Gunning et al.,2020 | S1 | M | In utero 38/40 | 3 days | HCM | Congenital Cataracts, Corneal opacity | seizures | ND | hypotonia, cryptorchidism and micropenis, fetal akinesia,encephalopathy | increased excretion of fumarate, malate,2-ketoglutarate,3-methylglutaconate,and 3-methylglutarate |
S2 | F | At birth 38/40 | 6 weeks | DCM | Corneal opacity | diffuse abnormalities on EEG | white matter changes; simplified gyral patterning; cerebellar atrophy (MRI) | hypotonia, fetal hydrops; edema | lactic acidosis |
S3 | M | At birth 40/40 | 5 days | DCM; cardiomegaly | Corneal opacity | ND | Widespread, hypoxic brain, damage (postmortem) | hypotonia, Contractures, fetal hydrops, encephalopathy | ND |
S4 | F | At birth 33/40 | 6 weeks | HCM; cardiomegaly | Corneal opacity | diffuse abnormalities on EEG | diffuse bilateral, abnormal subcortical, periventricular, and deep white matter; abnormal MR spectroscopy | hypotonia, | lactic acidosis; increased excretion of 2OH butyrate, fumarate, and 3OH is butyrate |
S5 | M | At birth 40/40 | 4 weeks | HCM; cardiomegaly | Corneal opacity | seizures | white matter changes, generalized reduction of brain volume (MRI); abnormal MR spectroscopy (lactate peak) on day 9 | hypotonia, hypospadias, contractures | lactic acidosis, increased excretion of fumarate, malate on day 22 |
Frazier et al.,2021 | P1 | F | At birth 37/40 | 38 days | HCM | Bilateral cataract | Seizures, burst-suppression pattern (EEG) | MRI: diffuse hyperintense and swollen cerebral white matter on T2, hyperintense basal ganglia on T1, bilateral subependymal pseudocysts, mild pontocerebellar hypoplasia, lactate peak on MRS | Ascites | Blood: lactate 1.7–2.9mmol/L, abnormal liver function tests CSF: lactate 8.7 mmol/L Urine: increased TG, PG, IBG, IVG, 3MCG, alanine |
P2a | M | At birth 37/40 | 6 days | HCM | Dense corneal clouding | Seizures, burst-suppression pattern (EEG) | Histopathology: widespread gliosis and microglial activation with some neuronal loss but no other apparent structural abnormalities | hypotonia | Blood: lactate > 3.5mmol/L (persistent metabolic acidosis) Urine: slight increase in MMA, MC |
P2b | M | At birth 37/40 | 5 days | HCM | Dense corneal clouding | seizures | Histopathology: microglial activation, gliosis with some neuronal loss and occasional necrotic neurons in the brainstem, cerebellar dentate nucleus, basal ganglia, thalamus, and subiculum. Cerebral white matter was relatively spared | hypotonia, contractures | Blood: lactate > 3.5mmol/L (persistent metabolic acidosis) Urine: slight increase in MMA, MC |
P3 | M | In utero 38/40 | 9 days | HCM | Bilateral corneal opacification | burst-suppression pattern (EEG) | MRI: mild swelling and diffuse cerebral white matter hyperintensities on T2, bilateral cysts in the temporal lobes (particularly right side), lactate peak on MRS | IUGR, hypotonia, abnormal posturing | Blood: lactate 3–7 mmol/L (persistent metabolic acidosis) CSF: lactate 15.8 mmol/L (1.5 hours postmortem) Urine: slight increase in 3MGA, lactate |
P4 | F | In utero 3rd trimester | 4 days | Borderline contractility | ND | seizures | MRI: increased cerebral white matter signal, high lactate peak and low NAA on MRS Cranial US: Echogenicity of the basal ganglia and left lenticular striate artery | IUGR, hip flexion contractures, hepatic hemosiderosis and steatosis | Blood: increasing lactates (persistent metabolic acidosis) 7mmol/L (at birth) to 21 mmol/L (50 hours > delivery) |
P5 | F Mauritian | In utero 36/40 | 3 days | HCM | Probable cataracts | ND | Not performed | IUGR, hypotonia | Blood: lactate 9.1 mmol/L (persistent metabolic acidosis) |
P6 | M | In utero 38/40 | 3 days (64 hours) | HCM endocardial fibroelastosis | Corneal opacities, microphthalmia, possible cataracts | Seizures, burst-suppression pattern (EEG) | MRI: severely abnormal cerebral and cerebellar white matter signal and cerebral swelling, subtle basal ganglia signal abnormality | hydrops fetalis, hepatomegaly with macrovesicular steatosis, dysmorphic feature (low-set, posteriorly rotated ears and short palpebral fissures) | Blood: lactate peak 13 mmol/L (persistent metabolic acidosis) Urine: grossly elevated lactate and βOHB with TCA cycle intermediates including moderate increases in fumarate and 3MGA |
