Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation

Dominant Demyelinating CMT1A PMP-22 17p11.2-12 (duplication/point mutations) myelination, cell growth, differentiation progressive distal muscle weakness and atrophy, mostly at lower extremities, peroneal gait, areflexia MNCV< 38 m/s, median MNCV 15-30m/s, no conduction block CMT1B MPZ/P0 1q22 adhesion proteins onset in first decade, variable degree of progressive distal muscle weakness MNCV < 20 m/s (in patients with early onset) > 38 m/s (in patients with late onset) CMT1C LITAF/SIMPLE 16p13 protein degradation typical CMT1 MNCV 1625 m/s CMT1D EGR2/Krox20 10q21-22 transcription factor upregulation of myelin genes cranial nerve involvement progressive scoliosis MNCV 942 m/s CMT1F NEFL 8q21 neurofilaments organization, axonal transport onset in early childhood, delayed motor development, severe CMT1 phenotype, similar to DSS MNCV 1538 m/s Special forms: HNPP PMP-22 17p11.2-12 deletion/point mutations) episodes of painless weakness, calf hypertrophy, asymmetrical, CNS demyelination, dystonia rarely, corticosteroid efficient in some patients normal, or mild decreasing, conduction block at pressure site, prolonged distal latencies Neuropathy with hearing impairment connexin -31 (GJB3) 1p35.1 ion channel formation predominantly sensory neuropathy, variable disease severity, asymmetrical hearing loss MNCV and SNCV mildly reduced SNAPs and CMAPs mildly decreased Hypomyelinating neuropathy without clinical symptoms ARGHEF 10 8p23 development of peripheral nerve myelination clinically asymptomatic MNCV 2742 m/s, CMAPs and SNAPs normal Dominant:Axonal CMT2A MFN2 1p33-36 GTP-ase, axonal transport of mitochondria severe, early onset, hearing loss, CNS and pyramidal tract involvement very low CMAPs and SNAPs normal or slightly reduced NCV KIF1B 1p33-36 synaptic vesicle transport CMT2B RAB7 3q13-q22, intracellular membrane traffic sensory loss, feet ulcerations distal motor weakness, hyperkeratosis Normal MNCV CMT2C unknown 12q23-q24 diaphragmal and vocal cord paresis, death normal MNCV CMT2D GARS 7p15 translation process, motor neuron integrity small hand muscles atrophy normal MNCV CMT2E NEFL 8p21 axonal transport, neurofilament organization sensory loss of all modalities MNCV 13-38 m/s CMT2F HSPB1 (HSP27) 7q11-q21 protection of the structure of cell proteins sensory loss, motor impairment of different severity, small hand muscles atrophy later in the course of disease reduced or absent CMAPs CMT2G unknown 12q12-13.3 slowly progressive walking difficulties, preserved knee jerks, absent triceps surae jerks MNCV normal or mildly reduced CMT2H/K GDAP1 8q13-21.1 mitochondrial protein expressed mostly in neurons, regulation of mitochondrial dynamics mild clinical phenotype, vocal cord paralysis, slowly progressive course MNCV slightly decreased or in intermediate range CMT 2I/J MPZ 1q22-23 deafness, Adie pupils MNCV <38 m/s, progress to reduced MNCV CMT2L HSPB8/HSP22 12q24.3 mild sensory loss, scoliosis normal MNCV Dominant:Intermediate DI-CMTA unknown 10q24.1-q25.1 CMT phenotype of moderate severity MNCV 25-45 m/s DI-CMTB dynamin 2 19q12-q13.2 vesicular traffic, endocytosis protein synthesis normal or increased tendon reflexes neutropenia DI-CMTC YARS 1p34-p35 CMT phenotype of moderate severity DI-CMTD MPZ 1q22 variable and moderate severity Dominant: X-linked CMTX1 GJB1 Xq13.1 encodes connexin32, transfer of low weight material between cells hand/thenar muscles, CNS involvement, deafness, visual impairment, white matter lesion conduction block, temporal dispersion MNCV 30-40 m/s in males, MNCV 10-37 m/s in severely affected males MNCV 3050 m/s in females, low CMAPs CMT 3A (DSS) PMP22 17p11.2-12 onset<3y,palpable nerves, ataxia, progressive weakness, severe disability, increased CSF protein content, short stature NCV <10 m/s, fibrillation, positive denervation waves CMT 3B MPZ 1q22-23 onset in infancy, hypotonia, respiratory insufficiency and early deaths occasionally MNCV < 15 