1. HMSN IA  
         PMP 22; Chromosome 17p11.2-p12; dominant
          Duplication (3 copies) 

   Clinical-genetic correlations 
      Chromosomal duplication containing PMP-22 is identical to region 
      deleted 
      in HNPP 
      Homozygotic twins: Similar NCV but often dissimilar clinical severity 
      "Sporadic" cases 
         Usually have duplications of paternal origin. 
            Due to unequal crossing over of homologous Chromosome 17s
            'Mariner' insect transposon-like element (MITE) near break site 
               ? Promotes DNA cleavage by transposase
               ? Cleavage leads to unequal cross-over 
         Rare maternal origin: Due to intrachromosomal rearrangement
   Clinical features 
      Distal weakness in feet & hands 
      Mild sensory loss 
      Hypo- or areflexia 
      Onset: Teens to 30's
   Electrophysiology 
      Demyelinating Neuropathy 
         NCV: Uniformly slow; No conduction block 
         NCV slow before clinical signs appear
   Pathology: Early excess myelin production 
      Onion bulbs 
         Small to moderate size & frequency 
         Many develop > 6 y.o. 
      Myelin sheaths thicker than normal 

          Point mutation, intramembrane domain  

   Clinical features: More severe than duplication 
   Electrophysiology 
      Demyelinating Neuropathy: More severe than duplication 
   Pathology: Early reduced myelin production 
      Onion bulbs 
         Large & on most axons
         Most develop < 6 y.o. 
      Myelin sheaths thinner than normal 

          Homozygotes
           PMP-22 duplication (4 copies); Chromosome 17p11.2-p12 

   Clinical features 
      Most severe weakness 
      Earlier onset < 1 year 
   Electrophysiology: Very slow NCV 

          Autosomal Recessive 
           PMP-22 point mutation - Thr118Met; Chromosome 17, and
           PMP-22 deletion 

   Clinical features: Severe phenotype 

2. HMSN IB  
         P0 protein ; Chromosome 1; Dominant

   Genetic features 
      Mostly point mutations 
      Exons 2 & 3 most common 
         Corresponds to immunoglobulin-like extracellular domain 
      2 mutations in exon 4: Margins of transmembrane domain 
      1 mutation in transmembrane domain 
         Pathology with severely hypomyelinated axons 
   Clinical features 
      Distal > proximal weakness; Sensory loss 
      Areflexia 
      Onset 
         Often in 1st decade: Delayed walking 
      Progression: Severe disability in some by 20 to 40 years 
      Nerves not usually clinically enlarged 
      Electrophysiology: Marked slowing of NCV < 20 M/s 
   Pathology: Demyelinating; 2 types depending on site of mutation 
      Uncompacted myelin 
         23% to 68% of myelinated fibers 
         Fewer demyelinated axons 
         Mutations in amino acids 5, 34 & 69 
         ? mutations interfere with homophilic adhesion function of P0 
      Focally folded myelin 
         Mutations in amino acids 101 & 106 
         Also seen in type 4B 
   Other P0 gene-defect syndromes 
      Dejerine-Sottas phenotype 
      Congenital hypomyelinating neuropathy 

3. HMSN: X-linked 

   Type 1; semidominant
           Connexin-32; Chromosome Xq13.1; Semi-dominant  
      Clinical features 
         Motor: Hand & foot weakness 
         Sensory: Early proprioceptive loss 
         Reflexes: Absent distal; preserved elsewhere 
         Different phenotypes 
                    Mild or moderate: Missense point mutation 
               Mixed Neuropathy (NCV: Intermediate (35-40 M/s)) 
                    Severe: Out of frame deletion or insertion 
               Demyelinating Neuropathy (NCV: Slow (10-37 M/s)) 
                    Females: Heterozygotes 
               Mild signs & less demyelination, or
               Asymptomatic carriers
   Cowchock Syndrome: with mental retardation and deafness  
           Chromosome Xq22 
      ?allelic with connexin syndrome
   Type 2; Recessive  
           Chromosome Xp22.2 
      Onset 1st decade 
      Distal weakness
   Type 3; Recessive  
           Chromosome Xq26 
      Onset end of 1st decade 
      Distal weakness 

