Hereditary Motor and Sensory Neuropathy, Overview, HMSN, CMT
Klinische Symptomatik
HMSN (hereditary motor and sensory neuropathy) or CMT (Charcot-Marie-Tooth) is a group of clinically and genetically heterogenous disorders of the peripheral nervous system. Patients develop symmetric, distally pronounced pareses and muscle atrophies, frequently accompanied by sensory impairment, reduced or absent deep tendon reflexes and foot deformities (e. g. pes cavus). This disease frequently results in an increasing handicap with age; in some cases, a wheelchair is required.
A prevalence of 1: 2 500 - 7: 100 000 indicates that these are the most frequent inherited neuromuscular disorders.
Clinical diagnosis
- Positive family history; pattern of inheritance or sporadic
- Characteristic symptoms (distal > proximal atrophy, gait disturbance, foot deformities, hypesthesia, reduced vibration sense, etc.)
- Electrophysiological examination:
Nerve conduction velocity (NCV) > 38 m/s; reduced amplitudes: primary axonal neuropathy
Nerve conduction velocity (NCV) < 38 m/s: primary demyelinating neuropathy
Electromyogramm (EMG)
- Sural nerve biopsy (if required)
Classification:
The demyelinating types, indicated by reduced nerve conduction velocity, are clinically differentiated from the axonal types, which are characterized by normal NCV and reduced amplitudes. Recent findings point to intermediate neuropathies that show signs of myelin- as well as axonal impairment. Further classifications take the predominant symptoms, family history, and causative mutations as well as the associated chromosomal loci into account. In later stages of the disease, axonal damage is common to almost all subtypes. The follwing table is based on the traditional classification according to Dyck and Lambert.
| Type | Synonyms | Age of onset (years) | Symptoms |
| HMSN1, CMT1 |
Hypertrophic Form of peroneal muscle atrophy Charcot-Marie-Tooth |
10 - 30 |
Demyelinating polyneuropathy, lslowly progredient distal pareses, frequently autosomal dominant |
| HMSN2, CMT2 |
Neuron form of peroneal muscle atrophie Charcot-Marie-Tooth |
20 - 40 |
Axonal neuropathie, clinical signs similiar to HMSN 1, frequently autosomal dominant |
| HMSN3, DSS |
Hypertrophic neuropathy Dejerine-Sottas-Syndrom |
< 15 |
Demyelinating neuropathie, progredient pareses, pronounced sensory loss, trophic impairment, frequently autosomal rezessiv |
Congenital hypomyelinating neuropathy (CHN) is the most severe inherited form to date, manifest in newborns as well as in early childhood.
All Mendelian patterns of inheritance have been observed:
- Autosomal dominant and recessive
- X-chromosomal dominant and recessive
Multiple gene mutations and loci are known. Additional symptoms (deafness, pupillary anomalies, optic atrophy or visual loss, scoliosis, diaphragm impairment, vocal cord paresis, etc.) may point to the underlying gene and mutation. Particular mutations, however, may result in a broad spectrum of phenotypes, partially overlapping with other diseases - e. g., Friedreich Ataxia, Roussy-Levy syndrome, distal hereditary neuropathy or hereditary spastic paraparesis. Amyotrophic lateral sclerosis is also known as a spinal form of CMT. Severe courses of the disease are also designated as Dejerine-Sottas Syndrome (DSS) or Dejerine Sottas Neuropathy (DSN), as well as Congenital Hypomyelinating Neuropathy (CHN). A further subgroup comprises the hereditary sensory and autonomous neuropathies, most frequently disorders of early childhood with severe progression and additional symptoms (insensitivity to pain, anhidrosis, etc.). It is therefore not always possible to clinically define the underlying genetic defect. In such cases, differential genetic diagnostics may be of help.
