Mol Genet Metab Rep. 2025 Dec;45 101260
Pyridoxine-Dependent Epilepsy (PDE) is an autosomal recessive disorder caused by biallelic variants in ALDH7A1. The most common presentation is intractable seizures in the neonatal/early infantile period, which respond to pyridoxine. Other manifestations include perinatal asphyxia, hypoglycemia, and neuroimaging abnormalities. Despite early treatment, patients often have neurodevelopmental abnormalities. Treatment guidelines recommend triple therapy with pyridoxine, dietary lysine restriction, and arginine supplementation. We report an individual presenting with laboratory abnormalities suggestive of mitochondrial disease. Born full-term, via NSVD, with normal Apgar scores and cord gases. At 30 min, grunting developed, and at 4 h of life, jerky movements with eye deviation were noted. Laboratory results revealed acidosis (pH 7.15) and increased lactate (11.4 mMol/L, rr <2.1). The patient was started on IV fluids, given 1 mEq/kg of sodium bicarbonate, and transferred for higher-level care. Upon arrival, the evaluation was notable for hypotonia, non-rhythmic jerking movements, rapid eye blinking, and a critically low pH (6.92), high lactate (15.3 mMol/L), hyperammonemia (153 μMol/L, rr < 75), and a creatine kinase level of 15,742 U/L (rr 35-230). A single dose of phenobarbital was given, and the baby was intubated and ventilated. Video electroencephalogram (vEEG) showed a discontinuous background with abnormal, sharply contoured bursts alternating with suppression, with no clinical correlation. The patient was treated with continuous sodium bicarbonate drip and IV fluids, restricting glucose. Abnormal movements, lactic acidosis, and hyperammonemia resolved within 24 h. An electroencephalogram (EEG) at 5 days of life (DOL) showed a mildly discontinuous background with no epileptic activity, and MRI showed a thin corpus callosum, cysts, and cerebellar hypoplasia. Creatine kinase peaked at 30,995 U/L and normalized on DOL 8. Organic acids revealed significant increases in lactate, 2-OH-butyrate, pyruvate, 3-OH-butyrate, 2-OH-isovalerate, and a mild increase in Krebs-cycle intermediates. Rapid whole genome sequence (rWGS) was available on DOL 9, disclosing two variants in ALDH7A1: c.1559C > T p.Ser520Phe, previously reported, and c.1540 A > G p.Lys514Glu, considered a VUS. Treatment with pyridoxine started at 30 mg/kg/day. Pre-treatment biomarkers were consistent with the diagnosis of PDE-ALDH7A1: urine Pipecolate 117.8 mMol/mol, RR ≤10, 6-oxo-Pipecolate 8.4 mMol/mol, RR ≤2.0 and plasma alpha-aminoadipic semialdehyde (AASA) 5.2 uMol/L, RR <0.4. Treatment with arginine was added on DOL 10 (200 mg/kg/day) and a lysine-restricted diet on DOL 12, after TPN was discontinued. Clinical exam improved, no seizures were observed, and EEG normalized. PDE biomarkers decreased, and the patient was discharged home on DOL 25. Elevated lactic acid has been reported in up to 70.3 % of PDE-ALDH7A1 patients with neonatal-onset; however, there is limited information about its severity, etiology, or pathophysiologic mechanism. We, therefore, conducted a review of published cases of neonatal-onset PDE-ALDH7A1 whose actual lactic acid values were reported. A total of 12 patients were analyzed and compared to this case. In most instances, a trigger (such as pulmonary hemorrhage, postnatal hypoxia, or status epilepticus) could be identified as the cause of elevated lactic acid; nevertheless, in many individuals, lactic acidosis remained unexplained. This case expands on the biochemical presentation of PDE-ALDH7A1 and highlights the importance of identifying increased lactic acid as another of its manifestations. We also provide evidence to support the reclassification of the c.1540 A > G (p.Lys514Glu) variant as pathogenic.
Keywords: ALDH7A1; Mitochondrial disease; PDE; Pyridoxine-dependent epilepsy; Rhabdomyolysis; hyperCKemia