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GARS-Associated Axonal Neuropathy

, PhD, , MD, and , MD.

Author Information

Initial Posting: ; Last Update: November 29, 2018.

Estimated reading time: 19 minutes

Summary

Clinical 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 weakness in the hands that may be preceded by transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. This is followed by progressive weakness and atrophy of thenar and first dorsal interosseus muscles; hypothenar eminence is spared until later in the course of illness. The lower limbs are involved in about half of affected individuals, with severity varying from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop. 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.

Diagnosis/testing.

The diagnosis of GARS-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS identified by molecular genetic testing.

Management.

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

Surveillance: Assessment every six months by a neurologist and/or neuromuscular disorders specialist to assess 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 pathogenic variants is unknown. Each child of an individual with GARS-associated axonal neuropathy has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic diagnosis are possible if the pathogenic variant has been identified in an affected family member.

GeneReview Scope

GARS-Associated Axonal Neuropathy: Included Phenotypes 1
  • Charcot-Marie-Tooth neuropathy type 2D (CMT2D)
  • Distal spinal muscular atrophy V (dSMA-V)

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Charcot-Marie-Tooth neuropathy type 2D (CMT2D) characterized by distal motor and sensory neuropathy [Ionasescu et al 1996] and distal spinal muscular atrophy V (dSMA-V) with 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] determined that they represent the clinical spectrum associated with pathogenic variants in GARS. In this GeneReview the term "GARS-associated axonal neuropathy" comprises both allelic disorders.

Suggestive Findings

GARS-associated axonal neuropathy should be suspected in individuals with the following findings:

  • Adolescent or early-adult onset of bilateral weakness and atrophy of thenar and first dorsal interosseus muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild to moderate impairment of vibration sense developing in advanced illness in some individuals (dSMA-V phenotype)
  • Presence of sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern (CMT2D phenotype)
  • 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.
  • Family history consistent with autosomal dominant inheritance
    Note: Individuals with a negative family history and a more severe, early-onset phenotype have been described [Eskuri et al 2012].

Electrophysiologic Studies

EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities (see Table 1):

  • 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 <2 mV in most individuals and <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.

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. See Nerve Biopsy.

Table 1.

Results of Electrophysiologic Studies in GARS-Associated Axonal Neuropathy by Subtype

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 latencyMedian <5.6 ms00
Ulnar <4.5 ms011
Peroneal & tibial <7.5 ms00
Nerve conduction velocityMedian & ulnar <39 m/s00
Peroneal & tibial <29 m/s00
Sensory nerve conduction:
sensory nerve action potential
Median <10 µV; ulnar <8 µV012
Sural <6 µV1729

ADM = abductor digiti minimi; AH = adductor halluces; APB = abductor pollicis brevis; EDB = extensor digitorum brevis

Establishing the Diagnosis

The diagnosis of GARS-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS identified by molecular genetic testing (see Table 2).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GARS-associated axonal neuropathy is potentially broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from other inherited disorders with neuromuscular weakness or sensory deficits in whom the diagnosis of GARS-associated axonal neuropathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When phenotypic and laboratory findings suggest the diagnosis of GARS-associated axonal neuropathy, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of GARS detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A multigene panel that includes GARS and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from other inherited disorders characterized by neuromuscular weakness or sensory deficits or when the diagnosis of GARS-associated axonal neuropathy is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in GARS-Associated Axonal Neuropathy

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
GARSSequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

In this GeneReview the term "GARS-associated axonal neuropathy" includes both Charcot-Marie-Tooth neuropathy type 2D (CMT2D) characterized by distal motor and sensory neuropathy) and distal spinal muscular atrophy V (dSMA-V) with exclusively motor distal involvement.

Onset. Both disease subtypes, CMT2D and dSMA-V, are characterized by adolescent or early-adult onset of unique patterns of motor and sensory manifestations. Age of onset ranges from eight to 36 years, with most individuals (75%) developing symptoms during the second decade of life [Sivakumar et al 2005, James et al 2006]. However, infantile onset has also been reported in individuals who have de novo GARS pathogenic variants [Eskuri et al 2012].

Presentation. The presenting symptom is typically muscle weakness in the hands. 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 interosseus muscles are the major complaints in affected individuals (Figure 2, Table 3). The hypothenar eminence is spared until later in the course of illness.

