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Hereditary neuropathies

Hereditary neuropathies are a diverse group of inherited conditions affecting the peripheral nervous system. They are frequently underdiagnosed due to their indolent onset over decades and lack of clear family history in some cases. Charcot-Marie-Tooth disease is the most common inherited neuropathy, with two main types - CMT1 characterized by demyelination and CMT2 characterized by axonal loss. CMT1 results from mutations affecting myelin protein zero or peripheral myelin protein 22 genes, causing demyelination and onion bulb formation. Accurate diagnosis relies on detailed family history, neurological examination, and electrodiagnostic testing to distinguish inherited from acquired neuropathies.

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Hereditary Neuropathies Dr. Sunil Kr. Sharma Senior Resident Dept. of Neurology GMC Kota
Introduction – Inherited neuropathies are diverse in both genetic causes and clinical phenotypes. – They are frequently underdiagnosed or misdiagnosed. – Family history –most imp. but difficult to obtain.
Introduction – ≈ 40% of chr. polyneuropathies, – ≈50% of previously unidentified PN. – Inherited nature may go unrecognized in a large percentage of patients (Klein, 2007).
– Insidious onset and indolent course over years to decades. – Classification depends on the clinical phenotype, mode of inheritance, and class of neurons predominantly affected. (Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
– Major advances -molecular basis of inherited neuropathies. – Gene defect coding for a specific gene product essential to myelin or axonal function (Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
Clues to diagnosis – Long-standing neuromuscular symptoms – Detailed family histories – Skeletal abnormalities such as hammer toes, High arches, or scoliosis – Neurological evaluations in relatives
– Negative F/H cannot rule out an inherited neuropathy. e.g. 1. Early death of one or both parents 2. Few blood relatives 3. AR dis. – About 1/3 - de novo gene mutations (Boerkoel et al., 2002).
Acquired vs. Inherited – Often difficult, especially in the absence of +ve history. – An acquired etiology may compound an inherited neurologic defect. – Rapid or accelerated neurologic declines - suggest superimposed acquired etiologies.
Acquired vs. Inherited – More susceptible to injury from metabolic, toxic, and other nervous system insults e.g. CTx. – Major deficits with limited toxic or metabolic exposure. – HN frequently misdiagnosed as diabetic neuropathy(less likely in the absence of retinopathy or nephropathy). Chaudhry V, Chaudhry M, Crawford TO, Simmons-O’Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003; 60:337–340. [PubMed: 12552058] Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993; 43:817–824. [PubMed: 8469345]
Historical and Examination Clues of Inherited Neuro-pathy History- – Frequent childhood ankle sprains and toe- catching falls – Slowest child in foot races – Recurrent acral calluses, and ulcers in sensory predominant forms.
Physical examination – Foot drop – High arches and hammer toes – Inverted champagne bottle appearance of the legs – Recurrent painless foot ulcers – Thickened nerves in hypertrophic demyelinating varieties – Refractory response to the treatment of acquired disease – Major sensory loss without positive sensory symptoms (e.G., Paresthesia, burning, or lancinating pain).
Neurophysiology – Temporal dispersion and conduction blocks are often absent Exceptions -CX32 mutations, temporal dispersion can occur. – NCV <38 m/s -demyelinating, – NCV =38– 45 m/s-intermediate. – NCV >45 m/s -primary axonal process Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982; 32:592–596. [PubMed: 6283420] Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, et al. Unusual electrophysiological findings in X-linked dominant Charcot–Marie–Tooth disease. Muscle Nerve. 2000; 23:182–188. [PubMed: 10639608]
– Inheritence may be AD,AR and X linked. – Can be divided into 3 groups: (1) Isolated neuropathy involving PNS exclusively (2) Multisystem neuropathy involving both CNS and PNS (3) Neuropathy with multiorgan involvement affecting nonneurologic organs such as skin, kidney, heart, and liver
Neuropathy with isolated nerve involvement – Hereditary motor and sensory neuropathy (HMSN, or Charcot– Marie–Tooth) – Hereditary sensory and autonomic neuropathy (HSAN) – Hereditary sensory neuropathy (HSN)
Neuropathy with isolated nerve involvement… – Distal hereditary motor neuropathy (dHMN) – Hereditary brachial plexus neuropathy (HBPN) – Hereditary neuropathy with liability to pressure palsies (HNPP)
Neuropathy with brain and/or spinal cord involvements – Spinocerebellar atrophy (SCA) – Friedreich ataxia (FA) – Hereditary spastic paraplegia neuropathy (i.e., complicated HSP, HMSN 5)
Neuropathy with non- neurologic organ involvement – Familial amyloid (transthyretin, gelsolin, ApoA1) – Leukodystrophy – Peroxisomal – Lipoprotein deficiency – Porphyrias – Defective DNA maintenance – Mitochondrial defects
Miscellaneous – Giant axonal neuropathy – Neurofibromatosis type 1 – Neurofibromatosis type 2 – Others
Charcot–Marie–Tooth Disease(HMSN) and Related Disorders
Charcot–Marie–Tooth Disease (Hereditary Motor and Sensory Neuropathy) – First described in 1886 by Charcot and Marie in Paris and Tooth in London (Charcot and Marie, 1886; Tooth, 1886). – Most common inherited neuropathy – Prevalence of 10 to 41 per 100,000 (Martyn and Hughes, 1997).
– two main groups: 1. CMT1 [HMSN-I]- chara. By motor NCVs (<38 m/sec in forearm) and nerve biopsy findings of demyelination and onion bulb formation 2. CMT2 [HMSN-II]- chara. By - normal or near normal motor NCVs , and nerve biopsy reveals axonal loss without prominent demyelination (Harding, 1995).