4. HMSN II: Axonal Neuropathy (NCV: Axonal Loss) 

   IIA  
           Chromosome 1p36; Dominant 
      Clinical features 
         Moderate Phenotype 
         Upper & lower extremities involved 
         Distal weakness, sensory & tendon reflex loss 
         Tunisian families 
   IIB 
           Chromosome 3q; Dominant 
      Clinical features 
         Onset: 2nd decade 
         Distal & symmetric sensory loss & weakness 
         Lower limbs > upper 
         Acromutilation & foot ulcers 
         Phenotype variable in family: Severe in some, Mild in others 
      Electrodiagnostic 
         Axonal loss with absent sural potentials 
         Preserved tibial H-reflexes 
   IIC
           Autosomal Dominant 
      Clinical features 
         Diaphragm & vocal cord paralysis 
         Distal weakness 
         Depressed tendon reflexes 
      Electrodiagnostic: Median NCV > 50 M/s 
   IID
           Chromosome 7p; Dominant 
      Clinical features 
         Onset: 16 to 30 years 
         Weakness: Distal; Arms & Legs 
         Sensory loss: Distal; Arms & Legs; Pansensory 
         Tendon reflexes: Absent arms; Decreased legs 
         Progression: slow over years 
      Electrodiagnostic: Axonal loss; Normal NCV 
   Other: Rule out HMSN X-linked 

5. HMSN III (Dejerine-Sottas): Severe, infant onset, non-progressive  

   3 genetic types
           PMP-22 point mutations, intramembrane domain
           Chromosome 17; dominant 

           P0 point mutation  
           Chromosome 1q22; Recessive

           Chromosome 8q23-q24; Dominant  
   Clinical features 
      Weakness: Diffuse; Distal > Proximal 
      Onset: Infancy 
      Progression: Minimal 
      Demyelinating Neuropathy (NCV: Very Slow (< 12 M/s)) 

6. Hereditary Liability to Pressure Palsies (HNPP) 
         PMP-22 deletion; Chromosome 17p11.2-p12; Dominant
          Chromosomal deletion containing PMP-22 is identical to region
duplicated in HMSN IA 

   Clinical - Genetic Correlations 
      Variable penetrance 
      37% of patients with gene deletion have no family history 
      "Sporadic" cases often have deletions of paternal origin. 
         Due to unequal crossing over of homologous Chromosome 17s 
         Rare maternal origin: Due to intrachromosomal rearrangement 

         Clinical features 

   Onset 
      Mean: 26 years 
      Range: 8 to 64 years 
      Some patients asymptomatic 
   Nerve pareses with acute onset 
   1 to 10 episodes, usually painless 
      Prodrome 
         After mild trauma or compression in 40% 
         Repeated local exercise 
         On awakening 10% 
      Recovery: Complete 50%; Severe long term motor defecit 9% 
   Neuropathy distribution 
      Often asymmetric 
      Pressure-related lesions in 62% 
      Focal signs at usual sites of nerve compression 
         Radial: spiral groove of humerus 
         Ulnar: elbow 
         Median: wrist 
         Peroneal: head of fibula 
         Brachial plexopathy: not painful vs. Hereditary neuralgic 
         amyotrophy (HNA) 
      Focal signs & sensory loss at unusual sites of compression 
      Progressive generalized sensory-motor neuropathy 
         May occur without pressure palsies 
      Normal tendon reflexes in 62% 
   Diagnoses in patients with multifocal neuropathies without a deletion 
      Recurrent neuralgic amyotrophy 
      Multiple lesions at common entrapment sites 
      Patchy axonal neuropathy 
   NCV 
      Mild Slowing; Prolonged Distal Latencies 
      Worse changes @ common entrapment sites 
      Asymptomatic carriers abnormal even in childhood 
         Prolonged distal motor latency: median or peroneal 
         Slow NCV: Sensory or peroneal 
   Pathology 
      Focal thickening of myelin sheath: Tomaculae 

