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Roussy–Lévy syndrome

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Roussy–Lévy syndrome
SpecialtyNeurology Edit this on Wikidata

Roussy–Lévy syndrome, also known as Roussy–Lévy hereditary areflexic dystasia, is a rare genetic disorder of humans that results in progressive muscle wasting. It is caused by mutations in the genes that code for proteins necessary for the functioning of the myelin sheath of the neurons, affecting the conductance of nerve signals and resulting in loss of muscles' ability to move. Symptoms include foot deformity, weakness and atrophy of distal limb muscles, especially the peronei, absent tendon reflexes, decreased excitability of muscles to galvanic and faradic stimulation, some distal sensory loss, static tremor of the upper limbs and gait ataxia.

The condition affects people from infants through adults and is inherited in an autosomal dominant manner. Currently, no cure is known for the disorder.

This syndrome is very rare and is also known by other names. Synonyms of this disorder include Charcot-Marie-Tooth disease, Hereditary Areflexic Dystasia and Hereditary Motor Sensory Neuropathy.


Signs and symptoms

Person with arched feet, known as pes cavus.

Symptoms of the Roussy–Lévy syndrome mainly stem from nerve damage and the resulting progressive muscle atrophy. Neurological damage may result in absent tendon reflexes (areflexia), some distal sensory loss and decreased excitability of muscles to galvanic and faradic stimulation. Progressive muscle wasting results in weakness of distal limb muscles (especially the peronei), gait ataxia, pes cavus, postural tremors and static tremor of the upper limbs, kyphoscoliosis, and foot deformity.[1][2] Pes cavus, in its simplest form, is characterized by an excessively high medial longitudinal arch, an inverted rearfoot. [3]

A distinguishing characteristic of Roussy-Lévy syndrome is peripheral neuropathy with prominent tremor. Neuropathic tremors develop in association with peripheral neuropathy when no other neurological condition associated with tremor is encountered. It is typically presented as an action tremor and is observed mainly in patients with hereditary motor and sensory neuropathies (HMSN), or chronic inflammatory demyelinating polyneuropathies (CIDP).[4]

These symptoms frequently translate into delayed onset of ability to walk, loss of coordination and balance, foot drop, and foot-bone deformities. They are usually first observed during infancy or early childhood, and slowly progress until about age 30, at which point progression may stop in some individuals, or symptoms may continue to slowly progress.[5]

Causes

The Roussy–Lévy syndrome has been associated with two genetic mutations: a duplication of the PMP22 gene that carries the instructions for producing the peripheral myelin protein 22, a critical component of the myelin sheath; and a missense mutation in the MPZ gene which codes for myelin protein zero, a major structural protein of peripheral myelin.[6][7][1][8] When this gene is overexpressed, the function and structure of the myelin sheath becomes abnormal, which is what ultimately leads to weakness and atrophy of the muscles.

As PMP22 mutations are also associated with Charcot–Marie–Tooth disease type 1A and MPZ mutations are associated with Charcot–Marie–Tooth disease type 1B, it remains the subject of discussion whether the Roussy–Lévy syndrome is a separate entity or a specific phenotype of either disorder.[7] [9] The genetic phenotype caused by the MPZ mutation varies considerably, from early onset and severe symptoms to later onset and milder symptoms.

Pathophysiology

In common with other types of Charcot–Marie–Tooth disease, neurological examination reveals decreased nerve conduction velocity and histologic features of a hypertrophic demyelinating neuropathy.[10] For a nerve conduction study, electrodes are placed on the skin over peripheral nerves. The electrode produces a small, mild discomforting electrical shock. This electrical impulse allows the doctor to measure how well the nerve conducts an electrical signal. Patients with Roussy-Levy syndrome have slow nerve conduction velocities and histologic features of a hypertrophic demyelinating neuropathy. [11] Electromyography shows signs of mild neurogenic damage[8][12] while nerve biopsy shows onion bulb formations; the appearance of these formations is what primarily led Gustave Roussy and Gabrielle Lévy, the scientists who first described the disorder, to classify it as a variant of Charcot–Marie–Tooth disease.[7]In an electromyography (EMG), a needle electrode is inserted through the skin to measure the electrical activity of the muscles. This allows the doctor to assess how well the peripheral nerves in target muscle react to the electrical signal. [13] A nerve biopsy, on the other hand, is an invasive procedure which involves removing a small piece of the nerve through an incision in the skin. The nerve is examined under a microscope for signs of abnormal myelination. [14]

To create a working nerve, neurons, Schwann cells, and fibroblasts must work together. Molecular signals are exchanged between Schwann cells and neurons to regulate survival and differentiation of a nerve. However, these signals are disrupted in patients with the Roussy–Lévy syndrome.

Diagnosis

While the clinical picture may point towards the diagnosis of the Roussy–Lévy syndrome, the condition can only be confirmed with absolute certainty by carrying out genetic testing in order to identify the underlying mutations. Diagnostic procedures for Roussy-Levy Syndrome are similar to those of other forms of CMT.

Treatment and management

There is no pharmacological treatment for Roussy–Lévy syndrome.

