Case# Subject 1, F, 4yo onset, Hispanic
CasePresentingHPOs HP:0002373, HP:0001260, HP:0006957, HP:0002913, HP:0007359, HP:0002104, HP:0003236, HP:0001987, HP:0001943, HP:0002058, HP:0000252, HP:0006801, HP:0003487, HP:0000577, HP:0002376, HP:0003236, HP:0001249, HP:0003201, HP:0000252
HPOcont: Febrile seizures, Dysarthria, loss of ability to walk, Myoglobinuria, Focal autonomic seizures, Apnea, Hyperammonemia, Hypoglycemia, Myopathic facies, Microcephaly, Brisk DTR, Babinski sign, Exotropia, Developmental regression, Elevated CPK, Hypoglycemia, Intellectual Disability, Rhabdomyolysis, Microcephaly
HPOFreeText: Febrile seizure at 1 year of age, developmental regression in the following 3 years with recurrent seizures, losing the ability to ambulate and speak, as well as right focal seizure, apnea, and unresponsiveness triggered by fever. On hospital admission she was noted to have elevated urine myoglobin, elevated creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, ammonia and hypoglycemia. MRI showed mild diffuse atrophy of the left cerebral hemisphere. "Ophthalmology evaluation showed intermittent exotropia. Echocardiogram and electrocardiogram (ECG) were unremarkable. Hysical examination was relevant for microcephaly (FOC 47.5 cm; <5th percentile for age), myopathic facies with drooling, increased tone in all extremities, and brisk deep tendon reflexes (DTRs) throughout with positive Babinski sign.
CaseNotHPOs HP:0011675
NotHPOcont: Arrhythmia
CasePreviousTesting "urine myoglobin of 94 ng/ml (normal range 10–65 ng/ml), serum creatine phosphokinase (CPK) of 205,000 U/l (normal range 75–230 U/l), elevated aspartate aminotransferase (AST) of 1,618 U/l (normal range 15–50 U/l), alanine aminotransferase (ALT) of 571 U/l (normal range 10–25 U/l), ammonia of 122 μmol/l (normal range 22–48 μmol/l), and hypoglycemia (blood glucose 30 mg/dl; normal range 70–110 mg/dl)."
CaseMethod1 WES
CaseMethod2 Sanger
CaseGenotypingMethod WES and cSNP results confirmed with Sanger
Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg)
ClinVar (1) 208823
CAID (1) CA358646
gnomAD (1) 0.001549(Other), 0.0001208(Overall)
VariantEvidence (Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.
CaseAddInfo nonconsanguineous, mother tested heterozygous, father unavailable. cSNP data showed no evidence of deletion or uniparental isodisomy of the region.
CasePMIDs n/a