History

Fact Explanation
Gait disturbances [1] Usually these symptoms start as early as 2nd year of life but can be delayed till 5th decade. The cause is due to demyelination and/or axonal loss of the peripheral nerves. As a result there is progressive weakness of the distal musculature particularly peroneal muscular atrophy which is accompanied by progressive weakness of dorsiflexion of the ankle and eventual foot drop. Pes cavus deformities invariably develop as well further destabilizing the gait [1], [2], [4]
Proximal muscle weakness [1] This is a late manifestation and axial muscles are usually spared. [1]
Tingling or burning sensations of the feet [1] This is due to involvement of sensory nerves particularly large myelinated nerve fibers that convey proprioception and vibration but the threshold for pain and temperature can increase too. [1]
Easy traumatization [1] Due to reduced muscle mass and sensory disturbance, the nerves are vulnerable to trauma and compression. [1]
Blotching or pallor of the skin of the feet and inappropriately cold feet. [1] Due to involvement of autonomic nerves and poor vasomotor control [1]
Auditory nerve deafness [1], [3] This is due to a unique point mutation in PMP22 which causes progressive auditory nerve deafness in addition. [1], [3]
References
  1. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  2. BURNS J, OUVRIER R, ESTILOW T, SHY R, LAURá M, EICHINGER K, MUNTONI F, REILLY MM, PAREYSON D, ACSADI G, SHY ME, FINKEL RS. Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie-Tooth disease Clin Biomech (Bristol, Avon) [online] 2012 Aug, 27(7):744-747 [viewed 14 June 2014] Available from: doi:10.1016/j.clinbiomech.2012.02.006
  3. KOVACH MJ, LIN JP, BOYADJIEV S, CAMPBELL K, MAZZEO L, HERMAN K, RIMER LA, FRANK W, LLEWELLYN B, JABS EW, GELBER D, KIMONIS VE. A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet [online] 1999 Jun, 64(6):1580-1593 [viewed 14 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377901
  4. FERRARIN M, LENCIONI T, RABUFFETTI M, MORONI I, PAGLIANO E, PAREYSON D. Changes of gait pattern in children with Charcot-Marie-Tooth disease type 1A: a 18 months follow-up study J Neuroeng Rehabil [online] :65 [viewed 14 June 2014] Available from: doi:10.1186/1743-0003-10-65
  5. ØSTERN R, FAGERHEIM T, HJELLNES H, NYGåRD B, MELLGREN SI, NILSSEN Ø. Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies BMC Med Genet [online] :94 [viewed 14 June 2014] Available from: doi:10.1186/1471-2350-14-94

Examination

Fact Explanation
Wasted muscles in the anterior compartment of the lower legs and characteristic stork-like contour [1], [2] Due to peroneal muscle atrophy [1], [2]
Weakness of dorsiflexion of the ankle and an ultimate foot drop [1] [2], [3] Due to peroneal muscle atrophy [1]
Contractures of the wrists and ultimately a claw hand [1] Due to wasting of forearm and hand muscles [1]
Ankle contractures and painful Pes cavus deformities [1], [2] Due to denervation of intrinsic foot muscles [1], [2]
Palpably enlarged nerves [1] Due to hypertrophy of affected nerves due to demyelination followed by attempts of remyelination [1], [4]
Lost tendon reflexes [1] Due to demyelination and/or axonal loss of the peripheral nerves.[1], [2]
References
  1. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  2. BURNS J, OUVRIER R, ESTILOW T, SHY R, LAURá M, EICHINGER K, MUNTONI F, REILLY MM, PAREYSON D, ACSADI G, SHY ME, FINKEL RS. Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie-Tooth disease Clin Biomech (Bristol, Avon) [online] 2012 Aug, 27(7):744-747 [viewed 14 June 2014] Available from: doi:10.1016/j.clinbiomech.2012.02.006
  3. FERRARIN M, LENCIONI T, RABUFFETTI M, MORONI I, PAGLIANO E, PAREYSON D. Changes of gait pattern in children with Charcot-Marie-Tooth disease type 1A: a 18 months follow-up study J Neuroeng Rehabil [online] :65 [viewed 14 June 2014] Available from: doi:10.1186/1743-0003-10-65
  4. LISSAUER, Tom. CLAYDEN, Graham. Illustrated textbook of Paediatrics. 3rd ed. London: Mosby Elsevier, 2007, pp 465

Differential Diagnoses

Fact Explanation
Peroneal Muscular Atrophy (Axonal Type) [1] This is clinically similar to HMSN type I, but the rate of progression is slower and the disability is also less. Sural nerve biopsy reveals axonal degeneration rather than the demyelination. The locus is on chromosome 1 at 1p35-p36. [1]
Dejerine-Sottas Disease (HMSN Type III). [1] This is more severe. Symptoms develop in early infancy and are rapidly progressive. Pupillary abnormalities, such as lack of reaction to light and Argyll Robertson pupil, are common as well as Kyphoscoliosis and pes cavus deformities.[1]
Roussy-Lévy Syndrome [1] This is a combination of HMSN type I and cerebellar deficit resembling Friedreich ataxia, but it does not have cardiomyopathy.[1]
Refsum Disease [1], [2] This is a rare disease with a clinical onset of 4 and 7 yr of age, with intermittent motor and sensory neuropathy, Ataxia, progressive neurosensory hearing loss, retinitis pigmentosa and loss of night vision, ichthyosis, and liver dysfunction also develop in various degrees [1], [2]
Giant Axonal Neuropathy [1] This is another rare autosomal recessive disease with onset in early childhood is a progressive mixed peripheral neuropathy and degeneration of central white matter. Ataxia and nystagmus are also present with signs of progressive peripheral neuropathy [1]
Congenital Hypomyelinating Neuropathy [1] This is due to lack of normal myelination of motor and sensory peripheral nerves and this is present from birth with hypotonia and developmental delay as the hallmark clinical findings [1]
Leukodystrophies [1], [2] This accounts for several hereditary degenerative diseases of white matter of the CNS which also cause peripheral neuropathy. [1], [2]
Diabetes Mellitus neuropathy [2] Diabetes mellitus is the most common cause of neuropathy and in DM, a distal symmetrical sensory polyneuropathy is seen and is usually axonal, but can also show demyelinating features on electrophysiology. But in contrast to CMT, diabetic neuropathy has predominantly sensory and autonomic manifestations. [2]
chronic inflammatory demyelinating polyneuropathy (CIDP) [2] CIDP shows a subacute or fluctuating course and multi-focal demyelinating features on electrophysiology together with high protein levels in cerebrospinal fluid but no pes cavus and a family history [2]
Friedreich's ataxia [3] Initial presentation can be similar [3]
References
  1. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  2. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 14 June 2014] Available from: doi:10.1186/1750-1172-9-38
  3. LISSAUER, Tom. CLAYDEN, Graham. Illustrated textbook of Paediatrics. 3rd ed. London: Mosby Elsevier, 2007, pp 465

