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

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

3. CMT2 -AD - axonal motor and sensory neuropathies. CMT2 -AD - axonal motor and sensory neuropathies. In contrast to CMT1 and CMT2, which begin in childhood or early adult life, CMT3 begins in infancy and is associated with severe demyelination/hypomyelination. In contrast to CMT1 and CMT2, which begin in childhood or early adult life, CMT3 begins in infancy and is associated with severe demyelination/hypomyelination.

4. Charcot-Marie-Tooth Disease Type I CMT1 :The most common. CMT1 :The most common. The ratio of CMT1 to CMT2 is approximately 2:1. The ratio of CMT1 to CMT2 is approximately 2:1. CMT1 usually manifests in the first to third decades, 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. 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. Recurrent ankle sprains. Some patients note frequent stubbing of toes during ambulation. 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. 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. 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. 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. 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," As an alternative name to this disorder implies, "peroneal muscular atrophy," Rare patients have asymmetric pseudohypertrophy of the calves. 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." 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. Intrinsic foot muscle wasting is also prominent. Weakness of the anterior compartment muscles of the distal lower limbs causes footdrop. Weakness of the anterior compartment muscles of the distal lower limbs causes footdrop. steppage gait :excessive degree of hip and knee flexion. 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. 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. 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. 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. 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. 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. 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. 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. Approximately one-third of patients with CMT1 have an essential tremor. These patients were previously referred to as having Roussy-Levy syndrome. 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. 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. HistopathologyHistopathology The gross appearance of the peripheral nerve reveals an overall increase in the fascicle size leading to the so-called "hypertrophic neuropathy" designation. 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. 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. 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. 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 axonal atrophy are slightly more prominent distally. Demyelination, neuronal loss, and axonal atrophy are slightly more prominent distally. The mean internode length is reduced compared to normal. 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. 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. 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. 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. The CMAP amplitudes also continue to diminish over time, indicative of axon loss.

17. Distal motor latencies at birth are commonly borderline abnormal. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 ). 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. 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… 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 ……………….. 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. 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). 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. A nerve commonly forgotten is the phrenic nerve. Patients with CMTI can have significantly prolonged phrenic CMAP latencies.“ 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. 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. 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. 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. 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). 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). 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. 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. Alternatively, the motor nerves may be slightly more severely affected than sensory nerves in regards to conduction velocities.

27. Somatosensory evoked Somatosensory evoked These evoked potential studies have demonstrated slowing of spinal and cortical conducting pathways when central conduction times are calculated. 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 The slowing is less dramatic than that seen peripherally Visual evoked potentials also reveal similar slowing of the optic pathways. 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. 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. 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. 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. 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. 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 fire at high rates and in reduced numbers (reduced recruitment). The MUAPs are typically of long duration, high amplitude, and polyphasic. 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. 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. 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-EMG studies reveal extensive collateral reinnvervation in CMT1 compared to CMT2. Macro-EMG studies reveal extensive collateral reinnvervation in CMT1 compared to CMT2.

32. Charcot-Marie-Tooth Disease Type 2 (CMT2) CMT2 refers to the autosomal dominant neuronal" hereditary motor and sensory neuropathies. CMT2 refers to the autosomal dominant neuronal" hereditary motor and sensory neuropathies. CMT2A and CMT2B (CMT2A/B) are the most common subtypes of CMT2 and are discussed together. 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 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. 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, 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. 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. 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 in CMT 1 Complete lack of deep tendon reflexes is found in only a small percentage of patients with CMT2A/B, while it is common in CMT 1

34. Ankle reflexes are usually absent in both types of disease. 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. 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.‘ 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………………….. 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). …………………. 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…………………………………………. 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…………….. 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 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. 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. 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. 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. 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. 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. 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. 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. 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. Deep tendon reflexes are generally absent in the arms and reduced in the legs. Pes cavus, hammertoes, and scoliosis are variably present. Pes cavus, hammertoes, and scoliosis are variably present. Enlarged palpable nerves are not appreciated. Enlarged palpable nerves are not appreciated. This disorder is allelic to distal spinal muscular atrophy type 5. 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. Distal sensory loss, hypo- or areflexia, and pes cavus deformities were common. Some patients exhibited hyperkeratosis of the hands and feet. 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. 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. 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. 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 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 distal motor latencies are normal or only mildly prolonged. The CMAPs are often preserved in the upper limbs; The CMAPs are often preserved in the upper limbs; however, the peroneal and posterior tibial CMAPs are absent or reduced in size. however, the peroneal and posterior tibial CMAPs are absent or reduced in size.

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

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

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

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

46. EDX NCVs are 5-10 m/s or less. NCVs are 5-10 m/s or less. Proximal muscles:increased IA,Psw,Fib Proximal muscles:increased IA,Psw,Fib Distal muscles:Reduced IA,Little in the way of sustained Fib &Psw 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 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 FIRST 2 YEARS OF LIFE MILD SENSORY LOSS MILD SENSORY LOSS SCOLIOSIS SCOLIOSIS

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

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

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

51. CMT 4E PMP-22,,,,EGR- 2…………………………… PMP-22,,,,EGR- 2…………………………… Same as CMT 3…………………………….. Same as CMT 3……………………………..

52. CMT 4F ATAXIA……………………………………… ATAXIA……………………………………… KYPHOSCOLIOSIS……………………….. KYPHOSCOLIOSIS……………………….. PES CAVUS………………………………… PES CAVUS…………………………………

53. LAB CSF protein is reportedly normal in CMT4A and CMT 4C CSF protein is reportedly normal in CMT4A and CMT 4C Elevated in some reported cases of CMT4B Elevated in some reported cases of CMT4B

54. EDX NCVs are markedly in CMT4A,4B &4F NCVs are markedly in CMT4A,4B &4F CMT 4A,4B &4F:less than 20 m/s CMT 4A,4B &4F:less than 20 m/s CMT 4C :24 m/s CMT 4C :24 m/s Fib,Psw,polyphasic &decreased recruitment Fib,Psw,polyphasic &decreased recruitment

55. CMT X Similar to CMT 1 Similar to CMT 1 MEN MEN Foot drop,pes cavus,hammertoes &claw-hand Foot drop,pes cavus,hammertoes &claw-hand DTR:Diminished DTR:Diminished Unlike CMT1,the nerves are not profoundly hypertrophic Unlike CMT1,the nerves are not profoundly hypertrophic

56. EDX SAME AS CMT1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, SAME AS CMT1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, BUT NCVs IN MEN WITH CMTX ARE APPROXIMATELY 10 m/s FASTER THAN THOSE RECORDED IN Pt WITH CMT1………….. BUT NCVs IN MEN WITH CMTX ARE APPROXIMATELY 10 m/s FASTER THAN THOSE RECORDED IN Pt WITH CMT1…………..

57. CMT 2X Axonal motor-sensory neuropathy Axonal motor-sensory neuropathy Deafness Deafness MR MR First few years of life First few years of life

58. HMSN-L AR AR Demyelinating neuropathy Demyelinating neuropathy First decade: gait difficulties due to distal leg weakness First decade: gait difficulties due to distal leg weakness Second decade: hands Second decade: hands Third decade: hearing loss Third decade: hearing loss

59. EDX BAVP reveal both peripheral and central slowing of auditory conduction….. BAVP reveal both peripheral and central slowing of auditory conduction….. VEP is normal………… VEP is normal…………

60. HMSNP AD AD Same as Kennedy Same as Kennedy Muscle cramp Muscle cramp 30 y/o 30 y/o Fasciculations in trunk and limbs Fasciculations in trunk and limbs Mild facial weakness Mild facial weakness Neck Flx &Ext are spared Neck Flx &Ext are spared Tongue,Dysphagia & Dysarthria Tongue,Dysphagia & Dysarthria Tremor Tremor DM 2 DM 2 Decreased vibratory and position Decreased vibratory and position

61. LAB CK is often elevated……………………… CK is often elevated……………………… DM 2………………………………………… DM 2………………………………………… HLP…………………………………………. HLP………………………………………….

62. EDX SNAPs are markedly reduced in amp or absent…………………….. SNAPs are markedly reduced in amp or absent…………………….. CMAP amps are moderately decreased CMAP amps are moderately decreased Distal motor and sensory latencies are preserved…….. Distal motor and sensory latencies are preserved…….. Fasciculation,Fib,Psw,Polyphasic &Decreased recruitment…………… Fasciculation,Fib,Psw,Polyphasic &Decreased recruitment……………

63. HNA AD,Axonal AD,Axonal Pain,weakness &sensory loss Pain,weakness &sensory loss Childhood Childhood Parsonage-Turner Sx Parsonage-Turner Sx Multifocal sensory neuropathy(Wartenberg’s migrant neuropathy) Multifocal sensory neuropathy(Wartenberg’s migrant neuropathy) Hypotelorism,Epicanthal fold,Cleft palate,Syndactylly,Micrognathia & Facial asymmetry Hypotelorism,Epicanthal fold,Cleft palate,Syndactylly,Micrognathia & Facial asymmetry

64. EDX Distal latencies and conduction velocities of the CMAP and SNAPs are relatively preserved Distal latencies and conduction velocities of the CMAP and SNAPs are relatively preserved Fib,Psw,Decreased recruitment& Polyphasic…………………………….. Fib,Psw,Decreased recruitment& Polyphasic……………………………..

65. HSAN1 AD AD 2nd-4th Decades 2nd-4th Decades Slowly progressive Slowly progressive Small myelinated & unmyelinated Small myelinated & unmyelinated Numbness:-,lancinating pain,burning,aching Numbness:-,lancinating pain,burning,aching Bladder dysfunction,reduced sweating Bladder dysfunction,reduced sweating Pain,temperature,DTR absent at ANKLES Pain,temperature,DTR absent at ANKLES Pes cavus,Hammertoe Pes cavus,Hammertoe

66. LAB CSF normal CSF normal Increased IgA Increased IgA

67. EDX Normal or only mildly reduced CMAPs and SNAPs amplitudes Normal or only mildly reduced CMAPs and SNAPs amplitudes Near nerve recordings:reduced amp of A delta and C-fibers Near nerve recordings:reduced amp of A delta and C-fibers Abnormal QST Abnormal QST SSR:absent SSR:absent

68. HSAN 2 Infancy Infancy AR AR Severe loss of sensation to all modalities(particularly touch pressure/vibration) Severe loss of sensation to all modalities(particularly touch pressure/vibration) Whitlow Whitlow Lancinating pains:neg Lancinating pains:neg Romberg Romberg Impaired sweating,bladder dysfunction &impotence Impaired sweating,bladder dysfunction &impotence Postural hypotension:neg Postural hypotension:neg Scoliosis Scoliosis

69. PATHOLOGY Virtual absence of large myelinated fibers Virtual absence of large myelinated fibers Mild loss of small myelinated and unmyelinated fibers Mild loss of small myelinated and unmyelinated fibers

70. EDX Absent SNAP Absent SNAP Normal or only mildly reduced CMAPs amp Normal or only mildly reduced CMAPs amp Abnormal QST(particularly vibration) Abnormal QST(particularly vibration) EMG:Reduced recruitment,long duration EMG:Reduced recruitment,long duration polyphasic,Fib&Psw polyphasic,Fib&Psw

71. HSAN 3 Riley-day Sx;Familial dysautonomia Riley-day Sx;Familial dysautonomia AR AR Infancy Infancy Poor suck Poor suck Alacrima,Blothy skin,Fluctuations in body temperature and blood pressure,Vomiting,Imfections of lungs,Esophageal and gastrointestinal dysmotility,Sweating excessive,Delay in normal development Alacrima,Blothy skin,Fluctuations in body temperature and blood pressure,Vomiting,Imfections of lungs,Esophageal and gastrointestinal dysmotility,Sweating excessive,Delay in normal development

72. Seizures Seizures Intelligence is normal Intelligence is normal Impairment in position,vibration,pain,taste & corneal reflexes Impairment in position,vibration,pain,taste & corneal reflexes Tonic pupils Tonic pupils Postural hypotension Postural hypotension MMT: nl but DTR:absent MMT: nl but DTR:absent Short stature & scoliosis Short stature & scoliosis

73. PATHOLOGY Marked reduction of small myelinated and unmyelinated fibers and to a lesser extent large myelinated fibers Marked reduction of small myelinated and unmyelinated fibers and to a lesser extent large myelinated fibers