P7 | M | At birth 37/40 | 3 days | HCM endocardial fibrosis | Corneal opacities, periorbital conjunctival edema | seizures | Neuropathology: cerebral edema, poor demarcation between cortex and white matter, few areas of apparent softening in the subcortical white matter (right caudate nucleus and right fronto-parietal region) | IUGR, edema, brother died at 6 days following fetal distress/birth asphyxia | Blood: lactate 4 mmol/L, pyruvate 74 uMol/L, total carnitine 18 µM, free carnitine 12 µM CSF: lactate 4.5 mmol/L Urine: traces of fumaric, 3-methylglutaric and 3MGA |
P8 | M | In utero 38/40 | 8 days | HCM endocardial fibroelastosis | ND | NO | Cranial US: intraventricular hemorrhages, patchy hyperechogenicity in the basal ganglia consistent with calcium, right caudate cysts | Edema, hepatomegaly and steatosis, dysmorphic feature (prominent forehead and relatively small jaw), hypotonia | Blood: lactate peak 23.2 mmol/L, minimum pH 7.14 |
P9 | F | In utero IUGR 26/40, reduced fetal movement 34/40 | 6 days | Dilated phase of HCM | ND | ND | Cranial US: sub-ependymal cysts and lenticular striate artery echogenicity | IUGR, oligohydramnios, hepatic hemosiderosis, renal failure | Blood: lactate 8.6–25mmol/L (persistent metabolic acidosis) CSF: lactate 13.5 mmol/L |
P10 | M | At birth | 2 months | HCM | Corneal clouding | ND | MRI: cerebral white matter hyperintense lesions on T2 | neonatal asphyxia, bilateral hearing loss, hypotonia | Blood: lactate 9.9 mmol/L, pyruvate 0.36 mmol/L CSF: lactate 9.9 mmol/L, pyruvate 0.34 mmol/L |
P11 | M | At birth | 1 month | HCM | ND | ND | Cranial US: bilateral bright thalami | Neonatal asphyxia, cardiac tamponade | Blood: lactate 12.3mmol/L, pyruvate 0.46 mmol/L |
P12 | F | In utero 36/40 | 1 month | Heart failure, mild hypertrophy | Corneal clouding, microphthalmia, abnormal iris | ND | Brain CT: mild calcification in lenticular nucleus | IUGR, arthrogryposis neonatal asphyxia | Blood: lactate 12.6mmol/L, pyruvate 0.35 mmol/L |
P13 | F | At birth | 10 days | HCM | ND | ND | Brain CT: diffuse cerebral white matter hypodensity and swelling plus low density in the basal ganglia and thalamus | Neonatal asphyxia | Blood: lactate12.3 mmol/L, pyruvate 0.25 mmol/L |
P14 | M | In utero 37/40 | 3 days | DCM | Bilateral corneal opacity, bilateral cataracts | Seizures, burst-suppression pattern (EEG) | Cranial US: bilateral subependymal hemorrhages Histopathology: widespread gliosis and microglial activation with some neuronal loss | Hydrops, congenital alveolar dysplasia, hepatic siderosis and microvesicular steatosis | Blood: lactate 2.3 − 15mmol/L (persistent metabolic acidosis) Urine: grossly elevated lactate, slight fumarate and 3MGA |
P15 | M | In utero 31/40 | Fetal death in utero 36 + 6/40 | HCM endocardial fibroelastosis | ND | ND | Histopathology: gliosis and microglial activation with some neuronal loss in the brainstem, cerebellum, thalamus and basal ganglia | IUGR, hydrops fetalis | No investigations performed (fetal death in utero) |
P16 | M | At birth | 7 days | HCM | Corneal clouding | Seizures | Brain MRI: mild signal abnormality and swelling of cerebral white matter, severe generalised encephalopathy, increased lactate on MRS | renal failure | Blood: lactate 6.7 ཞ50mmol/L (persistent metabolic acidosis) Urine: increased 3MGA, 3methylglutarate, fumarate and lactate |
Present case | M | 4months | 6 months and 17 days | normal | normal | Focal myoclonic seizures, Video-EEG showed interictal: persistent diffuse high amplitude slow activity predominantly in the left hemisphere; ictal: focal onset myoclonic seizures. | Brain MRI: widening of the extra-cerebral space in the frontotemporal lobe and slight enlargement of the lateral ventricle | global development delay, abnormal liver function | lactic acidosis 2.7mmol/L ཞ 6.8mmol/L |