Genetic, clinical, and biochemical features in 3 patients with constitutional PIGA deficiency
| . | Patient 1 . | Patient 2 . | Patient 3 . |
|---|---|---|---|
| Constitutional PIGA mutation | c.230G>A (p.R77Q) | c.1031T>C (p.L344P) | c.380 C>T (p.S127L) |
| Inheritance | Maternal | Maternal | Maternal |
| Sex | Male | Male | Male |
| Age at time of data collection | 13 y | 7 y | 2 y |
| Degree of developmental delay | Moderate | Severe | Severe |
| Hypotonia | No | Yes | Yes |
| Age at seizure onset | 11 mo | 9 mo | 6 mo |
| Seizure type and severity | Focal and generalized tonic-clonic seizures partially controlled by valproate, stiripentol, and clobazam | Focal and generalized tonic-clonic seizures partially controlled by topiramat, zonisamid and levetiracetam | Focal and atonic seizures, seizure free under the administration of topiramat and lacosamid |
| Brain anomalies | No | Multifocal cortical dysplasia of the right hemisphere (possibly explained by a hemizygous pcdh19 variant) | No |
| Other congenital anomalies | Hypospadia glandis, primary enuresis nocturna | Cryptorchidism, cortical visual impairment, ichthyosis, hyper-/ hypopigmentation on the neck, widely spaced teeth | Somatomegaly |
| Biochemical | |||
| Ferritin (µg/L) | 188 (RR: 7-140) | 96 (RR: 7-140) | 79 (RR: 2-63) |
| Transferrin saturation (%) (RR: 16-45) | 96 | 87 | 70 |
| Transferrin (g/L) (RR: 2.0-3.6) | 1.87 | 1.97 | 2.23 |
| Serum iron (μmol/L) (RR: 14-32) | 45.1 | 43.2 | 39.0 |
| Hepcidin (ng/mL)17 | 2.9 (R:16.58-74.57) | 4.82 (R:6.78-118.86) | 3.1 (R:10.32-115.73) |
| FerriScan (MRI) (mg/g dry tissue) (RR: 0.17-1.8) | 4.0 | 1.8 | NA* |
| Serum transaminases (U/L) | Normal | Normal | Elevated (GOT 57 (RR: < 56); GPT 69 (RR: < 39)) |
| Serum alkaline phosphatase (U/L) | 243 (RR: 118-518) | 223 (RR: 86-315) | 411 (RR: 75-316) |
| Deficiency of GPI-anchored proteins and GPI anchors | ↓ CD48 on a subpopulation of B- and T-lymphocytes (nonsignificant, 0.22%) | ↓ CD157 on a subpopulation of monocytes (nonsignificant; 0.13%) | ↓ CD58 and CD59 on a subpopulation of reticulocytes (not significant due to a very low number of reticulocytes) |
| . | Patient 1 . | Patient 2 . | Patient 3 . |
|---|---|---|---|
| Constitutional PIGA mutation | c.230G>A (p.R77Q) | c.1031T>C (p.L344P) | c.380 C>T (p.S127L) |
| Inheritance | Maternal | Maternal | Maternal |
| Sex | Male | Male | Male |
| Age at time of data collection | 13 y | 7 y | 2 y |
| Degree of developmental delay | Moderate | Severe | Severe |
| Hypotonia | No | Yes | Yes |
| Age at seizure onset | 11 mo | 9 mo | 6 mo |
| Seizure type and severity | Focal and generalized tonic-clonic seizures partially controlled by valproate, stiripentol, and clobazam | Focal and generalized tonic-clonic seizures partially controlled by topiramat, zonisamid and levetiracetam | Focal and atonic seizures, seizure free under the administration of topiramat and lacosamid |
| Brain anomalies | No | Multifocal cortical dysplasia of the right hemisphere (possibly explained by a hemizygous pcdh19 variant) | No |
| Other congenital anomalies | Hypospadia glandis, primary enuresis nocturna | Cryptorchidism, cortical visual impairment, ichthyosis, hyper-/ hypopigmentation on the neck, widely spaced teeth | Somatomegaly |
| Biochemical | |||
| Ferritin (µg/L) | 188 (RR: 7-140) | 96 (RR: 7-140) | 79 (RR: 2-63) |
| Transferrin saturation (%) (RR: 16-45) | 96 | 87 | 70 |
| Transferrin (g/L) (RR: 2.0-3.6) | 1.87 | 1.97 | 2.23 |
| Serum iron (μmol/L) (RR: 14-32) | 45.1 | 43.2 | 39.0 |
| Hepcidin (ng/mL)17 | 2.9 (R:16.58-74.57) | 4.82 (R:6.78-118.86) | 3.1 (R:10.32-115.73) |
| FerriScan (MRI) (mg/g dry tissue) (RR: 0.17-1.8) | 4.0 | 1.8 | NA* |
| Serum transaminases (U/L) | Normal | Normal | Elevated (GOT 57 (RR: < 56); GPT 69 (RR: < 39)) |
| Serum alkaline phosphatase (U/L) | 243 (RR: 118-518) | 223 (RR: 86-315) | 411 (RR: 75-316) |
| Deficiency of GPI-anchored proteins and GPI anchors | ↓ CD48 on a subpopulation of B- and T-lymphocytes (nonsignificant, 0.22%) | ↓ CD157 on a subpopulation of monocytes (nonsignificant; 0.13%) | ↓ CD58 and CD59 on a subpopulation of reticulocytes (not significant due to a very low number of reticulocytes) |
c.230G>A (p.R77Q): ClinVar18 VCV000810512, likely pathogenic; PolyPhen-219 prediction, probably damaging; c.1031T>C (p.L344P): ClinVar VCV000444793, uncertain significance; PolyPhen-2 prediction: probably damaging; c.380 C>T (p.S127L): ClinVar, not annotated; PolyPhen-2 prediction, likely damaging.
NA, not available; R, range; RR, reference range.
Not indicated at the age of 2 y because sedation would be necessary.