– Hereditary distal spinal muscular atrophy- The peroneal muscular atrophy phenotype without sensory involvement on either clinical or electrophysiological examination . – Dejerine-Sottas disease (or syndrome, DSS) – A severe form of demyelinating neuropathy with onset occurring in early childhood .
– CMT1 and the vast majority of subtypes of CMT2 display autosomal dominant inheritance. – A minority of cases occur sporadically or in siblings only -attributed to AR inheritance or to de novo gene mutations.
– CMT may be classified by- 1. Mode of inheritance (AD, X linked and rarely AR) 2. Chromosomal locus 3. Causative genes
A, CMT 1,HNPP,CMTX, DSS,CMT4-inherited disorders of myelin. CMT2 is a primary axonal disorder. B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2, periaxin) result in CMTX, CMT1B, CMT1A, DSS, and CMT4. Mutations of the LITAF gene result in CMT1C. C, Point mutations of the KIF1B and NFL genes and specific MPZ missense mutations result in CMT2.
Charcot–Marie–Tooth Disease Type 1 – Onset- first or second decade . – Chara. By slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs. – Symmetrical weakness and wasting in the intrinsic foot, peroneal, and anterior tibial muscles.
CMT-1 – In 2/3 rd Pt., the UL are involved later in life. – Foot deformities 1. Pes cavus and hammer toes ≈3/4 of adult pt. 2. Mild kyphosis ≈ 10% 3. Palpably enlarged hypertrophic peripheral nerves ≈ 1/4
CMT-1… – Absent ankle reflexes are universal - frequently a/w absent or reduced knee and UL reflexes. – Some degree of distal sensory impairment (↓ vibration and light touch) – Rarely - positive sensory symptoms. – Occasionally, a/w essential or postural upper-limb tremor-referred to as roussy-lévy syndrome-not a separate clinical or genetic entity
CMT-1… – Severity varies considerably. – ≈10% Pt. with slowed NCVs -asymptomatic. – May exacerbate during pregnancy-temporary in ≈ 1/3rd of pt. , becomes progressive in the remainder.
CMT-1… – Slow deterioration in strength and decline in axonal function continues throughout adulthood (Verhamme et al., 2009). – Motor nerve conduction studies show uniform slowing to less than 75% of the lower limits of normal in all nerves
CMT-1… – Motor conduction of upper-limb nerves proves more useful than studies of lower-extremity nerves because distal denervation in the feet is often severe and virtually complete. – A motor NCV <38 m/sec in the forearm segment of the median nerve -as a cutoff value to distinguish between CMT1 and CMT2. – SNAPs are usually absent with surface recordings – Uniform conduction slowing
CMT-1… – Neurological deficits correlate with reductions in CMAP and SNAP amplitudes rather than conduction velocity. – Uniform conduction slowing 1. CMT1A with PMP22 dupli. or pm. 2. CMT1B with MPZ pm 3. DSS, including PMP22, MPZ, and EGR2 gene mutations 4. Metachromatic leukodystrophy 5. Cockayne disease (Lewis et al., 2000).
CMT-1… – Routine hematological and biochemical studies and CSF are normal(D/W CIDP) – Sural nerve biopsy-onion bulb formation. A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar = 20 μm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are surrounded by multiple layers of Schwann cell processes.
CMT-1… – Gene mutations-account for about 3/4th CMT1 . – CMT1A is the most common CMT subtype-70%– 80% of CMT1 cases and more than 50% of all CMT cases. – The disease is caused by duplication in the 17p11.2-12 -PMP22,rarely by PMP22 point mutation.
CMT-1… – PMP22 -membrane glycoprotein of myelin sheath. – Deletion of the same 1.5-Mb region on chromosome 17p11.2 results in a single copy of the normal PMP22 gene-observed in 85% of patients with HNPP – CMT1B is clinically indistinguishable from CMT1A accounts- for 10–20% of all CMT cases.
CMT-1… – CMT-1B-mutations(pm) in MPZ gene- 1q22-23. MPZ – 1. major peripheral myelin glycoprotein 2. adhesion molecule 3. member of the immunoglobulin superfamilywith extracellular, transmembrane and intracellular domains. – Mutations in MPZ -also a/w DSS, and congenital hypomyelination neuropathy.
CMT-1… – Different MPZ mutations - uncompacting of myelin or focal myelin foldings (Gabreëls-Festen et al., 1996). – Motor conduction block -rarely in CMT1B (Street et al., 2002). – Specific MPZ missense mutations in CMT2 phenotype- only mild slowing of NCVs (Marrosu et al., 1998).
CMT-1… – CMT1C -mutation in lipopolysaccharide-induced TNF-alpha (LITAF/SIMPLE) gene, chr.16p13-12 . – Encodes a lysosomal protein - protein degradation pathways (Street et al., 2003). – CMT1C used to be reserved for autosomal dominant CMT1 families not linked to either CMT1A or CMT1B – Manifest characteristic CMT1 symptoms.
CMT-1… – CMT1D -mutation of the early growth response 2 gene (EGR2) -chro. 10q21-q22 . – Regulates the expression of myelin proteins including PMP22, P0, Cx32, and periaxin (Kamholz et al., 2000). – Respiratory compromise and cranial nerve dysfunction a/w EGR2 mutations. – Other rare CMT1 subtypes include CMT1E and CMT1F Szigeti et al., 2007.
Charcot–Marie–Tooth Disease Type 2 – CMT2-1/3rd of all AD CMT disease. – A/W mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation. – Onset later than in CMT1, MC 2nd decade,-may be delayed until middle age or beyond.
CMT-2 – Foot and spinal deformities -less prominent than in CMT1. – Peripheral nerves are not enlarged – Upper limb involvement, tremor, and general areflexia - less frequent. – 20% -asymptomatic.
