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CHILDHOOD ONSET POLYNEUROPATHIES

STORAGE INCLUSIONS
Type	Disease	Cellular localization
Osmophilic   with periodicity Bilbao	Metachromatic Leukodystrophy	Schwann cell Macrophage Axon
	Fabry's	Vascular Perineurial Schwann cell, non-myelinating
	Niemann-Pick, Type 1	All except axon
	Batten-Kufs	Schwann cell Vascular Fibroblast
	Toxic (Lysosomal)   Amiodarone   Chloroquine   Perhexiline   Similar inclusions: Cockayne	Vascular: Endothelial & smooth muscle Nerve: Perineurial;   Schwann cells (Non-myelinating)
Zebra bodies	Metachromatic Leukodystrophy	Schwann cell Macrophage
	Mucopolysaccharidosis	Schwann cell-myelinating Fibroblast
	Fabry's	Vascular Perineurial
	Niemann-Pick	Schwann cell Endothelial Macrophage
	Pi granules	Schwann cell
Membrane-bound   cleft or polygonal space	Krabbe	Schwann cell Macrophage
	Adrenoleukodystrophy	Schwann cell Macrophage
	Farber's disease	Endothelial cell
Empty vacuoles	Tangier disease	Schwann cell, non-myelinating
	GM1 gangliosidosis	Vascular Fibroblast
	I-cell disease	Schwann cell, non-myelinating Fibroblast Perineurial
	Mucopolysaccharidosis	Fibroblast Vascular Schwann cell
	Cerebrotendinous xanthomatosis	Schwann cell
	Wolman's disease	All
	Sialidosis, type 1	Schwann cell

• Clinical
  • Nerve: Hypotonia; Distal atrophy
  • Skin: Lipogranulomatosis; Nodules: Periarticular subcutaneous
  • CNS: Mental & motor retardation; Hoarse cry
  • Systemic: Hepatomegaly; Splenomegaly; Nephropathy
  • Joints: Painful, Swollen
  • Eyes: Macular cherry-red spots
  • Prognosis: Respiratory insufficiency; Death 2 to 20 years
• Lab
  • Neuronal & glial storage of nonsulfonated acid mucopolysaccharide
  • Elevated urine ceramide levels
  • N-laurylsphingosine deacylase deficiency
  • Ceramidase deficiency
  • Electrophysiology
    • Nerve conduction velocities: Slow
• Pathology ¹⁰
  • Systemic: Granulomatous infiltration of liver, spleen, lungs, and thymus
  • Farber bodies: Curved, tubular; Vacuolar & cytoplasmic; Ceramide
  • Nerve
    • Hypomyelination
    • Schwann cells: Inclusions
      • Myelinating: Electron-lucent membrane-bound clefts
        
      • Non-myelinating: Membrane bound, elongated bodies

Epidemiology: > 70 patients Genetics Mutation types; Missense; Nonsense; Frameshift; Recurrent uniparental isodisomy > 46 mutations: All regions of gene Founder mutations Mexico: c.851+1G>A Turkey: c.1502+1G>T Few genotype-phenotype corelations Variants Tunisian CMT+ Heterozygotes ? Subclinical polyneuropathy on electrophysiology Gigaxonin protein Subcellular localization: Cytoskeletal Binds to Microtubule-associated protein (MAP)1B light chain Via kelch domain Associated with microtubules: Stabilizes microtubule network Tissue localization: Ubiquitous expression Functions Ubiquitin ligase adapter protein Needed for regulation of intermediate filament turnover Loss of function Accumulation of intermediate filaments in many cell types Disregulated intermediate filaments: Vimentin, Desmin, Cytokeratins,   Glial fibrillary acidic protein (GFAP), Peripherin, Neurofilaments BTB/kelch superfamily Intracellular proteins Functions Coordinate cell morphology & growth: Calicin Cytoplasmic sequestration of transcription factors: Keap 1 BTB domain: Interacts with proteins involved in ubiquitination & protein chaperones Kelch domain: Interacts with intermediate filaments targeted for degradation or turnover Ubiquitin-proteasome system Controls degradation of ubiquitin-mediated microtubule-associated protein 1B (MAP1B) Interacts with UBE1 May function as scaffold protein Association with actin & cytoskeleton Mayven; kelch; ENC-1 Over-expression: Enhanced degradation of MAP1B-LC May contribute to viral pathogenesis Kelch disorders, other Clinical features Onset Age: Mean = 2 to 3 years; Most < 10 years Gait disorder Polyneuropathy Distribution: Legs > Arms Weakness: Diffuse; Distal > Proximal Sensory loss: Especially vibratory & proprioception Tendon reflexes: Reduced in Lower limbs or Generally Cranial nerves: Facial weakness; Dysarthria Onset May be presenting feature: See Recessive, Axonal CMT Ages 6 to 10 years (Algerian family) 4 Autonomic Lacrimation: Reduced Hypohidrosis Respiratory Later in disease course FVC may be reduced Sleep disorders Gastrointestinal Dysphagia (31%) Constipation (45%) Lactose intolerance (40%) Episodic vomiting CNS: Variable Ataxia: Clumsy gait; Present in most patients Eyes: Optic atrophy; Nystagmus Mental retardation Corticospinal tract: Spastic paraplegia; Plantar responses extensor Hair (100%) Frizzy (Tightly curled) scalp hair; Long curly eyelashes Changes more common in severe cases Skeletal Short stature Forehead: Prominent, High Macrocephaly Progression Wheel chair or Death by 3rd decade Some patients with slower progression over 20 years Differential diagnosis: GAN2, Dominant Laboratory CSF: Normal MRI Diffuse T2 hyperintensities: Cerebral & cerebellar white matter Spinal cord: Atrophy Electrophysiology: Axonal, length-dependent neuropathy SNAPs: Absent or Reduced amplitude CMAPs: Reduced amplitude Motor nerve conduction velocity: Normal or Mild reduction Pathology Axon loss: Distal; Progressive with age; All axon sizes Axon swellings Contain densely packed, swirled neurofilaments Begin at nodes of Ranvier Myelin sheaths: Thin or absent around swellings Size: Average 20 μM; Up to 50 μM Microtubule distribution: Abnormally clustered Axon atrophy: Distal to swellings Microfilament accumulations Locations: Schwann cells, Fibroblasts, Vascular endothelium GAN Variant: Giant axonal neuropathy, Tunisian form Genetics Inheritance: Recessive GAN mutation: Arg15Ser Clinical Onset age: Infancy Weakness: Distal; Bulbar Sensory loss: Legs Tendon reflexes: Brisk Hair: Normal CNS Multisystem degeneration Motor neuron syndrome Progression: Slow Laboratory: Sensory-Motor polyneuropathy GAN Variant: CMT+ 34 Epidemiology: 20% of GAN Genetics Inheritance: Recessive Mutations: At least 1 missense; P315L Clinical Onset age: Mean = 5 years Polyneuropathy Spasticity: Legs > Arms; Hyperreflexia Curly hair: Mild CNS & Systemic features: Few Laboratory Brain imaging: Normal or Minimal white matter changes Other: Cytoskeletal disorders

From: T Mozaffar Giant Axonal Neuropathy

• Epidemiology: German family
• Genetics
  • Mutation: Arg317Cys
• DCAF8 protein
  • Substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex
• Clinical
  • Onset
    • Age: Childhood
    • Pes cavus
  • Polyneuropathy
    • Weakness
      • Distal
      • Symmetric
      • Legs > Arms
    • Cramps
    • Sensory loss
      • Distal
      • Pan-modal
    • Tendon reflexes: Reduced at ankles
    • Gait disorder
    • Course: Slowly progressive
  • Cardiomyopathy: Some patients
    • LVH
    • Conduction abnormalities
• Laboratory
  • EMG: Denervation
    • Chronic: Large motor unit potentials
    • Distal
    • Legs > Arms
  • NCV
    • Velocity: Normal or Mildly slowed
    • CMAP amplitudes: Reduced or absent distally
  • Nerve pathology
    • Axon loss: Large > Small
    • Large axons
      • Contain: Neurofilament accumulations
      • Scattered
      • Myelin sheaths: Thin
    • Onion bulbs: Occasional; Small
• Differential diagnosis: GAN1, Recessive

