Peroneal muscular atrophy

From Ganfyd

Background

Peroneal muscular atrophy (Charcot-Marie-Tooth disease, CMT, hereditary motor and sensory neuropathy, HMSN) is the most common inherited sensorineural peripheral polyneuropathy affecting approximately 1 in 2,500 individuals. This is partially because so many genes (at least 39) confer susceptibility. Recent investigations have shown that a recessive form involving mutations at 5q32 of the ST3TC2 gene in hetrozygotes is associated with increased incidence of carpal tunnel syndrome with more implications for the genetics of neuropathic conditions^[1].

Presentation

The variable presentation has in common a distal symmetrical polyneuropathy, with slowly progressive distal muscle weakness and in particular peroneal muscular atrophy. Pes cavus or pes planus is common.

Classification

1. Charcot-Marie-Tooth disease type 1 (HMSN I)
   • Primary peripheral demyelinating neuropathies
   • Nerve conduction velocity less than 38m/s
   • Nerve biopsy segmental demyelination and remyelination with onion bulb formations
   • Affects the glia-derived myelin
   • Charcot-Marie-Tooth disease type 1A (CMT1A)
     • Duplication of, or mutation in, the PMP22 gene at 17p11.2 encoding peripheral myelin protein-22 causing an autosomal dominant inheritance
   • Charcot-Marie-Tooth disease type 1B (CMT1B)
     • Mutation in the MPZ gene at 1q22 encoding myelin protein zero causing an autosomal dominant inheritance
   • Charcot-Marie-Tooth disease type 1C (CMT1C)
     • Mutation in the LITAF gene at 16p13.3-p12 causing an autosomal dominant inheritance
   • Charcot-Marie-Tooth disease type 1D (CMT1D)
     • Mutation in the EGR2 gene at 10q21.1-q22.1 causing an autosomal dominant inheritance
   • Charcot-Marie-Tooth disease and deafness (Charcot-Marie-Tooth disease type 1E, CMT1E)
     • Some cases associated with mutation in the PMP22 gene at 17p11.2
   • Charcot-Marie-Tooth disease type 1F (CMT1F)
     • Mutation in the NEFL gene at 8p21 that codes for neurofilament light polypeptide causing an autosomal dominant inheritance
   • Charcot-Marie-Tooth disease X-linked with aplasia cutis congenita of the scalp
2. Charcot-Marie-Tooth disease type 2 (HMSN II)
   • Primary peripheral axonal neuropathies
   • Normal or mildly reduced nerve conduction velocity
   • Nerve biopsy chronic axonal degeneration and regeneration
   • Charcot-Marie-Tooth disease X-linked 1 (CMTX1)
     • Mutation in the GJB1 gene at Xq13.1 causing X-linked dominant or X-linked intermediate transmission
   • Charcot-Marie-Tooth disease X-linked 2 (CMTX2)
     • Mutation in the GJB1 gene at Xp22.2 causing X-linked recessive transmission
     • Sometimes associated with mental retardation
   • Charcot-Marie-Tooth disease X-linked 3 (CMTX3)
     • Mutation in the GJB1 gene at Xp26 causing X-linked recessive transmission
   • Cowchock syndrome (Charcot-Marie-Tooth disease X-linked 4, CMTX4. NAMSD, NADMR)
     • Sensorineural peripheral polyneuropathy, deafness and mental retardation
   • Charcot-Marie-Tooth disease X-linked 5 (CMTX5)
     • Polyneuropathy, optic atrophy and deafness
     • Caused by mutation in the PRPS1 gene at Xq22-q24 that encodes for ribose-phosphate pyrophosphokinase 1 but possibly other mutations as well (non X-linked)
   • Charcot-Marie-Tooth disease type 2A1 (CMT2A1)
     • Mutation in the KIF1B gene at 1p36.2
   • Charcot-Marie-Tooth disease type 2A2 (CMT2A2)
     • Mutation in the MFN2 gene at 1p36.2
   • Charcot-Marie-Tooth disease type 2B1 (CMT2B1)
     • Mutation in the LMNA gene at 1q21.2 that encodes for lamin A and lamin C
   • Charcot-Marie-Tooth disease type 2B2 (CMT2B2)
     • Mutation in the MED25 gene at 19q13.3 causing recessive transmission