Figure 2.

Figure 2.

Distribution of muscle weakness and atrophy in individuals with two major clinical subtypes of GARS-associated disease A. Thenar and first dorsal interosseus muscle wasting with relatively preserved hypothenar in an individual with dSMA-V phenotype

The lower limbs are involved in about half of affected individuals. Lower extremity involvement, when present, varies in severity from weakness and atrophy of the extensor digitorum brevis 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.

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

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). In individuals with the dSMA-V subtype, sensory deficits are absent.

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

Table 3.

Phenotypic Features of GARS-Associated Axonal Neuropathy by Subtype

Symptoms and SignsSubtype
CMT2D (%)dSMA-V (%)
Progressive bilateral weakness and wasting of thenar and FDI muscles 1100100
Peroneal weakness with atrophy and pes cavus10057.5
Pyramidal dysfunction012.5
Reduced sensation for touch, pain, and temperature1000
Reduced vibration sense10037.5
1.

FDI = first dorsal interosseus

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 >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 1.

Sural nerve morphology in GARS-related dSMA-V and CMT2D phenotypes A. dSMA-V. Pathologic changes are minimal with a near-normal myelinated nerve fiber density.

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 <7 mm in diameter is only 46%. Denervation of Schwann cell subunits as indicated by an increased number of profiles is seen on EM.

Genotype-Phenotype Correlations

The GARS variants p.Leu183Pro and p.His472Arg are exclusively associated with the dSMA-V clinical subtype; p.Gly294Arg, p.Ile334Phe, and p.Gly580Arg are associated with the CMT2D subtype. The variants p.Glu125Gly, p.Pro298Leu, and p.Asp554Asn are identified in families with both subtypes. Finally, the variant p.Gly652Ala has been associated with infantile-onset GARS-associated axonal neuropathy [Eskuri et al 2012] (see Table 4).

Penetrance

Penetrance is incomplete in this disorder, although specific data are not available.

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 alone.

Using the classification system (based on the results of molecular genetic testing in the context of inheritance, neurologic examination, and gene) proposed by Magy et al [2018], CMT2D would be referred to as AD-CMTAx-GARS.

Prevalence

Disease prevalence is unknown; GARS-associated axonal neuropathy is likely very rare. For example, fewer than 25 disease-associated GARS alleles have been described and the vast majority are specific to individual pedigrees [Meyer-Schuman & Antonellis 2017].

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.

Charcot-Marie-Tooth disease type 2 (CMT2). Other subtypes of 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.

Distal spinal muscular atrophy (dSMA). Other types of dSMA (also referred to as distal hereditary motor neuropathy [dHMN]) – a genetically heterogeneous group of disorders [Irobi et al 2004a, Irobi et al 2004b] caused by progressive degeneration of anterior horn neurons – are 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 is associated with dHMN-V subtypes [Irobi et al 2004a, Irobi et al 2004b]. The pattern of hand involvement before leg involvement distinguishes dHMN-V from other dHMN subtypes.

Silver syndrome is associated with spasticity in the legs and amyotrophy in the hands. Caused by pathogenic variants in BSCL2, Silver syndrome is 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 showing 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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GARS-associated axonal neuropathy, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Nerve conduction studies and EMG of arms and legs
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Appropriate treatment includes the following:

  • 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 assessment every six months 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 in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

In a mouse model of GARS-associated axonal neuropathy, reduced acetylated α-tubulin levels were found in primary dorsal root ganglion neurons [Benoy et al 2018]. Selective HDAC6 inhibition increased α-tubulin acetylation in peripheral nerves and partially restored nerve conduction, indicating possible therapeutic potential.

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.
  • A proband with GARS-associated axonal neuropathy may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or, theoretically, germline mosaicism in a parent.
  • 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, a milder phenotypic presentation, early death of a parent before the onset of symptoms, and/or late onset of the disease. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed on the parents of the proband.

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 and/or known to have the GARS pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Intrafamilial clinical variability and reduced penetrance have been observed.
  • If the GARS pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents have not been tested for the GARS pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GARS-associated axonal neuropathy because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents; if a parent is affected and/or has the GARS pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GARS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.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.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    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)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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

Gene. GARS spans 40 kb and contains 17 exons. The 2.7-kb GARS transcript is ubiquitously expressed.

