Neuropathy: Childhood

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CHILDHOOD ONSET POLYNEUROPATHIES

See storage inclusions

Hereditary
Axonal or Neuronal	Myelin disorders
A-beta-lipoproteinemia Adrenomyeloneuropathy An-α-lipoproteinemia (Tangier's) Andermann Syndrome Ataxia telangectasia Autonomic: Acute Brachial Plexopathy CEDNIK Cerebrotendinous xanthomatosis Chediak-Higashi Fabry's Friedreich Ataxia Giant Axonal Neuropathy Glycogenosis, Type 3 HMSN: II & 6 Infantile axonal + Respiratory failure Infantile Onset Spinocerebellar Ataxia (IOSCA) LCHADD Lethal neonatal Methylenetetrahydrofolate Reductase Minifascicles & Gonadal dysgenesis Mitochondrial: MNGIE; NARP; Leigh; Other Navajo neuropathy with arthropathy Navajo neurohepatopathy Neuroaxonal Dystrophies Riley-Day RPIA deficiency Sensory Neuropathies Spinal muscular atrophy: Proximal; Distal Tyrosinemia	Carbohydrate-deficient glycoprotein Cataracts & Facial Dysmorphism (CCFDN) Cockayne: A; B Congenital muscular dystrophy Merosin deficient Congenital hypomyelinating Farber's lipogranulomatosis HMSN Dominant: CMT: IA, IB, III, EGR2 HNPP, Thermosensitive Recessive: CMT: III; 4A; 4B; ?4C 4D (LOM); 4E; 4F; HMSN-R; CNS X-linked: IX Dejerine-Sottas Hypomyelination & Congenital cataract Krabbe Marinesco-Sjögren Metachromatic Leukodystrophy Niemann-Pick Pelizaeus-Merzbacher Refsum SOX10 Thermosensitive

Acquired
Immune	Toxic
Guillain Barré CIDP Acute motor axonal neuropathy (AMAN)	Diphtheria Botulism Heavy Metals Drugs
Metabolic	Other
Diabetes Mellitus Vitamin B₁₂ deficiency	Carpal tunnel syndrome

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

Farber's disease (Lipogranulomatosis)

l Acid ceramidase

; Chromosome 8p22-p21.3; Autosomal Recessive

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
Electrophysiology
- Nerve conduction velocities: Slow
Lab
- Neuronal & glial storage of nonsulfonated acid mucopolysaccharide
- Elevated urine ceramide levels
- N-laurylsphingosine deacylase deficiency
- Ceramidase deficiency
Pathology¹⁰
- 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

Giant Axonal Neuropathy

l Gigaxonin

; Chromosome 16q24; Recessive

From: T Mozaffar

Giant Axonal Neuropathy

Gene mutations; Missense; Nonsense; Frameshift
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
- BTB/kelch superfamily
  - Intracellular proteins
  - Functions
    - Coordinate cell morphology & growth: Calicin
    - Cytoplasmic sequestration of transcription factors: Keap 1
  - Ubiquitin-proteasome system
    - Controls degradation of ubiquitin-mediated microtubule-associated protein 1B (MAP1B)
    - Interacts with UBE1
    - May function as scaffold protein in ubiquitin-proteasome system
  - Association with actin & cytoskeleton
    - Mayven; kelch; ENC-1
  - Over-expression: Enhanced degradation of MAP1B-LC
  - May contribute to viral pathogenesis
Onset
- Age: Typically 3 years; Most < 10 years
- Gait disorder
Clinical features
- 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
- CNS: Variable
  - Ataxia: Clumsy gait; Present in most patients
  - Eyes: Optic atrophy; Nystagmus
  - Mental retardation
  - Corticospinal tract: Extensor plantar responses
- Hair
  - Frizzy (Tightly curled) scalp hair; Long curly eyelashes
  - Changes more common in severe cases
- Skeletal: Short stature; Prominent high forehead
- Progression
  - Wheel chair or Death by 3rd decade
  - Some patients with slower progression over 20 years
Laboratory
- CSF: Normal
- MRI
  - Diffuse hyperintensities: Cerebral & cerebellar white matter
Electrophysiology: Axonal neuropathy
- SNAPs: Absent
- Motor nerve conduction velocity: Normal or Mild reduction
Pathology
- Axonal loss: Distal; Progressive with age; All axon sizes
- Axonal 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
- Axonal atrophy: Distal to swellings
- Microfilament accumulations
  - In Schwann cells, fibroblasts, vascular endothelium
Heterozygotes
- ? Subclinical polyneuropathy on electrophysiology
Variant: Giant axonal neuropathy, Tunisian form
l Autosomal Recessive
- Onset: Infancy
- Clinical
  - Weakness: Distal; Bulbar
  - Sensory loss: Legs
  - Tendon reflexes: Brisk
  - Normal hair
- Multisystem degeneration with motor neuron syndrome
- Slow progression
Other cytoskeletal disorders
- Neurofilament light chain: CMT 2E
- Neurofilament heavy chain: Amyotrophic lateral sclerosis
- α-Actin: Nemaline (Rod) Myopathy
- Dystrophin: Duchenne muscular dystrophy