   • Hereditary motor and sensory neuropathy type IIC (HMSN2C, Charcot-Marie-Tooth disease type 2C, CMT2C)
     • Mutation in the TRPV4 gene at 12q24 causing early onset muscle weakness of limbs, vocal cords, and intercostal muscles and asymptomatic sensory loss with autosomal dominance.
   • Charcot-Marie-Tooth disease type 2D (CMT2D)
     • Mutation in the GARS gene at 7p15 encoding for glycyl-tRNA synthetase with autosomal dominant transmission
   • Charcot-Marie-Tooth disease type 2E (CMT2E)
     • Mutation in the NEFL gene at 8p21 that codes for neurofilament light polypeptide with autosomal dominance.
   • Charcot-Marie-Tooth disease type 2F (CMT2F)
     • Mutation in the HSPB1 gene at 7q11.23 that codes for heat shock protein beta-1 with autosomal dominant transmission and onset in early adulthood
   • Charcot-Marie-Tooth disease type 2G (CMT2G)
     • Associated with 12q12-q13.3. Can have late onset.
   • Charcot-Marie-Tooth disease type 2H (CMT2H)
     • Maps to 8q13-q21.1 close to GDAP1 gene
   • Charcot-Marie-Tooth disease type 2I (CMT2I)
     • Mutation in the MPZ gene at 1q22 encoding myelin protein zero causing an autosomal dominant inheritance of a late onset polyneuropathy
   • Charcot-Marie-Tooth disease type 2J (CMT2J)
     • Mutation in the MPZ gene at 1q22 encoding myelin protein zero causing polyneuropathy and Adie pupil
   • Charcot-Marie-Tooth disease type 2K ((CMT2K)
     • Mutation in the GDAP1 gene at 8q13-q21.1 causing late-onset polyneuropathy with autosomal dominant transmission.
   • Charcot-Marie-Tooth disease type 2L (CMT2L)
     • Mutation in the HSPB8 gene at 12q24 causing autosomal dominant transmission
3. Dejerine-Sottas hypertrophic neuropathy (Charcot-Marie-Tooth disease type 3, Hereditary motor and sensory neuropathy type III, HMSN3, CMT3) - see also Charcot-Marie-Tooth disease type 4F for autosomal recessive forms
   • Nystagmus, distal muscular weakness, distal sensory neuropathy, pes cavus with exacerbations and remissions, sometimes as severe as paralysis
   • Multiple mutations can cause this including those in MPZ , PMP22, PRX, EGR2 and GJB1 genes with possible polygenetic causes
4. Demyelinating Charcot-Marie-Tooth disease with with autosomal recessive transmission (CMT4)
   • Charcot-Marie-Tooth disease type 4A (CMT4A)
     • Mutation in the GDAP1 gene at 8q13-q21.1 that codes for ganglioside-induced differentiation-associated protein 1
   • Charcot-Marie-Tooth disease type 4B1 (CMT4B1)
     • Mutation in the MTMR2 gene at 11q22 that codes for myotubularin-related protein 2
   • Charcot-Marie-Tooth disease type 4B2 (CMT4B2)
     • Mutation in the SBF2 gene at 11p15 .
   • Charcot-Marie-Tooth disease type 4C (CMT4C)
     • Mutation in the SH3TC2 gene at 5q32.
   • Charcot-Marie-Tooth disease type 4D (CMT4D)
     • Mutation in the NDRG1 gene at 8q24.3 that codes for protein NDRG1 (N-myc downstream-regulated gene-1)
   • Congenital hypomyelinating neuropathy (Charcot-Marie-Tooth disease type 4E, CMT4E)
     • Mutations in either the EGR2 or the MPZ genes.
   • Dejerine-Sottas syndrome (Hereditary motor and sensory neuropathy type III, HMSN3, Charcot-Marie-Tooth disease type 4F, CMT4F)
     • Nystagmus, distal muscular weakness, distal sensory neuropathy, pes cavus with exacerbations and remissions, sometimes as severe as paralysis
     • Multiple mutations can cause this including those in MPZ , PMP22, PRX, EGR2 and GJB1 genes with possible polygenetic causes
   • Charcot-Marie-Tooth disease type 4G (Hereditary motor and sensory neuropathy Russe type, NMSNR, CMT4G)
     • Mutation at 10q23.2
   • Charcot-Marie-Tooth disease type 4H (CMT4H)
     • Mutation in the FGD4 gene at 12p11.2 that codes for frabin a guanine nucleotide exchange factor.

References