neuropatii ereditare

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Review

Hereditary NeuropathiesSafwan S. Jaradeh, MD

Abstract The spec trum of hereditary neuropathi es hasevolved recently as a result of the exponential growth of genetic research. For the purpose of thisreview, wewill use Charcot-Marie-Tooth (CMT), he-reditary liability to pressure palsy (HNPP) and he-reditary sensory and autonomic neuropathies(HSAN) to illustrate the current clinical and geneticapproach to such neuropathies.

Key Words: hereditary motor and sensory neurop-

athies, hereditary sensory and autonomic neurop-athies, peripheral nervous system diseases, genet-ics in neuropathy

( J Clin Neuromusc Dis 2003;5:7280)

Jean Martin Charcot, Pierre Marie, and Henry Tooth described Charcot-Marie-Tooth neu-ropathy (CMT) in 1886. Their patients haddistal muscular weakness, peroneal atrophy,and reduced reflexes. Roussy and Lvy de-scribed patients with sensory motor neurop-

athy associated with profound tremor that re-sembled essential tremor, and with astasiaand imbalance but without cerebellar dys-function. Subsequent major classifications of CMT were made by Dyck and Lambert in1968, and by Thomas in 1974, and werebased on nerve conduction testing. These au-thors described 2 major types of Charcot-Marie-Tooth neuropathy: a demyelinatingform associated with slow nerve conduction(HMSN-I or CMT1) and an axonal form asso-ciated with normal nerve conduction (HMSN-

II or CMT2).1

A smaller, third group had in-termediate conduction velocities, and these were found later to represent the X-linked variant of CMT (CMTX).

CMT is the most common hereditary motor and sensory neuropathy (HMSN). 1 Theoverall prevalence is 20 to 40 in 100,000 per-sons. 2 Common CMT features include distalmuscle weakness and wasting, distal sensory

impairment usually greater for the vibrationor proprioceptive modalities, and absence of ankle jerks. These patients have high archedfeet or pes cavus and hammertoes. In severecases, the distal atrophy can progress to thedistal portion of the thigh (inverted bottle of champagne). Two main types are distin-guished based on electrophysiological andhistologic criteria. CMT1 is the more com-mon and is characterized by slowed nerveconduction velocities (NCV) and hyper-trophic nerves secondary to demyelin-ation/remyelination and formation of onionbulbs. CMT2 is characterized by normal or minimally slowed nerve conduction veloci-ties, and the nerve biopsy shows predomi-nantly chronic axonal loss.

In CMT1, the onset is usually before age20. The inheritance is dominant and family history is positive. Pes cavus and hammertoes

are present in 50% to 75% of the patients. Thehand intrinsic muscles become involved inup to two thirds of the patients. Sensory im-pairment is usually asymptomatic, and pa-tients rarely report numbness or other posi-tive sensory symptoms such as prickling or tingling. Generalized areflexia can occur in50% of the patients. Palpable enlarged nervesare present in 25% to 35% of the patients; thehypertrophy is best appreciated in branchesof the superficial cervical plexus or thegreater auricular nerve. Approximately 10%

have scoliosis. Essential or postural tremor can be present in up to one third of patients(Roussy-Lvy variant).

The hallmark of CMT1 is significantslowing of NCV to


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ing NCV can test the autosomal-dominant na-ture of CMT1. The penetrance is full and NCV abnormalities present at a very early age. 5 8

However, there is some variability of NCV, ashigh as 10 to 15 m/s, among affected mem-bers in each pedigree. 5

Three important factors help differenti-ate CMT1 from acquired demyelinating neu-ropathies. First, there is little change in NCV over time. One study, which evaluated CMT1subjects over a 25-year span, found a changeless than 3 to 4 m/s for the peroneal NCV andless than 2 or 3 m/s for the median NCV. 7

Second, the NCV slowing is uniform betweenhomologous nerves and within a given limb.Third, conduction block is absent, providedthat the negative area under the curve of thecompound muscle action potential is mea-sured, supramaximal stimulation is ensured,and if confined short segments of the nerveare tested. Practically, a greater than 50% or 60% drop in the proximal to distal motor area/amplitude ratio should raise the possibil-ity of conduction block.

