Abstract
Background:
The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase. Defects in this gene have been linked with autosomal recessive inheritance of a variety of different clinical phenotypes.
Case:
A 13 year-old boy developed behavioral and psychiatric problems following a mild head injury. At age 21 he developed tremor, parkinsonism, and eye nystagmus. MRI revealed white matter changes consistent with a leukoencephalopathy. Genetic studies revealed two pathogenic mutations in the AARS2 gene (c.647dupG and c.595C > T).
Literature review:
Only 47 cases of AARS2-associated disorders have been reported, with equal numbers of males and females, and age at onset ranging from infancy to 44 years. The most common clinical problems include movement disorders (71%), cognitive impairment (67%), corticospinal signs (64%), behavioral or psychiatric features (46%), and eye signs (34%). Imaging evidence suggestive of leukoencephalopathy is common, but not invariant. Premature ovarian failure is frequent in females, but not universal.
Conclusions:
Defects in the AARS2 gene are a rare cause for a variety of movement disorders, often associated with brain imaging evidence suggestive of leukoencephalopathy.
Keywords: AARS2, Leukodystrophy, Movement disorders, Neuropsychiatric symptoms
A previously healthy 13-year-old male had a concussion with loss of consciousness while playing basketball. A CT scan on the same day was unremarkable. A few days later, he developed hypersomnia and social isolation. Brain MRI showed bifrontal and biparietal white matter changes interpreted to reflect trauma-related shear injury. He was managed conservatively and returned to school with good academic performance.
At age 19, he was admitted to a psychiatric unit with paranoia and manic behavior and was diagnosed with bipolar disorder. He was evaluated neurologically because of hand tremors. Repeat brain MRI demonstrated multiple confluent areas of abnormal T2 and FLAIR signal in the corpus callosum and subcortial white matter. There were also multiple small foci interpreted to be microbleeds within the subcortical white matter. He had additional studies that were unrevealing including hematology and chemistry tests, and a panel for paraneoplastic encephalopathy and neuromyelitis optica.
At age 21, he was admitted to a community psychiatric unit following an altercation with his mother. After discharge, he was further evaluated at an academic medical center. At the time of admission, he had delusions, hallucinations, disorganized and concrete thoughts, abnormal psychomotor behavior, and disheveled appearance. He had an odd affect and avoided social interactions, different from his childhood behavior. Repeat MRI revealed findings similar to prior studies, but an alternative interpretation raised concern for an inherited leukodystrophy rather than head trauma (Fig. 1). His neurological exam showed low-amplitude and high frequency postural and kinetic tremors of the hands with a similar but milder tremor in the lower limbs. He exhibited hypomimia, tachyphemia, and hypokinesia. He also had vertical and gaze-evoked horizontal nystagmus, along with mild difficulties in heel-shin testing.
Fig. 1.
Brain magnetic resonance imaging (MRI) of the patient. (A) Parasagittal and (B) midline sagittal T1-weighted images demonstrate focal low-signal in the splenium of the corpus callosum and adjacent to the genu of the corpus callosum with sparring of the body of the corpus callosum. White matter involvement extends to the adjacent frontal and parietal white matter. (C–D) Axial diffusion-weighted imaging and axial apparent diffusion coefficient sequences demonstrate restricted diffusion with high diffusion-weighted signal and associated low apparent diffusion coefficient in the periventricular white matter. (E–F) Axial fluid-attenuated inversion recovery (FLAIR) and axial T2-weighted sequences show abnormal hyperintensity in the bilateral frontal and parietal periventricular white matter and adjacent corpus callosum.
The clinical picture was thought consistent with a leukodystrophy. A leukodystrophy gene panel demonstrated heterozygous genetic variants of c.647dupG (p.C218LfsX6) and c.595C>T (p.R199C) in exon 4 of the AARS2 gene (NM_020745.2). The duplication is pathogenic because it leads to frame-shift and early termination. The substitution is pathogenic because it has been linked with disease in multiple other cases. These results established a diagnosis of AARS2-leukodystrophy.
