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'''Roussy–Lévy syndrome''', also known as '''Roussy–Lévy hereditary areflexic dystasia''', is a rare condition caused by [[genetic mutations]] in the ''[[PMP22]]'' gene (associated with [[Charcot–Marie–Tooth disease]] type 1A) and/or the ''[[MPZ]]'' [[gene]] (associated with [[Charcot–Marie–Tooth disease]] type 1B). It is unclear whether it is a separate medical entity or a specific [[phenotype]] of either. Similarly to both, it is also inherited in an [[autosomal dominant]] manner.<ref name="Auer">Auer-Grumbach, M.; Strasser-Fuchs, S.; Wagner, K.; Körner, E.; Fazekas, F. (1998). "Roussy–Lévy syndrome is a phenotypic variant of Charcot–Marie–Tooth syndrome IA associated with a duplication on chromosome 17p11.2". Journal of the Neurological Sciences 154 (1): 72–75.</ref><ref name="Plante">Plante-Bordeneuve, V., Guiochon-Mantel, A., Lacroix, C., Lapresle, J., & Said, G. (1999). The Roussy-Levy family: From the original description to the gene. [Article]. Annals of Neurology, 46(5), 770-773. doi: 10.1002/1531-8249(199911)46:5<770::aid-ana13>3.0.co;2-u</ref>
'''Roussy–Lévy syndrome''', also known as '''Roussy–Lévy hereditary areflexic dystasia''', is a rare condition caused by [[genetic mutations]] in the ''[[PMP22]]'' gene (associated with [[Charcot–Marie–Tooth disease]] type 1A) and/or the ''[[MPZ]]'' [[gene]] (associated with [[Charcot–Marie–Tooth disease]] type 1B). It is unclear whether it is a separate medical entity or a specific [[phenotype]] of either. Similarly to both, it is also inherited in an [[autosomal dominant]] manner<ref name="Auer">{{cite doi|10.1016/S0022-510X(97)00218-9}}</ref><ref name="Plante">{{cite doi|10.1002/1531-8249(199911)46:5<770::AID-ANA13>3.0.CO;2-U}}</ref>


Syndroms include foot deformity, weakness and [[atrophy]] of [[distal]] limb muscles, especially the [[peroneus|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]].
Syndroms include foot deformity, weakness and [[atrophy]] of [[distal]] limb muscles, especially the [[peroneus|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]].
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.



== History ==
== History ==
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[[Image:Picture of foot.jpg|thumb|300px|right|Person with arched feet, or drop-foot]]
[[Image:Picture of foot.jpg|thumb|300px|right|Person with arched feet, or drop-foot]]
People who suffer from the Roussy-Levy Syndrome experience symptoms such as gait [[ataxia]], [[pes cavus]], areflexia, eventually associated with [[muscle atrophy]], postural tremors, limb [[ataxia]], [[kyphoscoliosis]](when the spine curves sideways), and [[sensory loss]].<ref name="Zubair">Zubair, S., Holland, N. R., Beson, B., Parke, J. T., & Prodan, C. I. (2008). A novel point mutation in the PMP22 gene in a family with Roussy-Levy syndrome. [Letter]. Journal of Neurology, 255(9), 1417-1418. doi: 10.1007/s00415-008-0896-5</ref> It is also characterized by slow nerve conduction and demylination of nerve fibers with onion bulb formations in nerve biopsy specimens.<ref name="Plante" /> Other symptoms include muscle weakness and loss in the extremities, delay in onset of ability to walk, loss of coordination and balance, [[foot drop]], and foot-bone deformities.
People who suffer from the Roussy-Levy Syndrome experience symptoms such as gait [[ataxia]], [[pes cavus]], areflexia, eventually associated with [[muscle atrophy]], postural tremors, limb [[ataxia]], [[kyphoscoliosis]](when the spine curves sideways), and [[sensory loss]].<ref name="Zubair">Zubair, S., Holland, N. R., Beson, B., Parke, J. T., & Prodan, C. I. (2008). A novel point mutation in the PMP22 gene in a family with Roussy-Levy syndrome. [Letter]. Journal of Neurology, 255(9), 1417-1418. doi: 10.1007/s00415-008-0896-5</ref> It is also characterized by slow nerve conduction and demylination of nerve fibers with onion bulb formations in nerve biopsy specimens.<ref name="Plante" /> Other symptoms include muscle weakness and loss in the extremities, delay in onset of ability to walk, loss of coordination and balance, [[foot drop]], and foot-bone deformities.

Symptoms of this disease usually are 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. Distinctive characteristics of this disease include tremors (rhythmic shaking) in the hands and arms and unsteadiness of [[gait]].<ref name="Haubrich">Haubrich, C., Krings, T., Senderek, J., Zuchner, S., Schroder, J. M., Noth, J., & Topper, R. (2002). Hypertrophic nerve roots in a case of Roussy-Levy syndrome. [Article]. Neuroradiology, 44(11), 933-937. doi: 10.1007/s00234-002-0847-2</ref>
Symptoms of this disease usually are 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. Distinctive characteristics of this disease include tremors (rhythmic shaking) in the hands and arms and unsteadiness of [[gait]].<ref name="Haubrich">{{cite doi|10.1007/s00234-002-0847-2}}</ref>

Like with the majority of [[genetic disease]]s, there is no known cure to Roussy–Lévy syndrome.


