[MIM 118 200]

(Peroneal amyotrophy, peroneal muscular atrophy, Roussy-Levine syndrome, Dejerine-Sottas syndrome, hereditary sensorimotor neuropathy, hypertrophic neuropathy of infancy)

Hereditary sensorimotor neuropathy. Prevalence: 1/2500. Large genetic heterogeneity 

(> 30 described genes) with a highly variable genotype-phenotype correlation. Transmission: variable modalities and many cases are sporadic. The longest motor nerves are the first affected: the first signs are therefore usually present in the lower limb: unassured walking, muscular atrophy mostly peroneal , hollow feet ("stork legs") and hypo- or areflexia. Phrenic nerve involvement can cause diaphragmatic paralysis that responds well to surgical plication of the diaphragm.

Different clinical forms that can be distinguished among other things with nerve conduction velocity:

• CMT 1 or AD CMT1 (55%):  demyelinating or hypertrophic form, the most common (autosomal dominant transmission): slowing of conduction velocities < 38 m/s with segmental demyelination and 'onion bulb'-type hypertrophy in Schwann cells; onset at the age  of 6-8 years or in adolescence with walking difficulties.: very early dysplasia of the hip Pain and cramping after prolonged exercise especially in the lower limbs; weakness of the muscles of the hand with thenar eminence atrophy. In the adult patient,  one can palpate enlarged nerve trunks. Many subtypes according to the involved gene

-        CMT1A: duplication of PMP22 gene (peripheral myelin protein 22) on 17p11.2

-        CMT1B: MPZ gene mutation (peripheral myelin zero protein) on 1q22.23.1 [MIM 118 200] This protein is one of the major structural protein of the peripheral nervous system. A few cases of equina cauda syndrome due to hypertrophy of the caudal roots at the lumbar level have required emergency spinal decompression.

-        CMT1C: mutation of the SIMPLE gene  16p13.1-q22.1

-        CMT1D: EGR2 gene mutation (early growth factor 2) on 10q21.1-q22.1: cranial nerves are often affected with facial as well as vocal cords paralysis, and bulbar signs

-        CMT1E: the PMP22 gene in 17p11.2

-        CMT1F: mutation of the NEFL gene (neurofilament triplet L protein)  on 8p21 [MIM 607 734]

• CMT 2 or AD CMT2 (30%): neuronal or axonal form; autosomal dominant transmission; normal nerve conduction velocities but decrease in amplitude of the responses; histology: loss of axons but little or no demyelination nor 'onion bulb' pictures; onset in adolescence or later.

-        CMT2A1: mutation in the KIF1B gene on 1p36.22 [MIM 118 210]

-        CMT2A2: mutation in gene MFN2 encoding  mitofusine (GTPase activating protein controlling the fusion of mitochondria) on 1p36 [MIM 609 260]

-        CMT2B: RAB7 gene mutations on 3q21 [MIM 600 882]

-        CMT2B1: mutations in the LMNA gene on 1q21.2 [MIM 605 588]

-        CMT2B2: a not yet identified gene mutation  on 1q21.2

-        CMT2C: a not yet identified gene mutation  on 12q23-q24

-        CMT2D: mutation of the GARS gene on 7p15  [MIM 601 472]

-        CMT2E/F1: NEFL gene mutations on 8p21: with hyperkeratosis and juvenile glaucoma [MIM 607 684]

-        CMT2F: mutation of the HSB1 gene on 7q11-q21 [MIM 606 595] 

-        CMT2G: a not yet identified gene mutation on   12q12-q13

-        CMT2H: a not yet identified gene mutation on 8q21.3

-        CMT2I [MIM 607 677] and CMT2J [MIM 607 736]: MPZ gene mutations on 1q22.23

-        CMT2K: mutations in the GDAP1 gene on 8q13-q21.1 [MIM 607 831]

-        CMT2L: mutation in the HSB8 gene n 12q24

• - CMT3 or HMSN III: severe demyelination, or Dejerine-Sottas disease [MIM 145 900], rare; early onset (around   1 year of age) with hypotonia and muscle weakness; rapid progression, sometimes bilateral facial paralysis; enlargement of the peripheral nerves, scoliosis; autosomal recessive or dominant mutations in the PMP22 gene on 17p11.2, MPZ gene on 1q22.23.1 [MIM 145 900], EGR2 gene on 10q21.1-q22.1, FGD4 on 12p11.21-q13.11, or NEFL gene on 8p21
• DICMT or CMTI :  intermediate forms (EMG, histology) between CMT1 and CMT2:

-        DI-CMTA: mutation in a  not yet identified  gene on 10q24.1-q25.1

-        DI-MTBC: DNM2 gene mutation (dynamin-2, which encodes a part of the actin cytoskeleton) on 19p12-13.2,

-        DI-TLC: YARS gene mutations on 1p35

-        DI-CMTD: MPZ gene mutations on 1q22.23.1

• Congenital polyneuropathy with hypomyelination [MIM 605 253]: onset in the prenatal (see LCCS types 6 and 7), or neonatal period or in the first weeks of life with hypotonia and muscular weakness , especially at distal level of the 4 limbs. No involvement of respiratory muscles nor cranial nerves. It can look like arthrogryposis (see this term). Collapsed nerve conduction velocities but absence of 'onion bulb'-like pictures in histology. Mutations of the gene MPZ, EGR2, PMPP22, MTMR2
• CMT4 or AR CMT1 : demyelinating, autosomal recessive transmission, rare; onset in infancy, motor and sensory pathology, many subtypes according to the involved gene ;

-        CMT4A: mutations in the GDAP1 gene on 8q13-q21.1 [MIM 214 400]

-        CMT4B1: MTMR2 gene mutations on 11q22

-        CMT4B2: SBF2 gene mutations on 11p15

-        CMT4C: mutation in the gene SH3TC2 on 5q32 [MIM 601 596]

-        CMT4D: mutation in the NRDG1 gene on 8q24.22 [MIM 601 455]

-        CMT4E: EGR2 gene mutations on 10q21.1-q22.1

-        CMT4F: PRX gene mutations on 19q13.1-q13.2

-        CMT4G: a not yet identified gene mutation on 10q23.3

-        CMT4H:  FGD4 gene mutation on 12p11.21-q13.11

-        CMT4J: FIG4 gene mutations on 6q21 [MIM 611 228]

• CMTX : women carry the mutations but only men are clinically affected; communication defect between axons and Schwann cells; onset in late childhood or adolescence with a weakness of the distal limb muscles, with progressive muscular atrophy and loss of distal sensation, hollow feet, sometimes scoliosis. Inhomogeneous reduction of conduction velocity to 30-45 m/sec. An involvement of the central nervous system is observed in some forms: spastic paraplegia  (CMTX3), deafness (CMTX 4 and 5, sometimes 1) , optic atrophy (CMTX5)

-        CMTX1 [MIM 302 800]:  the most common form; mutation of gene GJB1 that codes for connexine 32 on X q13.1

· CMTX2 [MIM 302 801]: mutation on Xp22.2

· CMTX3 [MIM 302 802]: mutation on Xq26.3-q24

· CMTX4 [MIM 310 490] or Cowchock syndrome: mutation of gene AIFM1 on Xq24-q26, with mental retardation

· CMTX5 [MIM 311 070]: mutation of PRSP1 gene coding for pyruvate dehydrogenase kinase isoenzyme 3 on Xq22.11

· CMTX6 [MIM 300 906]: mutation of PDK3 gene on Xp22

• Roussy-Levy syndrome [MIM 180 800]: (hereditary areflexic dystasia): originally described as a demyelinating form associated with ataxia and static tremor; it is in fact a severe form of CMT1B.

Anesthetic implications: 

-        no risk of malignant hyperthermia; a well-documented case (positive contracture test) of malignant hyperthermia has been observed in a patient with CMT2; the association between such a clinical presenttaion and malignant hyperthermia is nevertheless considered unlikely (no molecular genetics)

-        recent ECG and echocardiography: mitral valve prolapse ? rhythm disorders, atrioventricular block, long QT ?

-        frequent osteoarticular and muscular pain

-        involvement of the phrenic nerves ? signs of autonomic denervation ?

-        precautions with muscle relaxants: slow peripheral nerve conduction velocities can render the interpretation of monitoring of curarization:  use preferably accelerometry (rather than EMG) and facial nerve monitoring. It is important to record baseline values before administering the myorelaxant.

-        sugammadex has been successfully used to antagonize rocuronium even if a case of failure has been described.

-        positioning during anesthesia (hypertrophied and fragile nerves)

-        the use of N2O could aggravate the progression of the lesions due to its inhibitory action on methionine synthetase

-        avoid succinylcholine: theoretical risk of  hyperkalemia

-        cases of epidural anesthesia have been described.

-        peripheral nerve blocks have been performed under ultrasound guidance (neurostimulation is useless considering the motor neuropathy) and without neither adrenaline nor a tourniquet without any impact on the progression of the disease

-        increased risk of postpartum bleeding

-        depending on the severity of the disease: increased risk of postoperative respiratory complications (restrictive syndrome, involvement of the diaphragm).

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Updated: July 2022