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CHILDHOOD ONSET POLYNEUROPATHIES

Hereditary Acquired
Axonal or Neuronal Myelin disorders
A-β-lipoproteinemia: MTP
Adrenomyeloneuropathy: ABCD1
An-α-lipoproteinemia (Tangier): ABC1
Andermann Syndrome: KCC3
  Motor neuropathy
ANOAC: STXBP5L
Ataxia, Infant Onset: c10orf2
Ataxia telangectasia
Autonomic: Acute
Biotinidase deficiency
Brachial Plexopathy
CEDNIK: SNAP29
Cerebrotendinous xanthoma: CYP27A1
Chediak-Higashi: LYST
CMT
Congenital: UBA5
D-bifunctional protein: HSD17B4
DCIDP: PSMC3
Fabry: GLA
Friedreich Ataxia: FRDA
Giant Axonal Neuropathy: GAN
Glycogenosis, Type 3: AGL
GPI biosynthesis: PIGB; 15q21
HMSN: II; 6; ARCMT2
IDDSAPN: NEMF
Infant PN + Respiratory failure
LCHADD: HADHA & HADHB
Lethal neonatal
Leukoencephalopathy: HMBS
MEDNIK: AP1S1
Minifascicles & Gonad Δ : DHH
Mitochondrial
  MNGIE; NARP; Leigh; Other
MTHFR deficiency
Navajo PN + Arthropathy: MPV17
Navajo neurohepatopathy: MPV17
NEDMAGA: ZSWIM6
Neuroaxonal Dystrophies
  NAD: PLA2G6
  NAD2
  INNFD: NALCN
PLDECO: ACER3; 11q13
PSATD: PSAT1
Riley-Day: IKBKAP
Leukoencephalopathy: RPIA
SACS
Sensory Neuropathies
Sensory PN + CNS: DNM1L
Spinal muscular atrophy
  Proximal; Distal
Tyrosinemia: FAH
Xeroderma pigmentosum
Arthrogryposis
  CASPR
  ADCY6
Cataract & Face (CCFDN): CTDP1
Cockayne: A (ERCC8); B (ERCC6)
Congenital muscular dystrophy
  Merosin deficient: LAMA2
Congenital hypomyelinating
D-bifunctional protein: DBP
Farber's lipogranulomatosis: ASAH
Glycosylation disorders
  CDG 1A: PMM2
  CDDG: NGLY1
Hemolytic anemia: CD59
HMSN
  Dominant
    CMT: IA, IB, III, EGR2
    HNPP
  Recessive
    CMT: III; 4A; 4B; 4C
      4D (LOM); 4E; 4F; CNS
      HMSN-R; Dejerine-Sottas
  X-linked
Hypomyelin & Cataract: FAM126A
IMNEPD: PTRH2
Krabbe: GALC
Marinesco-Sjögren: SIL1
Metachromatic Leukodystrophy: ARSA
Myoclonus Epilepsy (EPM4): SCARB2
NEDCPMD: NFASC
Neurodevelopmental: NARS1
Niemann-Pick: NPC1; NPC2
NMIHBA: PRUNE1
Pelizaeus-Merzbacher: PLP1
Refsum
Hypomyelination: SOX10
Thermosensitive PN
Immune
Guillain Barré
CIDP
AMAN

Toxic
Diphtheria
Botulism
Heavy Metals
Drugs & Toxins

Metabolic
Diabetes Mellitus
B12 deficiency
Uremia
HIV

Other
Carpal tunnel
See: Storage inclusions


STORAGE INCLUSIONS
TypeDiseaseCellular localization
Osmophilic
  with periodicity



Bilbao
Metachromatic Leukodystrophy Schwann cell
Macrophage
Axon
Fabry'sVascular
Perineurial
Schwann cell, non-myelinating
Niemann-Pick, Type 1All except axon
Batten-KufsSchwann 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
MucopolysaccharidosisSchwann cell-myelinating
Fibroblast
Fabry's Vascular
Perineurial
Niemann-Pick Schwann cell
Endothelial
Macrophage
Pi granulesSchwann 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 gangliosidosisVascular
Fibroblast
I-cell diseaseSchwann cell, non-myelinating
Fibroblast
Perineurial
MucopolysaccharidosisFibroblast
Vascular
Schwann cell
Cerebrotendinous xanthomatosisSchwann cell
Wolman's diseaseAll
Sialidosis, type 1Schwann cell



Farber's disease (Lipogranulomatosis; FRBRL)
  Acid ceramidase (ASAH) ; Chromosome 8p22; Recessive
Giant Axonal Neuropathy 1 (GAN1)
33
  Gigaxonin (GAN) ; Chromosome 16q23.2; Recessive
  • 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
    • 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
      • Autonomic
    • 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
    • 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
      • 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

HMSN2 with Giant Axons (GAN2)
23
  DDB1- and CUL4-associated factor 8 (DCAF8) ; Chromosome 1q23.2; Dominant
Neuroaxonal Dystrophy (Late infantile; NBIA2A)
  Phospholipase A2, Group VI (PLA2G6) ; Chromosome 22q13.1; Recessive


Neuroaxonal Dystrophy 2
19
  Recessive

Infantile Neuroaxonal Degeneration with Facial Dysmorphism (INNFD; IHPRF)
  Sodium leak channel, nonselective (NALCN) ; Chromosome 13q33.1; Recessive

