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GARS-Associated Axonal Neuropathy

Includes: Charcot-Marie-Tooth Neuropathy Type 2D (CMT2D), Distal Spinal Muscular Atrophy V (dSMA-V)

, MD and , MD.

Author Information
, MD
Clinical Neurogenetics Unit
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, Maryland
, MD
Neuromuscular Research Center
Barrow Neurological Institute
St Joseph's Hospital and Medical Center
Phoenix, Arizona

Initial Posting: ; Last Update: August 25, 2011.

Summary

Disease characteristics. GARS-associated axonal neuropathy (Charcot-Marie-Tooth neuropathy type 2D/distal spinal muscular atrophy V [CMT2D/dSMA-V]) is characterized by adolescent or early-adult onset of bilateral weakness and atrophy of thenar and first dorsal interosseus muscles, sparing of the hypothenar eminence until later in the course of illness, and mild to moderate impairment of vibration sense in the hands and feet later in the disease course in a minority of individuals. The phenotype is considered the CMT2D subtype when sensory deficits (reduction of pinprick, temperature, touch, and vibration perception in a stocking and [less often] glove pattern) are present and dSMA-V when sensory deficits are absent. The lower limbs are involved in about half of affected individuals. The earliest elicited manifestations in many individuals are transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion.

Diagnosis/testing. The diagnosis of GARS-associated axonal neuropathy is based on clinical findings, electromyography (EMG), and molecular genetic testing of GARS, encoding glycyl-tRNA synthetase.

Management. Treatment of manifestations: Assistive devices for weak hands, ankle support, toe-up braces, ankle-foot orthotics as necessary.

Surveillance: Periodic assessment by a neurologist and/or neuromuscular disorders specialist to asses progression of weakness in the limbs and determine the need for prosthetic or assistive devices.

Genetic counseling. GARS-associated axonal neuropathy is inherited in an autosomal dominant manner. Most individuals diagnosed with the disorder have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with GARS-associated axonal neuropathy has a 50% chance of inheriting the mutation. Prenatal testing is possible if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

GARS-associated axonal neuropathy (Charcot-Marie-Tooth neuropathy type 2D/distal spinal muscular atrophy V [CMT2D/dSMA-V]) is characterized by the following:

  • Adolescent or early-adult onset of bilateral weakness and atrophy of thenar and first dorsal interosseus muscles. The disease progresses to involve hypothenar, foot, and peroneal muscles in most (not all) individuals.
  • Mild to moderate impairment of vibration sense developing in advanced illness in a minority of individuals
  • Chronic denervation on EMG in distal muscles with reduced compound motor action potentials at near-normal or normal motor conduction velocities and preserved sensory nerve action potentials (SNAPs), including the sural response. See Electrophysiologic studies.
  • Mild to moderate selective loss of small- and medium-size myelinated and small unmyelinated axons on sural nerve biopsy. See Nerve biopsy.
  • CMT2D phenotype only: presence of sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern
  • Family history consistent with autosomal dominant inheritance

Electrophysiologic studies are consistent with motor axonopathy. A demyelinating neuropathy is not associated with this entity (Table 1). EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities:

  • Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [Sivakumar et al 2005].
  • Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation.
  • CMAP amplitude recorded by stimulation of the peroneal nerve is below 2 mV in most individuals and below 1 mV in individuals having clinically evident leg atrophy.
  • Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency.
  • In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles.
  • The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V.

Table 1. Results of Electrophysiologic Studies in GARS-Associated Axonal Neuropathy Subtypes

Results of Electrophysiologic StudiesSubtype
CMT2D (%)dSMA-V (%)
Motor Nerve ConductionCompound muscle action potential
Median-APB <4.5 mV100100
Ulnar-ADM <3.5 mV00
Peroneal-EDB <2 mV10062.5
Tibial-AH <2.5 mV050
Distal motor latency
Median <5.6 ms00
Ulnar <4.5 ms011
Peroneal & tibial <7.5 ms00
Nerve conduction velocity
Median & ulnar <39 m/s00
Peroneal & tibial <29 m/s00
Sensory Nerve ConductionSensory nerve action potential
Median <10 µV; ulnar <8 µV012
Sural <6 µV1729

APB = Abductor pollicis brevis

ADM = Abductor digiti minimi

EDB = Extensor digitorum brevis

AH = Adductor hallucis

Nerve biopsy. The dSMA-V subtype shows clear signs of axonal pathology with two or more regenerative clusters per fascicle (Figure 1A). No evidence of active degeneration and no obvious signs of demyelination or typical onion bulb formation are present. Myelin structures appear normal. Overall myelinated fiber density is normal (Figure 1B). Fibers less than 7 mm in diameter represent 52% of the overall number of fibers in the affected individual compared to 65% in control specimens. Electron microscopy (EM) shows denervated Schwann cell subunits as indicated by an increased number of profiles, suggesting damage to small unmyelinated nerve fibers (UMNFs) (Figure 1C). The UMNF density is at the low normal level.