CMT-2 – CMT2A -MC of CMT2 cases- 30%. – CMT2A1-chro. 1p35, -mutation in kinesin protein involved in axonal transport of synaptic vesicles (Saito et al., 1997; Zhao et al., 2001). – CMT2A2- most CMT2 families, similar to CMT2A1 but has an earlier onset and is more severe. – May be a/w optic atrophy.
CMT-2… – Mutations in the mitofusin 2 (MFN2) gene-chro. 1p36-p35. – MFN2 -mitochondrial fusion protein ubiquitously expressed in many tissues including PN. – CMT2B-chro. 3q13-22- RAB7 gene - prominent sensory loss with foot ulcerations. – Clinically very similar to HSN1 but lacks spontaneous lancinating pain
CMT-2… – CMT2C –chromo.12q24-vocal cord, intercostal, and diaphragmatic muscle weakness (Klein et al., 2003). – Life expectancy -shortened. – CMT2D- chromo . 7p14, is chara. by weakness and atrophy - more severe in the hands than in the feet (Ionasescu et al., 1996b). (De Jonghe et al., 1997 & Verhoeven et al., 2003).
CMT-2… – CMT2E- typical CMT2 phenotype with slowed motor nerve conduction that is < 38 m/sec – More severe clinical phenotype. – Mutations in genes that encode neurofilament light (NEFL) subunit. – May have axonal swelling (giant axons) and signi. sec. demyelination on sural nerve biopsies (Fabrizi et al., 2006; Jordanova et al., 2003)
CMT-2… – CMT2F- heat shock protein 27 (Hsp27)- unstable neurofilament network . – Chara. by later onset (35–60 years), mild sensory impairment, and moderate to severely slowed NCVs of lower limbs but normal or mildly reduced velocities in the upper limbs. – CMT2G- Spanish family chromo. 12q12-q13.3, with the age onset from 9 to 76 years.
CMT-2… – CMT2J- also designated as CMT2 with MPZ (myelin protein zero) gene mutation, is associated with pupillary abnormalities (Adie pupil) and hearing loss. – CMT2L -HSPB8 gene muta. with typical features of the CMT2 phenotype.
CMT-2… – Motor NCV may be normal or mildly reduced. – SNAPs - either absent or reduced in amplitude. – Sural nerve biopsy -preferential loss of large myelinated fibers, without signi. demyelination. – There may be clusters of regenerating myelinated fibers, a hallmark of axonal regeneration.
X-Linked Charcot–Marie– Tooth Disease – Phenotypically similar to CMT1. – male -more severely affected, and females -mild neuropathy or be asymptomatic. – No male-to-male transmission occurs. – 7% to 16% of all forms of CMT-second most common form of CMT (following CMT1A).
CMTX… – Mutations in GJB1-connexin 32 (Cx32) - channel-forming proteins - gap junction protein found in - Schwann cell cytoplasm chromo. Xq. – Most missense mutations -mild clinical phenotype – Nonsense and frameshift muta.- more severe phenotypes (Ionasescu et al., 1996a). – Some mutations of Cx32 - CNS involvement with white-matter MRI and MR spectroscopy abnormalities, abnormal BAER, and deafness (Murru et al., 2006).
CMTX… – Significant slowing in NCV in male – BAER responses are often abnormal. – Nerve biopsy - both axonal loss and demyelination. – NCV- near normal to intermediate slowing in the 30- to 40-m/sec range. – CMTX - primary axonal or demyelinating disorder- debated (Birouk et al., 1998).
CMTX… – Nonuniform conduction slowing consistent with demyelination (Gutierrez et al., 2000; Lewis, 2000). – NC slowing paralleling the loss of CMAP amplitude. – No male-to-male transmission, the presence of intermediate conduction velocities (>42 m/sec) in female carriers and delayed brainstem auditory evoked response latencies in affected men is highly suggestive of Cx32 mutations (Nicholson et al., 1998).
Charcot–Marie–Tooth Disease Type 3, or Dejerine-Sottas Disease – Uncommon progressive hypertrophic neuropathy with onset in childhood. – Motor development is delayed; proximal weakness, global areflexia, enlarged peripheral nerves, and severe disability are the rule. – Originally thought to be AR, most cases are sporadic and in some AD. – Motor conduction velocities are severely slowed, often to less than 10 m/sec.
CMT-3… – Temporal dispersion and amplitude reduction on proximal stimulation may be found in such cases. – CSF protein ↑. – Defective myelination is confirmed by an increased axon-to-fiber diameter ratio. – Cases of congenital hypomyelination neuropathy probably represent a variant of CMT3. – DSS is genetically heterogeneous .
Charcot–Marie–Tooth Disease Type 4 – AR ,<10% of all CMT cases. – Onset in early childhood and progressive weakness leading to inability to walk in adolescence. – Both demyelinating and axonal types have been identified (Dubourg et al., 2006). – Disturbance in normal myelination of the axons. – Clinical and electrophysiological features are similar iwith CMT3. – Conduction velocities are slowed (20–30 m/sec).
– CSF protein N. – Nerve Bx -loss of myelinated fibers, hypomyelination, and onion bulbs. – Sev. subgroups: CMT4A, CMT4B1 and 2, CMT4C, CMT4D, CMT4E, CMT4F, and CMT4H.
Complex Forms of Charcot– Marie-Tooth Disease – AD -features intermediate between CMT1 and CMT2, with conduction velocities between 38 m/sec and normal. – classified separately as dominant intermediate CMT (DI-CMT) and include types A, B, C, and D. – DI-CMTA -Chromo. 10q24-25, -gene defect -not discovered. – DI-CMTB -dynamin 2 (DNM2) gene ,chromo. 19p12-13.
Complex Forms of Charcot– Marie-Tooth Disease – Mild to moderately severe CMT phenotype. – May have neutropenia and early cataracts (Claeys et al., 2009). – DI-CMT- tyrosyl-tRNA synthetase gene chromo. 1p34-35 – Mild, very slowly progressive course (Jordanova et al., 2006). – DI-CMTD maps to chromosome 1q22 MPZ gene mutations.