== Causes ==
== Causes ==
⚫
Roussy Levy Syndrome is characterized as being an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 ([[PMP22]]), which is a critical component of the [[myelin]] sheath.<ref name="Auer" /><ref name="Zubair" /><ref>Pareyson, D., Dangelo, A., Mandich, P., Pandolfo, M., & Sghirlanzoni, A. (1993). ROUSSY-LEVY SYNDROME - A KINDRED WITH CHROMOSOME-17P11.2 DUPLICATION. [Meeting Abstract]. Neurology, 43(4), A214-A214.</ref><ref name="Thomas">Thomas, P. K., Marques, W., Davis, M. B., Sweeney, M. G., King, R. H. M., Bradley, J. L., . . . Harding, A. E. (1997). The phenotypic manifestations of chromosome 17p11.2 duplication. [Article]. Brain, 120, 465-478. doi: 10.1093/brain/120.3.465</ref>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 in the legs and [[foot drop]], translating to hand weakness and [[sensory loss]].
⚫
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 Roussy Levy Syndrome.


⚫
Roussy–Lévy syndrome is associated with a duplication of the ''[[PMPP]]'' gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 ([[PMP22]]), which is a critical component of the [[myelin]] sheath.<ref name="Auer" /><ref name="Zubair" /><ref>Pareyson, D., Dangelo, A., Mandich, P., Pandolfo, M., & Sghirlanzoni, A. (1993). "Roussy–Lévy Syndrome: A Kindred With Chromosome-17P11.2 Duplication". [Meeting Abstract]. Neurology, 43 (4), A214–A214.</ref><ref name="Thomas">{{cite doi|10.1093/brain/120.3.465}}</ref>When this gene is overexpressed, the function and structure of the [[myelin sheath]] becomes abnormal, which ultimately leads to weakness and [[atrophy]] of the muscles in the legs and [[foot drop]], translating to hand weakness and [[sensory loss]].
== Diagnosis ==
The diagnosis for Roussy-Levy Syndrome can be made based on which of the signs and symptoms are recognized.


⚫
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 Roussy–Lévy syndrome.
=== Nerve Conduction Study===
[[Image:Sensory neurography median nerve example.png|thumb|300px|left|An example of the results of a sensory nerve conduction velocity study]]
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.<ref>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</ref>


=== Electromyography (EMG)===
== Pathophysiology ==
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. In both Roussy-Levy Syndrome and [[Charcot-Marie-Tooth disease]], an EMG will show signs of mild neurogenic damage.<ref name="Thomas" /><ref>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. </ref>


Pathophysilological picture includes lowered [[nerve conduction velocity]] and histologic features of a hypertrophic demyelinating neuropathy.<ref>{{cite doi|10.1159/000117254}}</ref> As with other types of [[Charcoot–Marie–Tooth disease]], [[electromyography]] shows signs of mild neurogenic damage.<ref name="Thomas" /><ref>{[cite pmid|10451742}} while [[nerve biopsy]] shows onion bulb formations; the appearance of these formations is what primarily led scientists Roussy and Lévy to classify this disorder as a variant of [[Charcot–Marie–Tooth disease]].<ref name="Plante" />
=== Nerve Biopsy ===
A [[nerve biopsy]] 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.<ref name="Breit">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</ref> Onion bulb formations on nerve biopsy formations is what primarily led scientists Roussy and Levy to classify this disorder as a variant of Charcot-Marie tooth disorder. <ref name="Plante" />


== Treatment ==
== Diagnosis ==


While the clinical picture described above may point towards the diagnosis of Roussy–Lévy syndrome, only [[genetic testing]] can confirm or deny the diagnosis with absolute surety.
=== Physical Therapy ===
[[Image:Physical Therapists at work.jpg|thumb|400px|right|Example of different types of physical therapy procedures.]]
[[Physical therapy]] and moderate activity are often recommended to maintain movement, flexibility, muscle strength and endurance. Water therapy or swimming is usually recommended because it does not cause undue stress on the joints. 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. <ref name="Auer" />


== Treatment and management ==
=== Surgery ===

⚫
For some patients, surgery may be beneficial in correcting foot deformities. This, however, is usually a last resort. Most surgeries are done to correct or stabilize the feet problems. These procedures include 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.There also some medications that people with Roussy-Levy Syndrome should usually avoid as these medications may increase symptoms. <ref name="Plante" /><ref name="Thomas2">Thomas, P. K. (1999). Overview of Charcot-Marie-Tooth disease type 1A. In M. E. Shy, J. Kamholz & R. E. Lovelace (Eds.), Charcot-Marie-Tooth Disorders (Vol. 883, pp. 1-5). New York: New York Acad Sciences.</ref>
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.<ref name="Auer" />

⚫
Patients with foot deformities may benefit from [[corrective surgery]], which, however, is usually a last resort. Most such surgeries include 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.<ref name="Plante" /><ref name="Thomas2">Thomas, P. K. (1999). Overview of Charcot-Marie-Tooth disease type 1A. In M. E. Shy, J. Kamholz & R. E. Lovelace (Eds.), Charcot-Marie-Tooth Disorders (Vol. 883, pp. 1-5). New York: New York Acad Sciences.</ref>

While no medicines are reported to treat the disorder, patients are advised to avoid certain medications as they may aggravate the symptoms.