Figure 1

Figure

Figure 1. Sural nerve morphology in GARS mutation-related dSMA-V and CMT2D phenotypes

A. dSMA-V. Pathologic changes are minimal with a near-normal myelinated nerve fiber density.
B. CMT2D. Myelinated nerve fiber density is moderately (more...)

The CMT2D subtype shows clear evidence of axonal pathology in nerve biopsy in one individual. Axonal swelling with filamentous accumulations (Figure 1D) and four to eight regenerative clusters per fascicle are observed (Figure 1E). Pseudo onion bulb formations and a few thinly myelinated fibers are seen. Myelin structures appear intact. Overall myelinated fiber density is reduced. The proportion of fibers less than 7 mm in diameter is only 46%. Denervation of Schwann cell subunits as indicated by an increased number of profiles is seen on EM.

Molecular Genetic Testing

Gene. GARS-associated axonal neuropathy is caused by mutations in GARS, the gene encoding glycyl-tRNA synthetase.

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in GARS-Associated Axonal Neuropathy

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
GARSSequence analysisSequence variants 2Unknown 3
Deletion / duplication analysis 4Exonic or whole-gene deletions / duplicationsUnknown; none reported 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Sequence analysis of GARS detects all known pathologic mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

5. No deletions or duplications of GARS have been reported to cause GARS-associated axonal neuropathy. Therefore, the usefulness of this testing is unknown.

Testing Strategy

Confirming/establishing the diagnosis in a proband. A preliminary diagnosis can be made based on clinical data and electrophysiologic findings (i.e., EMG); confirmation of the diagnosis requires molecular genetic testing of GARS. Note: EMG is more widely available than nerve biopsy, which can be used in a single individual in a family or in diagnostically difficult cases.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

CMT2D (distal motor and sensory neuropathy) [Ionasescu et al 1996] and dSMA-V (exclusively motor distal involvement) [Christodoulou et al 1995] were originally thought to be distinct entities, but family studies [Sambuughin et al 1998, Ellsworth et al 1999] and later molecular genetic studies [Antonellis et al 2003, Del Bo et al 2006] determined that they are allelic. In this GeneReview the term GARS-associated axonal neuropathy includes these two allelic disorders.

Both disease subtypes, CMT2D and dSMA-V, are characterized by adolescent or early-adult onset of unique patterns of motor and sensory manifestations. The hallmark is the onset of weakness and atrophy in the thenar and the first dorsal interosseus muscles and the sparing of the hypothenar eminence until later in the course of illness. The lower limbs are involved in about half of affected individuals; mild loss of vibration sense is observed in a third of individuals in advanced disease.

The presenting symptom is muscle weakness in the hands occurring between age eight and 36 years, with most individuals (75%) developing symptoms during the second decade of life [Sivakumar et al 2005]. The earliest elicited manifestations of illness in many individuals are transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interossei muscles are the major complaints in affected individuals (Figure 2, Table 3)

Figure 2

Figure

Figure 2. Distribution of muscle weakness and atrophy in individuals with two major clinical subtypes of GARS mutation associated disease

A. Thenar and first dorsal interosseus muscle wasting with relatively preserved hypothenar in an (more...)

Lower extremity involvement, when present, varies in severity from weakness and atrophy of the extensor digitorum brevis (EDB) and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop. Peroneal muscles are affected earlier and more severely than the calf muscles. If peroneal muscular atrophy develops, it is associated with pes cavus and moderate sensory abnormalities in stocking distribution and (less often) glove distribution. Individuals with lower leg involvement have a high steppage gait.

Proximal limb muscle weakness is not observed in the upper or lower extremities.

Sensory examination is either normal or shows mild to moderate impairment of vibration sense in the hands and feet; in individuals with the CMT2D subtype, reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern is observed (Table 3).

Reflexes at the ankles are diminished or absent in individuals with leg muscle weakness and sensory deficits.

