#605285
Table of Contents
Alternative titles; symbols
A number sign (#) is used with this entry because the Russe type of hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease type 4G (CMT4G), is caused by homozygous mutation in the HK1 gene (142600) on chromosome 10q22.
For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).
HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by Sevilla et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).
During studies of Romany (Gypsy) families with the Lom type of hereditary motor and sensory neuropathy (CMT4D; 601455), Rogers et al. (2000) identified a large kindred with 2 independently segregating autosomal recessive neuropathies. The novel disorder, which the authors called 'hereditary motor and sensory neuropathy/Russe' (HMSNR), presented as a severe disabling form of Charcot-Marie-Tooth disease with prominent sensory loss, moderately reduced motor nerve conduction velocity, and a high threshold for electrical nerve stimulation.
Thomas et al. (2001) reported 21 affected individuals from 10 families with HMSNR. Distal lower limb weakness began between ages 8 and 16 years, and upper limb involvement began between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in 2 instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was a loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve.
Navarro and Teijeira (2003) provided a detailed review of neuromuscular disorders among the Romani Gypsies.
Sevilla et al. (2013) reported 11 patients from 7 unrelated Spanish Gypsy families with HMSNR. All except 1 developed distal lower limb weakness in the first decade; 1 had onset at age 16 years. Distal upper limb weakness was also present in all patients, but showed a slightly later and more variable onset. About half of patients later had proximal muscle involvement. All patients had distal sensory loss with areflexia and pes cavus, and 5 had scoliosis. The majority of patients walked with difficulty, 4 needed orthoses, and an older patient was wheelchair-bound. Neurophysiologic studies were mostly consistent with demyelination, although some were in the intermediate range. Sural nerve biopsy of 1 patient showed thin myelin sheath thickness and clusters of regenerative fibers.
The transmission pattern of HMSNR in the families reported by Hantke et al. (2009) was consistent with autosomal recessive inheritance.
By genome scan in 2 branches of a large kindred with hereditary motor and sensory neuropathy, Rogers et al. (2000) detected linkage to the 10q22-q23 region containing the early growth response-2 gene (EGR2; 129010). By sequence analysis and the detection of an intragenic polymorphism, Rogers et al. (2000) excluded EGR2 as the site of mutation in HMSNR. By further linkage analysis and recombination mapping, the authors refined the position of HMSNR to a small interval on 10q23.2, flanked by markers telomeric to EGR2. In this interval, a conserved 7-marker haplotype was shared by all disease chromosomes, suggesting a single founder mutation.
Claramunt et al. (2007) found that 3 of 20 Spanish Gypsy families with autosomal recessive demyelinating neuropathy had HMSN-Russe as indicated by positive linkage results to the 10q23 region.
In all 34 individuals with Russe type of hereditary motor and sensory neuropathy who were studied, Hantke et al. (2009) identified 2 homozygous sequence changes in the HK1 gene (142600), which maps within the candidate disease interval on chromosome 10q. One was a G-to-C transversion at a highly conserved nucleotide in the putative AltT2 exon located in the 5-prime region upstream of HK1 (142600.0003), and the other was an intronic G-to-A transition downstream of the AltT2 change; the G-to-A transition was not highly conserved, and thus not thought to be pathogenic. These 2 variants were found in heterozygous state in 5 of 790 control individuals representing a cross-section of the Gypsy population, but not in 233 Bulgarian controls. AltT2-containing transcripts in the mouse peripheral nerve were rare compared to the coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms were found, with expression patterns differing between the peripheral nerve and the brain and between newborn and adult tissues in mice. There was no difference in HK1 mRNA in Schwann cells derived from patients or controls, and patient cells showed no evidence of HK1 enzyme activity compared to controls. Bioinformatic tools did not suggest an effect of the G-C change on HK1 gene splicing or binding sites for interacting proteins. However, there was evidence that the G-C change may cause a ter-to-tyr substitution in 1 upstream open reading frame that had a non-AUG start codon, which could potentially disrupt HK1 translation regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may play a role in the pathogenesis of HMSNR.
Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families were homozygous for the HK1 variant (g.9712G-C; 142600.0003) identified by Hantke et al. (2009), and haplotype analysis confirmed a founder effect in this population.
HMSNR is the second most common cause of Charcot-Marie-Tooth disease in the Spanish Gypsy population (Roma) after CMT4C (601596), and is associated with a homozygous founder variant in the HK1 gene (142600.0003). Sevilla et al., 2013 found that 11 patients from 9 Roma Gypsy families with the disorder were homozygous for the HK1 variant, and haplotype analysis indicated a founder effect. The founding ancestor was estimated to have lived at the end of the 18th century, when a population split occurred from a tribal group and the Gypsy population in Spain increased under the rule of Charles III.
De Sandre-Giovannoli et al. (2005) suggested that HMSNR be referred to as Charcot-Marie-Tooth disease type 4G (CMT4G).