m/s CMT 3C unknown 8q23-q24 Charcot joints decreased MNCV DSS-EGR EGR2 10q21-22 phenotype consistent with DSS, cranial nerve involvement, respiratory difficulties MNCV < 8 m/s CMT 3D or CMT 4F periaxin 19q13.1 q13.2 maintenance of the peripheral nerve myelin extracelular matrix signaling unusual facies, deafness very slow MNCV Recessive:demyelinating CMT 4A GDAP1 8q13-21.1 early onset, severe motor retardation, progressive scoliosis MNCV 2535 m/s CMT 4B-1 MTMR2 11q22 transcription and cell proliferation cranial nerves affection, blindness, glaucoma, severe disability MNCV 922m/s CMT 4B-2 MTMR13/SBF2 11p15 onset at 5 years, early onset glaucoma, similar to CMT4B1 phenotype MNCV 1530 m/s CMT 4C KIAA1985 5q23-33 unknown function early onset, severe motor retardation, scoliosis respiratory insufficiency MNCV 1034 m/s CMT 4D (HSMN-Lom) NDRG1 8q24.3 cell growth arrest and differentiation deafness, tongue atrophy Roma population MNCV 920 m/s CMT 4E EGR2 10q 21.1-22 17p onset presented at birth, generalized hypotonia, arthrogryposis, cranial nerves involvement MNCV< 8m/s CMT 4F periaxin 19q13.1-q13.3 maintenance of peripheral nerve myelin, extracellular matrix signaling severe DSS or CMT1 phenotype, curvilinear inclusions in nerves MNCV <15 m/s, CMAPs absent or very low CMT 4G (Russe) unknown 10q23.2 severe distal muscle weakness, prominent sensory loss, frequently in Roma population MNCV 3035 m/s CMT 4H unknown 12p11.21 delay in motor development, scoliosis MNCV < 15 m/s low amplitudes CMT 4J FIG4 6q21 phosphoinositides content vesicular trafficking early onset, coordination disorder, severe disability MNCV 27 m/s CMAPs reduced CCFDN CTDP1 18q23 regulation of proteins involved in transcription and mRNA processing congenital cataract, mental retardation, facial dysmorphism, growth retardation, chorea, tremor, rhabdomyolisis, more frequently in Roma population MNCV 1933 m/s Recessive:Axonal CMT4C1 or AR CMT 2B1 lamin A/C 1q21.2-q21.3 nuclear lamina component, gene transcription rapid evolution involvement of proximal muscles reduced CMAPs, normal MNCV CMT4C2 or AR-CMT 2C or AR CMT 2H unknown 8q21.3 brisk patellar and upper limbs reflexes, ankle reflexes absent, plantar anattainable normal or mildly reduced MNCV, reduced CMAPs amplitude CMT4C3 Or AR CMT2B2 ARC 92/ACID1 (MED 25) 19q13.3 mediator complex associated with RNA polymerase II typical CMT2 phenotype reduced CMAPs mild decrease of MNCV CMT4C4 Or AR CMT 2K GDAP1 8q13-21.1 early onset, hypotonia, kyphoscoliosis, progressive course, hoarse voice, vocal cord paralysis, respiratory insufficiency MNCV> 40 m/s, absent CMAPs Recessive-X-linked CMTX2 unknown Xq 22.2 areflexia, pes cavus, mental retardation, unaffected females decreased NCV, low CMAPs CMTX3 unknown Xq26.3-q27.1 onset 313 years, progressive muscle weakness, normal mental development low CMAPs and median MNCV 2557 m/s CMTX4 Chowchock syndrome unknown X q24-q26.1 onset in infancy, deafness, mental retardation in 60% MNCV 3356 m/s, decreased sensory NCV CMTX5 unknown Xq21.32-q24 hearing loss, optic neuropathy, females unaffected low or absent CMAPs, mild decreasing of MNCV (4351 m/s) Dominant:axonal CMT (AD) with pyramidal features (HMSN V) mitofusin 2 (MFN2) 1p36.2 mitochondrial GTP-ase regulator of mitochondrial fussion and transport ankle jerk absent, tendon jerks present or increased MNCV decreased, low SNAPs and CMAPs amplitudes CMT with optic atrophy (HMSN VI or CMT 6) MFN2 1p36.2 early onset, optic atrophy MNCV slightly decreased Dominant:distal motor Distal HMN I unknown early onset 220 years, reflexes present or increased, ankle jerks absent, distal weakness and wasting MNCV normal or mildly decreased, SNAPs mildly reduced Distal HMN II HSP22, HSP27 12q24.3, 7q11-21 development of thermotolerance onset 1520 years, rapid progression, exstensor muscle weakness MNCV normal, CMAPs normal or reduced, SNCV normal Distal HMN V (HMN 5A) GARS 7p15 protein biosynthesis, role in translation phase pronounced hand muscles wasting