Table 3. Phenotypic Features of GARS-Associated Axonal Neuropathy Subtypes

Symptoms and SignsSubtype
CMT2D (%)dSMA-V (%)
Progressive bilateral weakness and wasting of thenar and FDI muscles 1 100100
Peroneal weakness with atrophy and pes cavus 10057.5
Pyramidal dysfunction012.5
Reduced sensation for touch, pain, and temperature1000
Reduced vibration sense10037.5

Sivakumar et al [2005]

1. FDI = First dorsal interosseus

Genotype-Phenotype Correlations

The GARS variants p.Lys129Pro and p.His418Arg are exclusively associated with the dSMA-V clinical subtype; p.Gly240Arg, p.Ile280Phe, and p.Gly526Arg are associated with the CMT2D subtype. The variants p.Glu71Gly, p.Pro244Lys, and p.Asp500Asn are identified in families with both subtypes.

Penetrance

GARS variants p.Lys129Pro and p.His418Arg are incompletely penetrant; however, data regarding the actual penetrance are limited.

Anticipation

Anticipation is not observed.

Nomenclature

The term GARS-associated axonal neuropathy includes an axonal form of CMT type 2 and a similar group of clinical syndromes classified as distal hereditary motor neuropathy or distal spinal muscular atrophy (dSMA-V). GARS-associated axonal neuropathy is considered the CMT2D subtype when sensory deficits (reduction of pinprick, temperature, touch, and vibration perception in a stocking and [less often] glove pattern) are present and dSMA-V when sensation is normal or a sensory response is present on nerve conduction studies.

Prevalence

Disease prevalence is unknown and is likely very rare. Within the past eight years, only a dozen families with GARS-associated axonal neuropathy have been identified worldwide [Motley et al 2010].

Differential Diagnosis

GARS-associated axonal neuropathy needs to be distinguished from other forms of CMT, spinal muscular atrophy (SMA), and unrelated but similar neurologic conditions.

Other subtypes of Charcot-Marie-Tooth disease type 2 (CMT2) have a wide range of onset age and diverse manifestations. Generally, individuals with CMT2 present with distal muscular atrophy, loss of reflexes, sensory deficits, reduced sensory nerve action potentials (SNAPs), and normal or mildly slowed motor nerve conduction velocity. The unique pattern of hand involvement before leg involvement and preserved SNAPs helps distinguish CMT2D from other CMT2 subtypes.

Other types of distal spinal muscular atrophy (dSMA), a genetically heterogeneous group of disorders caused by progressive degeneration of anterior horn neurons, is characterized by slowly progressive muscle weakness and atrophy in the distal limbs without sensory deficits. SNAPs are preserved and motor conduction velocities are nearly normal. A separate set of genes in which mutation is disease-causing have been associated with dSMA subtypes [Irobi et al 2004a, Irobi et al 2004c]. The pattern of hand involvement before leg involvement distinguishes dSMA-V from other dSMA subtypes. A dSMA-V variant associated with spasticity in the legs and amyotrophy in the hands is known as Silver syndrome [Silver 1966]. Caused by mutations in BSCL2, encoding seipin [Irobi et al 2004b, Windpassinger et al 2004], Silver syndrome is now known to be part of the spectrum of the BSCL2-related neurologic disorders. In contrast to Silver syndrome, in which most individuals have spasticity, only a minority of individuals with GARS-associated axonal neuropathy show mild pyramidal signs and spasticity (Table 3) [Christodoulou et al 1995, Sivakumar et al 2005, Dubourg et al 2006].

Other neurologic disorders. The clinical pattern of disease onset with hand weakness and atrophy rather than foot involvement and absent sensory deficits in the early stages of the illness should raise a suspicion of carpal tunnel syndrome, neurogenic thoracic outlet syndrome, or multifocal motor neuropathy:

  • In the absence of family history, paresthesia, and pain, the clinical pattern of median nerve dysfunction at the wrist in individuals with carpal tunnel syndrome may be similar to that seen in the early stages of GARS-associated axonal neuropathy. Carpal tunnel syndrome is usually asymmetric and limited to median nerve.
  • Compression of the lower cervical and T1 roots caused by a cervical rib may result in neurogenic thoracic outlet syndrome. In this condition, thenar, hypothenar and interossei weakness/atrophy is associated with ulnar and medial antebrachial cutaneous hypesthesia that could be validated by nerve conduction studies that show reduced SNAP amplitudes in the medial antebrachial cutaneous and ulnar nerves.
  • Multifocal motor neuropathy is a sporadic autoimmune demyelinating disease causing slowly progressing motor disturbances in peripheral nerve distributions, predominantly in the distal upper extremities. It is often asymmetric and eventually involves hand muscles innervated by two or more motor nerves. Electrophysiologic conduction block can be demonstrated in the motor nerves and anti GM1 antibody titers are often elevated.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to distal spinal muscular atrophy V, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the diagnosis and extent of disease in an individual diagnosed with GARS-associated axonal neuropathy, nerve conduction studies and EMG of arms and legs are recommended.