The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase, which plays a role in protein synthesis. Although the enzyme functions in mitochondria, the gene is encoded by the nucleus, and inheritance of related disorders is autosomal recessive. This gene was initially linked with 3 cases of fatal infantile hypertrophic cardiomyopathy with pulmonary hypoplasia [1]. Subsequently, the gene was linked with numerous other clinical phenotypes including premature ovarian failure in females, and varied neurological disorders with or without brain MRI abnormalities. The degree of impairment of aminoacylation activity may explain some, but not all of the phenotypic variation [2]. So far, 47 cases have been reported (Table 1). Among these cases, the age at onset varied from infancy to 44 years of age, with equal numbers of males and females. White matter changes on brain MRI are common, so AARS2 defects are often classified among the leukoencephalopathies. However, leukoencephalopathy is not invariant, and several neurological cases without MRI evidence for white matter disease have been reported (Table 1).
Table 1.
AARS2 cases in the literature.
| Case | Sex | Onset age | Reporting age | AARS2 variant | Corticospinal signs | Cognitive impairment | Movement disorders | Psychiatric/behavioral | POF | Brain MRI | Other features |
|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||
| 1 [1] | F | <1 | 1 | c.1774C > T c.1774C > T |
NA | NA | NA | NA | NA | NA | Hypertrophic CM, pulmonary hypoplasia |
| 2 [1] | F | <1 | <1 | c.464T>G c.1774C >T | NA | NA | NA | NA | NA | NA | Hypertrophic CM pulmonary hypoplasia |
| 3 [1] | M | <0 | <0 | c.1774C>T c.464T > G |
NA | NA | NA | NA | NR | NA | Hypertrophic CM, pulmonary hypoplasia |
| 4 [7] | F | 2 | 15 | c.149T > G c.1561C > T |
− | + | A, T | + | + | WMC | Eye signs |
| 5 [7] | M | <1 | 17 | c.1213G > A c.2893G > A |
+ | + | A, D | − | NR | WMC | Eye signs |
| 6 [7] | F | 28 | 36 | c.595C > T and c.2188G > A c.1609C > T and c.2350del |
+ | T | + | + | WMC | Eye signs, seizures | |
| 7 [7] | F | 23 | 28 | c.230C > T c.595C > T and c.2188G > A |
+ | + | A, D | + | + | WMC | |
| 8 [7] | F | 40 | 46 | c.595C > T and c.2188G > A c.390_392del |
+ | + | + | WMC | |||
| 9 [7] | F | 20 | 25 | c.595C > T and c.2188G > A c.2611dup |
+ | A | + | + | WMC | ||
| 10 [8] | F | 30 | 38 | c.1145C > A c.2255+1G > A |
+ | + | R | + | + | WMC | |
| 11 [9] | M | 18 | 29 | c.578T > G c.595C > T |
+ | + | B, IT | + | NR | WMC | − |
| 12 [10,11] | F | 26 | 40 | c.595C > T c.1041–1G > A |
+ | + | A | + | + | WMC | |
| 13 [10,11] | M | 37 | NA | c.1188G.A c.1709delG |
− | + | T | + | NR | WMC | − |
| 14 [10,11] | M | 20s | NA | c.1188G.A c.1709delG |
− | − | T | − | NR | WMC | |
| 15 [10,11] | M | 15 | NA | c.892_894del c.2234_2235del |
+ | + | A, B, D | + | NR | WMC | |
| 16 [10,11] | M | 44 | NA | c.595C > T c.595C > T |
+ | + | D, P | + | NR | WMC | Eye signs |
| 17 [12] | F | 33 | 35 | c.452T > C c.963C > A |
+ | + | B, T | − | + | WMC | |
| 18 [12] | M | 35 | 37 | c.452T > C c.963C > A |
+ | + | A, D | − | NR | WMC | |
| 19 [13] | F | Teens | 41 | c.595C > T c.647dupG |
− | + | − | + | + | Cystic WMC | |
| 20 [14] | M | 17 | 23 | c.650C > T c.2265dupA |
+ | + | A, T | − | NR | WMC | Eye signs |
| 21 [15] | F | 44 | NA | c.390_392del c.595C > T |
+ | + | IT | − | + | WMC | |