Pathogenic variants. The pathogenic variants are distributed throughout the protein in multiple functional domains. Currently, all neuropathy-associated GARS mutations are missense changes or in-frame deletions.

To date, more than 20 pathogenic variants in GARS have been reported:

• Variants such as p.Glu125Gly, p.Leu183Pro, and p.Gly294Arg, which segregate in pedigrees with LOD scores >5, are known causal variants [Christodoulou et al 1995, Ionasescu et al 1996, Sambuughin et al 1998, Antonellis et al 2003].

• Variants identified by sequencing GARS in small families and simplex cases (i.e., a single occurrence of axonal neuropathy in a family) – including p.Ala111Val, p.Pro298Leu, p.Ile334Phe, p.Asp554Asn, p.Gly580Arg, p.Ser635Leu, and p.Gly652Ala – are less clearly implicated [Sivakumar et al 2005, Del Bo et al 2006, James et al 2006, Rohkamm et al 2007, Abe & Hayasaka 2009, Hamaguchi et al 2010].

The p.Leu183Pro and p.His472Arg GARS variants are associated exclusively with the dSMA-V clinical subtype; p.Gly294Arg, p.Ile334Phe, and p.Gly580Arg are associated with the CMT2D subtype. Families with the p.Glu125Gly, p.Pro294Leu, and p.Asp554Asn variants had both subtypes.

Table 4.

GARS Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.332C>Tp.Ala111Val
(p.Ala57Val)
NM_002047​.2
NP_002038​.2
c.374A>Gp.Glu125Gly
(p.Glu71Gly)
c.548T>Cp.Leu183Pro
(p.Leu129Pro)
c.880G>Cp.Gly294Arg
(p.Gly240Arg)
c.893C>Tp.Pro298Leu
(p.Pro244Leu)
c.1000A>Tp.Ile334Phe
(p.Ile280Phe)
c.1415A>Gp.His472Arg
(p.His418Arg)
c.1660G>Ap.Asp554Asn
(p.Asp500Asn)
c.1738G>Cp.Gly580Arg
(p.Gly526Arg)
c.1904C>Tp.Ser635Leu
(p.Ser581Leu)
c.1955G>Cp.Gly652Ala
(p.Gly598Ala)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

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 the amino acid that matches its anticodon [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. To date, all neuropathy-associated GARS variants are missense changes or in-frame deletions. The vast majority impair enzyme function as assessed in enzyme kinetic and yeast complementation assays [Griffin et al 2014]. However, haploinsufficiency is an unlikely disease mechanism based on the above alleles, the frequency of null alleles in the human populations, and mouse models displaying that mice carrying one null allele have no phenotype while those carrying a missense or in-frame deletion have a neuropathic phenotype [Seburn et al 2006]. Since the identification of GARS as a causal gene for CMT2D and dSMA-V, the challenge has been to determine how pathogenic missense variants in this critical and widely expressed protein cause selective degeneration of axons in peripheral nerves; both gain- and loss-of-function mechanisms have been proposed [Meyer-Schuman & Antonellis 2017]. Further research efforts are needed for identification of specific disease mechanisms affecting peripheral axons.