• Nosology: Seitelberger’s disease; Neurodegeneration with brain iron accumulation 2A
• Epidemiology: Multiple families
• Genetics
  • PLA2G6 mutations: V691del; Tyr790Ter; Lys545Thr; Val310Glu; Arg632Trp (Karak syndrome)
  • Allelic disorders
    • Atypical Neuroaxonal Dystrophy: Childhood onset
    • Karak syndrome (NBIA2B)
    • Neurodegeneration with brain iron accumulation 2 (NBIA2A)
    • Parkinson Disease 14, Recessive (PARK14; Dystonia-Parkinson, Adult)
• PLA2 enzymes
  • General: Catalyze release of fatty acids from phospholipids
  • PLA2G6 activity high in brain
  • PLA2G6 mutations: Most probably cause loss of function
• Clinical features: Typical syndrome
  • Onset
    • 1 to 2 years
    • Gait difficulties
  • CNS
    • Cognitive
      • Mental & Motor milestones: Loss
      • Neuropsychiatric: Autistic; Disordered social communication
      • Cognitive decline: Progressive
    • Seizures
    • Tone: Increased
      • Extrapyramidal: Dystonia; Rigidity
      • Spasticity: Tetraparesis; Some patients
    • Gait disorder
    • Ataxia
    • Deafness
  • Neuropathy: Poorly defined by EMG or Pathology
    • Limb mutilation
    • Hypotonia
    • Tendon reflexes: Absent or reduced
  • Autonomic
    • Loss of tears (keratitis)
    • Poor temperature regulation
    • Urinary retention
  • Myopathy
    • No clinical signs
    • Serum CK: Mildly elevated in some cases
    • Muscle pathology
      • Necrosis
      • Fiber splitting
      • Endomysial macrophage activation
      • Axonal swellings in intramuscular nerves & terminals
  • Endocrine
    • Diabetes insipidus
    • Hypothalamic hypothyroid
  • Course: Death < 10 years
• Laboratory
  • Diagnosis: Swellings may be present on conjuctival, skin or muscle biopsy
  • Brain MRI
    • Cerebellar atrophy
    • Iron accumulation in globus pallidum & substantia nigra
  • Pathology
    • Spheroids: In CNS & Peripheral nerves
      • Contents: Membranes & abnormal mitochondria
      • Staining: PAS positive
    • Peripheral nerve
      • Swellings may be present
      • Little axonal loss or Wallerian degeneration
      • Ultrastructure: Tubulovesicular profiles; Mitochondrial aggregates
    • CNS
      • Iron deposition
      • Cerebellar atrophy
      • Optic nerve atrophy
• Infantile variant ⁸
  • Clinical
    • Movements: Hyperkinetic; Tonic spasms
    • Seizures
    • Apneic spells
    • Course: Progressive to hypotonia or plateau at 3 years
  • Laboratory
    • Skin nerves: Thin myelin; Condensed axonal filaments
    • Brain: Axon terminal degeneration in cortex, basal ganglia & cerebellum
• Differential Diagnosis: Overlaps clinically with
  • Pantothenate kinase-associated neurodegeneration (PKAN; NBIA1)
      ● PANK2 ; Chromosome 20p13-p12.3; Recessive
    • Later onset
    • Extrapyramidal: Dystonia; Chorioathetosis
  • Schindler & Kanzaki diseases
      ● N-acetyl-α-D-galactosaminidase (NAGA) ; Chromosome 22q11; Recessive
    • Lysosomal storage disorder presenting as INAD
    • Psychomotor retardation
    • Myoclonic seizures
    • Decorticate posture: Long-tract signs
    • Optic atrophy: blindness, marked
    • Loss of contact with environment by age 3–4 years
  • Also see: NBIA3 (FTL gene )
  • INAD 2

• Epidemiology: Roma family; 3 infants
• Clinical
  • Onset age: Birth
  • Motor
    • Hypotonia: Predominantly axial
    • Difficulty swallowing
    • Respiratory failure
  • Myoclonic seizures
  • Dysmorphic features: Micrognathia
  • Course: Death in 5th month; Respiratory insufficiency
• Laboratory
  • EEG: Focal epileptiform abnormalities
  • CNS MRI: Normal
  • EMG: Chronic denervation in some
  • Muscle: Fiber type grouping
• Pathology
  • Brains: Small without malformation
  • Axonal spheroids
    • Locations: Most prominent in
      • Middle cerebellar peduncle
      • Anterior thalamic reticular nuclei
      • Spinal cord: Anterior horns & columns
      • Lower motor neurons
        • Size: Especially large
        • Proximal, Not in anterior roots or distal motor axons
    • Contents
      • Neurofilaments
      • NCAM: On surface
      • Vesicles: At center
      • Ubiquitin & Calretinin: Some spheroids; Less in motor neurons
      • No synuclein
      • PAS: Negative
    • Axon Sprouting: From surface of many spheroids

• Epidemiology: 3 Turkish & Saudi families
• Genetics
  • Mutations: Gln642X; Trp1287Leul 1-BP DEL, 1489T
  • Allelic disorder
    • CLIFAHDD (Dominant): DA2A arthrogryposis
  • Pancreatic cancer: Somatic mutations
• NALCN protein
  • Cation leak channel
  • Voltage-independent
  • Nonselective
  • Non-inactivating
  • Permeable to Na⁺, K⁺, and Ca⁺⁺
  • Responsible for: Neuronal background sodium leak conductance
  • Expressed in: Brain & Spinal cord
• Clinical
  • Onset age: Infancy
  • Psychomotor regression, severe
  • Retardation: No eye contact, speech or cognitive development
  • Spastic tetraparaplegia
  • Ataxia: Episodic; Acetazolamide responsive
  • Truncal hypotonia
  • Seizures
  • Strabismus
  • Contractures
  • Microcephaly
  • Facial dysmorphism: Prominent forehead; Micrognathia; Large, low-set ears
  • Course: Alive at 2 decades
• Laboratory
  • Sural nerve: Infantile neuroaxonal dystrophy
    • Unmyelinated axons
    • Spheroids
    • Edema: Endoneurial & Perineurial; Generalized
  • Brain MRI: Cerebellar atrophy
  • NCV: Lower limit of normal
• NALCN variant syndrome: Congenital contractures of limbs & face, Hypotonia & Global developmental delay (CLIFAHDD) ²⁶
  • Nosology: DA2A arthrogryposis syndrome
  • Epidemiology: 14 patients
  • Genetics
    • Mutations: Missense; In or near S5 & S6 pore-forming segments of NALCN
    • Inheritance: Dominant
    • Allelic disorders
  • Clinical
    • Onset: Congenital
    • Eyes
      • Downslanting palpebral fissures
      • Strabismus
      • Esotropia
    • Face
      • Broad nasal bridge
      • Anteverted nasal tip
      • Large nares
      • Short columella
      • Long philtrum
      • Micrognathia
      • Pursed lips
      • H-shaped dimpled chin
      • Deep nasolabial folds
      • Full cheeks
    • Limb contractures
      • Camptodactyly
      • Ulnar deviation
      • Adducted thumbs
      • Clubfoot
      • Calcaneovalgus deformity
      • Other contractures: Hip; Elbow; Knee
    • Other skeletal: Scoliosis; Neck short
    • CNS
      • Cognitive & Speech delay
      • Respiratory insufficiency
      • Hypotonia
      • Seizures: 1 patient
    • GERD
    • Course: Death in childhood in some
  • Laboratory
    • Brain MRI: Cerebral or Cerebellar atrophy; May be normal