Claramunt, R., Sevilla, T., Lupo, V., Cuesta, A., Millan, J.M., Vilchez, J. J., Palau, F., Espinos, C. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin. Genet. 71: 343-349, 2007. [PubMed: 17470135, related citations] [Full Text]
De Sandre-Giovannoli, A., Delague, V., Hamadouche, T., Chaouch, M., Krahn, M., Boccaccio, I., Maisonobe, T., Chouery, E., Jabbour, R., Atweh, S., Grid, D., Megarbane, A., Levy, N. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. (Letter) J. Med. Genet. 42: 260-265, 2005. [PubMed: 15744041, related citations] [Full Text]
Hantke, J., Chandler, D., King, R., Wanders, R. J. A., Angelicheva, D., Tournev, I., McNamara, E., Kwa, M., Guergueltcheva, V., Kaneva, R., Baas, F., Kalaydjieva, L. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy - Russe (HMSNR). Europ. J. Hum. Genet. 17: 1606-1614, 2009. [PubMed: 19536174, images, related citations] [Full Text]
Navarro, C., Teijeira, S. Neuromuscular disorders in the Gypsy ethnic group: a short review. Acta Myol. 22: 11-14, 2003. [PubMed: 12966699, related citations]
Rogers, T., Chandler, D., Angelicheva, D., Thomas, P. K., Youl, B., Tournev, I., Gergelcheva, V., Kalaydjieva, L. A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23. Am. J. Hum. Genet. 67: 664-671, 2000. [PubMed: 10915613, images, related citations] [Full Text]
Sevilla, T., Martinez-Rubio, D., Marquez, C., Paradas, C., Colomer, J., Jaijo, T., Millan, J. M., Palau, F., Espinos, C. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth. Clin. Genet. 83: 565-570, 2013. [PubMed: 22978647, related citations] [Full Text]
Thomas, P. K., Kalaydjieva, L., Youl, B., Rogers, T., Angelicheva, D., King, R. H. M., Guergueltcheva, V., Colomer, J., Lupu, C., Corches, A., Popa, G., Merlini, L., Shmarov, A., Muddle, J. R., Nourallah, M., Tournev, I. Hereditary motor and sensory neuropathy-Russe: new autosomal recessive neuropathy in Balkan Gypsies. Ann. Neurol. 50: 452-457, 2001. [PubMed: 11601496, related citations] [Full Text]
Alternative titles; symbols
SNOMEDCT: 715799004; ORPHA: 99953; DO: 0110196;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q22.1 | Neuropathy, hereditary motor and sensory, Russe type | 605285 | Autosomal recessive | 3 | HK1 | 142600 |
A number sign (#) is used with this entry because the Russe type of hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease type 4G (CMT4G), is caused by homozygous mutation in the HK1 gene (142600) on chromosome 10q22.
For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).
HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by Sevilla et al., 2013).
For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).
During studies of Romany (Gypsy) families with the Lom type of hereditary motor and sensory neuropathy (CMT4D; 601455), Rogers et al. (2000) identified a large kindred with 2 independently segregating autosomal recessive neuropathies. The novel disorder, which the authors called 'hereditary motor and sensory neuropathy/Russe' (HMSNR), presented as a severe disabling form of Charcot-Marie-Tooth disease with prominent sensory loss, moderately reduced motor nerve conduction velocity, and a high threshold for electrical nerve stimulation.
Thomas et al. (2001) reported 21 affected individuals from 10 families with HMSNR. Distal lower limb weakness began between ages 8 and 16 years, and upper limb involvement began between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in 2 instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was a loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve.
Navarro and Teijeira (2003) provided a detailed review of neuromuscular disorders among the Romani Gypsies.
Sevilla et al. (2013) reported 11 patients from 7 unrelated Spanish Gypsy families with HMSNR. All except 1 developed distal lower limb weakness in the first decade; 1 had onset at age 16 years. Distal upper limb weakness was also present in all patients, but showed a slightly later and more variable onset. About half of patients later had proximal muscle involvement. All patients had distal sensory loss with areflexia and pes cavus, and 5 had scoliosis. The majority of patients walked with difficulty, 4 needed orthoses, and an older patient was wheelchair-bound. Neurophysiologic studies were mostly consistent with demyelination, although some were in the intermediate range. Sural nerve biopsy of 1 patient showed thin myelin sheath thickness and clusters of regenerative fibers.
The transmission pattern of HMSNR in the families reported by Hantke et al. (2009) was consistent with autosomal recessive inheritance.
By genome scan in 2 branches of a large kindred with hereditary motor and sensory neuropathy, Rogers et al. (2000) detected linkage to the 10q22-q23 region containing the early growth response-2 gene (EGR2; 129010). By sequence analysis and the detection of an intragenic polymorphism, Rogers et al. (2000) excluded EGR2 as the site of mutation in HMSNR. By further linkage analysis and recombination mapping, the authors refined the position of HMSNR to a small interval on 10q23.2, flanked by markers telomeric to EGR2. In this interval, a conserved 7-marker haplotype was shared by all disease chromosomes, suggesting a single founder mutation.