Hereditary Neuropathy with Liability to Pressure Palsies – AD-chara. by increased susceptibility to mechanical traction or compression. – 2nd -3rd decade. – Prevalence -16 per 100,000 population. – Recurrent episodes of sudden onset ,painless, isolated mononeuropathies – Provoked by compression, slight traction, or other minor trauma. – Nerve inv.-Order of decreasing freq- PUB RuM. – Painless brachial plexopathy -1/3 pt.
HNPP… – Less-common presentations 1. transient positionally induced sensory symptoms, 2. progressive mononeuropathy, 3. chronic sensory polyneuropathy, 4. CMT phenotype with pes cavus 5. diffuse chronic sensorimotor neuropathy resembling CIDP (Mouton et al., 1999).
HNPP… – NCV in pt. with PMP22 deletion -prolonged DL and mild slowing in forearm segments of median and ulnar nerves. – Focal slowing and conduction blocks at compr. sites, and diffuse reduction of SNAP amplitudes – The median forearm motor NCV >38 m/sec – Sensory studies demonstrate velocities in the demyelinating range and reduced or absent SNAPs. – Asymptomatic carriers- Prolonged median DL and abnormal sensory conduction . (Dubourg et al., 2000; Mouton et al., 1999, Infante et al., 2001).
HNPP… – Sural nerve bx- focal sausagelike thickenings of myelin termed tomacula . – Segmental demyelination, and axonal loss. – Deletion of pmp22 gene chromo. 17p11.2-12 (duplicated region in CMT1A) in 85% . – Other mutations in PMP22 - frameshift or nonsense mutations (lenssen et al., 1998; van de wetering et al., 2002).
HNPP… – Exactly how the deletion of PMP22 causes HNPP remains unclear. – Molecular diagnosis has replaced nerve biopsy. – Testing should be considered - painless multiple mononeuropathies, brachial plexopathy, or recurrent demyelinating neuropathy, regardless of family history (Tyson et al., 1996). – The primary treatment strategy is to prevent nerve injury by avoiding pressure damage.
Hereditary Neuralgic Amyotrophy – AD – Recurrent brachial plexopathy, often preceded by severe ipsilateral limb pain-hallmark . – Recovery over weeks to a few months, with accumulating evidence of residual neurologic deficit over time. – Dysmorphic features- hypotelorism, epicanthal folds, microstomia, and dysmorphic ears. – Chromo. 17q25 - SEPT9 gene (Kuhlenbäumer et al., 2005).
Practical Molecular Diagnostic Testing for Patients with CMT and Related Disorders – Samples of peripheral blood . – Avoid the “battery” of available genetic tests. – Population studies confirmed that CMT1A (PMP22 duplication or PMP22 deletion), CMT1X (Cx32 mutation), CMT1B (MPZ mutation), and CMT2A (MFN2 mutation) account for about 65%–70% of all CMT cases (Bassam, 2014; Boerkoel et al., 2002).
1. ≥2 generations 2. male-to –male transmi. 3. <38 m/sec CMT1A. PMP22 duplication PMP22 sequencing Normal If normal MPZ DNA sequencing to excluded CMT1B
– CMT1A should be considered even in the absence of a positive family history. – Childhood severe demyelinating neuropathy - DSS/congenital hypomyelination -the PMP22 dupli.Test f/b DNA sequencing of PMP22, MPZ, EGR2, and periaxin. – Severe reactions to vincristine and other chemotherapeutic neurotoxic drugs in CMT1A –best to rule out . No PMP22 duplication No male-to-male transmission Screen for CMTX -Cx32 muta. Axonal pattern MFN2 muta. –MC CMT2 (England et al., 2009).
Treatment and Management – CMT1 and CMT2 are slowly progressive, disability occurs relatively late, and lifespan may be normal. – Mx- symptomatic. – Proper foot care and advised to wear broad, well-fitting shoes, insole. – Ankle-foot braces or orthopedic procedures -footdrop. – Warned to avoid neurotoxic drugs. – CMT may worsen during pregnancy -associated with higher risk for complication during delivery (Hoff et al., 2005).
Treatment and Management… – Still no effective treatment . – Rat model with PMP 22-progesterone antagonists for CMT1A-potentially unacceptable side effects prevented such trials. – Ascorbic acid 1 or 3 g/day -no signi. benefit at 12 months (Micallef et al., 2009). – Possibly beneficial role of neurotrophin 3 (NT3), in CMT1A -in a small pilot study (sahenk et al., 2005). – Some CMT2 pt. with MPZ muta. may respond to steroids (Donaghy et al., 2000).
Thank you
References – Bradley’s ;Neurology in clinical practice;7th edition. – Inherited Neuropathies: Clinical Overview And Update Christopher J. Klein, MD et al; Muscle Nerve. 2013 October ; 48(4): 604–622. doi:10.1002/mus.23775. – CharcotMarieTooth and Other Hereditary Motor and Sensory Neuropathies Clinical Presentation; Timothy C Parsons, MD et al ;Updated: Apr 12, 2017 . – Overview of hereditary neuropathies UpToDate; ;Peter B Kang, MD, FAAP, FAAN. et ;last updated: Mar 23, 2016.

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Hereditary neuropathies

  • 1.
    Hereditary Neuropathies Dr. Sunil Kr.Sharma Senior Resident Dept. of Neurology GMC Kota
  • 2.
    Introduction – Inherited neuropathiesare diverse in both genetic causes and clinical phenotypes. – They are frequently underdiagnosed or misdiagnosed. – Family history –most imp. but difficult to obtain.
  • 3.
    Introduction – ≈ 40%of chr. polyneuropathies, – ≈50% of previously unidentified PN. – Inherited nature may go unrecognized in a large percentage of patients (Klein, 2007).