The Medial Genetic Centre offers analyses covering nearly all known CMT genes:
Analyses for HMSN, CMT, DSN, CHN, HS(A)N at the MGZ
| Type | Inheritance | Locus |
Gene |
| HMSN type 1 - primaryly demyelinating | |||
| CMT1A (1E with deafness) |
AD |
17p12 |
PMP22 |
| CMT1B, CHN, DSS, intermediate form |
AD |
1q22.31 |
MPZ |
| CMTX, intermediate form | XR/XD | Xq13.1 | GJB1/Cx32 |
| CMT1D, CHN, DSS | AD | 10q21.3 | EGR2 |
| CMT1F | AD | 8p21 | NEFL |
| CMT1C | AD | 16p13.13 | LITAF/SIMPLE |
| CMT4A | AR | 8q21.11 | GDAP1 |
| CMT4C | AR | 5q32 | SH3TC2 |
| CMT4D (HMSNL) | AR | 8q24.3 | NDRG1 |
| CMT4F (DSS) | AR | 19q13.2 | PRX |
| CCFDN | AR | 18q23 | CTDP1 |
| HMSN type II, primaryly axonal | |||
| CMT2A2 | AD | 1p36.2 | MFN2 |
| CMT2I, J (deafness, pupillary anomalies) | AD | 1q23.3 | MPZ |
| CMTX, intermediate form | XR/XD | Xq13.1 | GJB1/Cx32 |
| CMT2B (ulcerations) | AD | 3q21.3 | RAB7 |
| CMT2D, dHMN 5 | AD | 7p15 | GARS |
| CMT2E | AD | 8p21 | NEFL |
| CMT2F | AD | 7q11.23 | HSPB1 |
| CMT2K | AD/AR | 8q21.11 | GDAP1 |
| CMT2L | AD | 12q24 | HSPB8 |
| CMT2B1 | AR | 1q22 | LMNA |
| HMSN type III, juvenile form of HMSN I | |||
| DSS/CHN | AD/AR | 17p12 | PMP22 |
| DSS/CHN | AD/AR | 1q23.3 | MPZ |
| DSS/CHN | AD/AR | 10q21.3 | EGR2 |
| DSS | AR | 19q13.2 | PRX |
| HMSN intermediate forms | |||
| DI-CMTB | AD | 19p13.2 | DNM2 |
| DI-CMTD | AD | 1q23.3 | MPZ |
| CMTX | XR/XD | Xq13.1 | GJB1/Cx32 |
| CMTRIA | AR | 8q21.1 | GDAP1 |
| Distal hereditary motor europathies HMN | |||
| Distal HMN 2, CMT2L | AD | 12q24 | HSPB8 |
| Distal HMN 5, CMT2D | AD | 7p15 | GARS |
| Distal HMN 7B/ALS associated | AD | 2p13 | DCTN1 |
| Distal HMN/ALS4 | AD | 9q34 | SETX |
| Distal HMN/Silver Syndrome/SPG17/DSMAV | AD | 11q13 | BSCL2 |
| Hereditary recurrend focal neuropathies | |||
| HNPP |
AD |
17p12 |
PMP22 |
| HNA | AD | 17q25 | SEPT9 |
| Giant Axon Neuropathie, GAN1 | AR | 16q24.1 | GAN |
| Hereditary sensory (autonomous) neuropathies | |||
| HSAN 1 | AD | 9p22.31 | SPTLC1 |
| HSAN 4 (CIPA) | AR | 1q23.1 | NTRK1 |
| HSAN 5 | AR | 1p13.1 | NGFB |
| AR | autosomal recessive |
| AD | autosomal dominant |
| XD | X-linked dominant |
| XR | X-linked recessive |
| DI-CMT | dominant-intermediate Charcot-Marie-Tooth-disease |
| CCFDN | Congenital Cataracts, Facial Dysmorphism & Neuropathy Syndrome |
| HNPP | Hereditary Neuropathy with Liability to Pressure Palsies |
| HNA | Hereditary neuralgic Amyotrophy |
| CHN | Congenital Hypomyelination Neuropathy |
| DSS | Dejerine-Sottas-Syndrome |
| CIPA | Congenital Insensitivity to Pain with Anhidrosis |