Another characteristic of the CMT1nerve biopsies is the presence of hypertro-phic changes in the nerve. There is enlarge-ment of the endoneurial area. Multiple layers

of Schwann cell processes surround thinly myelinated fibers resembling onion bulbs. 1

The electrophysiological and histologicchanges pointed to a genetic defect in themyelin. Peripheral nerve myelin surroundingthe axon has 3 major components. The mostabundant myelin protein is P0 , which consti-tutes 50% of the total myelin protein, pre-sumed to be the culprit for CMT1. However,studies on the trembler mouse, in which there is a signal for arrested myelination,found a defect on chromosome 11 that coded

for a transmembranous protein called periph-eral myelin protein 22 ( PMP22 ).9 Investiga-tors began to examine the possibility of a de-fect in PMP22 and chromosome 17, theequivalent of chromosome 11 in the mouse.The concomitant encounter of a severe formof CMT1 in a patient with trisomy 17 leadingto an abnormal PMP2 confirmed that CMT1phenotype is mainly linked to the PMP2 on

chromosome 17. 10 Subsequent studies foundthat the PMP2 gene locus is surrounded by 2repeat sequences, one is distal and one isproximal. An unequal crossover during meio-sis will end up with one chromosome 17 thathas and extra PMP22 repeat and will lead toa CMT1 phenotype. Fluorescent in situ hy-bridization (FISH) permits labeling these re-peats and allows genetic testing for CMT1. 15 17

Affected subjects will have 3 repeats indica-tive of DNA duplication leading to excessiveRNA and increased rather than decreased PMP22. 11

There are occasional cases of CMT1 whose genetic testing reveals a point muta-tion. 12 Phenotypically, it is difficult to distin-guish these patients, but they tend to havesomewhat slower conduction velocities andthinner myelin sheaths compared with theduplication cases. 13

Subsequently, the role of P0 was inves-tigated, because it is the major myelin pro-tein. The search was facilitated by the discov-ery of a link between some cases of CMT1and the Duffy blood group locus on chromo-some 1. 14 A marker for P0 was found onchromosome 1q22, and patients with its mu-tation are labeled as CMT1B. 15 Statistically,

CMT1B is much less common than CMT IA. P0 is a 28-kd protein with an intramembra-nous component that functions as a struc-tural molecule, an intracellular componentthat is important in signal transduction, andan extracellular component, which acts likean adhesion molecule. Its impairment willlead to a less compact myelin and slowedconduction velocities. 16 A recent study re- vealed that the Roussy-L vy family genotypeis actually CMT-1B rather than CMT1A. 17

A more recent variant of CMT1 was

linked to the chromosome 10q22-q23 regioncontaining the early growth response 2 gene( EGR2 ), a transcription factor with a key rolein peripheral nerve myelination. The neurop-athy was severe with prominent sensory lossand moderately reduced NCV. 18

Rare cases of CMT1 are autosomal-recessive. They present in early childhood with marked slowing of nerve conduction.

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The nerve biopsies show multiple layers of Schwann cell basal lamina. Some cases weremapped to chromosome 5q23-q33. 19,20 Thegenetic defect leads to abnormal axon Schwann cell signaling, and the neuregulin-2gene ( NRG2 ) appears to be the candidate for the 5q23 form. 20 In rare cases, linkage to the PMP22 or EGR2 loci was found. 21 The origi-nal pedigree linked to chromosome 8q24 isnow considered a variant of CMT4 (see sub-sequently in this article). 22

In summary, CMT1A can be the resultof either a duplication or point mutation of PMP22 on chromosome 17p11.2-12. CMT1Bis the result of a duplication of P0 on chro-mosome 1q22. CMT1C is mapped to the EGR2 locus on chromosome 10q22-q23. Au-tosomal-recessive CMT1 is linked to chromo-some 5q23-q33, chromosome 17p11.2-12 or,less often, chromosome 10q22-q23.