  • 4.
    – Insidious onsetand indolent course over years to decades. – Classification depends on the clinical phenotype, mode of inheritance, and class of neurons predominantly affected. (Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
  • 5.
    – Major advances-molecular basis of inherited neuropathies. – Gene defect coding for a specific gene product essential to myelin or axonal function (Bassam, 2014; Berger et al., 2002; Kamholz et al., 2000; Lupski, 1998; Scherer, 2006).
  • 6.
    Clues to diagnosis –Long-standing neuromuscular symptoms – Detailed family histories – Skeletal abnormalities such as hammer toes, High arches, or scoliosis – Neurological evaluations in relatives
  • 7.
    – Negative F/Hcannot rule out an inherited neuropathy. e.g. 1. Early death of one or both parents 2. Few blood relatives 3. AR dis. – About 1/3 - de novo gene mutations (Boerkoel et al., 2002).
  • 8.
    Acquired vs. Inherited –Often difficult, especially in the absence of +ve history. – An acquired etiology may compound an inherited neurologic defect. – Rapid or accelerated neurologic declines - suggest superimposed acquired etiologies.
  • 9.
    Acquired vs. Inherited –More susceptible to injury from metabolic, toxic, and other nervous system insults e.g. CTx. – Major deficits with limited toxic or metabolic exposure. – HN frequently misdiagnosed as diabetic neuropathy(less likely in the absence of retinopathy or nephropathy). Chaudhry V, Chaudhry M, Crawford TO, Simmons-O’Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003; 60:337–340. [PubMed: 12552058] Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993; 43:817–824. [PubMed: 8469345]
  • 10.
    Historical and Examination Cluesof Inherited Neuro-pathy History- – Frequent childhood ankle sprains and toe- catching falls – Slowest child in foot races – Recurrent acral calluses, and ulcers in sensory predominant forms.
  • 11.
    Physical examination – Footdrop – High arches and hammer toes – Inverted champagne bottle appearance of the legs – Recurrent painless foot ulcers – Thickened nerves in hypertrophic demyelinating varieties – Refractory response to the treatment of acquired disease – Major sensory loss without positive sensory symptoms (e.G., Paresthesia, burning, or lancinating pain).
  • 12.
    Neurophysiology – Temporal dispersionand conduction blocks are often absent Exceptions -CX32 mutations, temporal dispersion can occur. – NCV <38 m/s -demyelinating, – NCV =38– 45 m/s-intermediate. – NCV >45 m/s -primary axonal process Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982; 32:592–596. [PubMed: 6283420] Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, et al. Unusual electrophysiological findings in X-linked dominant Charcot–Marie–Tooth disease. Muscle Nerve. 2000; 23:182–188. [PubMed: 10639608]
  • 13.
    – Inheritence maybe AD,AR and X linked. – Can be divided into 3 groups: (1) Isolated neuropathy involving PNS exclusively (2) Multisystem neuropathy involving both CNS and PNS (3) Neuropathy with multiorgan involvement affecting nonneurologic organs such as skin, kidney, heart, and liver
  • 14.
    Neuropathy with isolated nerveinvolvement – Hereditary motor and sensory neuropathy (HMSN, or Charcot– Marie–Tooth) – Hereditary sensory and autonomic neuropathy (HSAN) – Hereditary sensory neuropathy (HSN)
  • 15.
    Neuropathy with isolated nerveinvolvement… – Distal hereditary motor neuropathy (dHMN) – Hereditary brachial plexus neuropathy (HBPN) – Hereditary neuropathy with liability to pressure palsies (HNPP)
  • 16.
    Neuropathy with brainand/or spinal cord involvements – Spinocerebellar atrophy (SCA) – Friedreich ataxia (FA) – Hereditary spastic paraplegia neuropathy (i.e., complicated HSP, HMSN 5)
  • 17.
    Neuropathy with non- neurologicorgan involvement – Familial amyloid (transthyretin, gelsolin, ApoA1) – Leukodystrophy – Peroxisomal – Lipoprotein deficiency – Porphyrias – Defective DNA maintenance – Mitochondrial defects
  • 18.
    Miscellaneous – Giant axonalneuropathy – Neurofibromatosis type 1 – Neurofibromatosis type 2 – Others
  • 19.
  • 20.
    Charcot–Marie–Tooth Disease (Hereditary Motor andSensory Neuropathy) – First described in 1886 by Charcot and Marie in Paris and Tooth in London (Charcot and Marie, 1886; Tooth, 1886). – Most common inherited neuropathy – Prevalence of 10 to 41 per 100,000 (Martyn and Hughes, 1997).
  • 21.
    – two maingroups: 1. CMT1 [HMSN-I]- chara. By motor NCVs (<38 m/sec in forearm) and nerve biopsy findings of demyelination and onion bulb formation 2. CMT2 [HMSN-II]- chara. By - normal or near normal motor NCVs , and nerve biopsy reveals axonal loss without prominent demyelination (Harding, 1995).
  • 22.
    – Hereditary distalspinal muscular atrophy- The peroneal muscular atrophy phenotype without sensory involvement on either clinical or electrophysiological examination . – Dejerine-Sottas disease (or syndrome, DSS) – A severe form of demyelinating neuropathy with onset occurring in early childhood .
  • 23.
    – CMT1 andthe vast majority of subtypes of CMT2 display autosomal dominant inheritance. – A minority of cases occur sporadically or in siblings only -attributed to AR inheritance or to de novo gene mutations.
  • 24.
    – CMT maybe classified by- 1. Mode of inheritance (AD, X linked and rarely AR) 2. Chromosomal locus 3. Causative genes
  • 28.
