Distal hereditary motor neuropathy, type V is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle weakness and affects movement of the hands and feet.

Symptoms of distal hereditary motor neuropathy, type V usually begin during adolescence, but onset varies from infancy to the mid-thirties. Cramps in the hand brought on by exposure to cold temperatures are often the initial symptom.

The characteristic features of distal hereditary motor neuropathy, type V are weakness and wasting (atrophy) of muscles of the hand, specifically on the thumb side of the index finger and in the palm at the base of the thumb. Foot abnormalities, such as a high arch (pes cavus), are also common, and some affected individuals eventually develop problems with walking (gait disturbance). People with this disorder have normal life expectancies.

The incidence of distal hereditary motor neuropathy, type V is unknown. Only a small number of cases have been reported.

Mutations in the BSCL2 and GARS1 genes cause distal hereditary motor neuropathy, type V.

The BSCL2 gene provides instructions for making a protein called seipin, whose function is unknown. Mutations in the BSCL2 gene likely alter the structure of seipin, causing it to fold into an incorrect 3-dimensional shape. Research findings indicate that misfolded seipin proteins accumulate in the endoplasmic reticulum, which is a structure inside the cell that is involved in protein processing and transport. This accumulation likely damages and kills motor neurons (specialized nerve cells in the brain and spinal cord that control muscle movement), leading to muscle weakness in the hands and feet.

The GARS1 gene provides instructions for making an enzyme called glycine--tRNA ligase, which is involved in the production of proteins. It is unclear how GARS1 gene mutations lead to distal hereditary motor neuropathy, type V. The mutations probably reduce the activity of glycine--tRNA ligase. A reduction in the activity of this enzyme may impair transmission of nerve impulses. As a result, nerve cells slowly lose the ability to communicate with muscles in the hands and feet.

Mutations in other genes may also cause distal hereditary motor neuropathy, type V.

Genetic Testing Information

• Genetic Testing Registry: Neuronopathy, distal hereditary motor, type 5
• Genetic Testing Registry: Neuronopathy, distal hereditary motor, type 5A
• Genetic Testing Registry: Neuronopathy, distal hereditary motor, type 5B
• Genetic Testing Registry: Neuronopathy, distal hereditary motor, type 5C

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5; HMND5
• NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 12; HMND12

Scientific Articles on PubMed

• PubMed

• Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. 2003 May;72(5):1293-9. doi: 10.1086/375039. Epub 2003 Apr 10. Citation on PubMed or Free article on PubMed Central
• Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung K, Burgess S, Fischbeck KH, Green ED. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J Neurosci. 2006 Oct 11;26(41):10397-406. doi: 10.1523/JNEUROSCI.1671-06.2006. Citation on PubMed
• Auer-Grumbach M, Loscher WN, Wagner K, Petek E, Korner E, Offenbacher H, Hartung HP. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study. Brain. 2000 Aug;123 ( Pt 8):1612-23. doi: 10.1093/brain/123.8.1612. Citation on PubMed
• Beetz C, Pieber TR, Hertel N, Schabhuttl M, Fischer C, Trajanoski S, Graf E, Keiner S, Kurth I, Wieland T, Varga RE, Timmerman V, Reilly MM, Strom TM, Auer-Grumbach M. Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet. 2012 Jul 13;91(1):139-45. doi: 10.1016/j.ajhg.2012.05.007. Epub 2012 Jun 14. Citation on PubMed or Free article on PubMed Central
• Dubourg O, Azzedine H, Yaou RB, Pouget J, Barois A, Meininger V, Bouteiller D, Ruberg M, Brice A, LeGuern E. The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V. Neurology. 2006 Jun 13;66(11):1721-6. doi: 10.1212/01.wnl.0000218304.02715.04. Erratum In: Neurology. 2006 Aug 22;67(4):727. Citation on PubMed
• Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R195-202. doi: 10.1093/hmg/ddh226. Citation on PubMed
• Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol. 2007 Mar;61(3):237-50. doi: 10.1002/ana.21070. Citation on PubMed
• Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain. 2009 Jan;132(Pt 1):8-15. doi: 10.1093/brain/awn216. Epub 2008 Sep 12. Citation on PubMed
• Rohkamm B, Reilly MM, Lochmuller H, Schlotter-Weigel B, Barisic N, Schols L, Nicholson G, Pareyson D, Laura M, Janecke AR, Miltenberger-Miltenyi G, John E, Fischer C, Grill F, Wakeling W, Davis M, Pieber TR, Auer-Grumbach M. Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome. J Neurol Sci. 2007 Dec 15;263(1-2):100-6. doi: 10.1016/j.jns.2007.06.047. Epub 2007 Jul 30. Citation on PubMed or Free article on PubMed Central
• Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain. 2005 Oct;128(Pt 10):2304-14. doi: 10.1093/brain/awh590. Epub 2005 Jul 13. Citation on PubMed
• Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004 Mar;36(3):271-6. doi: 10.1038/ng1313. Epub 2004 Feb 22. Citation on PubMed