Neurodevelopmental Disorder with Movement Abnormalities, Abnormal gait & Autistic features (NEDMAGA)
  Zinc finger swim domain-containing protein 6 (ZSWIM6) ; Chromosome 5q12.1; Dominant or Sporadic

Neurodevelopmental Disorder with Central & Peripheral Motor Dysfunction (NEDCPMD)
  Neurofascin (NFASC) ; Chromosome 1q32.1; Recessive

Intellectual Developmental Disorder + Speech delay & Axonal Peripheral Neuropathy (IDDSAPN)
  Nuclear Export Mediator Factor (NEMF) ; Chromosome 14q21.3; Recessive

Congenital Hypomyelinating Neuropathies (CHN)

ADCY6
ARHGEF10
CASPR (CNTNAP1): CHN3
EGR2: CHN1
FAM126A
GLDN
LGI4
P0 (MPZ): CHN2
PMP-22
  HMSN III (Dejerine-Sottas)
  Focally folded myelin sheaths
SOX10

Congenital hypomyelinating neuropathy (CHN2) 21
  P0 protein (MPZ) ; Chromosome 1q23.3; Recessive or Dominant

Congenital hypomyelinating neuropathy 1 (CHN1; CMT4E)
  Early growth response-2 (EGR2; KROX20) ; Chromosome 10q21.3; Dominant or Recessive
Congenital hypomyelinating neuropathy, Asymptomatic
  Rho Guanine-Nucleotide Exchange Factor 10 (ARHGEF10) ; Chromosome 8p23.3; Dominant 14
Hereditary relapsing thermosensitive neuropathy
  Autosomal Dominant

Lethal Neonatal Sensory-Motor Polyneuropathy 1
  Autosomal Recessive

Infantile Axonal Polyneuropathy with Respiratory Failure 5
  Recessive; Sporadic

Congenital Cataracts, Facial Dysmorphism & Neuropathy Syndrome (CCFDN) 2
  C-terminal domain of RNA polymerase II subunit A, phosphatase of, subunit 1 (CTDP1) ; Chromosome 18q23; Recessive

Navajo Neurohepatopathy
  Glomerulosclerosis gene MPV17 (MPV17) ; Chromosome 2p23.3; Recessive
Navajo Neuropathy + Arthropathy

From: Otto Appenzeller

Navajo sensory-autonomic neuropathy with arthropathy
  Glomerulosclerosis gene MPV17 (MPV17) ; Chromosome 2p23.3; Recessive
Hypomyelination in CNS & PNS; Hypopigmentation & Enteric aganglionosis (PCWH) 3
  SOX10 ; Chromosome 22q13.1; Dominant or Sporadic

Tyrosinemia 1 (TYRSN1)
  Fumarylacetoacete Hydrolase (FAH) ; Chromosome 15q25.1; Recessive

Chediak-Higashi
  Lysosomal trafficking regulator (LYST; CHS1) ; Chromosome 1q42.3; Recessive

Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Palmoplantar Keratoderma (CEDNIK) 16
  SNAP29 ; Chromosome 22q11.21; Recessive

Hypomyelination and Congenital cataract (HCC; HLD5) 17
  Hyccin (DRCTNNB1A; FAM126A) ; Chromosome 7p15.3; Recessive

Myoclonus Epilepsy & Demyelinating Polyneuropathy (EPM4) 18
  Scavenger receptor class B, Member 2 (SCARB2; LIMP2) ; Chromosome 4q21.1; Recessive

Hemolytic Anemia & Demyelinating Polyneuropathy
  CD59 antigen (Protectin) ; Chromosome 11p13; Recessive

Congenital Disorder of Deglycosylation (CDDG) 35
  N-Glycanase 1 (NGLY1) ; Chromosome 3p24.2; Recessive

Axonal neuropathy, Optic atrophy & Cognitive deficit (ANOAC) 25
  Syntaxin binding protein 5-like (STXBP5L; LLGL4) ; Chromosome 3q13.33; Recessive

Leukodystrophy, progressive, early childhood-onset (PLDECO)
  Alkaline ceramidase 3 (ACER3) ; Chromosome 11q13.5; Recessive

GPI Biosynthesis Defect with Axonal Neuropathy & Metabolic Abnormality 29
  Phosphatidylinositol glycan anchor biosynthesis class B protein (PIGB) ; Chromosome 15q21.3; Recessive

Mental retardation, Enteropathy, Deafness, Peripheral Neuropathy, Ichthyosis, Keratoderma (MEDNIK)
  Adaptor-related protein complex 1, sigma-1 subunit (AP1S1) ; Chromosome 7q22.1; Recessive

Deafness, Cataract, Impaired intellectual development & Polyneuropathy (DCIDP)
  Proteasome 26S subunit, ATPase, 3 (PSMC3; PRS6A) ; Chromosome 11p11.2; Recessive

Phosphoserine Aminotransferase Deficiency (PSATD) 32
  Phosphoserine aminotransferase 1 (PSAT1) ; Chromosome 9q21.2; Recessive

Childhood Carpal tunnel syndrome: Differential daignosis
Hereditary Sensory Neuropathies
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10/21/2021