and weakness, spasticity on lower extremities MNCV and CMAPs, normal or mildly reduced Distal HMN V- Silver's syndrome (HMN 5B) BSCL2, seipin 11q12q14 involved in RNA transport and glycosylation pronounced hand muscles wasting and weakness, mild lower extremities spasticity, no sensory/autonomic dysfunction reduced CMAPs, normal or mild reduction of MNCV Distal HMN VII B dynactin 2p13 role in prevention of neurodegeneration adult onset, bilateral vocal cord paralysis, progressive facial weakness and atrophy of hand muscles and distal legs normal MNCV, low CMAPs distally Distal HMN VII A unknown 2q14 onset in second decade, unilateral or bilateral vocal cord paralysis, breathing difficulties, weakness and atrophy of, hands and distal legs muscles Dist. HMN ALS4 SETX 9q34 possible role in RNA processing early onset, pyramidal tract involvement MNCV normal, CMAPs reduced Recessive:distal HMN Distal HMN III unknown telomeric to IGHMBP2 11q13 infantile onset, diaphragmal hypomobility CMAPs low, MNCV normal or mildly reduced Distal HMN IV unknown 11q13 mild neuropathy of late onset in third decade CMAPs low, MNCV normal or mildly reduced Distal HMN VI (SMARD1) IGHMBP2 11q13.2-13.4 RNA processing diaphragmal paresis, IURG, infantile onset, respiratory insufficiency, death low/absent CMAPs, mild decreased MNCV Distal HMN-J unknown 9p21.1-p12 onset between 610 years, first brisk reflexes and Babinski sign followed by areflexia and absent Babinski sign MNCV normal to mildly reduced, CMAP reduced amplitudes SNAP normal Cong. distal SMA unknown 12q23-q24 antenatal onset, arthrogryposis, severe course, paraplegia, scoliosis, trunk weakness MNCV normal X-linked distal HMN unknown Xq13-q21 juvenile onset, mild distal weakness and wasting CMAP amplitudes reduced, MNCV mildly reduced, and SNCV normal HSAN:Autosomal dominant HSAN I SPTLC1 9q22.1-q22.3 sphingolipid synthesis common features of all HSAN types: arthropathy, mutilating, paronychia, ulcers of fingers, pathological fractures, prolonged QT, syncopes, convulsions decreased SNCV HSAN 1B associated with cough and gastroesophageal reflux (GER) unknown 3p22-p24 cough, hoarse voice, syncopes, retinal detachment, hearing loss, GER, rarely ulcers, sensory loss decreased SNCV HSAN:Recessive HSAN II HSN 2 12p13.33 loss of pain, touch and temperature sensation, finger ulcerations, loss of tendon reflexes, mild muscle weakness SNCV decreased, SNAPs absent HSAN III or Riley-Day syndrome IKBKAP 9q31 transcription process onset at birth, hypotonia, defect in lacrimation, thermal dysregulation, postural hypotension, prominent autonomic dysfunction, gastrooesophageal reflux, chronic lung disease, ataxia, convulsions SNCV decreased, SNAPs absent or reduced HSAN IV TRKA/NGF NTRK1 1q21-q22 NGF signaling, thermal regulation via sweating, nociceptive system development pain insensitivity, anhydrosis normal reflexes, mild mental retardation normal MNCV and CMAPs, SNAPs and SNCV mildly reduced HSAN V TRKA/NGF NGF 1q21-q22 1p13.2-11.2 NGF signaling, CNS and peripheral pain pathways development onset at birth, pain insensitivity, bone/joint fractures, episodes of hyperpyrexia, anhydrosis less pronounced than in HSAN IV, hyperkeratosis, normal mental development NCV normal HSAN with deafness and global delay unknown unknown hypotonia, areflexia, developmental delay, hearing loss, dysmorphic features, renal tubular acidosis sensory neuropathy HSAN with spastic paraplegia unknown 5q15.31-14.1 severe sensory neuropathy, trophic ulcers and mutilation, MRI spinal cord atrophy axonal sensory neuropathy, SNAPs amplitudes reduced or absent, MNCV normal or mildly reduced X-linked HSAN associated with deafness (AUNX1) unknown AUNX1 locus Xq23-27.3 progressive auditory neuropathy, decreased otoacustic emission, progressive sensory neuropathy SNAPs reduced or absent, mildly reduced sensory NCV, normal MNCV

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Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation