HEREDITARY MOTOR AND SENSORY NEUROPATHIES

1. HEREDITARY MOTOR ANDSENSORY NEUROPATHIES Alireza Ashraf, M.D. Associate Professor of Physical Medicine & Rehabilitation Shiraz Medical school

2. CHARCOT-MARIE-TOOTH DISEASE ANDRELATED DISORDERS • The various categories of CMT are subclassified according to the nature of the pathology (demyelinating or axonal), mode of inheritance (AD,AR or X-linked), age of onset and the specific mutated gene. • CMT1 - AD - demyelinating motor and sensory neuropathies.

3. CMT2 -AD - axonal motor and sensory neuropathies. • In contrast to CMT1 and CMT2, which begin in childhood or early adult life, CMT3begins in infancy and is associated with severe demyelination/hypomyelination.

4. Charcot-Marie-Tooth Disease Type I • CMT1 :The most common . • The ratio of CMT1 to CMT2 is approximately 2:1. • CMT1 usually manifests in the first to third decades, • Most patients have pes cavus or equinovarus, hammertoes and exuberant callous formation, which lead to foot pain.

5. The distal leg weakness leads to a compensatory gait, which places undue stress on the lumbosacral region. Thus, some patients are initially evaluated for back pain………………….

6. Charcot-Marie-Tooth Disease Type I • Recurrent ankle sprains. • Some patients note frequent stubbing of toes during ambulation. patients typically do not complain about significant sensation loss in the distal regions of the feet or hands. • there is an absence of paresthesias or other "positive" phenomena, which can be helpful in distinguishing CMT from acquired forms of neuropathy. • some patients complain of severe cramps.

8. Charcot-Marie-Tooth Disease Type I • Physical examination reveals considerable muscle atrophy and weakness in the distal compared to proximal limb regions. • As an alternative name to this disorder implies, "peroneal muscular atrophy," • Rare patients have asymmetric pseudohypertrophy of the calves. • This distal muscle atrophy resulted in the original describers of the disease to compare the patients' legs to “inverted champagne bottle legs."

9. Intrinsic foot muscle wasting is also prominent. • Weakness of the anterior compartment muscles of the distal lower limbs causes footdrop. • steppage gait :excessive degree of hip and knee flexion . • Symmetric distal atrophy and weakness of the upper limbs is also evident in two-thirds of patients.

10. Severe claw deformities of the hand intrinsics can be seen in some individuals. • Despite the lack of sensory symptoms, diminished sensation to all modalities is apparent on examination. • Sensory loss is more apparent in the lower limbs than the upper limbs.

11. DTRs are usually markedly depressed or absent at the ankles and progressively diminish over the course of years in the more proximal lower limb regions and then upper limbs.

12. Careful inspection of the peripheral nerves, especially posterior to the ear and arm regions, may demonstrate neural hypertrophy and firmness compared to normal in about 25% of patients . • Importantly, rare patients have developed compression of the spinal cord and cauda equina due to marked hypertrophy of nerve roots.

13. Approximately one-third of patients with CMT1 have an essential tremor. • These patients were previously referred to as having Roussy-Levy syndrome. • However, this term has become outdated as advances in the molecular genetics have demonstrated that such tremors can be seen in all subtypes of CMT1 as well as some patients with CMT2.

14. Histopathology • The gross appearance of the peripheral nerve reveals an overall increase in the fascicle size leading to the so-called "hypertrophic neuropathy" designation. • There is a predilection for the loss of the relatively larger diameter fibers. • In addition, there is a decrease in axon caliber and an increase in the density of neurofilaments within these "atrophic" axons. • Schwann cell proliferation due to repeated bouts of demyelination and remyelination results in the formation of so-called onion bulbs.

15. Demyelination, neuronal loss, and axonalatrophy are slightly more prominent distally. • The mean internode length is reduced compared to normal. • The spinal cord is also affected with loss of myelinated libers in the fasciculus gracilis as noted at the cervical levels.

16. Patients with CMT1 may be born with normal or only minimally slowed nerve conduction velocities. • These velocities rapidly decline such that by the time the child is 3-5 years of age, a maximal reduction is achieved that changes little over the course of the patient's life. • The CMAP amplitudes also continue to diminish over time, indicative of axon loss.

17. Distal motor latencies at birth are commonly borderline abnormal. • These latencies continue to increase until approximately the age of 10 years, at which time there is little further prolongation of the distal latencies. .

18. Sensory Conduction Studies • The sensory nerve conduction studies in both the upper and lower limbs are usually markedly abnormal in most patients with CMT1. • SNAPs are unobtainable or very low in amplitude. • In addition, the distal latencies of obtainable responses are markedly prolonged and nerve conduction velocities are commonly less than 60% of normal.

19. Motor Nerve Conduction Studies • The CMAPs may be absent when recordings are attempted from severe wasted extensor digitorum brevis (EDB)and abductor hallucis (AH) muscles. • It may be necessary to perform motor conduction studies in the lower limb by recording from the tibialis anterior muscle. • When responses can be detected from either the EDB or AH, the CMAP amplitudes are frequently reduced.

20. CMAP amplitudes are only slightly decreased early in the disease course in the upper limbs. • Distal motor latencies are considerably prolonged in both the upper and lower limbs. • When stimulating at distal and proximal sites, there is no evidence of conduction block or temporal dispersion. • The most dramatic finding is a greater than 60% reduction in nerve conduction velocity compared to expected normal values.

21. Values in the 25 m/s range are characteristic for patients with CMT I A. • Patients with point mutations in PMP-22 gene have even slower conduction velocities approaching that seen in CMT3 (10 m/s or less).

22. There is little correlation between the patients clinical symptoms and the degree to which nerve conductions are affected. • NCVs can be quite profoundly affected during early childhood, when there is little in the way of clinical deficits… • It appears that weakness is more related to the degree of axon loss, rather than the extent of demyelination and slowing of nerve conduction………………..

23. As noted above, patients with CMT1 do not usually demonstrate conduction block or temporal dispersion. • This contrasts with the presence of conduction block or temporal dispersion in patients with acquired forms of demyelinating neuropathy (e.g., Guillain-Barre svndrome and chronic inflammatory demyelinating neuropathy).

24. A nerve commonly forgotten is the phrenic nerve. • Patients with CMTI can have significantly prolonged phrenic CMAP latencies.“ • CMTI patients can have reduced pulmonary function secondary to diaphragmatic and intercostal muscle weakness due to denervation.

25. F-waves latencies are usually absent but when obtainable are extremely prolonged. • Of note, when calculating, proximal conduction velocities using F-waves, the obtained values are almost but not quite as slowed as the distal limb values. • Slowing of facial nerve conduction is commonly found in CMTI. • This is reflected as a significant prolongation in the facial nerve's motor latency often approaching 14 ms (normal < 4.0 MS).

26. The blink reflex can also be markedly abnormal in that the R1 response may be as long as 26 ms (normal < 13 ms). • A reduction in the R1 to facial nerve latency ratio (R/D ratio) can be found in most patients indicating that the facial nerve (motor) latency is prolonged out of proportion to the trigeminal (sensory) latency. • Alternatively, the motor nerves may be slightly more severely affected than sensory nerves in regards to conduction velocities.

27. Somatosensory evoked These evoked potential studies have demonstrated slowing of spinal and cortical conducting pathways when central conduction times are calculated. • The slowing is less dramatic than that seen peripherally • Visual evoked potentials also reveal similar slowing of the optic pathways.

28. Needle electromyography If the CMAP is absent. e.g.. in the EDB or AH, one can anticipate a significant reduction or even absence of insertional activity. • Some patients may reveal evidence of very small amplitude (50 ЧV or less) sustained positive sharp waves and fibrillation potentials despite little activity during, needle insertion. • If these patients are followed over time, eventually complete electrical silence can be noted in these muscles.

29. The documentation of Psw and Fib potentials is quite common in the distal muscles of both the upper and lower limbs in CMT1. • Occasionally, other forms of spontaneous electrical activity can be seen, such as complex repetitive discharges and fasciculation potentials. • The tibialis anterior muscle is perhaps the best muscle to demonstrate spontaneous activity, even in patients with advanced disease.

30. The MUAPs fire at high rates and in reduced numbers (reduced recruitment). • The MUAPs are typically of long duration, high amplitude, and polyphasic.

31. The lack of appreciable peripheral sprouting in sensory nerves often results in a complete absence of SNAPs. • In motor nerves, the larger size of the recorded potential combined with the motor nerve's ability to peripherally sprout and reinnervate denervated muscle fibers staves off a complete absence of CMAPs for a longer period compared to the SNAPs. • Macro-EMGstudies reveal extensive collateral reinnvervation in CMT1 compared to CMT2.

32. Charcot-Marie-Tooth Disease Type 2 (CMT2) CMT2 refers to the autosomal dominantneuronal" hereditary motor and sensory neuropathies. • CMT2A and CMT2B (CMT2A/B) are the most common subtypes of CMT2 and are discussed together. • The clinical features of CMT2A/B are rather similar to CMT1 with several important exceptions. • The peak age of symptom onset in CMT2A/B is usually in the second decade with some patients becoming symptomatic only in their seventh decade.

33. Also, there is a distinct absence of enlarged nerves in CMT2, • Patients with CMT2A/B tend to have less severe involvement of the intrinsic hand muscles and tremor is not as common as seen in CMT1. • There is more significant atrophy of the distal lower limbs and weakness of the posterior tibial and calf muscles (in addition to atrophy and weakness of the anterior lateral compartment muscles) in CMT2A/B corripared to CMT1. • Complete lack of deep tendon reflexes is found in only a small percentage of patients with CMT2A/B, while it is common inCMT 1

34. Ankle reflexes are usually absent in both types of disease. • About 50-70% of patients with CMT1 have significant reductions in light touch, pain, joint position and vibration sense, while approximately 20-50% of patients with CMT2A/B have similar findings. • Severe mutilating neuropathic ulcerations similar to those typically seen in hereditary sensory and autonomic neuropathy type I (HSAN 1) have been demonstrated in some patients with CMT2B.‘

35. Pes cavus and hammer toe deformities are less common in CMT2A1B than in CMT1………………….. CMT2A/B needs to be distinguished from chronic idiopathic axonal neuropathy (CIAP). …………………. • Although there is electrophysiologic evidence of motor involvement in CIAP, sensory symptoms dominate the clinical picture…………………………………………. • This contrasts with CMT2A/B, in which motor symptoms and signs are the major features……………..

36. CMT2C • The distinguishing feature of CMT2C is vocal cord paralysis. • The age of onset is variable and symptoms can begin in infancy, manifesting with breathing difficulties and stridor. • More common is the insidious onset of laryngeal weakness causing progressive hoarseness. • The diaphragm and intercostal muscles are often weak leading to reduced respiratory function.

37. CMT2C • Atrophy of the distal limbs is common, and patients can develop proximal and distal weakness of the arms and legs. • There is mild sensory loss to all modalities and deep tendon reflexes are reduced. • Pes cavus can be appreciated in some patients, but such foot deformities are not as common as seen in CMTI, CMT2A, or CMT2B. • Similar cases have been reported as hereditary distal spinal muscular atrophy with vocal cord paralysis.

38. CMT2D • UnIike CMT2A and CMT2B, weakness and atrophy of the hands are more severe than in the distal legs. • Deep tendon reflexes are generally absent in the arms and reduced in the legs. • Pes cavus, hammertoes, and scoliosis are variably present. • Enlarged palpable nerves are not appreciated. • This disorder is allelic to distal spinal muscular atrophy type 5.

39. CMT2 E • Distal sensory loss, hypo- or areflexia, and pes cavus deformities were common. • Some patients exhibited hyperkeratosis of the hands and feet.

40. Sensory nerve conduction studies reveal reduced or absent SNAP amplitudes in both the upper and lower limbs. • Conduction velocities are comparatively well preserved and always greater than 70% of the lower limit of normal. • The distal sensory latencies are either normal or only mildly prolonged.

41. The motor conduction studies demonstrate normal or only mildly reduced nerve conduction velocities (usually in excess of 70% of the lower limit of normal). • The distal motor latencies are normal or only mildly prolonged. • The CMAPs are often preserved in the upper limbs; • however, the peroneal and posterior tibial CMAPs are absent or reduced in size.

42. The MUAPs can be increased in amplitude and duration • The recruitment may be reduced in some persons. • Occasional fasciculation and fibrillation potentials can be observed. • Complex repetitive discharges can also be documented in some patients. • A few patients with CMT2 have been reported to have neuromyotoniain that it is abolished with peripheral neuromuscular blockade.

43. HNPP • Tomaculous neuropathy • Pmp-22 • AD • MEDIAN,ULNAR,RADIAL,PERONEAL&BRACHIAL PLEXUS • DTR(diminished) • HAMMERTOES • PES CAVUS

44. EDX • CONDUCTION BLOCK • TEMPORAL DISPERSION • Fib &Psw • Fasciculation • CRD • Reduced recruitment • Polyphasic • Larg amp &Long duration

45. CMT 3 • Dejerine Sottas • Infancy-early childhood • Congenital hypomyelination neuropathy • Pmp-22 ,EGR-2 • Hypotonia-Respiratory distress-arthrogryposis-Swallowing difficulties-Peripheral nerve enlargement-Ataxia-Hearing loss-Abnormal pupillary reaction-Pes cavus-Kyphoscoliosis • Elevated CSF.

46. EDX • NCVs are 5-10 m/s or less. • Proximal muscles:increased IA,Psw,Fib • Distal muscles:Reduced IA,Little in the way of sustained Fib &Psw • Near the terminal stage of the disease,low-amplitude MUAP with long or short durations may be documented

47. CMT 4A • FIRST 2 YEARS OF LIFE • MILD SENSORY LOSS • SCOLIOSIS

48. CMT 4B • FLOPPY AT BIRTH • DTR:absent • TOMACULAE

49. CMT 4C • Delay in walking until 18-24 months • Deformities in the feet and spine by 5 years of age • Sensory loss • DTR:absent • HYPERTROPHY OF NERVES

50. CMT 4D • HEREDITARY MOTOR AND SENSORY NEUROPATHY WITH DEAFNESS-LOM • (HMSN-L)