Neuroaxonal Dystrophy (Late infantile)

l Phospholipase A2, Group VI (PLA2G6)

; Chromosome 22q13.1; Recessive

Allelic with: Karak syndrome
Nosology: Overlaps clinically with
- Pantothenate kinase-associated neurodegeneration (PKAN)
  l PANK2 ; Chromosome 20p13-p12.3; Recessive
  - Later onset
  - Extrapyramidal: Dystonia; Chorioathetosis
- Schindler & Kanzaki diseases
  l 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
Genetics: PLA2G6 mutations
- V691del; Tyr790Ter; Lys545Thr; Val310Glu; Arg632Trp (Karak syndrome)
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
  - Loss of mental & motor milestones
  - Seizures
  - Increased tone
    - Extrapyramidal: Dystonia; Rigidity
    - Spasticity: Some patients
  - 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
Diagnosis: Swellings may be present on conjuctival, skin or muscle biopsy
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
Infantile variant⁸
- 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

Congenital Hypomyelinating Neuropathies

Congenital hypomyelinating neuropathy

l P0 protein

; Chromosome 1q22; Recessive

Clinical
- Severe generalized weakness & wasting
- Arthrogryposis
- Onset: Birth
- Course
  - Severe cases: Death before 3 months
  - Milder cases: Static weakness; Increased disability with growth
Electrodiagnostic
- Demyelinating: Very slow NCV; No conduction block
- Similar to HMSN III
Pathology: Thin or absent myelin sheaths around axons

Congenital hypomyelinating neuropathy
l CMT4E; Early growth response-2

; Chromosome 10q21.1-q22.1; Dominant or Recessive

Gene
- Mutations
  - Ile268Asn (Homozygous); Ser382 Arg & Asp383Tyr (Heterozygous)
  - Recessive mutations in repressor binding domain (R1): ? alter transcriptional activity
- Also defective in: Krox20 knockout mice; CMT1; Dejerine-Sottas
Protein: Zinc finger
Clinical
- Onset: Infantile hypotonia
- 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

Congenital hypomyelinating neuropathy, Asymptomatic

l Rho Guanine-Nucleotide Exchange Factor 10 (ARHGEF10)

; Chromosome 8p23; Dominant¹⁴

Epidemiology: Single family
Genetics: Missense mutation; Thr109Ile
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 GEF: Faciogenital dysplasia
  - ARHGEF6 (aPIX): X-linked nonsyndromic mental retardation
  - ALS2 (alsin): Autosomal recessive amyotrophic lateral sclerosis
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: Hyopmyelination
  - 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

Congenital hypomyelinating neuropathies: Other

HMSN III (Dejerine-Sottas) (PMP-22 mutations)
Neuropathy with focally folded myelin sheaths
EGR2