The second major type of Charcot-Marie-Tooth is the so-called axonal variant or CMT2. These patients characteristically haveno slowing or borderline slowing in their nerve conduction velocities. CMT2A and 2Bare usually disorders of adulthood and sel-dom begin before the age of 20. 23 The family history is present in a least 70%, but pes ca-

vus and hammertoes are present in less that50%. Nerve enlargement is absent. Thetremor is rare and usually parallels the degreeof intrinsic hand weakness. CMT2C begins inchildhood with hoarseness and dyspnea thatfollow exercise or emotional stress. 24 This isthe result of early laryngeal and diaphrag-matic weakness. Sensory loss is quite mild inCMT2A and C, but nociceptive loss in CMT2Bis significant and often leads to ulceration of the distal foot. Patients have scoliosis and wasting of their truncal muscles. The electro-

physiological features show primarily an axo-nal neuropathy. The sensory nerve action po-tential tends to be reduced or absent in thefoot, and there are chronic neurogenicchanges as shown by needle electromyogra-phy, which are greater distally. The nerve bi-opsy shows loss of myelinated fibers to a vari-able degree. The gene for CMT2A wasmapped to the Kinesin KIF1B locus on

chromosome 1p35-36, and the defect prob-ably disrupts synaptic vesicle transport alongthe axons. 25 CMT2B was mapped to 3q13-q22, but the nature of the genetic defect isnot known. 26 CMT2C has not been mapped yet.23

Recently, additional phenotypes of au-tosomal-dominant CMT2 were described.One form, designated CMT2D, presented with greater upper limb involvement; thisform was mapped to multiple T-cell gammareceptor genes on chromosome 7p14. 27 An-other variant with proximal limb involve-ment was mapped to 3q13.1 region. 28 Somefamilies with CMT2 had missense mutationsinvolving the neurofilament light chain geneon chromosome 8p21; this form was desig-nated CMT2E. 29 One French family from Nor-mandy presented after the fourth decade with lancinating pain, pharyngeal dysphagia,deafness, and Argyll-Robertson pupils. Thedefect was a mutation in the P0 gene locus. 30

D jerine and Sottas described CMT3 ashypertrophic interstitial neuropathy or neuri-tis. Most cases are sporadic. The onset is usu-ally in early childhood but can be neonatal with hypotonia. There is proximal limb andtrunk weakness and a characteristic marked

sensory ataxia. Practically, it is the only CMTin which there is loss of joint position sensein the fingers at an early age. There is gener-alized areflexia and nerve enlargement in allpatients and skeletal changes are prominent.This corresponds to Dr. Dyck s classificationof HMSN-III. The nerve biopsies show absentor very thin myelin with markedly prominentonion bulbs. Electrophysiologically, there issevere slowing of nerve conduction veloci-ties to less than 10 m/s, and the responses aretemporally dispersed. By analogy to CMT1,

CMT3A is linked to the PMP 22 gene on chro-mosome 17; CMT3B is linked to the P0 pro-tein gene on chromosome 1, whereasCMT3C is linked to a mutation in the EGR2transcription factor. An interesting discovery was that most sporadic CMT3 cases are asso-ciated with homologous duplication of either locus, and therefore represent an autosomal-dominant gene rather than a recessive one. 31

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The intermediate form of CMT is X-linked. 32 34 There is pes cavus and distal leg wasting. Patients need a cane by their fifth decade. There is some wasting in the handintrinsic muscles, but proximally the patientis very strong. The onset is usually in child-hood, and women are always either mildly affected or are asymptomatic. Like mostCMT, the sensory loss is mild. Men lose their reflexes but women only lose their ankle jerks. Pes cavus and hammertoes are com-mon particularly in men, and claw hand de-formity occurs in some men but virtually never in women. Some recessive cases beginin childhood and have mental retardation andspasticity. Other recessive cases begin inadulthood with spasticity without mental re-tardation. The nerve conduction velocitiescan be slow but are usually faster than 25m/s, which somewhat differentiate those pa-tients from CMT 1. Again, the slowing isgreater in the lower limbs, and slowing is very uncommon in women. The sensory nerve action potential tends to be absent or reduced in the feet. Subsequent studies 34

found some slowing in the upper extremitiesas the disease begins in childhood. On nervebiopsy, there is a dropout of nerve fibers

