Table 2.
Review of published cases and new patient with VARS2 deficiency – clinical characteristics, laboratory and molecular genetics findings [modified after (1)].
|
Patient/ family |
References | Sex | Mutation | Ethnicity | Current age/death | Onset | Hearth | Neurological signs | MRI + spectroscopy/other features |
Lab tests/ Lactate |
OXPHOS muscle |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Our caseP24/F20 | Kušíková et al., this study | M |
c.1168G>A c.2758T>C |
Caucasian (Austrian) |
Death 47 d. | From birth | HCM | Normal |
Normal MRI of the brain + PPHN |
Plasma(4–13 mmol/l) |
↓↓ CI ↓ CIII+CIV ↑ CII+CV |
| P1/F1 | Bruni et al. (1) | F | Homozygous c.1100C>T | Caucasian (Polish) | Alive at 5 y. | From birth | No HCM | Hypotonia, poor coordination, develompmental delay, seizures | Hyperintensity in the periventricular white matter bilaterally, cerebral atrophy; small lactate peak at MRS | N/A | N/A |
| P2/F2 | Bruni et al. (1) | F | c.2557-2A>G c.1100C>T |
Caucasian | Death at 3,5 m. | From birth | HCM | Hypotonia, hyporeflexia, exag. startle, staring episodes, vocal cord paralysis | Diffuse cerebral and cerebellar atrophy, focal gliosis around the Sylvian fissures bilaterally, cerebellum, scattered areas of cortical restricted diffusion, subtle thalamic restricted diffusion bilaterally, large lactate peak at MRS | Plasma (1.7–8.9 mmol/l) and urinaryelevation | Normal |
| P3/F3 | Bruni et al. (1) | M | c.1546G>T c.2239G>A |
Jewish comunity | Death at 19 m. | From birth | HCM | Hypotonia, severe stridor, poor sucking, hypertonia of the lower limbs | N/A | Plasma(3.5–4 mmol/l)and urinaryelevation | ↓ CIV |
| P4/F4 | Bruni et al. 2018 (1) | F | c.1100C>T c.1150G>A |
Italian | Death at 5 m. | From birth | HCM | Hypotonia, feeding difficulties and psychomotor delay | Cerebellar atrophy, corpus callosum hypotrophy | Plasma(4.2 mmol/l)and CSF(3 mmol/l;Nv <2.3 mmol/l) | Normal activities |
| P5/F5 | Bruni et al. (1) and Taylor et al. (4) | M | c.1135G>A c.1877C>A |
British | Alive at 18 y. | First few months | mild concentric ventricular hypertrophy | Developmental delay, ptosis and ophtalmoparesis, generalized epilepsy, fatigue, proximalweakness, dyspraxia | Symmetrical bilateral basal ganglia calcification, symmetrical increased T2 signal in the peri-trigonal white matter | N/A | ↓ CI+CIV |
| P6/F6 | Bruni et al. (1) and Pronicka et al. (9) | M | c.1100C>T c.1490G>A |
Polish | Death at 3 m. | Birth | HCM | Hypotonia, stridor andrespiratory failure, limbsspasticity | N/A | Plasma (4.4–8.7 mmol/l) | ↓CIV |
| P7/F6 | Bruni et al. (1) and Pronicka et al. (9) | M | c.1100C>T c.1490G>A |
Polish | Death at 9 y. | From birth | HCM | Hypotonia, stridor andrespiratory failure, limbsspasticity, epilepsy | Hypoplasia of vermis, mild cerebral atrophy, small symmetric hyperintense changes in thalamus and septum pellucidum | Plasma (2.9–10.6 mmol/l) | N/A |
| P8/F7 | Bruni et al. (1) | M | Homozygous c.1258G>A | Mexican | Death at 9 d. | From birth | HCM | Hypotonia, feeding difficulty | N/A | Plasma elevation | N/A |
| P9/F7 | Bruni et al. (1) | F | Homozygous c.1258G>A | Mexican | Death at 3 m. | From birth | HCM | Hypotonia, feeding difficulty | N/A | Plasma elevation | N/A |
| P10/F8 | Bruni et al. (1) | M | Homozygous c.1258G>A | Mexican | Alive at 3 m. | From birth | HCM | Hypotonia, feeding difficulty, respiratory distress, developmental delay, epilepsy | N/A | Plasma elevation | N/A |
| P11/F9 | Bruni et al. (1) | F | Homozygous c.1100C>T | Afganistan | Death at 7 y. | From 1st month | N/A | Severe hypotonia, feedingdifficulty, psychomotorretardation, nystagmus, intractable epilepsy | Cerebellar atrophy (cerebellar hemispheres + vermis), signal intensity in dentate nuclei, signal intensity and mild atrophy in thalami, corpus callosum slightly thin |
Plasmanormal(2.3 mmol/l) | N/A |
| P12/F9 | Bruni et al. (1) | F | Homozygous c.1100C>T | Afganistan | Death at 8 y. | From 1st month | N/A | Hypotonia, feeding difficulty (gastrostomy), psychomotor retardation, limb spasticity, intractableepilepsy | Cerebellar atrophy, signal intensity in dentatenuclei and thalami, thin corpus callosum, no lactatepeak in MRS | Plasma (2.8 mmol/l) | N/A |