74. EDX Decreased SNAP amp,mild slowing of CMAP velocities Decreased SNAP amp,mild slowing of CMAP velocities Abnormal QST Abnormal QST Normal SSR Normal SSR

75. HSAN 4 AR AR ANHYDROSIS ANHYDROSIS SELF MUTILATION SELF MUTILATION POSTURAL HYPOTENSIN POSTURAL HYPOTENSIN PAIN & TEMPERATURE PAIN & TEMPERATURE VIBRATORY :LESS AFFECTED VIBRATORY :LESS AFFECTED

76. EDX There can be slight reductions in CMAPs & SNAPs amplitudes and conduction velocities,but not as severe as that seen in HSAN2 or HSAN3…………… There can be slight reductions in CMAPs & SNAPs amplitudes and conduction velocities,but not as severe as that seen in HSAN2 or HSAN3…………… SSR:unobtainable SSR:unobtainable

77. HSAN 5 Fail to recognize or react to PAINFUL stimuli despite having normal sensitivity to other sensory modalities….. Fail to recognize or react to PAINFUL stimuli despite having normal sensitivity to other sensory modalities…..

78. EDX NCS,EMG,SSR,QST&SEP:normal NCS,EMG,SSR,QST&SEP:normal WITHDRAWAL TO PAIN:abnormal WITHDRAWAL TO PAIN:abnormal

79. FAP AXONAL AXONAL Transthyretin,apolipoprotein A1 &gelsolin Transthyretin,apolipoprotein A1 &gelsolin Small myelinated & unmyelinated fibers Small myelinated & unmyelinated fibers SNAP :Diminished in amp &normal or mildly prolonged in latency SNAP :Diminished in amp &normal or mildly prolonged in latency CMAP :Motor are less severely affected CMAP :Motor are less severely affected CTS CTS Fib & Psw,PPP,Long duration &Large Amp Fib & Psw,PPP,Long duration &Large Amp QST:Cold & heat …..No vibration QST:Cold & heat …..No vibration

80. PORTUGUESE Numbness,Pain,Temperature & Lancinating pains in feet Numbness,Pain,Temperature & Lancinating pains in feet CTS:neg CTS:neg Impotence,constipation,persistent diarrhea Impotence,constipation,persistent diarrhea Cranial neuropathy Cranial neuropathy Liver,kidney,heart &cornea Liver,kidney,heart &cornea Arrhytmia Arrhytmia Die:50 years Die:50 years

81. INDIANA/SWISS Nephropathy & cardiomyopathy:neg Nephropathy & cardiomyopathy:neg Impotence Impotence CTS CTS Mild sensorimotor polyneuropathy Mild sensorimotor polyneuropathy Survival:Long Survival:Long

82. VAN ALLEN Numbness and painfull dysesthesias Numbness and painfull dysesthesias Muscle weakness and atrophy Muscle weakness and atrophy Diarrhea,Constipation & Gastroparesis Diarrhea,Constipation & Gastroparesis Hypertension & renal failure Hypertension & renal failure

83. FINNISH Mild generalized sensorimotor polyneuropathy Mild generalized sensorimotor polyneuropathy Corneal dystrophy Corneal dystrophy Cranial neuropathy Cranial neuropathy

84. LIPID METABOLISM DISORDERS METACHROMATIC LEUKODYSTROPHY METACHROMATIC LEUKODYSTROPHY KRABBE’S DISEASE KRABBE’S DISEASE FABRY’S DISEASE FABRY’S DISEASE ADRENOLEUKODYSTROPHY ADRENOLEUKODYSTROPHY REFSUM’S DISEASE REFSUM’S DISEASE TANGIER DISEASE TANGIER DISEASE CEREBROTENDINOUS XANTHOMATOSIS CEREBROTENDINOUS XANTHOMATOSIS

85. MLD LATE INFANTILE(1-4) LATE INFANTILE(1-4) JUVENILE(3-21) JUVENILE(3-21) ADULT ONSET(after 21) ADULT ONSET(after 21) AR AR

86. Late infantile : Difficulty ambulating,muscle cramps,limb pain,weakness,hypotonia,hyporeflexi a.slurred speech,seizure,quadriparetic,spastic &blind Late infantile : Difficulty ambulating,muscle cramps,limb pain,weakness,hypotonia,hyporeflexi a.slurred speech,seizure,quadriparetic,spastic &blind

87. Adult –onset: Progressive psychosis,dementia,spasticity,visual impairment,urinary incontinence,cerebellar dysfunction & extrapyramidal signs……. Adult –onset: Progressive psychosis,dementia,spasticity,visual impairment,urinary incontinence,cerebellar dysfunction & extrapyramidal signs…….