again, and it gets worse as the disease pro-gresses without prominent onion bulbs. Elec-tron microscopy shows some wrapping of Schwann cell processes around thinly myelin-ated fibers but, for the most part, CMTX is anaxonopathy. CMT X has been linked primar-ily to the Connexin ( CX32 ) gene on Xq13.CX32 is predominantly a transmembranousmolecule that belongs to a family of mem-brane semichannels known as connexons.Cases that map to this gene locus are knownas CMTX1. The less common childhood-

recessive CMTX has been mapped to theshort arm of chromosome X, but the genedefect is unknown. 35 Adult-onset cases with spastic paraparesis are mapped to Xq26 butare not linked to Connexin. The defect con-sists of point mutation, not duplication, andat least 30 mutations have been described.

CMT4 is autosomal-recessive and rare.It begins in infancy or childhood with de-

layed motor milestones. Distal weakness andatrophy reach proximal muscles by the sec-ond decade and adults become wheelchair-bound. Facial muscles can be involved. Thereis generalized areflexia, but sensory loss ismild. Other skeletal abnormalities are com-mon. NCV are slowed to 15 to 30 m/s. His-tologically, there are irregular redundantloops of myelin on nerve biopsy. 37 Genotypi-cally, the Tunisian form was described first; itis termed CMT4A 36 and has been mapped tothe GDAP1 gene on chromosome 8q13-21.1.The gene encodes proteins expressed in re-sponse to gangliosides. The European form(CMT4B) is linked to chromosome 11q22-23 with mutations in the gene for a phosphataseknown as myotubularin-related protein-2.37,38 One recent CMT4 family had a muta-tion involving the PRX gene 39 on chromo-some 19q13.1-13.3. One variant occurs in theLom district in Bulgaria (CMT4D-Lom), which was mapped to the NDRG1 locus on chro-mosome 8q24. 22

HEREDITARY NEUROPATHY WITHLIABILITY TO PRESSURE PALSY

Hereditary neuropathy with liability to

pressure palsy (HNPP) is another major he-reditary sensory motor neuropathy. Theseare patients who usually present with recur-rent focal neuropathies. 40 The onset can beat any age but often after the second decade.The neuropathies are at common entrapmentsites. Brachial plexus involvement occurs inless than 25%. The key feature is that thepreceding trauma is very minor. Patients would lie on their arms for 5 minutes andhave radial nerve palsy, or would cross their legs for 5 to 10 minutes and develop foot-

drop. The neuropathy is often painless. Themore severe cases have pes cavus and ham-mertoes. There is mild generalized slowing of nerve conduction studies with disproportion-ately greater slowing of the distal latency when compared with the proximal veloc-ity. 41 The slowing is greater for the involvednerve and is not uniform. Occasional casescan have partial conduction block, particu-





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larly around the area of compression. 42 Thecarriers often exhibit mild slowing. Thenerve biopsy shows sausage-like swelling of the myelin sheath described as tomaculousformations (tomacula = sausage). Teased fi-bers disclose areas of segmental demyelin-ation adjacent to some of the tomaculae, which explains the focal conduction block seen in these patients. As shown on electronmicroscopy, there are redundant loops of my-elin. These patients were initially tested for duplications of the PMP22 gene on chromo-some 17, but instead, geneticists found a de-letion of this gene. It has been proposed thatthere is an unequal crossover in the region of the responsible gene during meiosis. Thekaryotype with 3 parts of the PMP22 gene will develop CMT1A, whereas ending up with only one 1.5-kb segment will result inHNPP. 43 Thus, HNPP and CMT1A representgenetic reciprocates.

Some cases of familial recurrent bra-chial plexopathy are painful and are not as-

sociated with a polyneuropathy. This disor-der was recently mapped to chromosome17q25. 44

Diagnostic Approach to HereditarySensory and Motor Neuropathies

HMSN should be suspected in any chronic insidious neuropathy. 45 Detailedfamily pedigree should be obtained from thepatient and relatives. Focused clinical evalu-ation and nerve conduction studies on thesiblings are very helpful. If the functional de-cline is rapidly progressive, other causes of neuropathy should be ruled out.

