Case# F1:II.2, F, 2yo onset, European
CasePresentingHPOs HP:0001263, HP:0006846, HP:0003201, HP:0011675, HP:0002925, HP:0001250, HP:0012444, HP:0001943, HP:0002151, HP:0045045, HP:0040145, HP:0001259, HP:0002133, HP:0002913, HP:0003128, HP:0002061, HP:0001664, HP:0008936, HP:0001344, HP:0000252, HP:0003236, HP:0001946, HP:0100543
HPOcont: Global developmental delay, Acute encephalopathy, Rhabdomyolysis, Arrhythmia, Elevated TSH, Seizures, Brain atrophy, Hypoglycemia, Elevated lactate, Elevated acylcarnitine, Dicarboxylic acidemia, Coma, Status epilepticus, Myoglobinuria, Lactic acidosis, Lower limb spasticity, Torsade de pointes, Trunk hypotonia, Absent Speech, Microcephaly, Elevated CK, Ketosis, Cognitive Impariment
HPOFreeText: "At the age of 2 7/12 years, she suffered from an infection and suddenly became comatose with status epilepticus. Her renal function was transiently impaired due to massive rhabdomyolysis with myoglobinuria. The girl’s condition subsequently improved but she was unable to sit due to truncal hypotonia. She developed progressive spasticity in the legs, and communicated only non-verbally. Two months later a second episode occurred, which was again
triggered by an infection and presented with similar clinical and laboratory findings. A third metabolic
decompensation with lactic acidosis, hypoglycemia and rhabdomyolysis occurred six weeks later. This
time, additional cardiac involvement with long QT syndrome and torsade de pointes tachyarrhythmia
required intensive care treatment and implantation of a cardioverter-defibrillator (ICD) device. Seizures
occurred which were responsive to antiepileptic medication. The girl remained with severely impaired
psychomotor capabilities, marked truncal muscular hypotonia, moderate spasticity in the lower limbs,
dystonic movements in the upper limbs, absent speech, and impaired social interaction. Secondary microcephaly became evident (head circumference < P3)."
CasePreviousTesting "marked hypoglycemia (18 mg/dl; normal range (NR) > 50 mg/dl). Initial laboratory testing documented massively elevated plasma creatine kinase (CK) activity (maximum 300,000 U/l, NR < 227 U/l) as well as elevated plasma lactate concentrations up to 3.8 mmol/l (NR < 1.6 mmol/l). Urine organic acid analyses during crises showed a massive excretion of ketone bodies (around 2,000 mmol/mol creatinine), lactate (2,000 mmol/mol creatinine; NR < 285 mmol/mol
creatinine), and dicarboxylic acids (values given in mmol/mol creatine: adipic (1,513; NR < 34), glutaric
(24; NR = not detectable), sebacic (712; NR < 1.4), suberic (494; NR < 10), decenedioic (581; NR =
not detectable), and of note malonic (145; NR = not detectable) acid). Acylcarnitine profiling in dried
blot spots collected during the crisis showed free carnitine concentrations within normal ranges while
several acylcarnitines were elevated 2-5-fold above the respective normal range (i.e. C5DC, C6DC,
C10:1, C12, C12:1, C14:1, C14:2). In addition, an elevated TSH concentration (16.6 mU/l; NR 0.5-4.5
mU/l) was detected and treatment with L-thyroxine was initiated. Targeted sequencing of CPT2, ETFA, ETFB, ETFDH, and GCDH did not reveal clinically relevant
variants."
CaseMethod1 WES
CaseMethod2 Sanger
CaseGenotypingMethod WES, confirmed with Sanger in patient and parents
Variant (1) NM_001283106.2(TANGO2):c.4delT (p.Cys2Alafs) (2) NM_152906.5:c.(56+1_57-1)(*1?)del
ClinVar (1) 224773
CAID (1) CA358861
gnomAD n/a
CaseAddInfo "measurement of pyruvate-dependent oxygen consumption rates in fibroblast cell lines from individuals F1:II.2 and F2:II.2 was unremarkable." Healthy twin brother.
CasePMIDs n/a