• Epidemiology: 7 patients
• Genetics
  • Mutation: de novo; Heterozygous; c.C2737T (R913X)
  • Allelic disorder: Acromelic frontonasal dysostosis
• ZSWIM6 protein
  • Expression: CNS; Lens
• Clinical
  • Onset age: Infancy
  • Developmental delay: Global; Severe; Absent speech; autism
  • Walking: Delayed; Broad based
  • Seizures (50%): Mild, some patients
  • Spasticity (50%)
  • Movements: Tongue; Hands
  • Peripheral neuropathy
    • High pain threshold
    • Weakness (1 patient): Distal; Legs
  • Face: Dysmorphic features
• Laboratory
  • Brain MRI: Normal or Mild cortical atrophy
  • Nerve pathology: Axon loss; Neurofilament accumulation

• Epidemiology: 9 families, 15 patients
• Genetics
  • Mutations
    • Stop or Missense: N124D; Arg370Pro, P705T; S831P; Arg846X, V1077A (Nf186); Val1122Glu
    • Homozygous
• NFASC protein
  • Development: Nodes of Ranvier (CNS & PNS) & Initial segment
  • L1 family immunoglobulin cell adhesion molecule
  • Mutation effects
    • Arg846X → Loss of Nf155 (Glial, Paranodal)
    • Reduced interaction with CNTN1/CASPR1
  • Other disorders: Immune neuropathies & other disorders
• Clinical
  • Onset
    • Age: 0 to Infancy
    • Prenatal: Reduced movements (Some patients)
  • CNS
    • Developmental delay
    • Behavioral: Aggression; Anxiety
  • Polyneuropathy, Demyelinating
  • Motor
    • Hypotonia
    • Respiratory distress
    • Amyotrophy
  • Dysmorphic features
    • Hypertelorism
    • Nasal bridge: High & Wide
    • Mouth: Cleft palate; Glossoptosis
    • Skeletal
      • Fingers: Long, Thin & Hyperextensible
      • 11 ribs
      • Contractures
  • Later features
    • Ataxia
      • Eyes: Saccadic pursuit
      • Limbs: Dysmetria
    • Spasticity
    • Myoclonus
• Laboratory
  • Brain MRI: Cerebellar atrophy; Some WM changes
  • Central conduction velocities: Slow (SSEP)
  • PNS
    • NCV: Length-dependent demyelination; Velocities reduced or normal
    • EMG: Chronic denervation
  • Muscle: Normal

• Epidemiology: 11 families, 21 patients
• Genetics
  • Mutations: Nonsense; Frameshift; Missense
• NEMF protein
  • Location: Ribosome
  • Resolves stalled ribosomes during translation
  • Facilitates recruitment of LTN1 E3 ligase : Leads to proteasomal degradation
• Clinical
  • Onset age: < 2 years
  • Developmental delay
    • Hypotonia
    • Intellectual
    • Autism
  • Speech: Delay; Dysarthria
  • Polyneuropathy
    • Weakness: Distal; Arms & Legs
    • Walking: Delayed
    • Tendon reflexes: Reduced
    • Gait: Ataxic; Difficulty running
  • Skeletal
    • Scoliosis
    • Equinovarus
    • Hands: Deformities; Polydactyly
  • Course: Progressive
• Laboratory
  • Brain MRI: Normal or Atrophy
  • NCV: Axon loss

Congenital Hypomyelinating Neuropathies (CHN)

• Genetics
  • Mutations: Asp61Asn, Arg98Cys, Ser111Phe, Gly123_Cys127del, Thr124Lys,
      Asn131Ser, Gly167Arg, Leu184fs, Gln186X, Gln215X
  • Allelic disorders
• Clinical
  • Onset
    • Age: Birth
    • Hypotonia
  • Weakness: Severe generalized; Face
  • Muscle bulk: Wasting or Normal
  • Tendon reflexes: Absent
  • Sensory loss: Variable
  • Joints: Arthrogryposis or Hyperextension
  • Course
    • Severe cases: Death before 3 months
    • Milder cases: Static weakness; Increased disability with growth
• Laboratory
  • Electrodiagnostic
    • Demyelinating: NCV Very slow; Distal latencies long; Temporal dispersion; No conduction block
    • SNAPs: Absent
    • Similar to HMSN III
  • Pathology
    • Myelin sheaths: Thin, Absent or Abnormally folded
    • Axon loss: Large > Small
    • Onion bulbs: Occasional small
    • Muscle: Type 1 atrophy; No fiber type grouping
  • MRI: Normal nerve size
  • CSF protein: Mildly high

• Genetics
  • Mutations
    • Ile268Asn (Homozygous); Ser382 Arg & Asp383Tyr (Heterozygous)
    • Recessive mutations
      • Repressor binding domain (R1): ? Alter transcriptional activity
      • 10 kB deletion involving myelin-specific enhancer: Congenital amyelinating neuropathy
  • Allelic disorcders
    • CMT 1D
    • Congenital Amyelinating Neuropathy
  • Also defective in: Krox20 knockout mice; CMT1; Dejerine-Sottas
• Protein: Zinc finger
• Clinical
  • Onset
    • Infantile hypotonia
    • Arthrogryposis
  • Weakness: Diffuse; Distal > Proximal; Ambulation ± walker
  • Wasting: Diffuse
• Nerve conduction velocities: 3 to 8 M/s
• Nerve pathology
  • Myelin: Absent or greatly reduced on most axons
  • Onion bulbs: Occasional
  • Axonal loss: Mild to moderate
• EGR2 Variant: Congenital Amyelinating Neuropathy, Recessive (CHN1) ²⁰
  • Epidemiology: Female Moroccan infant
  • Genetics
    • Mutation: 10 kB deletion involving myelin-specific enhancer
    • Inheritance: Recessive
  • Clinical
    • Oligohydramnios
    • Birth: Hypotonia; Respiratory failure; Reduced movements; Arthrogryposis
    • Death: 7.5 months
  • Nerve pathology
    • Complete absence of PNS myelin
    • Large axons: Ensheathed in Schwann cells
    • EGR2 staining: Absent
  • Parents: Normal

• Epidemiology: Single family
• Genetics
  • Mutation: Missense; Thr109Ile
  • Allelic with
    • Susceptibility to Paclitaxel toxic neuropathy: Heterozygous mutations
• ARHGEF10 protein
  • Rho family of GTPase proteins (RhoGTPases)
    • Regulate actin cytoskeleton
    • Influence cell development
      • Polarity; Microtubule dynamics; Membrane-transport pathways; Transcription-factor activity
    • Play role in neuronal morphogenesis
      • Cell migration; Axonal growth & guidance; Dendrite elaboration & plasticity; Synapse formation
  • Guanine-nucleotide exchange factor (GEF): Other disorders
    • FGD1 : Faciogenital dysplasia (Aarskog-Scott)
    • FGD4: CMT 4H
    • ARHGEF6 (aPIX) : X-linked nonsyndromic mental retardation 46
    • ALS2 (Alsin): Autosomal recessive amyotrophic lateral sclerosis
    • PLEKHG5: DSMA4; CMTRIC
    • HRAS: Congenital myopathy with excess spindles (Costello syndrome)
• Clinical
  • Most patients asymptomatic
  • Examination: Often normal: Normal tendon reflexes & muscle bulk
  • Occasional patients with Raynaud's phenomenon
• Electrodiagnostic testing
  • Nerve conduction velocities: Uniform slowing; Arms 33 to 42 m/s; Legs 27 to 36 m/s
  • CMAPs: Normal amplitude
  • SNAPs: Normal or mildly reduced amplitude
  • Similar values at all ages: ? Non-progressive
• Pathology
  • Nerve: Hypomyelination
    • Reduced number of myelinated axons: 50% of normal
    • Size of remaining myelinated axons: 2 to 6 μm
    • Axonal sheath: Thin for axon diameter
    • Onion bulbs: Rare
    • Regenerating clusters: Rare
    • Tomaculae: none
  • Muscle: Mild denervation changes