    A, CMT 1,HNPP,CMTX,DSS,CMT4-inherited disorders of myelin. CMT2 is a primary axonal disorder. B, Point mutations of these genes (connexin-32 [Cx32], myelin protein zero [MPZ, P0], PMP22, EGR2, periaxin) result in CMTX, CMT1B, CMT1A, DSS, and CMT4. Mutations of the LITAF gene result in CMT1C. C, Point mutations of the KIF1B and NFL genes and specific MPZ missense mutations result in CMT2.
  • 29.
    Charcot–Marie–Tooth Disease Type 1 –Onset- first or second decade . – Chara. By slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs. – Symmetrical weakness and wasting in the intrinsic foot, peroneal, and anterior tibial muscles.
  • 30.
    CMT-1 – In 2/3rd Pt., the UL are involved later in life. – Foot deformities 1. Pes cavus and hammer toes ≈3/4 of adult pt. 2. Mild kyphosis ≈ 10% 3. Palpably enlarged hypertrophic peripheral nerves ≈ 1/4
  • 31.
    CMT-1… – Absent anklereflexes are universal - frequently a/w absent or reduced knee and UL reflexes. – Some degree of distal sensory impairment (↓ vibration and light touch) – Rarely - positive sensory symptoms. – Occasionally, a/w essential or postural upper-limb tremor-referred to as roussy-lévy syndrome-not a separate clinical or genetic entity
  • 32.
    CMT-1… – Severity variesconsiderably. – ≈10% Pt. with slowed NCVs -asymptomatic. – May exacerbate during pregnancy-temporary in ≈ 1/3rd of pt. , becomes progressive in the remainder.
  • 33.
    CMT-1… – Slow deteriorationin strength and decline in axonal function continues throughout adulthood (Verhamme et al., 2009). – Motor nerve conduction studies show uniform slowing to less than 75% of the lower limits of normal in all nerves
  • 34.
    CMT-1… – Motor conductionof upper-limb nerves proves more useful than studies of lower-extremity nerves because distal denervation in the feet is often severe and virtually complete. – A motor NCV <38 m/sec in the forearm segment of the median nerve -as a cutoff value to distinguish between CMT1 and CMT2. – SNAPs are usually absent with surface recordings – Uniform conduction slowing
  • 35.
    CMT-1… – Neurological deficitscorrelate with reductions in CMAP and SNAP amplitudes rather than conduction velocity. – Uniform conduction slowing 1. CMT1A with PMP22 dupli. or pm. 2. CMT1B with MPZ pm 3. DSS, including PMP22, MPZ, and EGR2 gene mutations 4. Metachromatic leukodystrophy 5. Cockayne disease (Lewis et al., 2000).
  • 36.
    CMT-1… – Routine hematologicaland biochemical studies and CSF are normal(D/W CIDP) – Sural nerve biopsy-onion bulb formation. A, Semi-thin transverse section of sural nerve showing numerous onion bulbs. (Toluidine blue; bar = 20 μm.) B, Electron micrograph of an onion bulb formation; two small myelinated fibers are surrounded by multiple layers of Schwann cell processes.
  • 37.
    CMT-1… – Gene mutations-accountfor about 3/4th CMT1 . – CMT1A is the most common CMT subtype-70%– 80% of CMT1 cases and more than 50% of all CMT cases. – The disease is caused by duplication in the 17p11.2-12 -PMP22,rarely by PMP22 point mutation.
  • 38.
    CMT-1… – PMP22 -membraneglycoprotein of myelin sheath. – Deletion of the same 1.5-Mb region on chromosome 17p11.2 results in a single copy of the normal PMP22 gene-observed in 85% of patients with HNPP – CMT1B is clinically indistinguishable from CMT1A accounts- for 10–20% of all CMT cases.
  • 39.
    CMT-1… – CMT-1B-mutations(pm) inMPZ gene- 1q22-23. MPZ – 1. major peripheral myelin glycoprotein 2. adhesion molecule 3. member of the immunoglobulin superfamilywith extracellular, transmembrane and intracellular domains. – Mutations in MPZ -also a/w DSS, and congenital hypomyelination neuropathy.
  • 40.
    CMT-1… – Different MPZmutations - uncompacting of myelin or focal myelin foldings (Gabreëls-Festen et al., 1996). – Motor conduction block -rarely in CMT1B (Street et al., 2002). – Specific MPZ missense mutations in CMT2 phenotype- only mild slowing of NCVs (Marrosu et al., 1998).
  • 41.
    CMT-1… – CMT1C -mutationin lipopolysaccharide-induced TNF-alpha (LITAF/SIMPLE) gene, chr.16p13-12 . – Encodes a lysosomal protein - protein degradation pathways (Street et al., 2003). – CMT1C used to be reserved for autosomal dominant CMT1 families not linked to either CMT1A or CMT1B – Manifest characteristic CMT1 symptoms.
  • 42.
    CMT-1… – CMT1D -mutationof the early growth response 2 gene (EGR2) -chro. 10q21-q22 . – Regulates the expression of myelin proteins including PMP22, P0, Cx32, and periaxin (Kamholz et al., 2000). – Respiratory compromise and cranial nerve dysfunction a/w EGR2 mutations. – Other rare CMT1 subtypes include CMT1E and CMT1F Szigeti et al., 2007.
  • 43.
    Charcot–Marie–Tooth Disease Type 2 –CMT2-1/3rd of all AD CMT disease. – A/W mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation. – Onset later than in CMT1, MC 2nd decade,-may be delayed until middle age or beyond.
  • 44.
    CMT-2 – Foot andspinal deformities -less prominent than in CMT1. – Peripheral nerves are not enlarged – Upper limb involvement, tremor, and general areflexia - less frequent. – 20% -asymptomatic.
  • 45.