88. LAB Csf protein: elevated Csf protein: elevated Arylsulfatase A(PROSAPOSIN):decreased Arylsulfatase A(PROSAPOSIN):decreased

89. EDX SNAPs:mildly to moderately prolonged latencies,markedly reduced in amplitude. SNAPs:mildly to moderately prolonged latencies,markedly reduced in amplitude. CMAPs: mildly to moderately prolonged latencies,mildly to moderately reduced in amplitude. CMAPs: mildly to moderately prolonged latencies,mildly to moderately reduced in amplitude. Conduction block & dispersion:neg Conduction block & dispersion:neg

90. TREATMENT BONE MARROW TRANSPLANTATION BONE MARROW TRANSPLANTATION

91. KRABBE’S Early infantile Early infantile Late infantile or juvenile Late infantile or juvenile Adult Adult AR AR

92. Early infantile: Early infantile: First 6 months First 6 months Hypersensitivity,recurrent vomiting,seizure,MR,spasticity,deaf, blind…. Hypersensitivity,recurrent vomiting,seizure,MR,spasticity,deaf, blind…. death:2 years death:2 years

93. LAB B-Galactosidase activity:decreased B-Galactosidase activity:decreased CSF Protein:50% increased CSF Protein:50% increased

94. EDX SNAPs:mildly to moderately prolonged latencies,markedly reduced in amplitude. SNAPs:mildly to moderately prolonged latencies,markedly reduced in amplitude. CMAPs: mildly to moderately prolonged latencies,mildly to moderately reduced in amplitude. CMAPs: mildly to moderately prolonged latencies,mildly to moderately reduced in amplitude. Conduction block & dispersion:neg Conduction block & dispersion:neg

95. TREATMENT BONE MARROW TRANSPLANTATION BONE MARROW TRANSPLANTATION

96. FABRY’S DISEASE Angiokeratoma corporis diffusum Angiokeratoma corporis diffusum X-linked X-linked Burning & stabbing pain Burning & stabbing pain Angiokeratoma:umbilicus,scrotum,inguinal &perineum Angiokeratoma:umbilicus,scrotum,inguinal &perineum Angiectasias:oral mucosa,conjunctiva& nailbed Angiectasias:oral mucosa,conjunctiva& nailbed Atherosclerosis:HTN,RF,CVD,Stroke Atherosclerosis:HTN,RF,CVD,Stroke Death:Fifth decade Death:Fifth decade

97. LAB A-Galactosidase activity:decreased A-Galactosidase activity:decreased Accumulation of CERAMIDE Accumulation of CERAMIDE

98. EDX & EMG NORMAL NORMAL

99. ALD/AMN X-linked X-linked Young male Young male Progressive dementia,Seizure, Spasticity, Progressive dementia,Seizure, Spasticity, Blindness & hearing loss Blindness & hearing loss 90 % adrenal insufficiency 90 % adrenal insufficiency

100. LAB VLCFA : increased VLCFA : increased C22(docosanoic-erusic) : decreased C22(docosanoic-erusic) : decreased

101. EDX ALD:Normal ALD:Normal AMN:associated with a superimposed sensorimotor polyneuropathy AMN:associated with a superimposed sensorimotor polyneuropathy SEP:abnormal SEP:abnormal VEP:normal VEP:normal Conduction block :neg Conduction block :neg

102. EMG Increased IA, Psw, Fib &Fasciculation : neg Increased IA, Psw, Fib &Fasciculation : neg Alternation in voluntary MUAP characteristics Alternation in voluntary MUAP characteristics