• Epidemiology: 1 French family
• Clinical
  • Onset age: 6 to 43 years (Usually < 15)
  • Relapsing
    • Precipitated by fever > 38 °C
    • 2 to 5 attacks
    • Exam normal between attacks
    • ? Duration of symptoms correlated with duration of fever
  • Weakness: Paraparesis or quadriparesis
  • Sensory: Paresthesias & numbness
  • Occasional: Dysphagia; Dysuria
• Electrophysiology: Demyelinating
  • Conduction block
  • Prolonged distal latencies

• Epidemiology: 1 Mississippi family
• Clinical
  • Onset: Prenatal with reduced fetal movements
  • Hypotonia
  • Weakness
    • Distal > Proximal
    • Symmetric
    • Diaphragm: Onset birth to 6 months
  • Sensory: Pain reduced in some patients
  • Contractures (75%)
  • CNS: ? Changes related to hypoxia
  • Prognosis
    • Increasing disability
    • Late static phase with no recovery
    • Death < 8 months 2° Respiratory failure
• Laboratory
  • Electrophysiology
    • NCV: Reduced or absent CMAPs & SNAPs
    • EMG: Denervation
    • Brainstem evoked potentials: Reduced wave 5 suggesting sensorineural hearing loss
  • Nerve Pathology
    • Loss of sensory & motor, large & medium sized, myelinated axons
  • Muscle pathology: Grouped atrophy; Many small fibers
• Rule out
  • Spinal muscular atrophy
  • Infantile axonal neuropathy with respiratory failure
  • Congenital hypomyelinating neuropathy

• Epidemiology
  • 2 families
  • Male > Female
• Clinical
  • Onset
    • Age: < 6 months; Usually < 2 to 3 months
    • Hypotonia
    • Apneic spells
  • Weakness
    • Distal > Proximal
    • Symmetric
    • Cranial nerves
      • Feeding difficulties
      • Facial weakness
      • EOM: Nystagmoid eye movements
  • Sensory: Pain sense preserved
  • Autonomic dysfunction: Some patients ⁶
    • Tachycardia
    • Hyperhidrosis
    • Hyperthermia
    • Hypertension
  • Tendon reflexes: Reduced or Absent
  • Prognosis
    • Increasing disability: Quadriplegia & Respiratory failure
    • Death < 6 months 2° Respiratory failure
• Laboratory
  • Electrophysiology
    • NCV: Reduced or absent CMAPs & SNAPs
    • EMG: Denervation
      • Fibrillations
      • Some enlarged motor units firing at rapid rates
    • Brainsten evoked potentials: Reduced wave 5 suggesting sensorineural hearing loss
  • CSF: Normal
  • Nerve Pathology
    • Loss of sensory & motor, large & medium sized, myelinated axons
    • Normal myelination on remaining axons
    • Ultrastructure: Büngner bands; Normal unmyelinated axons
  • Muscle pathology
    • Grouped atrophy: Small fibers angular
    • Larger muscle fibers: Hypertrophy; Type 1 predominance in some
  • Spinal cord: Mild loss of anterior horn cells
• Differential diagnosis: SMARD
  • Neuropathic
    • SMARD1: IGHMBP2
    • SMARD2: LAS1L
    • Spinal muscular atrophy: SMN1
    • Lethal neonatal axonal neuropathy
    • Congenital hypomyelinating neuropathy: MPZ
    • Infantile Axonal Polyneuropathy with Respiratory Failure
    • Axonal neuropathy & Diaphragm palsy, Congenital: REEP1
    • MFN2, Recessive
    • Brown-Vialetto-van Laere: SLC52A2; SLC52A3
  • Myopathy
    • Mitochondrial phosphate carrier deficiency: SLC25A3
    • Early-onset Myopathy with Areflexia, Respiratory Distress & Dysphagia (EMARDD): MEGF10
  • Diaphragm weakness

• Epidemiology: Wallachian Gypsies (Vlax Roma; Rudari); Bulgaria
• Genetics: Transcription syndrome
  • Mutation: Single nucleotide substitution in antisense Alu element in intron 6
  • Produces: Aberrant splicing; Alu insertion in processed mRNA
  • Carrier rate in Rudari gypsies: 6.9%
  • No mutations in Marinesco-Sjögren patients
• FCP1 Protein
  • TFIIF-associating CTD phosphatase-1
    • Dephosphorylates C-terminal domain of largest RNA polymerase II subunit
    • Substrates are phopsphorylated serine residues
    • Regulates recruitment of proteins involved in transcription & mRNA processing machinery
  • Other functions
    • Involved in transcription regulation: Part of elongation complex
    • Opposes Srb 10 mediated repression of cell-cycle & growth control genes
• Clinical
  • Skeletal
    • Short stature: 100%
    • Facial dysmorphism: 80%; Prominent midface; Thickened perioral tissues; Hypognathism
    • Kyphoscoliosis
    • Foot: Pes cavus; Pes equinovarus
    • Claw hand
  • Eye
    • Congenital zonular cataracts: 100%
    • Microcornea
    • Pendular nystagmus
    • Strabismus: 100%
  • Neuropathy
    • Motor: Predominant
      • Initially lower extremities: By 8 months
      • Upper extremity weakness in childhood
      • Severe disability by 3rd decade
    • Sensory: Distal; Loss of all modalities
    • Tendon reflexes: Reduced or absent, especially in lower extremities
    • Nerve conduction velocities: Demyelinating
      • NCV: 20 to 34 M/sec
      • Distal latencies: Prolonged
    • Nerve biopsy
      • Hypomyelinated axons
      • Axonal degeneration & regeneration in older patients
  • Rhabdomyolysis: After viral infections
  • CNS
    • Upper motor neuron
      • Intellectual Retardation: Mild
      • Extensor plantar response: 40%
      • No spasticity
    • Choreiform movements: 36%; Face & Upper extremities
    • Ataxia: Mild; 22%
    • Tremor: 10%
    • EEG: Slowing
    • MRI
      • Cerebral atrophy (30%)
      • Ventricles: Enlarged
      • Spinal cord: Atrophy (25%)
      • White matter lesions: Periventricular; Progressive focal supratentorial
  • Endocrine: Mild hypogonadism
  • General anesthesia complications
    • Pulmonary edema
    • Epileptic seizures
• Differences from Marinesco-Sjögren ¹³
  • Present in CCFDN: Peripheral neuropathy; Facial dysmorphism; Microcornea; Linkage to 18qter
  • Less in CCFDN: Mental retardation severity; Cerebellar atrophy; Chronic myopathy