    CMT-2 – CMT2A -MCof CMT2 cases- 30%. – CMT2A1-chro. 1p35, -mutation in kinesin protein involved in axonal transport of synaptic vesicles (Saito et al., 1997; Zhao et al., 2001). – CMT2A2- most CMT2 families, similar to CMT2A1 but has an earlier onset and is more severe. – May be a/w optic atrophy.
  • 46.
    CMT-2… – Mutations inthe mitofusin 2 (MFN2) gene-chro. 1p36-p35. – MFN2 -mitochondrial fusion protein ubiquitously expressed in many tissues including PN. – CMT2B-chro. 3q13-22- RAB7 gene - prominent sensory loss with foot ulcerations. – Clinically very similar to HSN1 but lacks spontaneous lancinating pain
  • 47.
    CMT-2… – CMT2C –chromo.12q24-vocalcord, intercostal, and diaphragmatic muscle weakness (Klein et al., 2003). – Life expectancy -shortened. – CMT2D- chromo . 7p14, is chara. by weakness and atrophy - more severe in the hands than in the feet (Ionasescu et al., 1996b). (De Jonghe et al., 1997 & Verhoeven et al., 2003).
  • 48.
    CMT-2… – CMT2E- typicalCMT2 phenotype with slowed motor nerve conduction that is < 38 m/sec – More severe clinical phenotype. – Mutations in genes that encode neurofilament light (NEFL) subunit. – May have axonal swelling (giant axons) and signi. sec. demyelination on sural nerve biopsies (Fabrizi et al., 2006; Jordanova et al., 2003)
  • 49.
    CMT-2… – CMT2F- heatshock protein 27 (Hsp27)- unstable neurofilament network . – Chara. by later onset (35–60 years), mild sensory impairment, and moderate to severely slowed NCVs of lower limbs but normal or mildly reduced velocities in the upper limbs. – CMT2G- Spanish family chromo. 12q12-q13.3, with the age onset from 9 to 76 years.
  • 50.
    CMT-2… – CMT2J- alsodesignated as CMT2 with MPZ (myelin protein zero) gene mutation, is associated with pupillary abnormalities (Adie pupil) and hearing loss. – CMT2L -HSPB8 gene muta. with typical features of the CMT2 phenotype.
  • 51.
    CMT-2… – Motor NCVmay be normal or mildly reduced. – SNAPs - either absent or reduced in amplitude. – Sural nerve biopsy -preferential loss of large myelinated fibers, without signi. demyelination. – There may be clusters of regenerating myelinated fibers, a hallmark of axonal regeneration.
  • 52.
    X-Linked Charcot–Marie– Tooth Disease –Phenotypically similar to CMT1. – male -more severely affected, and females -mild neuropathy or be asymptomatic. – No male-to-male transmission occurs. – 7% to 16% of all forms of CMT-second most common form of CMT (following CMT1A).
  • 53.
    CMTX… – Mutations inGJB1-connexin 32 (Cx32) - channel-forming proteins - gap junction protein found in - Schwann cell cytoplasm chromo. Xq. – Most missense mutations -mild clinical phenotype – Nonsense and frameshift muta.- more severe phenotypes (Ionasescu et al., 1996a). – Some mutations of Cx32 - CNS involvement with white-matter MRI and MR spectroscopy abnormalities, abnormal BAER, and deafness (Murru et al., 2006).
  • 54.
    CMTX… – Significant slowingin NCV in male – BAER responses are often abnormal. – Nerve biopsy - both axonal loss and demyelination. – NCV- near normal to intermediate slowing in the 30- to 40-m/sec range. – CMTX - primary axonal or demyelinating disorder- debated (Birouk et al., 1998).
  • 55.
    CMTX… – Nonuniform conductionslowing consistent with demyelination (Gutierrez et al., 2000; Lewis, 2000). – NC slowing paralleling the loss of CMAP amplitude. – No male-to-male transmission, the presence of intermediate conduction velocities (>42 m/sec) in female carriers and delayed brainstem auditory evoked response latencies in affected men is highly suggestive of Cx32 mutations (Nicholson et al., 1998).
  • 56.
    Charcot–Marie–Tooth Disease Type 3,or Dejerine-Sottas Disease – Uncommon progressive hypertrophic neuropathy with onset in childhood. – Motor development is delayed; proximal weakness, global areflexia, enlarged peripheral nerves, and severe disability are the rule. – Originally thought to be AR, most cases are sporadic and in some AD. – Motor conduction velocities are severely slowed, often to less than 10 m/sec.
  • 57.
    CMT-3… – Temporal dispersionand amplitude reduction on proximal stimulation may be found in such cases. – CSF protein ↑. – Defective myelination is confirmed by an increased axon-to-fiber diameter ratio. – Cases of congenital hypomyelination neuropathy probably represent a variant of CMT3. – DSS is genetically heterogeneous .
  • 58.
    Charcot–Marie–Tooth Disease Type 4 –AR ,<10% of all CMT cases. – Onset in early childhood and progressive weakness leading to inability to walk in adolescence. – Both demyelinating and axonal types have been identified (Dubourg et al., 2006). – Disturbance in normal myelination of the axons. – Clinical and electrophysiological features are similar iwith CMT3. – Conduction velocities are slowed (20–30 m/sec).
  • 59.
    – CSF proteinN. – Nerve Bx -loss of myelinated fibers, hypomyelination, and onion bulbs. – Sev. subgroups: CMT4A, CMT4B1 and 2, CMT4C, CMT4D, CMT4E, CMT4F, and CMT4H.
  • 60.
    Complex Forms ofCharcot– Marie-Tooth Disease – AD -features intermediate between CMT1 and CMT2, with conduction velocities between 38 m/sec and normal. – classified separately as dominant intermediate CMT (DI-CMT) and include types A, B, C, and D. – DI-CMTA -Chromo. 10q24-25, -gene defect -not discovered. – DI-CMTB -dynamin 2 (DNM2) gene ,chromo. 19p12-13.
