Gars1-Associated Axonal Neuropathy
Summary
Clinical characteristics.
GARS1-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 GARS1-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS1 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.
GARS1-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 GARS1-associated axonal neuropathy has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.
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 GARS1. In this GeneReview the term "GARS1-associated axonal neuropathy" comprises both allelic disorders.
Suggestive Findings
GARS1-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 inheritanceNote: 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 GARS1-Associated Axonal Neuropathy by Subtype
| Results of Electrophysiologic Studies | Subtype | |||
|---|---|---|---|---|
| CMT2D (%) | dSMA-V (%) | |||
| Motor nerve conduction | Compound muscle action potential | Median-APB <4.5 mV | 100 | 100 |
| Ulnar-ADM <3.5 mV | 0 | 0 | ||
| Peroneal-EDB <2 mV | 100 | 62.5 | ||
| Tibial-AH <2.5 mV | 0 | 50 | ||
| Distal motor latency | Median <5.6 ms | 0 | 0 | |
| Ulnar <4.5 ms | 0 | 11 | ||
| Peroneal & tibial <7.5 ms | 0 | 0 | ||
| Nerve conduction velocity | Median & ulnar <39 m/s | 0 | 0 | |
| Peroneal & tibial <29 m/s | 0 | 0 | ||
| Sensory nerve conduction: sensory nerve action potential | Median <10 µV; ulnar <8 µV | 0 | 12 | |
| Sural <6 µV | 17 | 29 | ||
ADM = abductor digiti minimi; AH = adductor halluces; APB = abductor pollicis brevis; EDB = extensor digitorum brevis
Establishing the Diagnosis
The diagnosis of GARS1-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS1 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 GARS1-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 GARS1-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 GARS1-associated axonal neuropathy, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of GARS1 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 GARS1 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 GARS1-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 GARS1-Associated Axonal Neuropathy
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| GARS1 | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
Antonellis et al [2003], James et al [2006], Lee et al [2012], DiVincenzo et al [2014], Antoniadi et al [2015]
- 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 "GARS1-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 GARS1 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 1, Table 3). The hypothenar eminence is spared until later in the course of illness.
Figure 1.
Distribution of muscle weakness and atrophy in individuals with two major clinical subtypes of GARS1-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 GARS1-Associated Axonal Neuropathy by Subtype
| Symptoms and Signs | Subtype | |
|---|---|---|
| CMT2D (%) | dSMA-V (%) | |
| Progressive bilateral weakness and wasting of thenar and FDI muscles | 100 | 100 |
| Peroneal weakness with atrophy and pes cavus | 100 | 57.5 |
| Pyramidal dysfunction | 0 | 12.5 |
| Reduced sensation for touch, pain, and temperature | 100 | 0 |
| Reduced vibration sense | 100 | 37.5 |
Sivakumar et al [2005]
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 2A). 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 2B). 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 2C). The UMNF density is at the low normal level.
Figure 2.
Sural nerve morphology in GARS1-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 2D) and four to eight regenerative clusters per fascicle are observed (Figure 2E). 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 GARS1 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 GARS1-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 "GARS1-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). GARS1-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-GARS1.
Prevalence
Disease prevalence is unknown; GARS1-associated axonal neuropathy is likely very rare. For example, fewer than 25 disease-associated GARS1 alleles have been described and the vast majority are specific to individual pedigrees [Meyer-Schuman & Antonellis 2017].
Differential Diagnosis
GARS1-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 (see Charcot-Marie-Tooth Hereditary Neuropathy Overview). 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 GARS1-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 GARS1-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 GARS1-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
Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.
Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [Nishikawa et al 2008].
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 EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.
In a mouse model of GARS1-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.