Epidemiology Navajo: Up to 1 case/1,600 live births Especially Western reservation Genetics Mutation: Arg50Gln Allelic disorders MPV17 protein: Mitochondrial Clinical Onset: 1 year Polyneuropathy Sensory loss: Distal; PanModal; Acromutilation Weakness: Distal > Proximal; Progressive; Delayed walking Tendon reflexes: Reduced Nerve pathology: Severe loss of large & small myelinated axons CNS: Progressive white matter lesions on MRI Systemic Skeletal: Contractures; Short stature; Scoliosis Hepatic Clinical Hepatomegaly Reyes-like episodes (70%) Pathology Macronodular cirrhosis Cytochrome oxidase negative hepatocytes Ocular: Corneal ulceration Systemic infections (80%) Sexual infantilism Poor weight gain Prognosis: Death by Teens in 40% Laboratory Serum lactate: High Mitochondrial DNA depletion 11 Navajo Sensory-Autonomic Neuropathy + Arthropathy (MTDPS6)   ● Glomerulosclerosis gene MPV17 (MPV17) ; Chromosome 2p23.3; Recessive Epidemiology > 100 patients Navajo: 8 children in 3 families Korea: 2 families China Genetics Mutations: Arg50Gln (Navajo); R41Q (Korean); F61S & P98L (China) Allelic disorders Clinical Polyneuropathy Onset age: Neonatal to 2nd decade Motor Usual: Normal or Distal weakness & atrophy Variant: Acute, Child onset Proximal weakness Demyelinating neuropathy Sensory loss Deep Pain & Temperature sensation: Mild loss Cornea: Insensitivity Some patients with normal exam Autonomic Infantile fever (Recurrent) Heat intolerance Sweating: reduced Tendon reflexes: Present or Reduced Laboratory Electrodiagnostic Normal or CMAPS & SNAPs reduced amplitude or absent Nerve pathology Axon loss: Large + Small myelinated & Unmyelinated Muscle: Fibers with abnormal mitochondria Systemic Liver disease Chronic or Acute onset Hepatomegaly Progressive Skeletal Early: Joint deformities Painless fractures Arthropathy: Progressive Skin: Thick on hands Progression: Liver, Joint & Bone disorders Laboratory Serum lactate: May be high Hyperammonemia Anemia Bilirubin & AAT: High

Navajo Neuropathy + Arthropathy From: Otto Appenzeller

• Nosology: Waardenburg-Shah, Neurologic variant (WS4)
• SOX10 gene
  • Mutations ¹²
    • Specific mutations: 12 base pair deletion in exon 5; Q250Stop; 759delG; SOX10 deletions
    • Produces intact protein with extended tail added to transactivation domain in C-terminus
  • Disease Mechanisms
    • Severe disorders: ? Mutated protein acts as dominant negative
    • Haploinsufficiency: Milder phenotype disorders
  • Allelic disorders
    • Null mutations
      • SPG + Hypomyelinating neuropathy & Deafness
      • Dominant megacolon syndrome
      • Waardenburg syndrome, type 2E ± Neurologic involvement
      • Waardenburg-Shah syndrome (WS4C)
        • Clinical: Intestinal aganglionosis; Pigmentation defects; Deafness, sensorineural
        • Also due to mutations of: EDNRB (Endothelin B receptor) ; Endothelin-3 (EDN3)
      • Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, Hirschsprung disease (PCWH)
    • Loss of function, Missense mutations
      • Kallmann Syndrome (Anosmia & Hypogonadotropic hypogonadism) with Deafness
    • Other
      • Hearing loss
      • Anosmia
      • Neurodevelopment disorders
      • Cancer progression
      • Chemotherapy-induced neuropathy symptoms: SNP rs139887 ³⁶
    • Dom mouse (Dominant megacolon; intestinal aganglionosis, white belly spot & white paws)
• SOX10 protein
  • Marker for
    • Migratory multipotent Neural Crest progenitors
    • Neural Crest derivatives
  • Myelin-specific transcription factor
    • In Schwann cells & Oligodendroglia
  • Required for Schwann cell development & Myelination
    • Transition from Schwann cell precursor to Immature Schwann cell
  • Modulates other myelin-related transcription factors & proteins ⁹
    • Promotes expression of OCT6 (POU3F1)
      • Triggers events enabling myelin gene transcription
    • P₀ protein
    • Connexin-32: Activates expression by binding to promoter; Synergy with EGR2
    • Other: ERBB3; PLP; MBP; SIPA1L2
  • Plays role in neural crest development: Enteric ganglion cells & Melanocytes
• Clinical
  • Waardenburg syndrome: General features
    • Deafness: Sensorineural
    • Pigmentation disorders: Skin, Hair, Iris
    • Subtypes
      • WS1: Facial dysmorphisms; PAX3
      • WS2: No dystopia canthorum; SOX10; MITF
      • WS3: Facial dysmorphisms, Arm Musculoskeletal; PAX3
      • WS4: Hirschsprung disease; SOX10; Endothelin-3 , EDNRB
  • Onset
    • Congenital
    • Hirschsprung disease
  • CNS
    • Clinical
      • Developmental delay: Severe
      • Spastic paraplegia or quadriplegia
      • Seizures
      • Deafness: Sensorineural
    • MRI
      • Semicircular canals: Agenesis or hypoplasia of one or more
      • White matter: Absent myelination; Hyperintensity on T2
      • Olfactory bulbs: Agenesis (88%)
      • Lacrimal glands: Hypoplastic (79%)
      • Parotid glands: Hypoplastic (86%)
    • CSF: Protein mildly increased
    • Pathology: Absent central myelin
  • PNS
    • Muscle atrophy
    • ? Sensory loss
    • Tendon reflexes: Reduced
    • Electrophysiology: Demyelinating neuropathy
      • NCV: Slowing, Uniform
      • F-waves: Preserved; Long latency
      • CMAPs: Amplitude small
      • Stimulation threshold: High
    • Pathology: Nerve
      • Large axons
        • Absent or reduced myelin
        • Number: Normal or Reduced
        • Occasional excessively large axon
      • Small axons: Reduced number
      • Schwann cells: Present; Aligned with axons in 1 to 1 relationship
      • Endoneurial fibroblasts: Small vacuoles
  • Ocular
    • Nystagmus
    • Optic Atrophy
    • Dystopia canthorum
  • GI
    • Hirschsprung disease
    • Enteric aganglionosis
  • Depigmentation
    • Skin
    • Heterochromia iridis
    • Fundus: Depigmentation, patchy
  • Course
    • ? Non-progressive
    • Death at 3 months in 1 patient
• SOX10 variant: SPG + Hypomyelinating neuropathy & Hearing loss ²⁸
  • Epidemiology: 1 family, 2 patients
  • Genetics
    • Inheritance: Dominant
    • Mutation: c.1140C.A (p.Y380X)
    • Parental mosaicism
  • Clinical
    • Onset: Reduced fetal movements
    • Motor: Developmental delay
    • Spastic paraparesis
      • Legs > Arms
      • Loss of ambulation
      • Course: Slow progression
    • Tendon reflexes: Increased at knees; Reduced at ankles
    • Hearing loss
    • Neuropathy: Hypomyelinating
      • Sensory loss: Vibration & Pain
      • Weakness: Distal legs
    • Cerebellar
      • Dysmetria: Arms
      • Nystagmus
    • GI: Constipation, mild
    • Cutaneous hypopigmentation
    • Face: High arched palate; Small mouth; Thin, upturned nostrils
    • Eye: Macular pigment changes
  • Laboratory
    • Brain MRI: Absent semicircular canals
    • NCV
      • Velocities: Slowing, diffuse & symmetric (11 to 20 m/s)
      • SNAPs: Reduced amplitude or Absent
    • Nerve biopsy: Thin myelination; Axon loss