References

Literature Cited

  • Abe A, Hayasaka K. The GARS gene is rarely mutated in Japanese patients with Charcot-Marie-Tooth neuropathy. J Hum Genet. 2009;54:310–2. [PubMed: 19329989]
  • 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;72:1293–9. [PMC free article: PMC1180282] [PubMed: 12690580]
  • Antoniadi T, Buxton C, Dennis G, Forrester N, Smith D, Lunt P, Burton-Jones S. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015;16:84. [PMC free article: PMC4578331] [PubMed: 26392352]
  • Benoy V, Van Helleputte L, Prior R, d'Ydewalle C, Haeck W, Geens N, Scheveneels W, Schevenels B, Cader MZ, Talbot K, Kozikowski AP, Vanden Berghe P, Van Damme P, Robberecht W, Van Den Bosch L. HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease. Brain. 2018;141:673–87. [PMC free article: PMC5837793] [PubMed: 29415205]
  • Christodoulou K, Kyriakides T, Hristova AH, Georgiou DM, Kalaydjieva L, Yshpekova B, Ivanova T, Weber JL, Middleton LT. Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p. Hum Mol Genet. 1995;4:1629–32. [PubMed: 8541851]
  • Del Bo R, Locatelli F, Corti S, Scarlato M, Ghezzi S, Prelle A, Fagiolari G, Moggio M, Carpo M, Bresolin N, Comi GP. Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation. Neurology. 2006;66:752–4. [PubMed: 16534118]
  • DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD, Batish SD, Lupski JR, Higgins JJ. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014;2:522–9. [PMC free article: PMC4303222] [PubMed: 25614874]
  • 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;66:1721–6. [PubMed: 16769947]
  • Ellsworth RE, Ionasescu V, Searby C, Sheffield VC, Braden VV, Kucaba TA, McPherson JD, Marra MA, Green ED. The CMT2D locus: refined genetic position and construction of a bacterial clone-based physical map. Genome Res. 1999;9:568–74. [PMC free article: PMC310773] [PubMed: 10400924]
  • Eskuri JM, Stanley CM, Moore SA, Mathews KD. Infantile onset CMT2D/dSMA V in monozygotic twins due to a mutation in the anticodon-binding domain of GARS. J Peripher Nerv Syst. 2012;17:132–4. [PMC free article: PMC3572939] [PubMed: 22462675]
  • Freist W, Logan DT, Gauss DH. Glycyl-tRNA synthetase. Biol Chem Hoppe Seyler. 1996;377:343–56. [PubMed: 8839980]
  • Ge Q, Trieu EP, Targoff IN. Primary structure and functional expression of human Glycyl-tRNA synthetase, an autoantigen in myositis. J Biol Chem. 1994;269:28790–7. [PubMed: 7961834]
  • Griffin LB, Sakaguchi R, McGuigan D, Gonzalez MA, Searby C, Züchner S, Hou YM, Antonellis A. Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations. Hum Mutat. 2014;35:1363–71. [PMC free article: PMC4213347] [PubMed: 25168514]
  • Hamaguchi A, Ishida C, Iwasa K, Abe A, Yamada M. Charcot-Marie-Tooth disease type 2D with a novel glycyl-tRNA synthetase gene (GARS) mutation. J Neurol. 2010;257:1202–4. [PubMed: 20169446]
  • Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R. Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet. 1996;5:1373–5. [PubMed: 8872480]
  • Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004a;13(Spec No 2):R195–202. [PubMed: 15358725]
  • Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V, Vennekens K, Mazanec R, Tournev I, Hilton-Jones D, Talbot K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004b;36:597–601. [PubMed: 15122253]
  • James PA, Cader MZ, Muntoni F, Childs AM, Crow YJ, Talbit K. Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene. Neurology. 2006;67:1710–2. [PubMed: 17101916]
  • Lee HJ, Park J, Nakhro K, Park JM, Hur YM, Choi BO, Chung KW. Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V. J Peripher Nerv Syst. 2012;17:418–21. [PubMed: 23279345]
  • Magy L, Mathis S, Le Masson G, Goizet C, Tazir M, Vallat JM. Updating the classification of inherited neuropathies: results of an international survey. Neurology. 2018;90:e870–e876. [PubMed: 29429969]
  • Meyer-Schuman R, Antonellis A. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. Hum Mol Genet. 2017;26:R114–R127. [PMC free article: PMC5886470] [PubMed: 28633377]
  • Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, Antonellis A. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum Mutat. 2017;38:1412–20. [PMC free article: PMC5599332] [PubMed: 28675565]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rohkamm B, Reilly MM, Lochmüller H, Schlotter-Weigel B, Barisic N, Schöls L, Nicholson G, Pareyson D, Laurà 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;263:100–6. [PMC free article: PMC3272403] [PubMed: 17663003]
  • Sambuughin N, Sivakumar K, Selenge B, Lee HS, Friedlich D, Baasanjav D, Dalakas MC, Goldfarb LG. Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15. J Neurol Sci. 1998;161:23–8. [PubMed: 9879677]
  • Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron. 2006;51:715–26. [PubMed: 16982418]
  • 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;128:2304–14. [PubMed: 16014653]

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

  • 29 November 2018 (ha) Comprehensive update posted live
  • 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 live
  • 24 February 2006 (lgg) Original submission
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