| 22 [15] | F | 32 | 36 | c.236T > A c.595C > T |
+ | + | − | + | + | WMC | |
| 23 [15] | F | 25 | 30 | c.236T > A c.595C > T |
− | + | IT | − | + | WMC | |
| 24 [15] | F | 6 | 24 | c.595C > T C.2611_2612insA |
+ | − | A | − | + | WMC | Eye signs |
| 25 [16] | F | 32 | 34 | c.1691T > C c.179C > A |
+ | + | − | − | − | WMC | |
| 26 [17] | M | 1 | 3 | c.1519G > C c.2165G > A |
− | − | − | − | NR | WMC | neuropathy, optic atrophy |
| 27 [4] | M | 27 | 29 | c.427C > T c.7371T > A |
+ | − | − | − | NR | WMC | |
| 28 [18] | M | 20 | 20 | c.965G > A c.334G > C |
+ | + | A | + | NR | WMC | Eye signs |
| 29 [5] | M | 25 | 48 | c.595C > T c.2557C > T |
+ | − | T, A | + | NR | WMC, CRB atrophy | Seizures |
| 30 [5] | M | 9 | 34 | c.595C > T c.2598+1G > T |
+ | + | T, A, C, D | + | NR | WMC | Eye signs |
| 31 [5] | F | 7 | 57 | c.595C > T c.2557C > T |
− | + | T, A, C | + | − | WMC, atrophy |
Eye signs |
| 32 [19] | M | 29 | 30 | c.179C > A c.1703_1704del |
+ | − | A, R | − | NR | WMC | − |
| 33 [20] | M | 20 | 22 | c.130G > C c.130G > C |
+ | + | − | − | NR | WMC | − |
| 34 [21] | M | 40 | 44 | c.452T > C c.452T > C |
+ | + | A | + | NR | WMC | − |
| 35 [22] | F | 22 | 35 | c.1871G > A c.452T > C |
+ | − | T, D | − | + | NR | |
| 36 [22] | M | 12 | 29 | c.1871G > A c.452T > C |
+ | + | T | − | NR | WMC | Eye signs |
| 37 [22] | M | 0.25 | 26 | c.802A > G c.1871G > A |
+ | + | A | + | NR | WMC | Eye signs |
| 38 [22] | M | 29 | 31 | c.179C > A c.1703–1704del |
+ | + | R | − | NR | WMC | Eye signs |
| 39 [22] | M | 38 | 38 | c.452T > C c.452T > C |
+ | + | R | + | NR | WMC | Eye signs |
| 40 [23] | F | 25 | 26 | c.337G > C c.337G > C |
− | − | − | + | + | NR | |
| 41 [24] | F | 14 | 38 | c.385A > C c.446G > A |
− | − | T, A, D | − | + | normal | Eye signs |
| 42 [24] | F | childhood | 32 | c.385A > C c.446G > A |
+ | − | T, A | − | + | normal | Eye signs |
| 43 [25] | F | <1 | 7 | c.1150–4C > G | + | + | IT | − | NR | WMC | Myopathy, Seizures |
| 44 [26] | F | 24 | 29 | c.984C > G c.390_392del |
+ | − | A | − | − | CRB atrophy |
Eye signs |
| 45 [26] | M | 5 | 26 | c.984C > G c.390_392del |
+ | + | A, D | − | NR | CRB atrophy |
Eye signs, optic atrophy |
| 46 [27] | F | 14 | 18 | c.1774C > T c.1774C > T |
− | − | − | − | − | normal | dilated CM |
| 47 [6] | M | Teens | 27 | c.650C > T c.650C > T |
+ | + | IT | − | NR | WMC | |
| 48 (current case) | M | 13 | 23 | c.647dupG c.595C > T |
− | + | T, A | + | NR | WMC | Eye signs |
Corticospinal signs combine spasticity, hyper-reflexia and the extensor plantar reflex. Eye signs include nystagmus, slow saccades, and ophthalmoparesis. Myopathy includes only cases with clinically evident muscle weakness or wasting, and does not include cases where the only signs were abnormalities during electromyography or muscle biopsy histopathology. Movement disorders are listed wherever possible, but many reports used indeterminate terminology (IT) such as “extrapyramidal symtpoms” or “gait abnormality” or variations implying hypertonia. Abbreviations: ataxia, A; bradykinesia, B; chorea, C; cardiomyopathy, CM; cerebellum, CRB; dystonia, D; female, F, male, M, not available, NA; not relevant, NR; Parkinsonism, P; premature ovarian failure, POF; rigidity, R; tremor, T; white matter changes, WMC. Cases 12–16 have two citations because they were reported twice.
