New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches.

Carnitine acyl-carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long-chain fatty-acid transport. Most patients present in the first 2 days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Multi-centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Twenty-three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, six of these homozygous c.82G>T, had later onset manifestations and long-term survival without chronic hyperammonemia. Of the 16 classical cases, 15 had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15), and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer-term-most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High-energy intake seems necessary to prevent decompensation. Anaplerosis utilising therapeutic d,l-3-hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long-term survival is possible in classical early-onset cases with long-chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer-term outcomes.

The decision to discontinue screening for carnitine uptake disorder in New Zealand.

When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 µmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS. While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with high-dose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.

Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease.

Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5' UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3 Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.