Hereditary relapsing thermosensitive neuropathy

l Autosomal Dominant

Onset: 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

Lethal Neonatal Sensory-Motor Polyneuropathy¹

l Autosomal Recessive

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

Infantile Axonal Polyneuropathy with Respiratory Failure⁵
l Recessive; Sporadic

Epidemiology: 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 patients⁶
  - 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
Rule out

Congenital Cataracts, Facial Dysmorphism & Neuropathy Syndrome (CCFDN)²

l CTDP1

; Chromosome 18q23-qter; Recessive

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
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; 20 to 34 M/sec
- 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; Enlarged ventircles; Spinal cord atrophy; Periventricular WM changes
Endocrine: Mild hypogonadism
General anesthesia complications
- Pulmonary edema
- Epileptic seizures
Differences from Marinesco-Sjögren¹³
- Present in CCFDN: Peripheral neuropathy; Facial dysmorphism; Microcornea; Linkage to 18qter
- Less in CCFDN: Mental retardation severity; Cerebellar atrophy; Chronic myopathy

Navajo neurohepatopathy

l Glomerulosclerosis gene MPV17 (MPV17)

; Chromosome 2p21-p23; Recessive

Epidemiology
- Navajo: Up to 1 case/1,600 live births
- Especially Western reservation
- MPV 17 mutations also found in: Mitochondrial depletion syndrome
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 depletion¹¹

Navajo sensory-autonomic neuropathy with arthropathy

Epidemiology
- 8 children in 3 Navajo families
Polyneuropathy
- Motor: Normal
- Sensory loss
  - Mild loss of deep pain & temperature sensation
  - Corneal insensitivity
  - Some patients with normal exam
- Autonomic
  - Infantile fever (Recurrent)
  - Heat intolerance
  - Sweating: reduced
- Tendon reflexes: Present
- Electrodiagnostic: Often normal
- Nerve pathology: Reduced Small myelinated & unmyelinated axons
Skeletal: Painless fractures; Progressive arthropathy
Skin: Thickened on hands
Progression: Only of joint & bone disorders

SOX10 mutation: Hypomyelination in CNS & PNS; Hypopigmentation & Enteric aganglionosis³

l SOX10

; Chromosome 22q13; Dominant or Sporadic

SOX10 gene mutations¹²
- 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
- Null mutations in same gene produce
  - Dominant megacolon syndrome
  - Waardenburg-Shah syndrome (WS4)
    - Clinical: Intestinal aganglionosis; Pigmentation defects; Deafness, sensorineural
    - Also due to mutations of: EDNRB (endothelin B receptor) ; Endothelin-3 (EDN3)
- Mechanisms of disease
  - Severe disorders: ? Mutated protein acts as dominant negative
  - Haploinsufficiency: Milder phenotype disorders
SOX10 protein
- Myelin-specific transcription factor in Schwann cells & oligodendroglia
- Modulates other myelin-related transcription factors & proteins⁹
  - P₀ protein
  - Connexin-32: Activates expression by binding to promoter; Synergy with EGR2
  - Other: ERBB3; PLP; MBP
- Plays role in neural crest development: Enteric ganglion cells & Melanocytes
Clinical
- Onset
  - Congenital
  - Hirschsprung disease
- CNS
  - Developmental delay: Severe
  - Spastic quadriplegia
  - Seizures
  - Deafness: Sensorineural
  - MRI: Absent myelination in white matter; Hyperintensity on T2
  - CSF: Protein mildly increased
  - Pathology: Absent central myelin
- PNS
  - Muscle atrophy
  - ? Sensory loss
  - Tendon reflexes: Reduced
  - Electrophysiology: Demyelinating neuropathy
  - Pathology of nerve
    - Large axons: Absent or reduced myelin; Normal number; Occasional excessively large axon
    - Small axons: Reduced number
    - Schwann cells: Present; Aligned with axons in 1 to 1 relationship
- Ocular
  - Nystagmus
  - Optic Atrophy
  - Dystopia canthorum
- GI
  - Hirschsprung disease
  - Enteric aganglionosis
- Pigmentation: Heterochromia iridis
- Course
  - ? Non-progressive
  - Death at 3 months in 1 patient