Treatment of Manifestations

Appropriate treatment includes:

  • Prosthetic and adaptive devices for weak hands. Numerous devices are available for various activities of daily living.
  • Ankle support, toe-up braces, and ankle-foot orthotics, as necessary to improve gait.

Prevention of Secondary Complications

Stretching exercises, finger splints, and ankle braces to prevent contractures and deformities are appropriate.

Surveillance

Surveillance includes periodic assessment by a neurologist and/or a neuromuscular disorders specialist to assess progression of weakness in the limbs and determine the need for use of prosthetic and assistive devices.

Agents/Circumstances to Avoid

Avoid neurotoxic agents (chemotherapy that may cause peripheral nerve injury).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

GARS-associated axonal neuropathy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with GARS-associated axonal neuropathy have an affected parent. The family history may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or late onset of the disease.
  • A proband with GARS-associated axonal neuropathy may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic exam, a nerve conduction study, and molecular genetic testing if a mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but is greater than that of the general population because of the possibility of germline mosaicism.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with GARS-associated axonal neuropathy is at a 50% risk of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has a disease-causing mutation and/or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. GARS-Associated Axonal Neuropathy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for GARS-Associated Axonal Neuropathy (View All in OMIM)

600287GLYCYL-tRNA SYNTHETASE; GARS
600794NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VA; HMN5A
601472CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D; CMT2D

Normal allelic variants. GARS spans 40 kb and contains 17 exons. The 2.7-kb GARS transcript is ubiquitously expressed. There are six known sequence variants: two (p.Ser252Leu and p.Gln334Arg) are nonsynonymous and four are synonymous.

Pathologic allelic variants. The mutations are distributed throughout the protein in multiple functional domains.

To date, 11 mutations in GARS have been reported:

The variants p.Leu129Pro and p.His418Arg are associated exclusively with the dSMA-V clinical subtype; p.Gly240Arg, p.Ile280Phe, and p.Gly526Arg are associated with the CMT2D subtype. Families with the p.Glu71Gly, p.Pro244Leu, and p.Asp500Asn variants had both subtypes.

Normal gene product. Glycyl-tRNA synthetase, a class II aminoacyl-tRNA synthetase, performs an essential function in protein synthesis in the ribosome by catalyzing aminoacylation of glycyl-tRNA, which is required for charging tRNA with cognate amino acids [Ge et al 1994]. The enzyme must properly recognize the tRNA species and the amino acid in order to maintain fidelity of translation. In accordance with its function, glycyl-tRNA synthetase contains three domains: a catalytic core, a C-terminal anticodon recognition domain, and a domain that interacts with the acceptor stem of glycyl-tRNA [Freist et al 1996]. Glycyl-tRNA synthetase is ubiquitously expressed and absolutely necessary for protein translation in all cells.

Abnormal gene product. Some of the reported mutations cause loss of function as assayed by in vitro aminoacylation or yeast viability. These results are consistent with a disease mechanism of haploinsufficiency in charging function. However, other mutations do not alter enzyme activity in these assays, suggesting more complicated disease mechanisms apparently associated with GARS functions. Since the discovery of glycyl-tRNA synthetase role in CMT2D, the challenge has been to determine how missense mutations in this critical and widely expressed protein cause selective degeneration of axons in peripheral nerves.

Further research efforts are needed for identification of specific disease mechanisms affecting peripheral axons.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  20. 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;36:271–6. [PubMed: 14981520]

Suggested Reading

  1. Anderson K, Talbot K. Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol. 2003;16:595–9. [PubMed: 14501843]
  2. Barisic N, Claeys KG, Sirotković-Skerlev M, Löfgren A, Nelis E, De Jonghe P, Timmerman V. Charcot-Marie-Tooth disease: a clinico-genetic confrontation. Ann Hum Genet. 2008;72:416–41. [PubMed: 18215208]
  3. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy: I. Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol. 1968a;18:603–18. [PubMed: 4297451]
  4. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy: II. Neurologic, genetic and electrophysiologic findings in various neuronal degenerations. Arch Neurol. 1968b;18:619–25. [PubMed: 5652992]
  5. Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH, Ludlow CL, Fischbeck KH. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33:455–6. [PubMed: 12627231]
  6. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004;36:449–51. [PubMed: 15064763]

Chapter Notes

Acknowledgments

This work was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Revision History

  • 25 August 2011 (me) Comprehensive update posted live
  • 30 January 2007 (lgg) Revision: sequence analysis clinically available for mutations in GARS
  • 8 November 2006 (me) Review posted to live Web site
  • 24 February 2006 (lgg) Original submission
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