Investigations - for Diagnosis

Fact Explanation
Nerve conduction studies [1] Motor and sensory nerve conduction velocities are very much reduced as slow as 20% of normal conduction time [1]
Electromyography (EMG) [1] Shows denervation and reinnervation [1]
Muscle biopsy [1] Shows denervation and reinnervation [1]
Cerebrospinal fluid (CSF) for protein [1] May be elevated, but no cells appear in the CSF. [1]
Sural nerve biopsy [1] Characteristic onion bulb formations of proliferated Schwann cell cytoplasm surround axons is seen and this pathologic finding is called interstitial hypertrophic neuropathy. In addition large- and medium-sized myelinated fibers are reduced in number, collagen is increased, and extensive segmental demyelination and remyelination also occur. [1]
Genetic analysis [1], [2], [3] MT1A is predominantly caused by a 1.5 Mb duplication on chromosome 17p11.2 that includes the PMP22 gene. But due to the clinical and genetic heterogeneity, the low sensitivity of genetic testing for CMT2 and scarcity of clinical data, CMT can be difficult to be diagnosed by genetic testing always. [2], [3]
References
  1. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  2. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 14 June 2014] Available from: doi:10.1186/1750-1172-9-38
  3. ØSTERN R, FAGERHEIM T, HJELLNES H, NYGåRD B, MELLGREN SI, NILSSEN Ø. Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies BMC Med Genet [online] :94 [viewed 14 June 2014] Available from: doi:10.1186/1471-2350-14-94

Management - General Measures

Fact Explanation
Supportive care for the legs with stabilization of the ankles [1], [2] This includes exercise training, shoe inlays, orthopaedic shoes and orthoses for stabilization of ankles [1], [2]
Protection of the leg from compression neuropathies [1] Placement of soft pillows beneath or between the lower legs [1]
Medical treatment with Phenytoin or Carbamezapine [1] For burning paresthesias of the feet [1]
Optimal control of blood sugar level [2] Because co-existence of diabetes mellitus in a CMT1A patient can exacerbate symptoms of the peripheral neuropathy [2]
Avoidance of certain neurotoxic agents [2] Especially vincristine, can have a devastating effect, even in low dose therefore should be avoided [2]
Patient education and parental education [3] Education regarding the course of the disease, prognosis and the extent of exercise capacity should be explained. Patients should be advised not to exercise to exhaustion, because of the risk of exercised-induced muscle damage. [3]
Physiotherapy and occupational therapy [3] Patients with CMT appeared to benefit significantly from a strengthening programme [3]
Psychological support [3] Group and family counseling may be beneficial and patients should be referred to support groups for psychological support and problem solving. If necessary, a patient should be referred to a mental health professional [3]
References
  1. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  2. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 14 June 2014] Available from: doi:10.1186/1750-1172-9-38
  3. WALLACE HJ. [In memoriam Gordon B. Mitchell-Heggs 1904-1975]. Hautarzt [online] 1977 Feb, 28(2):117 [viewed 14 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/321397

Management - Specific Treatments

Fact Explanation
Surgical interventions [1] Flexor Digitorum Superficialis Opposition tendon transfer has showed improved hand function, reduce disability, and improve quality of life [1] Surgical fusion of the ankle can also be done [2]
Neurotrophin-3 (NT-3) [3] Treatment with this led to slight improvement of sensory and reflex scores in CMT1A patients. NT-3 therapy resulted in measurable NT-3 secretion levels in blood and improvement in motor function, histopathology, and electrophysiology of the peripheral nerves [3]
Genetic counselling and antenatal diagnosis [3] It maybe beneficial as these are autosomal dominant as well as could be recessive or X linked. [2]
References
  1. ESTILOW T, KOZIN SH, GLANZMAN AM, BURNS J, FINKEL RS. Flexor digitorum superficialis opposition tendon transfer improves hand function in children with Charcot-Marie-Tooth disease: Case series Neuromuscul Disord [online] 2012 Dec, 22(12):10.1016/j.nmd.2012.07.011 [viewed 14 June 2014] Available from: doi:10.1016/j.nmd.2012.07.011
  2. HARVEY B. Sarnat. Hereditary Motor-Sensory Neuropathies. In KLIGEMAN, Robert M, BEHRMAN, Richard E, STANTON, Bonita F, ST.GEME III, Joseph W, SCHOR, Nina F. Nelson textbook of Paediatrics. 19th ed. Philadelphia: Saunders Elsevier, 2011, pp 4214-4217
  3. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 14 June 2014] Available from: doi:10.1186/1750-1172-9-38