43 positive cytoplasmic

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Patient information

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