• Epidemiology
  • > 100 patients
  • 1 in 100,000 births
  • Unusual: Central America; Oceania
• Genetics
  • Mutations: Missense; Splice & Stop; > 40
  • Geography: Mutations often common in specific regions
    • Turkey: D233V
    • Finland: W262X
    • Asia: Gly64His
    • Saudi Arabia: Met1Val
    • Europeans & Caucasians: c.974C>T
• Fumarylacetoacetase protein
  • Tyrosine metabolism: Final step
  • Catalyzes hydrolysis of fumarylacetoacetate into fumarate & acetoacetate
  • Expression: Liver; Kidney
  • Mutated proteins: Reduced protein stability, Misfolding, Accelerated degradation (UPS) ³¹
• Clinical
  • Onset: Neonatal to Infant
  • Peripheral neuropathy: Attacks ³⁰
    • Clinical: Porphyria-like
      • Onset
        • Children: Mean 1 year
        • Adults: After discontinuation of, or intermittent, NTBC treatment
      • Multiple attacks
      • Pain: Severe; Abdomen, Extremities
      • Muscle weakness
        • May be severe
        • Respiratory failure
      • Autonomic
        • Blood presure fluctuations: Hypertension
        • GI: Vomiting; Ileus
      • CNS: Seizures; Confusion
      • Fever
      • Prognosis
        • Treatment: Full recovery
        • Mortality: High
      • Treatment
        • NTBC
          • 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione
          • Inhibitor of 4-hydroxy-phenylpyruvate dioxygenase
        • Diet
          • Protein restriction
          • Tyrosine- & Phenylalanine-free protein substitutes
        • Glucose: IV
        • Liver transplantation
    • Laboratory
      • Nerve conduction studies: Axon loss
      • Nerve Pathology: Axon degeneration, Acute
      • Hyponatremia
      • Succinylacetone: Increased blood spot
      • NTBC level: Below therapeutic range
  • Myopathy: 2° Carnitine deficiency ⁷
    • Epidemiology: Case report
    • Clinical
      • Onset: 2 years; Gait disorder
      • Weakness: Proximal; Hypotonia
      • Treatment: Carnitine, dietary supplementation
    • Laboratory
      • Plasma carnitine: Low
      • Hypophosphatemia
  • Systemic features
    • Hepatic failure
    • Renal: Fanconi syndrome
    • Cardiomyopathy: Mild
  • Natural history
    • With treatment: Survival to adulthood
    • No treatment: Death < 3 years
• Laboratory
  • Toxic metabolite accumulation
    • Succinylacetone, Maleylacetoacetate, Fumarylacetoacetate
    • Succinylacetone: Competitive inhibitor of δ-aminolevulinic acid (ALA)

• Genetics
  • Null mutations: Severe childhood forms
  • Missense mutations: Later onset
  • Allelic with: Hereditary Spastic Paraparesis, Complicated
• LYST (CHS1) protein
  • Functions
    • Interacts with N-ethylmaleimide-sensitive factor (NSF) attachment protein receptors (SNAREs)
    • Role in membrane fusion or fission
    • May regulate lysosome trafficking
  • Subcellular location: ? Cytoplasmic
  • Tissue specificity: Thymus; Peripheral blood leukocytes; Bone marrow; Brain
• Clinical
  • Polyneuropathy
    • Clinical
      • Weakness: Distal > Proximal; Feet & Hands
      • Sensory loss: Distal
      • Tendon reflexes: Reduced
    • EMG: Distal denervation
    • Pathology: Axonal loss
      • Relative sparing of smaller myelinated axons
      • Loss of unmyelinated axons: Moderate
      • Axon regenration
      • Inflammation: Perivascular; Occasional
      • Schwann cells: Giant lysosomal inclusions & Lipofuscin
      • Rule out: Neoplastic infiltrative neuropathy
    • Treatment: Transient improvement with corticosteroids ¹⁵
  • Motor neuropathy ²⁴
    • Epidemiology: 2 patients in 1 family
    • Mutations: Y3163C; S3475F
    • Onset age: Childhood to 4th decade
    • Weakness: Legs; Symmetric; Proximal & Distal
    • Tendon reflexes: Reduced
    • Sensation: Normal
  • CNS
    • Mental retardation
    • Spinocerebellar degeneration
    • Adult onset: Parkinsonism; Dementia
  • Pigmentation defective (Partial oculocutaneous albinism)
    • Skin: Giant melanosomes; Hypopigmentation
    • Ocular: Nystagmus; Photophobia
  • Systemic
    • Organomegaly: Liver; Spleen; Lymph nodes
    • Hematologic
      • Anemia; Pancytopenia
      • Hemorrhage: Platelets lack dense granules; Function is abnormal
      • Reduced natural killer cell & cytotoxic T lymphocyte function
        • Abnormal fusion of lysosomes
        • Defective granule killing
      • Bone marrow
        • Eosinophilic, peroxidase-positive inclusion bodies in myeloblasts & promyelocytes
        • External link: New Mexico
    • Lymphoreticular (Lymphohistiocytic) malignancy (90%)
      • "Accelerated phase" of CHS
      • Hemophagocytic lymphohistiocytosis
      • CD8 T-cells proliferate & infiltrate tissues
    • Susceptibility to infection
  • Heterozygotes: Granular anomaly of lymphocytes
  • Course
    • Death: Often < 7 years
    • If malignancy is absent
      • Longer survival
      • Progressive neurologic disorder
• Pathology: Giant lysosomal inclusions in CNS, Schwann cells & Leukocytes
• Animal model: Beige mouse
• Variant syndrome: Hereditary Spastic Paraparesis, Complicated ²²
  • Epidemiology: 6 Japanese families
  • Genetics
    • Inheritance: Recessive
    • Mutations: Misense (Leu58Val; Phe1397Val); Stop & Splice
    • Allelic with: Chediak-Higashi
  • LYST protein
  • Clinical
    • Onset age: 2nd to 6th decade
    • Spastic paraparesis: Gait disorder
    • Cerebellar ataxia: Arms
    • Peripheral neuropathy: Motor & Sensory axon loss
    • Tendon reflexes: Increased except at ankles
    • IQ: Low
  • Laboratory
    • MRI: Cerebellar & Thoracic spinal cord atrophy
    • NCV: Velocities mildly reduced in legs; SNAP & CMAP amplitudes low
    • SNAPS: Absent or Reduced amplitude
    • Motor-evoked potentials: Central delay
    • Granulocytes: Peroxidase stained giant granules
    • Nerve biopsy: Myelinated axon loss; Axon swelling

• Epidemiology: > 10 families
• Genetics
  • Mutations
    • Loss of function
    • Truncating; Small & large deletions; Small duplications
  • Associated with: 22q11.2 Deletion syndrome with mutation on other chromosome
• SNAP29 protein
  • Modulator of vesicle trafficking
  • Binds to syntaxin fusion proteins
  • Disease: Levels reduced in tissues
  • Other mutations in vesicle recycling genes
    • Chediak Higashi
    • Griscelli syndrome
    • Hermansky-Pudlak syndrome
    • Chylomicron retention disease
    • Familial hemophagocytic lymphohistiocytosis type 4
• Clinical
  • Onset
    • Age: < 4 months
    • Roving eye movements
    • Poor head & trunk control
    • Failure to thrive
  • Motor
    • Hypotonia
    • Delayed development
    • Late sitting & walking
  • Polyneuropathy
    • Clinical: Not well described
    • Tendon reflexes: Absent
    • Electrophysiology: Axon loss
    • Muscle biopsy: Denervation; Normal mitochondrial oxidative enzymes
  • CNS
    • Microcephaly: Progressive
    • Corpus callosum: Dysgenesis
    • Psychomotor retardation: Severe
    • Spasticity
    • Seizures
  • Face: Dysmorphism
    • Elongated faces
    • Antimongolian eye slant
    • Hypertelorism: Mild
    • Flat broad nasal root
  • Skin
    • Onset: Between 5 & 11 months
    • Palmoplantar keratoderma
    • Ichthyosis
    • Hypopigmentation
    • Progressive during 2nd year of life
  • Eye
    • Optic disk: Hypoplastic
    • Strabismus
    • Electrophysiology: Reduced conductance from peripheral retina & macular atrophy
  • Skeletal
    • Dislocated hips
    • Contractures: Legs
    • Short stature
  • Ear: Sensorineural deafness, mild
  • Course: Death in 40% due to pneumonia at ages 5 to 12 years
• Laboratory
  • Brain MRI
    • White matter
      • Corpus callosum Δ
      • Hypomyelination
      • Optic nerve atrophy
    • Cortical dysplasia: Pachygyria & Polymicrogyria
  • Skin
    • Ultrastructure: Clear vesicles in spinous & granular epidermal layers
    • Glucosylceramides: Retained, abnormally,in lower stratum corneum cells

