Patient 1
A male neonate, the first child of consanguineous Lebanese parents, was born at 38 weeks after an uncomplicated pregnancy with a birth weight of 2.945 kg (21st centile) and Apgar scores 9 at 1 and 5 min. He developed respiratory distress at 31 h of age, metabolic acidosis (pH 7.2, HCO3 9, base excess -17), and hypoglycaemia (1 mmol/L). He responded promptly to intravenous 10% dextrose correction, antibiotic coverage for 48 h, and was discharged home on day five, fully breastfed.
He represented on day six with respiratory distress, poor feeding, lethargy, approximately 10% weight loss (2.66 kg), hypothermia (33.0 °C), compensated metabolic acidosis (pH 7.38, pCO2 16 mmHg, HCO39 mmol/L, base excess -14 mmol/L) and hypoglycaemia (1.7 mmol/L). He was treated with intravenous dextrose 10% bolus correction and continuous positive airway pressure (CPAP). Liver function tests showed raised alanine aminotransferase (ALT; 220 µmol/L RR 0-45) and aspartate aminotransferase (AST 212 µmol/L, RR 20-90). Mild hyperammonemia (160 µmol/L) normalised with intravenous dextrose 10% maintenance fluid replacement. He was transferred by the Neonatal retrieval service to our tertiary Neonatal Intensive Care Unit the same day.
Upon presentation, he was clinically inactive, though his Moro’s reflex was intact, and appeared oedematous. His head circumference was 37 cm (63rd centile). Liver was palpable two cm below the right costal margin in the midclavicular line. Liver function tests showed hypoalbuminemia and transaminitis [Table 1]. Plasma amino acids were generally low, suggestive of poor oral intake which corroborated with the preceding history of decreased feeding for three to four days. Urgent urine organic acid analysis showed grossly increased HMG, MGC, MGL and 3IV, confirming a diagnosis of HMGCL deficiency. Plasma acylcarnitine analysis displayed an increase in C5-OH acylcarnitine (2.59 µmol/L, RR < 0.15). Day 2 newborn screening showed elevated C5-OH (2.8 µmol/L, RR < 1). Formal echocardiogram was normal. He commenced on a protein and fat-restricted diet, oral S-DL-3OHB 150 mg/kg/dose, QID in the acute phase and 150 mg/kg/dose BD when well (Veriton Pharma, Weybride, UK), and L-carnitine supplementation (50 mg/kg/dose, BD). Relevant data used to monitor clinical response is incorporated in Table 1. He gradually improved with increased caloric and protein intake and a discharge weight of 3.010 kg (0.33rd centile) on day 28. MRI brain aged two weeks showed mild homogeneously increased signal within the periventricular white matter of the cerebral, cerebellar hemispheres, and pontomedullary junction anteriorly, demonstrating equivocal diffusion restriction. On discharge, his daily feeds provided 1.7 g protein/kg and 26% of energy from fat from standard infant formula, carbohydrate polymer and Paediatric Seravit, with a maximum of 4 h of fasting. His unwell feeding plan consisted of carbohydrate polymer and Paediatric Seravit, providing 120% of estimated energy requirement (EER).
He attained age-appropriate developmental milestones and weight gain till 12 months of age. During an interim period, with a change in clinical care after 12 months, the dose of his S-DL-3OHB had decreased from approximately 530 mg/kg/day (when well) at 12 months (8.42 kg) to 300 mg/kg/day at 15 months (9.7 kg). His diet history showed an estimated fat intake of ~30% energy and protein intake of 1.9-2.6 g protein/kg. Nocturnal uncooked corn starch was commenced at 0.3 g/kg/day and subsequently increased to 0.6 g/kg/day 3 months later.