103. TREATMENT Diets low in VLCFAs and supplemented with LORENZO’ oil (erucic and olecic acids) Diets low in VLCFAs and supplemented with LORENZO’ oil (erucic and olecic acids) BONE MARROW TRANSPLANTATION BONE MARROW TRANSPLANTATION

104. REFSUM’S DISEASE AR AR Phytanic acid Phytanic acid 1-Peripheral neuropathy 2-Elevated CSF protein 3-Cerebellar dysfunction 4-Retinitis pigmentosa

105. Cardiac Cardiac Hearing loss Hearing loss Anosmia Anosmia Ichthyosis Ichthyosis Bilateral drop foot Bilateral drop foot Paresthesia & pain Paresthesia & pain Vibration &position Vibration &position DTR:Reduced DTR:Reduced Hypertrophic nerve Hypertrophic nerve

106. LAB Phytanic acid :elevated Phytanic acid :elevated CSF protein : elevated CSF protein : elevated

107. EDX&EMG SNAPs are pften reduced in Amp & prolonged latencies… SNAPs are pften reduced in Amp & prolonged latencies… Motor NCVs can range from 7 to 30 m/s Motor NCVs can range from 7 to 30 m/s while in some cases are only slightly slower than normal……… while in some cases are only slightly slower than normal……… CMAPs can be normal or moderately reduced……….. CMAPs can be normal or moderately reduced………..

108. TREATMENT Fishoils, dairy products, ruminant fats &plasma exchange :elimination Fishoils, dairy products, ruminant fats &plasma exchange :elimination

109. TANGIER DISEASE AR AR Deficiency of HDL Deficiency of HDL 1-Asymmetric peripheral polyneuropathy 2-Symmetric polyneuropathy 3-Pseudo-syringomyelia *Diminished vibration,proprioception,pain &temperature… *Reduction DTR *Lymph nodes enlargement & splenomegaly

110. LAB Serum HDL :reduced Serum HDL :reduced Serum triacylglycerol : elevated Serum triacylglycerol : elevated

111. EDX & EMG 1-MILD 1-MILD 2-NORMAL 2-NORMAL 3-SEVERE,motor NCVs are reduced by about 50% in upper and 20-30% in lower limbs…………Increased IA,Fib,Psw,PPP,Large Amp & Long duration 3-SEVERE,motor NCVs are reduced by about 50% in upper and 20-30% in lower limbs…………Increased IA,Fib,Psw,PPP,Large Amp & Long duration

112. CHOLESTANOLOSIS Progressive dementia Progressive dementia Spasticity Spasticity Ataxia Ataxia Mild sensory neuropathy Mild sensory neuropathy Cataracts Cataracts Xanthomas on tendons and skin. Xanthomas on tendons and skin. Premature atherosclerosis Premature atherosclerosis

113. Serum Cholestanol :increased Serum Cholestanol :increased

114. The sural nerve SNAPs can be absent or demonstrate a reduction in amplitude and prolongation in latency or slowing in conduction velocity… The sural nerve SNAPs can be absent or demonstrate a reduction in amplitude and prolongation in latency or slowing in conduction velocity… The median and ulnar motor nerve conduction velocities are normal or only slightly slow with normal or only mildly prolonged distal latencies…….. The median and ulnar motor nerve conduction velocities are normal or only slightly slow with normal or only mildly prolonged distal latencies……..

115. TREATMENT Chenodeoxycholic acid Chenodeoxycholic acid

116. HEREDITARY ATAXIAS FRIEDREICH’S ATAXIA FRIEDREICH’S ATAXIA VITAMIN E DEFICIENCY VITAMIN E DEFICIENCY ABETALIPOPROTEINEMIA ABETALIPOPROTEINEMIA ATAXIA-TELANGIECTASIA ATAXIA-TELANGIECTASIA SPINOCEREBELLAR ATAXIAS SPINOCEREBELLAR ATAXIAS MARINESCO-SJOGREN SYNDROME MARINESCO-SJOGREN SYNDROME

117. FRIEDREICH AR AR Gait ataxia Gait ataxia Clumsiness Clumsiness Tripping Tripping Scoliosis Scoliosis Tremor Tremor Cardiac symptoms Cardiac symptoms