• Nosology: Leukodystrophy, Hypomyelinating 5 (HLD5)
• Epidemiology: 6 families
• Genetics
  • Mutations
    • Type: Stop, Splice site & Missense
    • All homozygous
  • Missense mutations
    • Milder phenotype
    • May have no peripheral neuropathy
• Hyccin protein
  • Ubiquitously expressed in brain
  • Cell localization: Plasma membrane, patchy
  • Mutation effects
    • Absent or reduced levels of Hyccin protein
    • Mildest patient, without neuropathy, had residual protein
• Onset
  • Age: birth or in 1st 2 months of life
  • Cataract
• Clinical
  • Psychomotor
    • Birth: Normal
    • 1 year: Delayed
    • Walking only with support
      • Onset: 1 to 2 years
      • Loss: 8 to 9 years
    • Mental deficiency: Mild to Moderate
  • Other CNS
    • Pyramidal: Progressive
    • Cerebellar: Progressive
    • Seizures (30%)
  • Muscle
    • Weakness: Legs > Arms
    • Wasting
  • Eye: Cataracts (100%)
    • Congenital
    • Bilateral
    • Surgery often performed
  • Scoliosis (40%)
  • Survival
    • Most at least to 3rd decade
    • 1 death in 1st decade
• Laboratory
• Brain MRI: Diffuse cerebral hypomyelination
• Electrophysiology: Polyneuropathy (90%)
  • Motor nerve conduction velocity: Slightly to markedly slowed depending on the age
  • CMAP amplitude: Reduced
• Sural nerve biopsy
  • Deficiency of myelin sheath in several nerve fibers
  • Axonal loss: Mild
  • No active axonal degeneration

• Nosology: Action myoclonus-Renal failure (AMRF)
• Epidemiology: EPM4 in multiple populations
• Genetics
  • Mutations: Nonsense (Q288X; French Canadian), c.435_436insAG & Splice site (c11187.3insT)
• SCARB2 protein
  • Lysosomal membrane
  • Functions
    • Endosomal/lysosomal mediated protein degradation and recycling
    • Lysosomes: Cholesterol export
• Clinical
  • Onset age: Teens
  • Action myoclonus: Aggravated by action, tactile stimuli & startle
  • Dysarthria
  • Dysphagia
  • Seizures: Generalized; Myoclonic-tonic-clonic
  • Ataxia: Limb
  • Intellect: Normal or Dementia
  • Tendon reflexes: Present
  • Hearing loss: BAER reduced
  • Course: Rapid progression of renal failure
• Laboratory
  • Nerve conduction studies: Demyelinating polyneuropathy in 4 patients
    • CMAP & SNAP amplitudes: Reduced
    • F-wave latencies: Prolonged
    • Conduction velocities: 30 to 40 M/s
  • Renal failure: Proteinuria
  • EPM4 Brain pathology: Autofluorescent pigment

• Epidemiology: 5 North African (Libyan & Moroccan) Jewish patients
• Genetics
  • CD59 mutation: Cys89Tyr, Homozygous
  • Allelic with
    • Hemolytic anemia & Cerebral infarction
    • Early-onset chronic axonal neuropathy, Strokes & Hemolysis
• CD59 protein
  • Inhibits final step of membrane attack complex (MAC) formation
  • Protects cells from complement mediated lysis
  • CD59 deficiency: Common in adults with Paroyysmal Nocturnal Hemoglobinuria 1
  • Dermatomyositis, Juvenile
    • CD59 reduced on muscle fibers & capillaries
• Clinical
  • Onset age: 3 to 7 months
  • Polyneuropathy
    • Relapsing-remitting
    • Exacerbated by: Infection; Febrile episodes
    • Hypotonia
    • Weakness: Limbs
      • Legs > Arms
      • Distal > Proximal
      • Symmetric
    • Tendon reflexes: Reduced
  • Immunosuppression treatment
    • Eculizumab
    • IVIg
    • Reduced relapse length & severity
    • Improved arm strength
  • Hemolytic anemia, Chronic
• Laboratory
  • Red blood cells: Reduced CD59, especially on surface membrane
  • Sural nerve
    • Vessel endothelium: Loss of CD59 expression
    • Axon loss
    • Myelin sheath: Thin
  • NCV: Demyelination; Axon loss
  • CSF protein: High
• CD59 variant disorder: Early-onset chronic axonal neuropathy, Strokes & Hemolysis ²⁷
  • Epidemiology: Turkish family, 3 patients
  • CD59 mutation: c.A146T (p.Asp49Val); Homozygous
  • Clinical
    • Onset age: < 1 year
    • Polyneuropathy
      • Axon loss
      • Onset: Acute
      • Course: Relapsing
      • Treatment: Immunomodulation
    • Strokes
      • Anterior & Posterior circulation
      • Cerebral venous thrombosis
  • Laboratory
    • CD59: Reduced expression on blood cells
    • NCV: Axon loss, Motor & Sensory
    • Hemolysis: Chronic & Recurrent; Coombs negative
    • Indirect hyperbilirubinemia: Neonatal

• Nosology
  • Carbohydrate deficient glycoprotein syndrome, Type 1v (CDG1V)
  • Also see: Congenital disorders of glycosyation
• Epidemiology: 17 families; 43 patients
• Genetics
  • Mutations: Cys283Trp; Glu356Gly; Arg401Ter; Arg524Ter; Small deletions & duplications
• NGLY1 protein
  • Cytosolic enzyme
  • Cleaves intact glycan from N-linked glycoproteins
  • Proteasome
    • Deglycosylation of cytoplasmic proteins
    • Degrades aberrant glycoproteins synthesized in ER & translocated to cytoplasm
  • Endoplasmic reticulum–associated degradation (ERAD) pathway
  • Mitochondrial homeostasis
  • Mutations: Accumulation of misfolded proteins in cytosol
• Clinical
  • Onset age: Early childhood or Infancy
  • Intrauterine growth retardation (50%)
  • CNS
    • Hypotonia: Central
    • Development delay (Severe): Cognitive; Motor; Speech
    • Movements: Chorea & Athetosis; Lip smacking; Tremulousness
    • Epilepsy: Intractable; Multifocal; Myoclonic; Drop attacks; Staring or tonic episodes
    • Ocular apraxia (20%)
    • Microcephaly
  • Autonomic
    • Absent tears
    • Constipation
    • Anhidrosis
  • Peripheral neuropathy
    • Sensory loss: Especially pain
  • Tendon reflexes: Reduced
  • Skeletal: Hands & Feet small; Microcephaly; Scoliosis
  • Eyes: Corneal scarring & opacities; Strabismus
  • Course: Slow progression
• Laboratory
  • Liver
    • Transaminases: High
    • Vacuolar amorphous cytoplasmic storage material
  • EEG: Often abnormal
  • Electrodiagnostic studies
    • NCV: 20 to 30 M/s; Axon loss, Sensory > Motor
    • EMG: Denervation, Legs > Arms
  • Nerve pathology
    • Axon loss
      • Large & Small myelinated
      • Unmyelinated axons: Spared
    • Myelin sheath: Thin
  • Muscle
    • Fiber size: Varied
    • Fiber type: 1 predominant
    • Fiber typs grouping: Mild
    • Mitochondrial oxidative enzyme activities: Individual complexes reduced in some patients
    • Glycogen: May be increased
    • NGLY1 protein: Absent
  • Liver: Cytoplasmic accumulation of storage material in vacuoles
  • EEG: Generalized spikes
  • α-fetoprotein: High
  • Lactate: High in 50%