Claramunt et al. (2007) found that 3 of 20 Spanish Gypsy families with autosomal recessive demyelinating neuropathy had HMSN-Russe as indicated by positive linkage results to the 10q23 region.
In all 34 individuals with Russe type of hereditary motor and sensory neuropathy who were studied, Hantke et al. (2009) identified 2 homozygous sequence changes in the HK1 gene (142600), which maps within the candidate disease interval on chromosome 10q. One was a G-to-C transversion at a highly conserved nucleotide in the putative AltT2 exon located in the 5-prime region upstream of HK1 (142600.0003), and the other was an intronic G-to-A transition downstream of the AltT2 change; the G-to-A transition was not highly conserved, and thus not thought to be pathogenic. These 2 variants were found in heterozygous state in 5 of 790 control individuals representing a cross-section of the Gypsy population, but not in 233 Bulgarian controls. AltT2-containing transcripts in the mouse peripheral nerve were rare compared to the coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms were found, with expression patterns differing between the peripheral nerve and the brain and between newborn and adult tissues in mice. There was no difference in HK1 mRNA in Schwann cells derived from patients or controls, and patient cells showed no evidence of HK1 enzyme activity compared to controls. Bioinformatic tools did not suggest an effect of the G-C change on HK1 gene splicing or binding sites for interacting proteins. However, there was evidence that the G-C change may cause a ter-to-tyr substitution in 1 upstream open reading frame that had a non-AUG start codon, which could potentially disrupt HK1 translation regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may play a role in the pathogenesis of HMSNR.
Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families were homozygous for the HK1 variant (g.9712G-C; 142600.0003) identified by Hantke et al. (2009), and haplotype analysis confirmed a founder effect in this population.
HMSNR is the second most common cause of Charcot-Marie-Tooth disease in the Spanish Gypsy population (Roma) after CMT4C (601596), and is associated with a homozygous founder variant in the HK1 gene (142600.0003). Sevilla et al., 2013 found that 11 patients from 9 Roma Gypsy families with the disorder were homozygous for the HK1 variant, and haplotype analysis indicated a founder effect. The founding ancestor was estimated to have lived at the end of the 18th century, when a population split occurred from a tribal group and the Gypsy population in Spain increased under the rule of Charles III.
De Sandre-Giovannoli et al. (2005) suggested that HMSNR be referred to as Charcot-Marie-Tooth disease type 4G (CMT4G).
Claramunt, R., Sevilla, T., Lupo, V., Cuesta, A., Millan, J.M., Vilchez, J. J., Palau, F., Espinos, C. The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4. Clin. Genet. 71: 343-349, 2007. [PubMed: 17470135] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00774.x]
De Sandre-Giovannoli, A., Delague, V., Hamadouche, T., Chaouch, M., Krahn, M., Boccaccio, I., Maisonobe, T., Chouery, E., Jabbour, R., Atweh, S., Grid, D., Megarbane, A., Levy, N. Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. (Letter) J. Med. Genet. 42: 260-265, 2005. [PubMed: 15744041] [Full Text: https://doi.org/10.1136/jmg.2004.024364]
Hantke, J., Chandler, D., King, R., Wanders, R. J. A., Angelicheva, D., Tournev, I., McNamara, E., Kwa, M., Guergueltcheva, V., Kaneva, R., Baas, F., Kalaydjieva, L. A mutation in an alternative untranslated exon of hexokinase 1 associated with hereditary motor and sensory neuropathy - Russe (HMSNR). Europ. J. Hum. Genet. 17: 1606-1614, 2009. [PubMed: 19536174] [Full Text: https://doi.org/10.1038/ejhg.2009.99]
Navarro, C., Teijeira, S. Neuromuscular disorders in the Gypsy ethnic group: a short review. Acta Myol. 22: 11-14, 2003. [PubMed: 12966699]
Rogers, T., Chandler, D., Angelicheva, D., Thomas, P. K., Youl, B., Tournev, I., Gergelcheva, V., Kalaydjieva, L. A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23. Am. J. Hum. Genet. 67: 664-671, 2000. [PubMed: 10915613] [Full Text: https://doi.org/10.1086/303053]
Sevilla, T., Martinez-Rubio, D., Marquez, C., Paradas, C., Colomer, J., Jaijo, T., Millan, J. M., Palau, F., Espinos, C. Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth. Clin. Genet. 83: 565-570, 2013. [PubMed: 22978647] [Full Text: https://doi.org/10.1111/cge.12015]
Thomas, P. K., Kalaydjieva, L., Youl, B., Rogers, T., Angelicheva, D., King, R. H. M., Guergueltcheva, V., Colomer, J., Lupu, C., Corches, A., Popa, G., Merlini, L., Shmarov, A., Muddle, J. R., Nourallah, M., Tournev, I. Hereditary motor and sensory neuropathy-Russe: new autosomal recessive neuropathy in Balkan Gypsies. Ann. Neurol. 50: 452-457, 2001. [PubMed: 11601496] [Full Text: https://doi.org/10.1002/ana.1137]
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