Table 1.
Clinical information and results of diganotic studies of all cases and carriers of Glutaric Aciduria Type II (GA-II) identified by the New England Newborn Screening Program in the defined cohort during the period February 1999 through December 2012
| Clinical presentation | Confirmatory studies | Additional information | |||||
|---|---|---|---|---|---|---|---|
| ID | Prenatal and Birth history | Neonatal course | Urinary organic acids & acylglycines | Plasma acylcarnitines | Molecular analysis | Enzymatic studies | Autopsy findings |
| 1 | Born at 31 weeks gestation following premature rupture of membranes. Apgars 6 & 9*; Wt 1.3 kg. Agenesis of corpus callosum, complex heart defects, cleft lip & palate, enlarged echogenic kidneys and bilateral clubfeet noted at initial prenatal visit (2 weeks prior to delivery). Maternal history of a previous fetal demise at 28 weeks gestation with similar anomalies; she also had a healthy 6 year old son | Lethargic & hypotonic at birth and required endotracheal intubation. Metabolic acidosis noted that initially responded to acetate supplementation. Acute decompensation with hypotension, apnea and hypoglycemia developed on DOL 4. Investigations revealed hypoketotic hypoglycemia, hyperammonemia, metabolic acidosis, elevated CK. The hypoglycemia responded to increased IV glucose, but hyperammonemia & metabolic acidosis persisted. A severe FAOD (GA-II/CPT-II) suspected. Based on grim prognosis, ventilator support withdrawn and neonate died on DOL 7. NBS results, indicating a high risk for GA-II, were reported on DOL 7 after baby was deceased | Markedly increased lactic acid & glutaric acids. Mildly increased ethylmalonic acid, 2-hydroxyglutaric acid & its lactone, and isovalerylglycine | Elevations of acylcarnitine species of all chain lengths | … | … | Extensive lipid deposition in the heart, muscle, liver and kidneys. Bilateral cleft lip and palate, cardiomegaly with 2 small muscular ventriculoseptal defects, diffusely cystic kidneys with features of acute tubular necrosis. |
| 2 | Born at term. Apgars 9 & 9*; Wt 3.2 kg. Placental abruption during delivery suspected. No dysmorphic features noted | Pale and jittery few hours after birth with glucose of 10 mg/dl. Given dextrose bolus, and maintenance intravenous (IV) dextrose continued for 48 h. Was under observation in hospital and appeared to be doing well, when neonate turned pale and collapsed while being fed, 8 h after discontinuation of IV dextrose. NBS specimen collected a few hours prior to death indicated a high risk for GA-II | … | … | … | ETF Activity < 0.1 nmol/min/mg (Controls 0.8–2.4). Skin sample for fibroblast culture obtained post mortem | Extensive lipid deposition in heart, muscles, renal tubules and adrenal cortex. Marked thymic involution. |
| 3 | Delivered at 37 weeks of gestation due to IUGR. Apgars 7 & 8*; Wt 2.1 kg. Bilateral echogenic kidneys had been noted at 22 weeks, and IUGR & oligohydramnios noted at 32-weeks of gestation. Hypertelorism & low set ears noted at birth | Developed respiratory distress and seizures within an hour of birth and was extremely hypotonic and required endotrac heal intubation. Investigations revealed hypoketotic hypoglycemia, hyperammonemia, metabolic acidosis. A severe FAOD (GA-II/CPT-II) suspected. Head ultrasound revealed calcification in vessels around the midbrain. An echocardiogram revealed severe left ventricular dysfunction. Metabolic acidosis and hypotension refractory to treatment and baby died on DOL 2. The NBS results, indicating a high risk for GA-II, were reported after baby was deceased | Markedly increased ethylmalonic, glutaric, 2-hydroxyglutaric and adipic acids. Mildly increased methylsuccinic, suberic, sebacic, 5-hydroxyhexanoic & 7-hydroxyoctanoic acids and isovaleryl, 2-methylbutyryl & hexanoylglycines | Elevations of multiple acylcarnitine species (C4, C5, C6, C12, C14, C16, C12:1, C14:1, C14:2, C18, C18:1) suggestive of GA-II | ETFDH Gene: Two muations identified [ c.121C>T: p.R41X; c.1648_1649delCT : p.L550VfsX4] Confirmed to be in trans | … | Extensive lipid deposition in heart, muscles and adrenal cortex. Marked thymic involution. Pulmonary hypoplasia, bilobed lungs, renal dysplasia, particularly medullary with dilated tubules and cysts, focal polymicrogyria in the cerebrum and fetal osteosclerosis. |
| 4 | Born 37 weeks of gestation. Apgars 8 & 9*. Wt 3.2 kg. Hydrocephalus noted at 22 weeks of gestation. Head ultrasound at birth revealed prominent cystic areas adjacent to lateral ventricles with surrounding leukomalacia in addition to the hydrocephalus. Frontal bossing, large anterior fontanelle and hypertelorism reported | Feeding poorly on DOL-1 and had mild hypoglycemia that resolved with dextrose bolus. Lethargic and hypotonic on DOL-2, with severe hypoketotic hypoglycemia, hyperammonemia and metabolic acidosis. Hypoglycemia and metabolic acidosis resolved quickly with IV glucose, but hyperammonemia persisted. A severe FAOD (GA-II/CPT-II) suspected. Supportive measures initiated but neonate died on DOL-7. The NBS results, indicating a high risk for GA-II were reported on DOL-4 | Markedly increased lactic, ethylmalonic, methylsuccinic, glutaric & 2-hydroxyglutaric acids with mildly increased 3-hydroxybutyric, saturated & unsaturated dicarboxylic acids and isovaleryl, butyryl, hexanoyl & suberylglycines | … | … | … | |