Tyrosinemia

l Fumarylacetoacetase

; Chromosome 15q23-q25; Recessive

Onset: Neonatal & Infantile
Systemic features
- Hepatic disease
- Renal: Fanconi syndrome
- Cardiomyopathy: Mild
Peripheral neuropathy: Attacks
- Clinical: Similar to porphyria, but much younger patients
  - Onset: Mean 1 year
  - Pain: Severe
  - GI: Vomiting; Ileus
  - Muscle weakness: May be severe with respiratory failure
  - Other: Fever; Seizures; Hyponatremia; Hypertension
  - Mortality: High
- Nerve conduction studies: Axonal loss
- Pathology: Axonal degeneration, Acute
- Treatment
  - NTBC (Inhibitor of 4-hydroxy-phenylpyruvate dioxygenase)
  - Liver transplantation
Myopathy: 2° Carnitine deficiency⁷
- Epidemiology: Case report
- Onset: 2 years; Gait disorder
- Weakness: Proximal; Hypotonia
- Laboratory: Low plasma carnitine; Hypophosphatemia
- Treatment: Carnitine, dietary supplementation

Chediak-Higashi

l CHS1 (LYST)

; Chromosome 1q42.1-q42.2; Recessive

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
    - Axonal regenration
    - Inflammation: Perivascular; Occasional
    - Giant lysosomal inclusions in Schwann cells
    - Rule out: Neoplastic infiltrative neuropathy
  - Treatment: Transient improvement with corticosteroids¹⁵
- CNS
  - Mental retardation
  - Spinocerebellar degeneration
  - Adult onset: Parkinsonism; Dementia
- Pigmentation defective (Partial 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

Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Palmoplantar Keratoderma (CEDNIK)¹⁶

l SNAP29

; Chromosome 22q11.2; Recessive

Epidemiology: Arab Muslim families from northern Israel
Genetics
- Mutation: 1 bp deletion; 220delG
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
  - Delayed development
  - Late sitting & walking
- Polyneuropathy
  - Clinical: Not well described
  - Tendon reflexes: Absent
  - Electrophysiology: Axonal loss
  - Muscle biopsy: Denervation; Normal mitochondrial oxidative enzymes
- CNS
  - Microcephaly: Progressive
  - Psychomotor retardation: Severe
- Face: Dysmorphism
  - Elongated faces
  - Antimongolian eye slant
  - Hypertelorism: Mild
  - Flat broad nasal root
- Skin: Palmoplantar keratoderma & Ichthyosis
  - Onset: Between 5 & 11 months
  - Progressive during 2nd year of life
- Eye
  - Optic disk: Hypoplastic
  - Electrophysiology: Reduced conductance from peripheral retina & macular atrophy
- Ear: Sensorineural deafness, mild
- Course: Death in 40% due to pneumonia at ages 5 to 12 years
Laboratory
- Brain MRI
  - Corpus callosum abnormalities
  - Cortical dysplasia: Pachygyria & Polimicrogyria
- Skin
  - Ultrastructure: Clear vesicles in spinous & granular epidermal layers
  - Glucosylceramides: Retained, abnormally, within cells of lower stratum corneum

Hypomyelination and Congenital cataract

¹⁷
l Hyccin (DRCTNNB1A)

; Chromosome 7p21.3�p15.3; Recessive

Epidemiology: 4 families
Mutations
- Type: Stop, Splice site & Missense
- All homozygous
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
- Pyramidal: Progressive dysfunction
- Cerebellar: Progressive dysfunction
- Muscle
  - Weakness: Legs > Arms
  - Wasting
- Eye: Catatacts (100%)
  - Bilateral
  - Surgery often performed
- Seizures (30%)
- 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

Childhood carpal tunnel syndrome: Differential daignosis

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

Hereditary Sensory Neuropathies

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Return to Polyneuropathy Index

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7/14/2008