== Prognosis ==
== Prognosis ==

The Roussy-Levy is not a fatal disease. Children with Roussy-Levy Syndrome are expected to mature and become adults with a normal life expectancy.However, there are limitations and disabilities associated with the disorder. In some cases supportive orthopedic equipment or wheelchair assistance may be helpful. <ref name="Plante" />
The Roussy–Lévy syndrome is not a fatal disease and [[life expectancy]] is normal. However, due to progressive muscle wasting patients may need supportive orthopaedic equipment or wheelchair assistance.<ref name="Plante" />


== See also ==
== See also ==
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== References ==
== References ==
{{reflist|30em}}
{{reflist|30em}}





[[Category:Autosomal dominant disorders]]
[[Category:Autosomal dominant disorders]]

Revision as of 23:54, 19 November 2012

Roussy–Lévy syndrome
SpecialtyNeurology Edit this on Wikidata

Roussy–Lévy syndrome, also known as Roussy–Lévy hereditary areflexic dystasia, is a rare condition caused by genetic mutations in the PMP22 gene (associated with Charcot–Marie–Tooth disease type 1A) and/or the MPZ gene (associated with Charcot–Marie–Tooth disease type 1B). It is unclear whether it is a separate medical entity or a specific phenotype of either. Similarly to both, it is also inherited in an autosomal dominant manner[1][2]

Syndroms 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.

History

In 1926, scientists Gustave Roussy and Gabrielle Lévy reported 7 cases within a same family of a dominantly inherited disorder over 4 generations.[2] 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-Levy Syndrome was a variant of demyelinating Charcot-Marie-Tooth disease (CMT-1). [2]

Signs and Symptoms

Person with arched feet, or drop-foot

People who suffer from the Roussy-Levy Syndrome experience symptoms such as gait ataxia, pes cavus, areflexia, eventually associated with muscle atrophy, postural tremors, limb ataxia, kyphoscoliosis(when the spine curves sideways), and sensory loss.[3] It is also characterized by slow nerve conduction and demylination of nerve fibers with onion bulb formations in nerve biopsy specimens.[2] Other symptoms include muscle weakness and loss in the extremities, delay in onset of ability to walk, loss of coordination and balance, foot drop, and foot-bone deformities.

Symptoms of this disease usually are 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. Distinctive characteristics of this disease include tremors (rhythmic shaking) in the hands and arms and unsteadiness of gait.[4]

Like with the majority of genetic diseases, there is no known cure to Roussy–Lévy syndrome.

Causes

Roussy–Lévy syndrome is associated with a duplication of the PMPP gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22), which is a critical component of the myelin sheath.[1][3][5][6]When this gene is overexpressed, the function and structure of the myelin sheath becomes abnormal, which ultimately leads to weakness and atrophy of the muscles in the legs and foot drop, translating to hand weakness and sensory loss.

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 Roussy–Lévy syndrome.

Pathophysiology

Pathophysilological picture includes lowered nerve conduction velocity and histologic features of a hypertrophic demyelinating neuropathy.[7] As with other types of Charcoot–Marie–Tooth disease, electromyography shows signs of mild neurogenic damage.[6]Cite error: A <ref> tag is missing the closing </ref> (see the help page).

While no medicines are reported to treat the disorder, patients are advised to avoid certain medications as they may aggravate the symptoms.

Prognosis

The Roussy–Lévy syndrome is not a fatal disease and life expectancy is normal. However, due to progressive muscle wasting patients may need supportive orthopaedic equipment or wheelchair assistance.[2]

See also

References

  1. ^ 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.
  2. ^ a b c d e 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.
  3. ^ a b Zubair, S., Holland, N. R., Beson, B., Parke, J. T., & Prodan, C. I. (2008). A novel point mutation in the PMP22 gene in a family with Roussy-Levy syndrome. [Letter]. Journal of Neurology, 255(9), 1417-1418. doi: 10.1007/s00415-008-0896-5
  4. ^ 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.
  5. ^ Pareyson, D., Dangelo, A., Mandich, P., Pandolfo, M., & Sghirlanzoni, A. (1993). "Roussy–Lévy Syndrome: A Kindred With Chromosome-17P11.2 Duplication". [Meeting Abstract]. Neurology, 43 (4), A214–A214.
  6. ^ 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.
  7. ^ 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.
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