Table 1 Overview of mutations and phenotypes observed in patients with germline PIGA mutations
From: The genotypic and phenotypic spectrum of PIGA deficiency
| Â | (Johnston et al. [ 15 ] ) | (Johnston et al. [ 15 ] ) | (van der Crabben et al. [ 17 ] ) | (Swoboda et al. [ 16 ] ) | (Belet et al. [ 7 ] ) | (Kato et al. [ 18 ] ) | (Kato et al. [ 18 ] ) | (Kato et al. [ 18 ] ) | (Kato et al. [ 18 ] ) | (Kato et al. [ 18 ] ) | Our patient |
|---|---|---|---|---|---|---|---|---|---|---|---|
IV-2 | IV-4 | III-1 | III-9 | IV-2 | 1 | 2 | 3 | 4 | 5 | ||
Mother carrier | YES | YES | YES | YES | YES | Unknown | YES | YES | YES | YES | YES |
Mutation | c.1234C>T [R412*] | c.1234C>T [R412*] | c.278C>T [P93L] | c.328_330delCCT[L344Del] | c.76dupT [Y26Lfs*3] | c.1234C>T [R412*] | c.616A>T [I206F] | c.230G>T [R77L] | c.230G>T [R77L] | c.355C>T [R119W] | c.989G>A [S330N] |
Polyhydramnios | NO | YES | YES | NO | NO | YES | NO | NO | NO | YES | NO |
Current age | Death at 11wk | Death at 10wk | Death at 2.5 yrs | Death at 7 yrs | 24 yrs | 6 yrs | 10 yrs | 8 yrs | 18 mo | 15 mo | Death at 3.4 yrs |
Sex | M | M | M | M | M | M | M | M | M | M | M |
Neurology | |||||||||||
Developmental delay (severity) | Early death | Early death | Profound | Profound | Profound | Profound | Profound | Profound | Profound | Profound | Profound |
Hypotonia | YES | YES | YES | YES | YES | YES | NO | NO | NO | YES | YES |
Hyperreflexia | YES | YES | NO | YES | NR | NR | NO | NO | NO | YES | YES |
Seizure onset | Neonatal | Neonatal | 8.5 months | 7 months | 6 months | 1 month | 3 months | 7 months | 7 months | 3 months | 2.4 months |
Seizure types | Myoclonic | Myoclonic | Generalized clonic (febrile) | Febrile, myoclonic | Myoclonic epileptic seizures | Tonic seizures followed by frequent myoclonus | Myoclonus or epileptic spasm-like movement | Tonic seizures, secondarily generalized seizures | Tonic or clonic | Myoclonic seizures, tonic spasms | Infantile spasms, myoclonic seizures |
EEG findings | Suppression burst | Suppression burst | Symptomatic generalized epilepsy | Posterior bursts | Hyps-arrhythmia at 7 mo | Suppression burst at neonatal period | Hypsarrhythmia, periodic bursts of multifocal epileptic discharges | Irregular spike and slow wave and multifocal spikes at 2 and5 y | Normal at 7 mo | Hypsarrhythmia at 3 mo, suppression burst at 5 mo | Hypsarrythmia at 2.4 mos, suppression-burst pattern at 3.5 mos |
Seizure prognosis | Intractable | Intractable | Refractory | Intermittent | NR | Intractable | Intractable | Seizure-free at 3 y with TPM | Seizure-free at 15 mo | Intractable | Intractable |
Thin corpus callosum | YES | YES | YES | NR | NO | YES | YES | NO | NO | YES | YES |
White matter immaturity | YES | YES | YES | NR | NO | YES | YES | NO | NO | YES | YES |
Small cerebellum | YES | YES | YES | YES | NO | NR | NR | NR | NR | NR | YES |
Cortical atrophy | NR | NR | NR | YES | NO | YES | YES | NO | NO | YES | YES |
Restricted diffusion brainstem/cerebellum | NR | NR | NR | NR | NO | YES | YES | NO | NO | YES | YES |
Other organs | |||||||||||
Facial dysmorphism | YES | YES | YES | YES | NO | YES | YES | NO | NO | YES | YES |
Joints (contractures) | YES | YES | NR | NR | NR | YES | YES | NO | NO | NO | YES |
Cardiac | Systolic II–III/VI murmur with a fixed split S2, ASD | Small PDA | ASD type 2 | NR | NR | NR | NR | NR | NR | NR | RVH, arrhythmia (grade 1 AV block, Wenckebach type) |
Liver | NR | Hepatic microvesicular steatosis | NR | Hepatosplenomegaly | NR | Hepato-megaly, hepato-blastoma | NR | NR | NR | NR | Hepatomegaly, hyperechoic liver |
Kidney | Vesicoureteral reflux, duplicated collectingSystem | Vesicoureteral reflux | NR | NR | NR | Vesicoureteral reflux | NR | NR | NR | NR | Left hydronephrosis with renal calculi |
Ophthalmologic | NR | NR | NR | Blindness | NR | NR | NR | NR | NR | NR | Visual motor impairment, retinal dystrophy |
Hearing loss | NR | NR | NR | Deafness | NR | NR | NR | NR | NR | NR | Sensorineural hearing loss |
Dental | NR | Underdeveloped gums | Absence of teeth | NR, but III-10 microdontia, widely-spaced, delayed eruption | NR | NR | NR | NR | NR | NR | Microdontia, widely-spaced delayed eruption |
Other | Globulous chest and small nails, broad palms with short fingers | Absence of olfactory bulb and tracts | Accelerated linear growth, obesity | Ichthyosis | NR | Tracheostomy, micropenis, bilateral inguinal herniation, hypotonic quadriplegia | Spastic quadriplegia, bulbar palsy with gastrostomy and tracheostomy | NR | NR | Transverse palmar crease, prominent calcaneus, left inguinal hernia, hydrocele testicle, hypotonic quadriplegia | Stomatocytes |
Biochemical | |||||||||||
Elevated alkaline phosphatase | NR | YES | YES | NR | NR | NR | YES | NO | NO | YES | YES |
Mitochondrial abnormalities | NR | NR | Abnormal ATP production (muscle biopsy) | Disorganized mitochondria | NR | NR | NR | NR | NR | NR | Respiratory chain complex I and V reductions (muscle blue native gel) |
Iron storage | NO | NO | NO | CNS iron deposition | NR | NR | NR | NR | NR | NR | NO |
Other | Slightly elevated MCV and RDW and low ionized calcium, HgB and RBC | Slightly elevated MCV and RDW | NO | NR | NR | NR | NR | NR | NR | NR | Dyslipidemia (high triglycerides, hypercholesterolemia, LPL deficiency) |
Clinical diagnosis | |||||||||||
Clinical descriptor | MCAHS2 Bethesda– Utrecht syndrome | MCAHS2Bethesda–Utrecht syndrome | MCAHS2 Bethesda– Utrecht syndrome | Ferro-Cerebro-Cutaneous syndrome | MCAHS2-like syndrome X-linked infantile spasm syndrome (West syndrome) | Ohtahara syndrome, early myoclonic encephalopathy, Schinzel-Giedion syndrome | West syndrome with hypomyelination | Early-onset epileptic encephalopathy | Early-onset epileptic encephalopathy | West syndrome | PIGA deficiency |
Cause of death | Pneumonia | Respiratory failure | Cardiac arrest | Aspiration pneumonia | NA | NA | NA | NA | NA | NA | Cardiac arrest |