The age of onset, the presence of proxi-mal and cranial weakness, and the presenceof choreiform movements are very usefulclinical clues (see Table 1). Nerve conduc-tion studies are essential. When conduction velocities are under 25 m/s, CMT1A is statis-tically the most likely diagnosis. DNA testingfor PMP22 gene duplication or mutation onchromosome 17 has the highest yield in this

Table 1. Major Hereditary Motor and Sensory Neuropathies (HMSN)

CMT1 CMT2 CMT3 CMT4 CMTX

Onset Abolescence or adulthood

Adulthood Infancy or childhood

Infancy or childhood

Childhood or adulthood

Sex M = F M = F M = F M = F M > F Weak limb Distal

proximalDistal Distal and

proximalDistal >

proximalDistal

Cranial nerve Vere rare(VIII)

Absent, except2C

Rare(V, VII)

Rare (VII) Absent

Distal sensory loss

Mild Mild, except2B

Moderate tosevere

Mild Mild

Areflexia Distal >proximal

Distal Diffuse Diffuse Distal >proximal

Pyramidalsigns

Rare (1A) Rare (AR) Absent Absent Rare (AR)

Pes cavus Late > early Late Early Early Late > early Scoliosis Mild Absent, except

2CModerate Moderate Mild

Tremor Common Rare Choreiform Rare RareEnlarged

nervesPresent Absent Present Absent Rare

NCV 75% LLN


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situation. If negative, testing for P0 or EGR2mutations can be requested. If still negative,testing for CX32 mutation can be done, butthe yield is higher in men because women with CMTX do not have significantly slowedconduction velocities. All these tests are com-mercially available.

For intermediate conduction velocities(25 35 m/s), testing for the CX32 mutationshould be done first. If negative, testing for CMT1 can be pursued as described previ-ously. 46,47

If all testing is negative but family evalu-ation confirms an inherited etiology, other familial demyelinating neuropathies shouldbe suspected and tested for. These includemetachromatic leukodystrophy, Krabbe s dis-ease, Refsum s disease, and adrenomyeloneu-ropathy.

When nerve conduction velocities arenot significantly slow (above 35 m/s), asearch for the CX32 mutation can be pur-sued, particularly in women. If negative, test-ing for the CMT2 gene can be obtained, butthe yield is lower because only testing for theneurofilament light gene is commercially available.

If the diagnosis remains elusive, a sural

nerve biopsy should be considered.

HEREDITARY SENSORY ANDAUTONOMIC NEUROPATHIES

Hereditary sensory and autonomic neu-ropathies (HSAN; formerly hereditary sensory neuropathies) represent another major cat-egory of inherited neuropathies. 48 They arefar less common than HMSN. In HSAN, sen-sory and autonomic ganglia and axons areinvolved. The discovery of various neuro-

trophic factors and their respective tyrosinekinase (TRK) receptors led to an increasedunderstanding of these neuropathies.

HSAN I is the most common type.Symptoms usually begin in the second tothird decade. Some patients present with neuropathic foot ulcers that can lead to re-current cellulitis and osteomyelitis. Other pa-tients present with burning or painful feet.

Pain can involve the hands, but finger ulcer-ations are rare. On examination, sensory lossis mainly for nociceptive modalities. Distalanhidrosis with proximal hyperhidrosis iscommon, whereas visceral autonomic neu-ropathy is infrequently seen. Sensorineuralhearing loss can be present. Motor strength isusually preserved. There is distal areflexia.Some patients have pes cavus and othershave overt Charcot joints. Sensory nerve ac-tion potentials are reduced or absent distally.Motor conductions are usually normal, butthe electromyogram could show few largemotor unit potentials in distal muscles. Suralnerve biopsies reveal axonal loss of nerve fi-bers, greater for the unmyelinated and smallmyelinated nerve fibers. 48

Genetically, HSAN I is autosomal-dominant and has been linked to chromo-some 9q22.1-q22.3. 49 Recently, mutations inthe gene encoding for the long chain basesubunit-1 of serine palmitoyltransferase werediscovered. 50 The responsible gene locus isad jacent to the TRKB recep tor gene(NTRK2).