Among all 48 cases (including the current case), movement disorders were common, occurring in 71% (Table 1). The most common problems include ataxia, tremor, dystonia, chorea, and parkinsonism. Cognitive impairments were documented for 67%. Corticospinal signs such as spasticity or hyperrflexia occurred in 64%. Obvious behavioral changes or overt psychiatric symptoms (depression, psychosis, anxiety) were sometimes the presenting feature, and ultimately occurred in 46%. Eye signs such as nystagmus or ophthalmoplegia were noted for 38%. Less common features included optic atrophy, retinopathy, seizures, neuropathy, or clinically evident myopathy.
Our case presented with features initially interpreted to be related to trauma including behavioral changes, psychosis, and action tremor. Only later did he develop additional neurological features, and the possibility of a leukoencephalopathy was re-considered. Similar to prior cases, his main neurological problems included tremor and ataxia. He and other cases in the literature also had parkinsonian features, although contributions of medications used for psychosis cannot be excluded. The inherited leukoencephalopathies have overlapping clinical and radiological findings, with no specific features pointing to AARS2 aside from ovarian failure in females, so genetic diagnosis is often needed [3]. For many, psychiatric symptoms are a common initial problem, but corticospinal signs and a variety of movement disorders are common. Whether the initial trauma in our case contributed to the onset of his disorder remains unclear. However, it is interesting to note that a head trauma preceded onset of symptoms in 3 other cases [4–6].
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
SPP was a Parkinson Foundation Fellow. SHH has nothing to disclose. WRW has nothing to disclose. CDM has nothing to disclose. HAJ has active or recent grant support from the US government (National Institutes of Health), private philanthropic organizations (Cure Dystonia Now), academically oriented institutions (the Dystonia Study Group), and industry (Revance Therapeutics, Inc.). Dr. Jinnah has also served on advisory boards or as a consultant for Allergan Inc., CoA Therapeutics, Cavion Therapeutics, and Retrophin Inc. He has received honoraria or stipends for lectures or administrative work from the American Academy of Neurology, the American Neurological Association, the Dystonia Medical Research Foundation, the International Neurotoxin Society, and the International Parkinson’s Disease and Movement Disorders Society. Dr. Jinnah serves on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, the Dystonia Medical Research Foundation, the Tourette Association of America, and Tyler’s Hope for a Cure. He also is principle investigator for the Dystonia Coalition, which has received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke TR001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). The Dystonia Coalition has received additional material or administrative support from industry sponsors (Allergan Inc. and Merz Pharmaceuticals) as well as private foundations (The Benign Essential Blepharospasm Foundation, Cure Dystonia Now, The Dystonia Medical Research Foundation, and The National Spasmodic Dysphonia Association).
Footnotes
Declaration of competing interest
The authors declare no conflict of interest.
Ethical compliance statement
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. In particular, written informed consent is not required for description of a single de-identified case with literature review.
Contributor Information
Sahyli Perez Parra, Jean & Paul Amos PD & Movement Disorders Program Department of Neurology, Emory University, USA.
Stephan H. Heckers, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, USA
William R. Wilcox, Department of Human Genetics, Emory University, USA
Colin David Mcknight, Department of Radiology, Vanderbilt University Medical Center, USA.
H.A. Jinnah, Jean & Paul Amos PD & Movement Disorders Program Department of Neurology, Emory University, USA.
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