• Epidemiology: 1 Middle-Eastern family; 2 patients
• Genetics
  • Mutation: c.3127G>A, Val1043Ile
• STXBP5L protein
  • Expression: CNS & PNS
  • Inhibits neurotransmitter release
    • Inhibits formation of SNARE complexes between synaptic vesicles & plasma membrane
    • Rgulates docking & fusion of synaptic vesicles with presynaptic membrane
    • Neurosecretory cells
    • Insulin secretion: Negative regulator
• Clinical
  • Onset
    • Age: 3 months
    • Hypotonia: Proximal & Distal
    • Feeding dificulties
  • Weakness
    • Diffuse
    • Legs > Arms
    • No sitting or walking
    • Bulbar dysfunction
  • Tendon reflexes: Absent
  • Sensation: Normal
  • Skeletal
    • Scoliosis
    • Contractures: Distal
  • CNS
    • Optic atrophy: Progressive
    • Extra-pyramidal (50%): Dystonia; Dyskinesia
    • Seizures: Myoclonic & Tonic-Clonic
    • Eye movements: Slow saccades; Supranuclear paresis; Ophthalmoplegia
    • Cognition: Delayed
  • Course
    • Progressive
    • Death: 3rd to 8th year; Respiratory failure
• Laboratory
  • NCV: Axon loss, Sensory & Motor (Small SNAPs & CMAPs)
  • EMG: Motor unit potentials large
  • Muscle: Neurogenic atrophy
  • Nerve: Axon loss
  • EEG: Epileptic discharges with seizures
  • MRI: Brain atrophy

• Epidemiology: 1 Ashkenazi Jewish family, 2 patients
• Genetics
  • Mutation: Homozygous; Gly33Gly
• ACER3 protein
  • Hydrolysis of unsaturated long-chain ceramides
• Clinical
  • Onset age: 6 to 13 months
  • Developmental regression
  • Truncal hypotonia
  • Appendicular spasticity
  • Dystonia
  • Areflexia
  • Optic discs pale
  • Neurogenic bladder
  • Face dysmorphism
  • Course: Progressive
• Laboratory
  • Brain imaging: White matter pathology, Cerebral atrophy, Corpus callosum thin
  • Nerve biopsy: Axon loss

• Epidemiology: 11 families
• Genetics
  • Mutations: Missense; Few stop
  • Allelic disorder: EIEE80 (GPIBD20)
• PIGB protein
  • Endoplasmic reticulum transmembrane protein
  • Transfers 3rd mannose to glycosylphosphatidylinositol (GPI)
  • Disease class: Inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs)
    • Often caused by genes related to GPI synthesis
    • PIGK disorder
• Clinical
  • Onset age: Neonatal
  • Global delay: Developmental; Intellectual
  • Seizures
  • Peripheral neuropathy
    • More severe disorders
    • Axon loss: Motor > Sensory
  • Other
    • Deafness
    • Bone: Osteodystrophy; Terminal phalanges aplasia; Scoliosis
    • Onychodystrophy
  • Course: Often death < 4 years
• Laboratory
  • 2-Oxoglutaric aciduria
  • Alkaline phosphatase: High
  • Brain MRI: Polymicrogyria 20%; Cerebral atrophy; Hypomyelination
  • EEG: Spike wave discharges

• Epidemiology: 4 families
• Genetics
  • Mutations: Splice site & Insertion
• AP1S1 protein
  • SAP-1 complex subunit: Involved in protein trafficking by clathrin-coated vesicles
  • Main protein components of coat surrounding cytoplasmic face of coated vesicles
  • Golgi complex
  • Mutation: Abnormal trafficking of copper transporters
  • AP1B1 mutations: MEDNIK-like syndrome without neuropathy
• Clinical
  • Onset: Congenital
  • Mental retardation: Psychomotor
  • Enteropathy: Diarrhea; Hepatic fibrosis
  • Deafness: Sensorineural
  • Peripheral Neuropathy
  • Skin: Ichthyosis; Keratoderma; Hypopigmentation; Laxity
  • Treatment: ? Zinc acetate
• Laboratory
  • Brain MRI: Atrophy
  • Lactate: Increased
  • Serum copper & ceruloplasmin: Reduced
  • Very long chain fatty acids (VLCFAs): Increased

• Epidemiology: 1 Turkish family, 3 patients
• Genetics
  • Mutation: Homozygous; Intronic; c.1127+337A-G
• PSMC3 protein
  • Component of 26S ATP-dependent protease
    • 19S proteasome regulatory complex
  • ATPase activity
  • Proteasome related
  • ATP-dependent degradation of ubiquitinated proteins
  • Heterohexameric ring of AAA proteins
    • Unfolds ubiquitinated target proteins: Concurrently translocated into proteolytic chamber & degraded into peptides
• Clinical
  • Onset: Early childhood
  • Deafness: Rapidly progressive
  • Cataract: Congenital
  • Intellectual development: Severe delay
  • Face: Dysmorphism
  • Skin
    • Subcutaneous calcifications at elbows & knees
    • Hair: Depigmented (White) in legs
  • Polyneuropathy
  • Legs
  • Distal
• Laboratory
  • Auditory brainstem reflexes: Reduced
  • Heat CT: Lateral semicircular canal malformations

• Epidemiology
  • 31 patients
  • 4 patients diagnosed as adults
• Genetics
  • Mutations: Missense & Stop
  • Allelic disorder: Neu-Laxova syndrome 2
• PSAT1 protein
  • Serine synthesis
  • Reversible conversion of 3-phosphohydroxypyruvate to phosphoserine
• Clinical
  • Onset: Congenital to Childhood
  • Polyneuropathy
    • Weakness: Distal; Hands & Feet
    • Sensory loss: Panmodal; Acromutilation
    • Tendon reflexes: Absent at ankles; Brisk elsewhere
  • CNS
    • More severepatients
    • Psychomotor retardation
    • Spasticity
    • Seizures
  • Hearing loss: Sensorineural
  • Skin
    • Early in disease course
    • Ichthyosis
    • Xerotic
  • Hypertension
  • Joint contractures: Distal
  • Course: Progressive
  • Treatment
    • Serine supplementation (100 to 900 mg/kg/day)
    • Glycine (300 mg/kg/day)
• Laboratory
  • Serum serine: Low or Normal
  • Head imaging: Microcephaly; Brain atrophy or normal
  • NCV: Axon loss
  • Nerve pathology: Axon loss
    • Large & Small
    • Severe
  • Skin: Hyperkeratosis

• Storage disorders: Mucopolysaccharidoses ; Mucolipidoses
• Structural anomalies
  • Local: Bone; Tendon; Muscle; Band; Transverse carpal ligament hypertrophy
  • General: Skeletal (Spondyloepiphyseal) Dysplasia; Weill-Marchesani ; Melorheostosis
• Bleeding: Hemophilia
• Mass: Hemangioma; Hamartoma; Tumors; Abscesses
• Systemic disease: Disseminated angiomatosis; Lipoid proteinosis; Scleroderma
• Local injury
  • Overuse: Flexion-extension; Sustained flexion (Dystonia; Cerebral palsy)
  • Trauma; Burns
• Familial
  • Commonly autosomal dominant
  • Onset: 1 year to 3rd decade
  • Frequently bilateral or right hand
  • Associated with thickened transverse carpal ligament, or digital flexor tenosynovitis

• HSN: I, II, III, IV, V
• Large Fiber
  
• Large + Small Fiber
  
• Small Fiber
  
• With spasticity