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hereditary neuropathies

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hereditary neuropathies

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hereditary neuropathies

  1. 1. HEREDITARY NEUROPATHIES Bradly 2016
  2. 2. Charcot–Marie–Tooth Disease (Hereditary Motor and Sensory Neuropathy)
  3. 3. Charcot–Marie–Tooth Disease (Hereditary Motor and Sensory Neuropathy) * The syndrome of peroneal muscular atrophy. * CMT disease is the most common inherited neuropathy (10 to 41 per 100,000) * It is divided two main groups: (1) The demyelinating form, or CMT1 (sometimes known as hereditary motor and sensory neuropathy [HMSN-I]), in which there are marked reductions in motor NCVs (<38 m/sec in forearm) and nerve biopsy findings of demyelination and onion bulb formation. (2) The axonal form of CMT disease, or CMT2 (HMSN-II): in which motor NCVs are normal or near normal, and nerve biopsy reveals axonal loss without prominent demyelination.
  4. 4. 1- Charcot–Marie–Tooth Disease Type 1 * begin during the first or second decade of life. * slowly progressive weakness, muscular wasting, and sensory impairment predominantly involving the distal legs. * Foot deformities and wasting in the intrinsic foot, peroneal, and anterior tibial muscles * In two-thirds of patients, the upper limbs are involved later in life. * pes cavus and hammer toes in nearly three-quarters of adult patients, mild kyphosis in approximately a tenth, and palpably enlarged hypertrophic peripheral nerves in a quarter * Absent ankle reflexes are universal and frequently associated with absent or reduced knee and upper limb reflexes. * Essential or postural upper-limb tremor, Such cases have been referred to as Roussy-Lévy syndrome
  5. 5. * 10% of patients with slowed NCVs may remain asymptomatic. * In women with CMT1, the disease may exacerbate during pregnancy. Such worsening is temporary in about a third of patients but becomes progressive in the remainder. * Slow deterioration in strength and decline in axonal function continues throughout adulthood * Motor nerve conduction studies show uniform slowing to less than 75% of the lower limits of normal in all nerves. * 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 conduction velocity below 38 m/sec in the forearm segment of the median nerve is proposed as a cutoff value to distinguish between CMT1 and CMT2. Although this cutoff is useful, it can be misleading if applied too rigidly.
  6. 6. * SNAPs are usually absent with surface recordings * Uniform conduction slowing has been used to differentiate CMT1 from acquired demyelinating neuropathies. * Uniform slowing along the entire length of nerves and among neighbouring nerves suggests an inherited myelinopathy affecting conduction in all nerves and nerve segments to the same degree. * The conduction slowing evolves over the first 5 years of age and does not change appreciably afterward. * Neurological deficits correlate with reductions in CMAP and SNAP amplitudes rather than conduction velocity, indicating that clinical weakness results from loss of axons. *In contrast, acquired demyelinating neuropathies result in multifocal or nonuniform conduction slowing together with excessive temporal dispersion and conduction block.
  7. 7. * Routine hematological and biochemical studies are normal. * CSF is also normal, which helps differentiate the condition from CIDP in which the CSF protein is usually elevated. * Sural nerve biopsy typically shows the changes of a hypertrophic neuropathy, characterized by onion bulb formation, increased frequency of fibers with demyelinated and remyelinated segments, an increase in endoneurial area, and loss of large myelinated fibers . * Gene mutations, predominantly affecting genes for myelin and Schwann cell proteins, have been recognized that account for about three-quarters of families with CMT1 . * CMT1A is the most common CMT subtype, accounting for 70%–80% of CMT1 cases and more than 50% of all CMT cases.
  8. 8. * CMT1B is clinically indistinguishable from CMT1A but it only accounts for 10–20% of all CMT cases. * Motor conduction block was reported rarely in CMT1B patients with specific MPZ mutations * CMT2 phenotype (CMT2J) characterized by late onset, marked sensory loss, and sometimes deafness, chronic cough, and pupillary abnormalities * Other rare CMT1 subtypes include CMT1C,CMT1D, CMT1E and CMT1F. 2- Charcot–Marie–Tooth Disease Type 2 * one-third of all autosomal dominant CMT disease. * It is associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, and translation . * begin later than in CMT1, most commonly in the second decade, but may be delayed until middle age or beyond.
  9. 9. * Foot and spinal deformities tend to be less prominent than in CMT1. * peripheral nerves are not enlarged * Upper limb involvement, tremor, and general areflexia occur less frequently. * 20% of affected individuals are asymptomatic. * CMT2A is the most common CMT2 subtype 30% , it is of 2 types 1 and 2. * CMT2A1 is less common and less severe. * CMT2A2, has an earlier onset and is more severe, It may also be associated with optic atrophy * In CMT2B : prominent sensory loss with foot ulcerations is a key feature * This form of CMT is clinically very similar to hereditary sensory neuropathy type 1 (HSN1) but lacks spontaneous lancinating pain. * In CMT2C : develop vocal cord, intercostal, and diaphragmatic muscle weakness the life expectancy of these patients is shortened.
  10. 10. * CMT2D: weakness and atrophy that is more severe in the hands than in the feet * CMT2E: exhibits slowed motor nerve conduction that is much below the forearm cutoff value of 38 m/sec and a more severe clinical phenotype and patients may have axonal swelling (giant axons) and significant secondary demyelination on sural nerve biopsies. * CMT2F :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: reported in a Spanish family, the age onset from 9 to 76 years. * CMT2J: is associated with pupillary abnormalities (Adie pupil) and hearing loss. * CMT2L: is associated with typical features of the CMT2 phenotype,Motor NCV may be normal or mildly reduced. SNAPs are either absent or reduced in amplitude. Sural nerve biopsy specimens show preferential loss of large myelinated fibers, without significant demyelination; there may be clusters of regenerating myelinated fibers, a hallmark of axonal regeneration.
  11. 11. 3- X-Linked Charcot–Marie–Tooth Disease (CMTX) * Affected male tend to be more severely affected, and females with the gene mutation may have a mild neuropathy or be asymptomatic. * No male-to-male transmission occurs; hence, CMTX should be considered in any patient whose family history does not exhibit a male-to male transmission. * 7% to 16% of all forms of CMT, making it the second most common form of CMT (following CMT1A). * More than 200 different mutations in Cx32 have been identified in CMTX families. * Some mutations of Cx32 have been reported to be associated with central nervous system (CNS) involvement with white-matter MRI and MR spectroscopy abnormalities, abnormal brainstem auditory evoked potentials, and deafness * An interesting phenomenon of transient and acute ataxia, dysarthria, and weakness occurring after visiting high altitudes and associated with CNS white- matter MRI abnormalities
  12. 12. * It show significant slowing in NCV, whereas brainstem auditory evoked responses are often abnormal. * A picture of both axonal loss and demyelination is revealed on nerve biopsy. * Nerve conduction velocities : normal to intermediate slowing in the 30- to 40- m/sec range. * There is debate as to whether CMTX should be classified as a primary axonal or demyelinating disorder , However, careful studies of individual patients suggest non-uniform conduction slowing consistent with demyelination * it is important to review the family history. If there is no maleto-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
  13. 13. 4- Charcot–Marie–Tooth Disease Type 3 (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. * autosomal recessive or sporadic or dominant mutation. * Motor conduction velocities are severely slowed, often to less than 10 m/sec. * Temporal dispersion and amplitude reduction on proximal stimulation may be found in such cases, owing to high electrical stimulation thresholds in hypertrophic nerves. * CSF protein is increased. * Pathologically, pronounced onion bulb changes are associated with hypomyelination and loss of myelinated fibers. * Defective myelination is confirmed by an increased axon-to-fiber diameter ratio.
  14. 14. 5- Charcot–Marie–Tooth Disease Type 4 * autosomal recessive inheritance * less than 10% of all CMT cases. * early childhood and progressive weakness leading to inability to walk in adolescence. * Both demyelinating and axonal types have been identified * clinical and electrophysiological features are similar in several of these subtypes with CMT3. * Conduction velocities are slowed (20–30 m/sec). CSF protein is normal. Nerve biopsy shows loss of myelinated fibers, hypomyelination, and onion bulbs.
  15. 15. * Subgroups: CMT4A, CMT4B1 and 2, CMT4C, CMT4D, CMT4E, CMT4F, and CMT4H. * CMT4A is the most common and accounts for 25%–30% of all autosomal recessive cases. * Children affected with CMT4B2 also exhibit congenital glaucoma leading to loss of vision. * In CMT4C: there is severe scoliosis * CMT4D has onset in childhood but may progress into the fifth decade of life. It is associated with dysmorphic features and hearing loss. * CMT4E is a form of congenital hypomyelinating neuropathy * CMT4F is similar to that for CMT3. *CMT4H is similar to CMT2G but is more severe clinically, with an onset in early childhood and prominent nerve hypomyelination
  16. 16. 6- Complex Forms of Charcot–Marie-Tooth Disease * Some dominant forms of CMT have displayed features intermediate between CMT1 and CMT2, with conduction velocities between 38 m/sec and normal. * These forms have been classified separately as dominant intermediate CMT (DI- CMT) and include types A, B, C, and D. DI-CMTA * Some families with this variety have developed neutropenia and early cataracts * a mild, very slowly progressive course * Some exhibits additional features such as optic atrophy, pigmentary retinal degeneration, deafness, and spastic paraparesis. * Cardiac involvement is encountered in occasional patients, but prospective family studies find no association between cardiomyopathy and CMT disease.
  17. 17. * A syndrome of CIDP responding to prednisone and immunosuppression has been reported in patients with inherited CMT disease due to MPZ mutation providing evidence that non-genetic factors may play a role in clinical expression of the mutant gene. * It has been suggested that any patient with a hereditary neuropathy who suffers a recent rapid deterioration should be considered as having a secondary CIDP and be treated with immunosuppressants such as corticosteroids or high-dose intravenous immunoglobulin (IVIG). Practical Molecular Diagnostic Testing for Patients with Charcot–Marie–Tooth Disease and Related Disorders * It is advisable to use the clinical and electrodiagnostic findings supplemented by a detailed family history and plan a logical approach to obtaining DNA studies. * 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 .
  18. 18. • In families with at least two generations with the disease, known male-to-male transmission, and uniform conduction slowing (<38 m/sec if forearm), CMT1A should be considered first and the PMP22 duplication test should be obtained. • If normal, PMP22 sequencing should be done. • If normal, CMT1B should be excluded by obtaining MPZ DNA sequencing. • Patients who have neither the PMP22 duplication nor male to-male transmission should be screened for CMTX by looking for Cx32 mutations. • For patients displaying an axonal pattern, the MFN2 mutation should be investigated first, as this is the most common type of CMT2. • Given the high spontaneous mutation rate, the diagnosis of CMT1A should be considered even in the absence of a positive family history. • The PMP22 duplication test followed by DNA sequencing of PMP22, MPZ, EGR2, and periaxin should be considered in childhood cases with severe demyelinating neuropathy suggestive of DSS or congenital hypomyelination neuropathy
  19. 19. • Because of the severe reactions to vincristine and other chemotherapeutic neurotoxic drugs in CMT patients, before initiating cancer chemotherapy it is best to rule out CMT1A in any patient with either unexplained chronic neuropathy or a family history of neuropathy. Treatment and Management The rates of progression of CMT1 and CMT2 are slow, disability occurs relatively late, and lifespan may be normal. Management is mainly symptomatic. * Ankle-foot braces or orthopedic procedures are indicated to correct severe footdrop. * Patients should be warned to avoid neurotoxic drugs because of greater susceptibility to agents such as vincristine. * Recent studies suggest that CMT is associated with higher risk for complication during delivery Also during pregnancy the symptoms of CMT may worsen.
  20. 20. * use of ascorbic acid(vitamin C) at 1 or 3 g/day in CMT1A was found to be Of no benefit. * The possibly beneficial role of neurotrophins, particularly neurotrophin 3 (NT3), in CMT1A and nerve regeneration has recently been demonstrated in a small pilot study * Some CMT2 patients with MPZ mutations may respond to corticosteroids
  21. 21. Hereditary Neuropathy with Liability to Pressure Palsies
  22. 22. * HNPP is an autosomal dominant disorder of peripheral nerves leading to increased susceptibility to mechanical traction or compression. * 16 per 100,000 population. * Patients have recurrent episodes of isolated mononeuropathies, typically affecting, in order of decreasing frequency, the fibular nerve, ulnar nerve, brachial plexus, radial nerve, and median nerves. * Painless brachial plexopathy is seen in up to a third of patients. * the initial episode in the second or third decade of life. Attacks usually are provoked by compression, slight traction, or other minor trauma. * Most episodes are of sudden onset, painless, and usually followed by complete recovery within days or weeks. * Less-common presentations include transient positionally induced sensory symptoms, progressive mononeuropathy, chronic sensory polyneuropathy, CMT phenotype with pes cavus, and a diffuse chronic sensorimotor neuropathy resembling chronic inflammatory demyelinating polyneuropathy . * About 15% of mutation carriers remain asymptomatic.
  23. 23. * Nerve conduction demonstrate a characteristic pattern of prolonged distal motor latencies with only mild slowing in forearm segments of median and ulnar nerves * focal slowing and conduction blocks of median, ulnar, and fibular nerves at compression sites, and diffuse reduction of SNAP amplitudes * The median forearm motor nerve conduction is typically above 38 m/sec, but sensory studies demonstrate velocities in the demyelinating range and reduced or absent SNAPs. * Prolonged median distal motor latencies and abnormal sensory conduction studies are frequently found in asymptomatic carriers * Sural nerve biopsy specimens demonstrate focal sausage-like thickenings of myelin termed tomacula,segmental demyelination, and axonal loss. * The primary treatment strategy is to prevent nerve injury by avoiding pressure damage.