118. Dysarthria Dysarthria Deafness Deafness Optic atrophy Optic atrophy Pes cavus Pes cavus Finger to nose ataxia Finger to nose ataxia Dysdiadochokinesis Dysdiadochokinesis Distal weakness Distal weakness Heel-shin ataxia Heel-shin ataxia Reduction in vibration,position & pain Reduction in vibration,position & pain DTR DTR Extensor plantar response Extensor plantar response Dementia Dementia Wheelchair :16 Wheelchair :16 Death : 37 Death : 37

119. LAB MRI :Cervical spinal cord may reveal atrophy MRI :Cervical spinal cord may reveal atrophy ECG :low voltage QRS & deep Q waves ECG :low voltage QRS & deep Q waves

120. EDX SNAP: absent or profound reduction SNAP: absent or profound reduction Blink reflex :normal Blink reflex :normal H-reflex :absent H-reflex :absent SEP : Reduced SEP : Reduced VEP : Reduced VEP : Reduced BAEP :Reduced BAEP :Reduced Magnetic stimulation studies :Slowing of central conduction motor pathways Magnetic stimulation studies :Slowing of central conduction motor pathways CMAP : Less affected than SNAP CMAP : Less affected than SNAP

121. EMG Normal Normal Fib & Psw Fib & Psw

122. Vit E DEFFICIENCY AR AR Ataxia,disdiadochokinesis,dysarthria, clumsiness,romberg,reduced vibration & proprioception,pes cavus & scoliosis Ataxia,disdiadochokinesis,dysarthria, clumsiness,romberg,reduced vibration & proprioception,pes cavus & scoliosis Plantar responses extensor Plantar responses extensor DTR : reduced DTR : reduced Reduced pain & touch & temperature,ptosis,ophthalmoplegia and retinal pigmentation:Negative Reduced pain & touch & temperature,ptosis,ophthalmoplegia and retinal pigmentation:Negative

123. LAB Normal LDL,HDL,TG,VLDL & Vit A,D,K Normal LDL,HDL,TG,VLDL & Vit A,D,K Reduced Vit E Reduced Vit E

124. EDX & EMG Reduced or absent SNAPs Reduced or absent SNAPs SEP: reduced(central) SEP: reduced(central) Neurogenic type MUAP parameters Neurogenic type MUAP parameters A rare patient myopathic MUAP parameters A rare patient myopathic MUAP parameters

125. TREATMENT Vit E 400 mg twice a day and is increased up to 100 mg/kg/day Vit E 400 mg twice a day and is increased up to 100 mg/kg/day Injection of Vit E 100mg/week Injection of Vit E 100mg/week

126. ABETALIPOPROTEINEMIA Bassen disease Bassen disease Ataxia,,,,,steatorrhea,,,,,,retinitis pigmentosa,,,,,,loss of sensation in distal of upper and lower limbs Ataxia,,,,,steatorrhea,,,,,,retinitis pigmentosa,,,,,,loss of sensation in distal of upper and lower limbs Low weight and stature,reduced DTR,flexor plantar responses,reduced in vibration and proprioception,disdiadochokinesis,romber g,ophthalmoplegia,reduced touch and pain Low weight and stature,reduced DTR,flexor plantar responses,reduced in vibration and proprioception,disdiadochokinesis,romber g,ophthalmoplegia,reduced touch and pain Pes cavus,hammer toes,tremor Pes cavus,hammer toes,tremor

127. LAB Acanthocyte Acanthocyte Reduced LDL,VLDL,HDL,TG,Vit A,D,K Reduced LDL,VLDL,HDL,TG,Vit A,D,K

128. EDX SNAP: absent or profound reduction SNAP: absent or profound reduction Blink reflex :normal Blink reflex :normal H-reflex :absent H-reflex :absent SEP : Reduced SEP : Reduced VEP : Reduced VEP : Reduced BAEP :normal BAEP :normal Magnetic stimulation studies :Slowing of central conduction motor pathways Magnetic stimulation studies :Slowing of central conduction motor pathways CMAP : Less affected than SNAP CMAP : Less affected than SNAP

129. TREATMENT REPLACEMENT OF FAT SOLUBLE VITAMINS REPLACEMENT OF FAT SOLUBLE VITAMINS