HSAN II is less common and presentoften in childhood with painless injuries tothe limbs. Deformed feet occur because re-

peated small fractures lead to bone resorp-tion. There is distal anhidrosis. Mental retar-dation is rare. Some patients have absence of the fungiform papillae of the tongue. Facialand corneal sensations are impaired, andhearing loss can occur. Again, nociceptivemodalities are affected to a greater extent. Visceral pain perception and autonomicfunction are impaired. Areflexia is usually generalized. Muscle strength is normal. Sen-sory nerve action potentials are absent. Mo-tor nerve conduction and electromyograms

are similar to HSAN I. Sural nerve biopsiesreveal axonal loss of nerve fibers, greater for the myelinated nerve fibers. 48

Genetically, HSAN II is autosomal-recessive. The gene has not yet beenmapped. 51

HSAN III is also known as Riley-Day syn-drome or familial dysautonomia. Affectedchildren have low birthweight, failure to





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thrive, alacrima, swallowing problems, inter-mittent vomiting, and fever. Emotional upsetcan trigger autonomic dysreflexia with hy-perhidrosis, hypertension, and blotching of the skin. Later on, children develop posturalhypotension. Despite the frequency of frac-tures of the spine and limbs, acral mutilationsare uncommon. Scoliosis and Charcot s jointscan occur. On examination, there is absenceof fungiform papillae of the tongue, cornealinsensitivity, reduced gag reflex, areflexia,and generalized nociceptive hypesthesia.Nerve conductions show reduced sensory nerve action potentials amplitudes and bor-derline slowing of the motor conduction ve-locities. The amplitude of sensory nerve ac-

tion potentials was reduced. Pathologically,there is a severe loss of unmyelinated nervefibers with reduction of large myelinated fi-ber diameters to less than 12 m. There isalso a decreased number of neurons in allautonomic and dorsal root ganglia. 48,52 54

Genetically, HSAN III is autosomal-recessive. It has been mapped to chromo-some 9q31 and is almost exclusive to Ash-kenazi Jews. The gene for NTRK2 is locatedon chromosome 9 but is not the responsible

gene.55

Chadwick et al. recently mapped 2actin genes in the familial dysautonomia can-didate region on 9q31. 56

HSAN IV presents with congenital in-sensitivity to pain. 48,57 Affected childrenhave recurrent fever as a result of their anhi-drosis. Hyperhidrosis and alacrima are seenin HSAN III but not in HSAN IV. The nocicep-tive sensory modalities are diffusely de-creased. Many patients have a learning dis-ability or mild mental retardation. Sensory and motor nerve conduction studies are nor-mal. Anatomically, there is a loss of the first-order nociceptive neuron. Pathologically,there is an absence of small neurons in thedorsal root ganglia with corresponding lossof unmyelinated and small myelinated fibers.The trigeminal nerve is also involved.

Genetically, HSAN IV is autosomal-recessive. It has been mapped to chromo-

some 1q21-q22. Responsible mutations affectthe gene for NTRKA (NTRK1) located onchromosome 1. 58,59

Diagnostic Approach to HereditarySensory andAutonomic Neuropathies

HSAN should be suspected in any chronic small fiber neuropathy. 45 A detailedfamily pedigree should be obtained from thepatient and relatives. Noninvasive evaluationof small fiber function by quantitative auto-nomic testing, particularly measurement of sweat responses, is more helpful than nerveconduction studies in establishing the diag-nosis, as well as in the screening of siblings.

Other hereditary conditions presenting with small-fiber neuropathies should be evaluated:amyloidosis, Fabry s disease, Tangier s dis-ease, and porphyria. Once these are ruledout, HSAN become the likely diagnosis. If au-tonomic testing is not available, punch skinbiopsies represent a minimally invasive alter-native that allow direct evaluation of intra-epidermal nerve fibers. Fat aspirate biopsy isalso minimally invasive and is helpful for thediagnosis of amyloidosis. Genetic testing for various HSAN is not yet widely available. Su-ral nerve biopsy should be done as a last re-sort; it can also diagnose amyloidosis. Thetreatment is mainly supportive. Prophylaxisof acral ulcers and mutilation is paramount.Patients should avoid excessive heating.

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