Treatment options focus on palliative care and corrective therapy. Patients tend to benefit greatly from physical therapy (especially water therapy as it does not place excessive pressure on the muscles), while moderate activity is often recommended to maintain movement, flexibility, muscle strength and endurance.[6] A physical therapist will usually design a program that will fit a person’s strengths and flexibility, and that will work on strengthening the muscles that have not already been atrophied by Roussy-Levy syndrome.

Patients with foot deformities may benefit from corrective surgery, which, however, is usually a last resort. Neuropathic tremor generally responds poorly to medical treatment.[4] The surgical management of patients with pes cavus can be challenging for surgeons because of the underlying complex mechanisms of deformity. [3] Most surgeries are done to correct or stabilize the feet problems by straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability. Recovering from these surgeries is often times long and difficult. Proper foot care including custom-made shoes and leg braces may minimize discomfort and increase function.[7][15]

While no medicines are reported to treat the disorder, patients are advised to avoid certain medications as they may aggravate the symptoms. The Charcot Marie Tooth Association (CMTA) publishes a list of medications that people with Roussy-Lévy Syndrome should usually avoid as these medications may increase symptoms

Prognosis

The Roussy–Lévy syndrome is not a fatal disease and life expectancy is normal. It is a slowly progressing condition with spontaneous remission possible. However, due to progressive muscle wasting patients may need supportive orthopaedic equipment or wheelchair assistance.[7] Proper foot care including custom-made shoes and leg braces may minimize discomfort and increase function.

History

In 1926, scientists Gustave Roussy and Gabrielle Lévy reported 7 cases within a same family of a dominantly inherited disorder over 4 generations.[7] They noticed that prominent features of this disorder were an unsteady gait during early childhood and areflexia, or the absense of reflexes, which eventually lead to clumsiness and muscle weakness. During a nerve biopsy of a few of the original patients, the demyelinating lesions found led the scientists to believe that the Roussy–Lévy syndrome was a variant of demyelinating Charcot–Marie–Tooth disease (CMT-1).[7]

See also

References

  1. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/s00415-008-0896-5, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/s00415-008-0896-5 instead.
  2. ^ Müller, K. I., & Bekkelund, S. I. (2011). Epilepsy in a patient with ataxia caused by vitamin E deficiency. BMJ Case Reports, 2011.
  3. ^ a b Hewitt, S. M., & Tagoe, M. (2011). Surgical Management of Pes Cavus Deformity with an Underlying Neurological Disorder: A Case Presentation. The Journal of Foot and Ankle Surgery, 50(2), 235-240. doi: 10.1053/j.jfas.2010.12.003
  4. ^ a b Breit, S., Wachter, T., Schols, L., Gasser, T., Nagele, T., Freudenstein, D., & Kruger, R. (2009). Effective thalamic deep brain stimulation for neuropathic tremor in a patient with severe demyelinating neuropathy. [Case Reports Research Support, Non-U S Gov't]. J Neurol Neurosurg Psychiatry, 80(2), 235-236.
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/s00234-002-0847-2, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/s00234-002-0847-2 instead.
  6. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S0022-510X(97)00218-9, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S0022-510X(97)00218-9 instead.
  7. ^ a b c d e f g Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/1531-8249(199911)46:5<770::AID-ANA13>3.0.CO;2-U, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/1531-8249(199911)46:5<770::AID-ANA13>3.0.CO;2-U instead.
  8. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/brain/120.3.465, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/brain/120.3.465 instead.
  9. ^ Braathen, G. J. (2012). Genetic epidemiology of Charcot–Marie–Tooth disease. [10.1111/ane.12013]. Acta Neurologica Scandinavica, 126, iv-22.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1159/000117254, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1159/000117254 instead.
  11. ^ Sturtz, F. G., Chauvin, F., OllagnonRoman, E., Bost, M., Latour, P., Bonnebouche, C., . . . Rendu, M. (1996). Modelization of motor nerve conduction velocities for Charcot-Marie-Tooth (type-1) patients. [Article]. European Neurology, 36(4), 224-228. doi: 10.1159/000117254
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10451742, please use {{cite journal}} with |pmid=10451742 instead.
  13. ^ Dupre, N., Bouchard, J. P., Cossette, L., Brunet, D., Vanasse, M., Lemieux, B., . . . Puymirat, J. (1999). Clinical and electrophysiological study in French-Canadian population with Charcot-Marie-Tooth disease type 1A associated with 17p11.2 duplication. [Article]. Canadian Journal of Neurological Sciences, 26(3), 196-200.
  14. ^ Breit, S., Wachter, T., Schols, L., Gasser, T., Nagele, T., Freudenstein, D., & Kruger, R. (2009). Effective thalamic deep brain stimulation for neuropathic tremor in a patient with severe demyelinating neuropathy. [Article]. Journal of Neurology Neurosurgery and Psychiatry, 80(2), 235-236. doi: 10.1136/jnnp.2008.145656
  15. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1111/j.1749-6632.1999.tb08560.x, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1111/j.1749-6632.1999.tb08560.x instead.
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