7. HMSN 4A  
         Chromosome 8q; Recessive 

   Childhood Onset; Tunisian 
   Demyelinating Neuropathy 

8. HMSN with focally folded myelin sheaths  (HMSN 4B ) 
         Chromosome 11q23; Recessive 

   Clinical features 
      Onset: 2 to 4 years 
      Weakness 
         Distal & proximal 
         Symmetric 
         Progressive: Adults often wheelchair bound 
         Facial: some with synkinesis 
      Pansensory loss 
      Tendon reflexes: Absent 
      Pes equinovarus 
      Prominent thick lips 
   Electrophysiology: Demyelination; Myelinated axon loss 
   Pathology: Irregular folding & redundant loops of myelin; Myelinated 
   axon loss 

9. HMSN ?4C
         Chromosome 5q23-q33; Recessive 

   Demyelinating neuropathy 

10. Andermann Syndrome: Peripheral Neuropathy & Agenesis of 
      Corpus Callosum  
      Chromosome 15q13-q15; Recessive 

   Clinical Features 
      Sensory Motor Neur(on)opathy - Severe 
      Areflexia 
      Progressive weakness 
      Mental retardation; Atypical psychosis 
      Seizures; Optic atrophy 
      Face 
         Long; Hypertelorism 
         Diplegia; Ptosis 
      French-Canadian: Charlevoix-Saguenay geographical focus 
      Electrodiagnostic: Axonal loss; Absent sensory potentials 
      Agenesis of corpus callosum: Partial or complete (58%) 
      Pathology: Axonal swellings with few neurofilaments 

11. HMSN with pyramidal features (HMSN 5)  
         Autosomal Dominant 

   Weakness: Distal; Legs > Arms 
   Extensor plantar responses; No spasticity 
   Onset: < 20 years 
   Electrophysiology: Axonal loss 

12. Complex HMSN (HMSN 6) 

   Optic atrophy, retinopathy, deafness  
           Autosomal Dominant 
      Clinical features 
         Severe visual loss 
            Onset age 7 to 10
            To light perception only by age 30
            Red-Green dyschromatopsia
            Other dominant optic atrophies: Blue-Yellow defects 
         Asymptomatic sensory neuropathy 
            Distal sensory loss
            Reduced tendon reflexes 
         Electrodiagnostic: Axonal Sensory-motor neuropathy
   Optic atrophy & neuropathy  
           Autosomal Dominant
   Also Recessive & X-linked forms with optic neuropathy 1 hearing loss 

13. Metachromatic Leukodystrophy  
         Arylsulfatase A; Chromosome 22q13.31; Recessive 

   Clinical features 
      Mental retardation; Optic Atrophy; Spasticity; Polyneuropathy 
      Juvenile onset forms may present with polyneuropathy 
      High CSF protein 
      Demyelinating Neuropathy (NCV: Slow) 
      Pathology 
         Metachromatic inclusions in Schwann cells and macrophages 
         Lamellar or dark ultrastructure 
   Rule out: 
      Multiple Sulfatase Deficiency (Recessive)  
      Activator Protein (Prosaposin) Deficiency 
              Chromosome 10q21-q22; Recessive 

14. Galactosylceramide Lipoidosis (Krabbe)  

   Chromosome 14q31; Recessive 

   Mental retardation; Optic Atrophy; Spasticity; Polyneuropathy 
   High CSF Protein 
   Demyelinating Neuropathy (NCV: Slow) 

15. Refsum's Disease 

   Childhood onset (< 20 yrs): Classic form
           Phytanic Acid Oxidase ; Recessive 
      Retinitis Pigmentosa 
      Demyelinating Neuropathy 
         Course may be Progressive or Relapsing 
         High CSF Protein 
      Anosmia; deafness 
      Cardiac Failure (may cause sudden death) 
      Less common: Ataxia, Ichthyosis 
      Biochemistry 
         Elevated serum phytanic acid 
         Reduced oxidation of phytanic acid in fibroblasts 
      Treatment with low phytanic acid diet 
   Infantile onset 
           ?peroxisomal disorder; Autosomal recessive 
      Mental retardation 
      Demyelinationg neuropathy 
      Deafness 
      Retinitis pigmentosa 
      Biochemistry 
         Hepatomegaly; steatorrhea 
         Hypocholesterolemia 
         Accumulation of phytanic acid, pipecolic acid, very long chain 
         fatty acids Adult onset with increased pipecolicacidemia ; 
   ? peroxisomal disorder; Chromosome 10p; Recessive