  24. 24. Hereditary Neuralgic Amyotrophy
  25. 25. * Recurrent brachial plexopathy, often preceded by severe ipsilateral limb pain, is the hallmark of hereditary neuralgic amyotrophy * an autosomal dominant disorder. * Most patients recover over weeks to a few months, with accumulating evidence of residual neurologic deficit over time. * Patients also have dysmorphic features, including hypotelorism, epicanthal folds, microstomia, and dysmorphic ears.
  26. 26. Giant Axonal Neuropathy
  27. 27. • is a rare ,autosomal recessive multisystemic neurodegenerative disorder of intermediate filaments affecting the peripheral and CNS. • GAN presents as a slowly progressive axonal sensorimotor neuropathy in early childhood and leads to death by late adolescence. • Most affected children have tightly curled hair and distal leg weakness. • Some develop a peculiar gait disturbance with a tendency to walk on the inner edges of the feet With disease progression, evidence of CNS involvement occurs, including optic atrophy, nystagmus, cerebellar ataxia, upper motor neuron signs and intellectual decline, and abnormal visual, auditory, and somatosensory evoked potentials. • MRI of the brain : cerebellar and cerebral white-matter abnormalities. • NCS show reduced CMAP and SNAP amplitudes with normal to only slightly reduced conduction velocities. • Sural nerve biopsy demonstrates the pathognomonic changes of large focal axonal swellings that contain densely packed disorganized neurofilaments • Axonal function and axoplasmic transport are impaired.
  28. 28. Hereditary Sensory and Autonomic Neuropathy (HSAN)
  29. 29. • are a clinically and genetically heterogeneous group of neuropathies characterized by prominent sensory loss and variable autonomic features but without significant motor involvement • They are divided into five main groups based on the inheritance, clinical features, and type of sensory neurons involved
  30. 30. • Compared with CMT, HSANs are distinctly rare. * The pronounced sensory loss in HSAN predisposes these patients to unnoticed recurrent trauma, leading to neuropathic (Charcot) joints, nonhealing ulcers, infections, and osteomyelitis resulting in acral mutilations (acrodystrophic neuropathy). Hereditary Sensory and Autonomic Neuropathy Type I • AD, and the most common hereditary sensory neuropathy • begin in the second to fourth decade with sensory loss and subsequent tissue injury mainly affecting the feet and legs. • Sensory loss initially affects pain and temperature perception more than touch- pressure sensation, but it involves all modalities as the disease progresses. • Autonomic involvements are limited to hypohidrosis. • calluses on the soles, painless stress fractures of the feet, neuropathic foot and ankle joints, and recurrent plantar ulcers. • If ulcers are neglected and become infected, severe acromutilation may result (acrodystrophic neuropathy).
  31. 31. • Lancinating or shooting pains are often prominent and are considered the hallmark feature of HSAN-I. • Distal muscle weakness and wasting are present in advanced cases. • Variable neural hearing loss or rarely spastic paraparesis may be seen in HSAN-I. • SNAP amplitudes are reduced late in the disease. • Motor conduction velocities remain normal, but CMAP amplitudes are reduced in advanced cases. • Sural nerve biopsy confirms a severe loss of small myelinated axons and, to a lesser degree, of unmyelinated and large myelinated fibers • A subtype, HSAN-IB, is associated with paroxysmal cough, cough syncope, and gastroesophageal reflux • Additional features include hoarseness of voice and hearing deficit; motor involvement, acral mutilations and ulceration are usually absent. • The association of cough and gastroesophageal reflux is not unique to HSAN-IB, as it has also been associated with CMT2 with MPZ mutation.
  32. 32. Hereditary Sensory and Autonomic Neuropathy Type II HSAN-II is recessively inherited and rarely begins later than infancy. All sensory modalities of distal upper and lower limbs and, to a lesser extent, of trunk and face are affected. The hands, feet, lips, and tongue are at risk for mutilation because of generalized sensory loss and insensitivity to pain. Autonomic symptoms are minimal, and mental development is normal. There is loss of tendon reflexes. Rarely, associations with spastic paraplegia, retinitis pigmentosa, mild motor weakness, or neurotrophic keratitis have been described. The clinical course is slowly progressive, with progressive axonal loss. SNAPs are absent. Sural nerve biopsy specimens show almost complete absence of myelinated fibers and reduced unmyelinated fiber populations (eFig. 107.14). Mutations in the HSN2 nervous-system-specific exon of the with-nolysine(K)-1 (WNK1) gene on chromosome 12q13.33 cause HSAN-II (Shekarabi et al., 2008). All mutations result in a truncation of the HSN2 protein, with the protein loss or inactivation (or both) causing the peripheral neuropathy. The exact function of HSN2 protein remains unknown, but it may play a role in the development or maintenance of sensory neurons or accompanying Schwann cells.

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