| Follow-Up Information | |||||||
| 5 | Born 6 days post due date. Apgars 9 & 9*; Wt 3.6 kg. No dysmorphic features | No clinical issues were noted and was discharged home on DOL 3. NBS results suggesting high risk for GA-II were reported on DOL 6 and metabolic work-up initiated by specialist. The organic acid analysis was normal as was a follow-up screen collected on DOL 7. Plasma acylcarnitines revealed mild elevations of long chain acylcarnitines so a diagnosis of VLCAD suspected. Treatment (avoidance of fasting, a high carbohydrate and low fat) initiated for FAOD | During Illness at 1-1/2 years: Markedly increased ethylmalonic and adipic acids. Mildly increased methylsuccinic & 3-hydoxydicarboxylic acids and isovaleryl, butyryl, hexanoyl & suberylglycines | During Illness at 1-1/2 years: Elevations of multiple acylcarnitine species (C4, C5, C5DC, C6, C8, C10, C12, C14:2, C14:1, C14, C16) suggestive of GA-II | ETGDH Gene: Two mutations identified [c.121C>T : p.R41x; c.1448C>T : p.P483L] Confirmed to be in trans | ETF-DQ 1.4 nmol/min/mg (Controls 6.5–12.4) | Infant had 3 hospital admissions for dehydration and hypoglycemia in the first 6-months of life. Supplemental G-Tube feeding was initiated at 6 months of life. Elevations of ethylmalonic acid were noted in the urine during a hospitalization at 6 months of age, and skin samples for enzymatic studies on fibroblasts were sent out. These were supportive of SCAD and infant was diagnosed with SCAD. During another admission at 1-1/2 years of age laboratory findings suggestive of GA-II. Repeat enzymatic studies were performed and diagnosis confirmed. Riboflavin was initiated. Child continues to have episodes of biochemical abnormalities but frequency has decreased with age. Currently>10 years, child has mild hypotonia and difficulties with sustained activities but otherwise is doing well. Growth measurements are at the 50th %ile for age. |
| 6 | Born at term. Apgars 9 & 9*; Wt 3.7 kg. No dysmorphic features | Pallor and tachypnea noted at 25 h after birth attributed to an intrauterine bleed. Symptoms resolved quickly with a few hours of IV hydration and was discharged home on DOL 3. NBS results suggesting high risk for GA-II were reported on DOL 6 and metabolic work-up initiated by specialist on the same day | Markedly increased ethylmalonic & glutaric acids. Mildly increased isovaleryl, hexanoyl & suberylglycines | Elevations of multiple acylcarnitine species (C4, C5, C6, C8, C10:1, C10, C12, C14, C16, C12:1, C14:1, C14:2) suggestive of GA-II | ETFDH Gene: Two muations identified [c.1082A>G: p.Y361C; c.1648_1649delCT: p.L550VfsX4] Confirmed to be in trans | … | Treatment (avoidance of fasting, a high carbohydrate and low fat diet, carnitine and riboflavin) initiated. Supplemental G-Tube feeding initiated in 2nd year of life. Has a history of frequent episodes of biochemical abnormalities (abnormal PAC, UOA, CK and LFT’s) necessitating hospital admissions during minor illnesses but frequency has decreased with age (Current age>5 years). In addition has low energy levels and mild hypotonia but is otherwise doing well. Growth measurements are at the 50 th %ile for age. |
| 7 | Born at term. Apgars 9 & 9*; Wt 3.4 kg. No dysmorphic features | No clinical issues. NBS results suggesting high risk for GA-II were reported on DOL 4 and readmitted for diagnostic work-up. Mild hpoglycemia and abnormal LFT’s and CK noted on admission | Mildly increased ethylmalonic, glutaric, 2-hydroxyglutaric, methylsuccinic, suberic, sebacic & adipic acids and isovaleryl, 2-methylbutyryl & hexanoylglycines | Elevations of multiple acylcarnitine species (C4, C5, C6, C8, C10, C12, C14, C14:1) suggestive of GA-II | ETFDH Gene: Two mutations identified [c.250G>A:p.A84T; c.1110C>G:pG370G (Predicted to create novel splice donor site)] | … | Treatment (avoidance of fasting, a high carbohydrate and low fat diet, carnitine and riboflavin) initiated. Infant is doing well; current age 9 months. |
| 8 | Born at term. Apgars 9 & 9*; Wt 2.9 kg. No dysmorphic features | No clinical issues. NBS results suggesting risk for GA-II were reported on DOL 4 and neonate readmitted for diagnostic work-up. Mild hypoglycemia and abnormal LFT’s and CK noted on admission | No unusual organic acids detected | Mild elevations of multiple acylcarnitine species (C8, C10, C12, C14, C14:1) | ETGDH Gene: One mutation identified [858 G>A:p.W286X]. ETFA & ETFB: No mutations identified | ETF-DQ 0.70 nmol/min/mg (Controls 0.8–2.4); ETF 2.3 nmol/min/mg (Controls 0.79–2.1) | Asymptomatic. Current age 3 years. |
| 9 | Born at term. Apgars 9 & 9*; Wt 3.8 kg. No dysmorphic features | No clinical issues. NBS results suggesting risk for GA-II were reported on DOL 5 and metabolic work-up initiated by specialist the next day | No unusual organic acids detected | Normal | ETFB Gene: One variant identified [P94TfsX21]. ETFA and ETFDH: No mutations | … | Asymptomatic. Current age 1-1/2 years. |
CPT-II Carnitine palmitoyl transferase deficiency-Type II, DOL Day of life, FAOD Fatty acid oxidation defect, IV Intravenous, SCAD Short chain acyl CoA dehydrogenase deficiency, VLCAD Very long chain acyl CoA dehydrogenase deficiency
*At 1 and 5 min respectively