Table 4.
Relationship between genotype expressed in clusters of protein quantity and impairment effect to clinical phenotype. Individuals with no SSADH protein are compared to A) those with Single Homotetramers and Multiple Homo and Heterotetramers and B) those with different effects of protein impairments.
| Quantitative Protein Groups N = 58 (%) |
Impairment Effect Groups N = 58 (%) |
||||||
|---|---|---|---|---|---|---|---|
| Phenotype features | No Protein* N = 16(28) |
Single Homotetramers N = 35(60) |
Multiple Homo and Heterotetramers N = 7(12) |
p** | Folding/Stability/Oligomerization N = 29 (50) |
Catalysis N = 13 (22) |
P*** |
| Age, | |||||||
| years, median (IQR) | 9.8 (6.9–21.5) | 10.4 (5.3–15.0) | 7.8 (4.2–11.1) | 0.22 | 9.6 (4.2–14.2) | 11.1 (8.0–14.4) | 0.33 |
| Sex | |||||||
| Male/Female | 9 (56)/7 (44) | 16 (46)/19 (54) | 4 (57)/3 (43) | 0.72 | 4 (31)/9 (69) | 16 (55)/13 (45) | 0.28 |
| Consanguinity | 3 (19) | 6 (17) | 0 (0) | 0.45 | 6 (21) 0 (0) | 0.19 | |
| Gene expression, 2^ΔCT | |||||||
| ALDH5A1 (N = 23) | 0.01 ± 0.005 (N = 8) | 0.02 ± 0.01 (N = 14) | 0.05 ± 0.0 (N = 1) | 0.001 | 0.02 ± 0.01 (N = 11) | 0.01 ± 0.008 (N = 4) | 0.07 |
| Abat (N = 23) | 0.03 ± 0.03 (N = 8) | 0.02 ± 0.007 (N = 14) | 0.02 ± 0.0 (N = 1) | 0.43 | 0.02 ± 0.007 (N = 11) | 0.02 ± 0.009 (N = 4) | 0.43 |
| GLS (N = 23) | 0.11 ± 0.04 (N = 8) | 0.09 ± 0.02 (N = 14) | 0.11 ± 0.0 (N = 1) | 0.46 | 0.09 ± 0.09 (N = 11) | 0.09 ± 0.004 (N = 4) | 0.51 |
| Clinical Severity Score (CSS) | |||||||
| Total score | 15.5 ± 2.9 | 17.8 ± 2.6 | 18.5 ± 1.3 | 0.008 | 18.7 ± 1.9 | 16.2 ± 2.6 | 0.02 |
| Cognitive | 1.9 ± 0.8 | 2.6 ± 0.9 | 2.8 ± 0.3 | 0.01 | 2.8 ± 0.9 | 2.4 ± 0.7 | 0.008 |
| Communication | 2.5 ± 0.6 | 2.8 ± 0.9 | 3.1 ± 0.9 | 0.27 | 2.9 ± 0.9 | 3.0 ± 1.0 | 0.33 |
| Motor | 3.7 ± 1.0 | 3.7 ± 0.8 | 3.2 ± 0.7 | 0.47 | 3.7 ± 0.7 | 3.3 ± 0.9 | 0.42 |
| Psychiatry | 2.6 ± 1.3 | 3.4 ± 1.1 | 4.0 ± 0.8 | 0.04 | 3.6 ± 1.1 | 3.2 ± 1.0 | 0.10 |
| Epilepsy | 3.6 ± 1.2 | 4.1 ± 1.2 | 5.0 ± 0.0 | 0.04 | 4.5 ± 1.0 | 3.7 ± 1.2 | 0.10 |
| Neuropsychologic assessments | |||||||
| FSIQ (N = 27) | 47.8 ± 13.1 (N = 8) | 52.1 ± 13.1 (N = 18) | 57.0 ± 0.0 (N = 3) | 0.67 | 53.3 ± 13.4 (N = 14) | 49.6 ± 11.6 (N = 5) | 0.62 |
| Adaptive composite score (N = 33) | 56.5 ± 11.2 (N = 9) | 61.4 ± 15.1 (N = 23) | 75.0 ± 0.0 (N = 3) | 0.41 | 66.6 ± 12.9 (N = 16) | 52.8 ± 15.7 (N = 8) | 0.04 |
| ASD assessed by ADOS-2 (N = 30) | 6 (67) (N = 9) | 11 (52) (N = 21) | - | 0.37 | 6 (43) (N = 14) | 5 (71) (N = 7) | 0.35 |
| Movement disorders | |||||||
| Ataxia | 11 (69) | 17 (49) | 2 (29) | 0.17 | 8 (61) | 11 (38) | 0.10 |
| Dyskinesia | 7 (44) | 7 (20) | 0 (0) | 0.05 | 3 (10) | 4 (31) | 0.03 |
| Dystonia | 2 (12) | 5 (14) | 2 (29) | 0.58 | 3 (10) | 4 (31) | 0.22 |
| Epilepsy | |||||||
| Seizures | 9 (56) | 21 (60) | 0 (0) | 0.01 | 13 (45) | 8 (61) | 0.55 |
| Drug-resistant seizures | 3 (43) | 6 (29) | - | 0.48 | 2 (15) | 4 (50) | 0.20 |