| P13/F9 | Bruni et al. (1) | M | Homozygous c.1100C>T | Afganistan | Alive at 5 m. | From birth | No HCM | Hypotonia | Unilateral mild cerebellar hemispheric hypoplasia | Plasma (4.4 mmol/l), CSF (3.08 mmol/l) | N/A |
| P14/F10 | Diodato et al. (6) | M | Homozygous c.1100C>T | Italian | Alive at 8 y. | From birth | N/A | Psychomotor delay, microcephaly, epilepsy, status epilepticus | Hyperintense lesions in the periventricular regions, the insulae, and the frontotemporal right cortex, MRS: lactate peak in the frontal white matter + facial dysmorphy | N/A | ↓ CI |
| P15/F11 | San Millan et al. (8) | N/A | c.1010C>T stop codon |
N/A | Death 4 m. | From birth | HCM | Floppy infant, tongue fasciculation | N/A | N/A | ↓ CIV |
| P16/F12 | Baertling et al. (11) | M | c.601C>T c.1100C>T |
Greek | Alive at 5 m. | From birth | HCM | Epilepsy, burst suppression, spasticity, microcephaly, exotrophy | Hypoplasia of the corpus callosum and the cerebellum, edema of the brain stem and the frontal white matter, hyperintensities in basal ganglia displayed, MRS lactate peak | Plasma (>28 mmol/l) | N/A |
| P17/F13 | Alsemari et al. (10) | M | Homozygous c.3650G>A |
Saudi Arabia | 23 y. | 4 m. | N/A | Severe mental retardation, ataxia, speech impairment, epilepsy | Cerebellar atrophy + short stature, microcephaly, dysmorphia, excitable personality, excessive chewing mouth behaviors, severe growth hormone deficiency, hypogonadism, severe osteomalacia, Angelman-like syndrome |
N/A | N/A |
| P18/F14 | Ma et al. (12) | F | c.643C>T c.1354A>G |
Chinese | Death at 16 d. | From birth | HCM | Poor sucking, hypertonia | The brain ultrasonic examination: mild echo enhancement on the side of the bilateral paraventricular parenchyma, a left-ependymal cyst and a right-choroid plexus cyst + PPHN | Plasma (3-15.6 mmol/l) | N/A |
| P19/F15 | Pereira et al. (13) | F | Homozygous c.1100C>T | Portuguese | Death at 28 m. | From birth | No HCM | Microcephaly, severe global hypotonia, severe epileptic encephalopathy | Global atrophy and a small glioepithelial cyst associated with left hippocampal molding + progressive feedings difficulties, and failure to thrive |
Plasma (5.35 mmol/l) | Normal |
| P20/F16 | Ruzman et al. (14) | F | c.1100C>T c.603_606dupGATG |
N/A | Death at 10 m. | 1 month | HCM | Microcephaly, infantile spasms with hypsarrhytmia on EEG, later burstsuppression pattern, severe global hypotonia | Diffuse cerebral atrophy, hypoplasia of the cerebellum (vermis), brainstem, and corpus callosum, MRS high lactate peak |
Plasma (2.0–5.4 mmol/l), CSF (3 mmol/l), Alanin plasma and CSF (537 and 36.1 umol/l) | N/A |
| P21/F17 | Begliuomini et al. (15) | F | Homozygous c.1100C>T | Sardinian | Alive at 6 years | From 11 months | No HCM | Motor and language delays, hypotonia, brisk tendon reflexes | Atrophic progression of the cerebellum with T2-FLAIR hyperintensities of cerebellar white matter and dentate nuclei, MRS increased lactate and decreased N-acetyl aspartate peaks |
N/A | ↓ CI + CIII |
| P22/F18 | Begliuomini et al. (15) | F | Homozygous c.1100C>T | Sardinian | Alive at 5 years | From 12months | No HCM | Nystagmus with alternating strabismus, brisk tendon reflexes, global hypotonia and impaired coordination, swallowing difficulties | Cerebellar atrophy and vermis hypoplasia with normal MRS | increased | N/A |
| P23/F19 | Chin et al. (7) | M | c.1940C>T c.2318G>A |
Chinese | Alive at 14 months | From 1 month | No HCM | Developmental delay | Normal MRI of the brain + PPHN, moderate hypertrophy of RV and dilat. RA and RV, growth failure, gastroesophageal reflux |
Plasma (9.2 mmol/l) | N/A |
P/F, patient/family; F, female; M, male; d., day; m., month; y., year; HCM, hypertrophic cardiomyopathy; RV, right ventricle; RA, right atrium; PPHN, persistent pulmonary hypertension of the newborn; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; CSF, cerebrospinal fluid; N/A, not available information; CI-CV, OXPHOS complex I–V. Arrow down: reduced values compared to healthy controls. Arrow up: increased values compared to healthy controls.