His parents noted a decline in his overall well-being since approximately 15 months. He was described to be increasingly lethargic, irritable, and displayed regression of speech and language skills. He had nine presentations within 15 months to the emergency department and admissions, with the most severe at 2.5 years, when he had status epilepticus lasting 66 mins due to severe hypoglycemia (unrecordable blood glucose), hyperammonemic encephalopathy (ammonia 261 µmol/L), metabolic acidosis and lactic acidemia. The lack of dose increment of S-DL-3OHB, appropriate to his weight gain, was a potential cause for his decompensation as his dietary management had largely remained the same, and there were no triggering intercurrent illnesses or prolonged fasting preceding this event. His social and language skills further regressed after this acute decompensation. Formal developmental assessment using the Mullen Scales of Early Learning at 2 years 9 months concurred with clinical assessments of normal, age- related milestone till age 12 months, with subsequent regression thereafter. He was diagnosed with DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-fifth edition by the American Psychiatric Association, 2013) criteria for autism spectrum disorder and significant global developmental delay with severe speech and language impairment.
Following this, the dose of S-DL-3OHB was increased to 500 mg/kg/day, with no associated changes in his dietary management. Within 2 to 3 days of this dose adjustment, his parents noticed an improvement in his activity and energy levels, appetite, decreased irritability and subsequently, a gain of new developmental milestones over the following months. 3-day food diary at 3 years showed restriction of both fat and protein to approximately 11.5% energy. This provided 3.1 g protein/kg/day, predominantly from cereal and vegetable sources, and he was also taking high amylopectin starch (1.5 g/kg, Glycosade®) before bed. At his last review aged 6.5 years, he interacted well with his treating team, spoke in short sentences, and had good eye contact, which corroborated with encouraging feedback from his clinical psychologist who had observed improvements in his autistic behaviour. He was well thrived, weighing 22.0 kg (60th percentile) and height of 113.6 cm (27th percentile) on the Centers for Disease Control and Prevention (CDC) growth charts.
Molecular analysis by massively parallel sequencing determined a homozygous pathogenic frameshift variant, classified as per American College of Medical Genetics and Genomics guidelines[15], c.887_888del, in the last exon of the in the HMGCL gene, which was predicted to create a premature stop codon (p.Leu296Profs*19), resulting in a null allele. Both parents are heterozygous for the variant.
Patient 2
Prenatal diagnosis for the younger sibling of patient 1 was declined by the parents; hence, high-risk management was initiated at birth, before confirmatory diagnosis was available. The female neonate was born after an uncomplicated pregnancy with normal Apgar scores and a birth weight of 3.045 kg. She had an initial hypoglycaemia (1.7 mmol/L) noted soon after birth, which normalised with IV dextrose 10% maintenance fluids. Her ammonia levels, blood gas, and lactate levels remained normal. Day 2 newborn screening showed elevated C5-OH (1.9 µmol/L, RR < 1) and normal plasma amino acids. Upon confirmation of HMG CoA lyase deficiency through urine organic acid analysis (increased HMG, MGC, MGL and 3IV) and elevated plasma C5-OH acylcarnitine (0.45 µmol/L, RR 0.00-0.10) [Table 2], her oral feeds were graded to include a combination of breast milk, standard infant formula with glucose polymer solution to meet fluid and energy requirements, protein intake up to 1.5 g/kg and 30% energy from fat. She was supplemented with oral levocarnitine (50 mg/kg/dose, BD) and oral S-DL-3OHB (150 mg/kg/dose, TDS) when well, with double dose when unwell (150 mg/kg/dose, 4 hourly). The maximum fasting time was 3 to 4 h. She is homozygous for the familial variant, c.887_888del, p.(Leu296Profs*19), previously identified in her brother.
At 9 months of age, her total dietary intake provided 1.2 g protein/kg and 23% energy from fat. At all ages, prescribed unwell feeds provided 120% estimated energy requirements, with S-DL-3OHB maintained at approximately 150 mg/kg/dose TDS when well, and 150 mg/kg/dose, 4-hourly when unwell. Clinically, she has progressed well with satisfactory weight (10.48 kg, 43 percentile) and height (76 cm, 42nd percentile, CDC growth chart) gain and age-appropriate developmental milestones when last reviewed at 16 months. She is due to have a cardiac ECHO soon and has remained clinically asymptomatic.
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