| EEG abnormalities | 15 (94) | 30 (86) | 2 (29) | < 0.001 | 21 (72) | 11 (85) | 0.31 |
| EEG- diffuse background slowing | 9 (56) | 17 (49) | 1 (14) | 0.16 | 13 (45) | 4 (31) | 0.39 |
| EEG- epileptiform activity | 5 (31) | 12 (34) | 1 (14) | 0.58 | 6 (20) | 7 (54) | 0.10 |
| MRS GABA/NAA, EMM (SE) | |||||||
| Basal ganglia (N = 13) | 0.19 (0.02) (N = 3) | 0.20 (0.01) (N = 9) | - | 0.56 | 0.19 (0.01) (N = 7) | 0.22 (0.02) (N = 2) | 0.62 |
| Posterior cingulate gyrus (N = 19) | 0.21 (0.01) (N = 7) | 0.22 (0.01) (N = 11) | - | 0.46 | 0.21 (0.01) (N = 8) | 0.23 (0.01) (N = 3) | 0.42 |
| Occipital cortex (N = 12) | 0.16 (0.01) (N = 7) | 0.17 (0.02) (N = 5) | - | 0.62 | 0.16 (0.02) (N = 3) | 0.19 (0.03) (N = 2) | 0.74 |
| Biochemical metrics, EMM (SE) | |||||||
| GABA, μ/L (N = 43) | 3.1 (0.2) (N = 16) | 2.8 (0.2) (N = 24) | 3.0 (0.6) (N = 3) | 0.70 | 2.9 (0.2) (N = 20) | 2.5 (0.4) (N = 7) | 0. 52 |
| GHB, μ/L (N = 34) | 274.2 (224.4) (N = 11) | 467.5 (154.5) (N = 22) | 1009.6 (732.9) (N = 1) | 0. 59 | 580.2 (178.1) (N = 16) | 243.1 (290.9) (N = 7) | 0.47 |
| GBA, μ/L (N = 29) | 0.09 (0.009) (N = 9) | 0.07 (0.006) (N = 18) | 0.08 (0.018) (N = 2) | 0.20 | 0.07 (0.006) (N = 16) | 0.07 (0.01) (N = 4) | 0.21 |
| TMS, EMM (SE) | |||||||
| rMT, %MO (N = 23) | 72.2 (6.4) (N = 8) | 62.9 (4.6) (N = 15) | - | 0.26 | 66.0 (5.4) (N = 12) | 54.9 (8.8) (N = 3) | 0.31 |
| CSR ms (N = 21) | 221.7 (16.7) (N = 6) | 198.4 (12.4) (N = 15) | - | 0.39 | 175.6 (12.6) (N = 11) | 241.9 (17.3) (N = 4) | 0.10 |
| LICI, log (MEPt/MEPc) (N = 18) | −0.02 (0.27) (N = 6) | −0.01 (0.18) (N = 12) | - | 0.97 | −0.03 (0.22) (N = 10) | 0.24 (0.37) (N = 2) | 0.99 |
ADOS-2- Autism Diagnostic Observation Schedule-Second Edition; ASD- Autism Spectrum Disorder; CSP- cortical silent period; EEG- Electroencephalogram; EEM- estimated marginal means adjusted for age; FSIQ- full scale intellectual quotient; GABA- γ-aminobutyrate; GHB- γ-hydroxybutyrate; GBA-guanidinobutyrate; IQR- Interquartile ratio; LICI- long interval intracortical inhibition; MEPc- motor evoked potential, condition; MEPt- motor evoked potential, test; MO- machine output; MRS- Magnetic resonance spectroscopy; ms- milliseconds; NAA- N-acetyl aspartate; NAD- SD- Standard deviation; SE- standard error; SSADHD- succinic semialdehyde dehydrogenase deficiency; TMS- transcranial magnetic stimulation; Bold indicates significant.
The ‘No Protein’ group participates in two comparisons presented in this table: 1) with the ‘Single Homotetramers’ and ‘Multiple Homo and Heterotetramers’ groups; 2) with the two “Effect in impairment” groups.
These p values represent the comparison between the groups ‘No protein,’ ‘Single Homotetramers,’ and ‘Multiple Homo and Heterotetramers.’
These p values represent the comparison between the groups ‘No Protein,’ ‘Impairment effect in Folding/Stability/Oligomerization,’ and ‘Impairment Effect in Catalysis.’