  • 61.
    Complex Forms ofCharcot– Marie-Tooth Disease – Mild to moderately severe CMT phenotype. – May have neutropenia and early cataracts (Claeys et al., 2009). – DI-CMT- tyrosyl-tRNA synthetase gene chromo. 1p34-35 – Mild, very slowly progressive course (Jordanova et al., 2006). – DI-CMTD maps to chromosome 1q22 MPZ gene mutations.
  • 62.
    Hereditary Neuropathy with Liabilityto Pressure Palsies – AD-chara. by increased susceptibility to mechanical traction or compression. – 2nd -3rd decade. – Prevalence -16 per 100,000 population. – Recurrent episodes of sudden onset ,painless, isolated mononeuropathies – Provoked by compression, slight traction, or other minor trauma. – Nerve inv.-Order of decreasing freq- PUB RuM. – Painless brachial plexopathy -1/3 pt.
  • 63.
    HNPP… – Less-common presentations 1.transient positionally induced sensory symptoms, 2. progressive mononeuropathy, 3. chronic sensory polyneuropathy, 4. CMT phenotype with pes cavus 5. diffuse chronic sensorimotor neuropathy resembling CIDP (Mouton et al., 1999).
  • 64.
    HNPP… – NCV inpt. with PMP22 deletion -prolonged DL and mild slowing in forearm segments of median and ulnar nerves. – Focal slowing and conduction blocks at compr. sites, and diffuse reduction of SNAP amplitudes – The median forearm motor NCV >38 m/sec – Sensory studies demonstrate velocities in the demyelinating range and reduced or absent SNAPs. – Asymptomatic carriers- Prolonged median DL and abnormal sensory conduction . (Dubourg et al., 2000; Mouton et al., 1999, Infante et al., 2001).
  • 65.
    HNPP… – Sural nervebx- focal sausagelike thickenings of myelin termed tomacula . – Segmental demyelination, and axonal loss. – Deletion of pmp22 gene chromo. 17p11.2-12 (duplicated region in CMT1A) in 85% . – Other mutations in PMP22 - frameshift or nonsense mutations (lenssen et al., 1998; van de wetering et al., 2002).
  • 66.
    HNPP… – Exactly howthe deletion of PMP22 causes HNPP remains unclear. – Molecular diagnosis has replaced nerve biopsy. – Testing should be considered - painless multiple mononeuropathies, brachial plexopathy, or recurrent demyelinating neuropathy, regardless of family history (Tyson et al., 1996). – The primary treatment strategy is to prevent nerve injury by avoiding pressure damage.
  • 67.
    Hereditary Neuralgic Amyotrophy – AD –Recurrent brachial plexopathy, often preceded by severe ipsilateral limb pain-hallmark . – Recovery over weeks to a few months, with accumulating evidence of residual neurologic deficit over time. – Dysmorphic features- hypotelorism, epicanthal folds, microstomia, and dysmorphic ears. – Chromo. 17q25 - SEPT9 gene (Kuhlenbäumer et al., 2005).
  • 68.
    Practical Molecular Diagnostic Testingfor Patients with CMT and Related Disorders – Samples of peripheral blood . – Avoid the “battery” of available genetic tests. – Population studies confirmed that CMT1A (PMP22 duplication or PMP22 deletion), CMT1X (Cx32 mutation), CMT1B (MPZ mutation), and CMT2A (MFN2 mutation) account for about 65%–70% of all CMT cases (Bassam, 2014; Boerkoel et al., 2002).
  • 69.
    1. ≥2 generations 2.male-to –male transmi. 3. <38 m/sec CMT1A. PMP22 duplication PMP22 sequencing Normal If normal MPZ DNA sequencing to excluded CMT1B
  • 70.
    – CMT1A shouldbe considered even in the absence of a positive family history. – Childhood severe demyelinating neuropathy - DSS/congenital hypomyelination -the PMP22 dupli.Test f/b DNA sequencing of PMP22, MPZ, EGR2, and periaxin. – Severe reactions to vincristine and other chemotherapeutic neurotoxic drugs in CMT1A –best to rule out . No PMP22 duplication No male-to-male transmission Screen for CMTX -Cx32 muta. Axonal pattern MFN2 muta. –MC CMT2 (England et al., 2009).
  • 71.
    Treatment and Management – CMT1and CMT2 are slowly progressive, disability occurs relatively late, and lifespan may be normal. – Mx- symptomatic. – Proper foot care and advised to wear broad, well-fitting shoes, insole. – Ankle-foot braces or orthopedic procedures -footdrop. – Warned to avoid neurotoxic drugs. – CMT may worsen during pregnancy -associated with higher risk for complication during delivery (Hoff et al., 2005).
  • 72.
    Treatment and Management… – Stillno effective treatment . – Rat model with PMP 22-progesterone antagonists for CMT1A-potentially unacceptable side effects prevented such trials. – Ascorbic acid 1 or 3 g/day -no signi. benefit at 12 months (Micallef et al., 2009). – Possibly beneficial role of neurotrophin 3 (NT3), in CMT1A -in a small pilot study (sahenk et al., 2005). – Some CMT2 pt. with MPZ muta. may respond to steroids (Donaghy et al., 2000).
  • 73.
  • 74.
    References – Bradley’s ;Neurologyin clinical practice;7th edition. – Inherited Neuropathies: Clinical Overview And Update Christopher J. Klein, MD et al; Muscle Nerve. 2013 October ; 48(4): 604–622. doi:10.1002/mus.23775. – CharcotMarieTooth and Other Hereditary Motor and Sensory Neuropathies Clinical Presentation; Timothy C Parsons, MD et al ;Updated: Apr 12, 2017 . – Overview of hereditary neuropathies UpToDate; ;Peter B Kang, MD, FAAP, FAAN. et ;last updated: Mar 23, 2016.