ABSTRACT
FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), which is essential for charging mitochondrial (mt-) tRNAPhe with phenylalanine for use in intramitochondrial translation. Many biallelic, pathogenic FARS2 variants have been described previously, which are mostly associated with two distinct clinical phenotypes; an early onset epileptic mitochondrial encephalomyopathy or a later onset spastic paraplegia. In this study, we report on a patient who presented at 3 weeks of age with tachypnoea and poor feeding, which progressed to severe metabolic decompensation with lactic acidosis and seizure activity followed by death at 9 weeks of age. Rapid trio whole exome sequencing identified compound heterozygous FARS2 variants including a pathogenic exon 2 deletion on one allele and a rare missense variant (c.593G > T, p.(Arg198Leu)) on the other allele, necessitating further work to aid variant classification. Assessment of patient fibroblasts demonstrated severely decreased steady-state levels of mtPheRS, but no obvious defect in any components of the oxidative phosphorylation system. To investigate the potential pathogenicity of the missense variant, we determined its high-resolution crystal structure, demonstrating a local structural destabilization in the catalytic domain. Moreover, the R198L mutation reduced the thermal stability and impaired the enzymatic activity of mtPheRS due to a lower binding affinity for tRNAPhe and a slower turnover rate. Together these data confirm the pathogenicity of this FARS2 variant in causing early-onset mitochondrial epilepsy.
Subject(s)
Epilepsy , Mitochondrial Diseases , Phenylalanine-tRNA Ligase , Humans , Infant , Infant, Newborn , Epilepsy/pathology , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Mitochondrial Proteins/genetics , Mutation , Phenylalanine-tRNA Ligase/genetics , Phenylalanine-tRNA Ligase/chemistry , RNA, Transfer/genetics , RNA, Transfer, Phe/metabolismABSTRACT
Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease resulting in acute liver failure in early infancy, hypophosphataemic rickets, neurological crises, liver cirrhosis and risk of hepatocellular carcinoma later on in life. It is caused by the deficiency of the enzyme fumarylacetoacetate hydrolase which is involved in the terminal step of the catabolic pathway of tyrosine. Diagnosis is made through clinical suspicion supported by biochemical abnormalities that result from accumulation of upstream metabolites. Detection of succinylacetone (SA) in dried blood spot or urine remains pathognomonic, however it is not always detectable. Here we describe three cases of HT1 presenting with atypical biochemistry, where SA was not always detectable, highlighting the importance of an additional disease biomarker, 4-oxo-6-hydroxyheptanoate.
ABSTRACT
In urea cycle disorders (UCDs) ammonia scavenger drugs, usually sodium-based, have been the mainstay of treatment. Increasingly, glycerol phenylbutyrate (GPB, Ravicti®) is being used but scant real-world data exist regarding clinical outcomes. A retrospective study of UCD patients initiated on or switched to GPB was performed at a UK centre. Data on population characteristics, treatment aspects, laboratory measurements, and clinical outcomes were collected before and after patients started GPB with a sub-group analysis undertaken for patients with ≥12 months of data before and after starting GPB. UCDs included arginosuccinate synthetase deficiency (n = 8), arginosuccinate lyase deficiency (n = 6), ornithine carbamoyltransferase deficiency (n = 3), and carbamoyl phosphate synthetase 1 deficiency (n = 3). In the sub-group analysis (n = 11), GPB resulted in lower plasma ammonia (31 vs. 41 µmol/L, p = 0.037), glutamine (670 vs. 838 µmol/L, p = 0.002), annualised hyperammonaemic episodes (0.2 vs. 1.9, p = 0.020), hospitalisations (0.5 vs. 2.2, p = 0.010), and hyperammonaemic episodes resulting in hospitalisation (0.2 vs. 1.6, p = 0.035) reflecting changes seen in the whole group. Overall, patients exposed to sodium and propylene glycol levels above UK daily limits reduced by 78% and 83% respectively. Mean levels of branched chain amino acids, haemoglobin, and white cell count were unchanged. Two adverse drug reactions (pancytopenia, fatigue/appetite loss) resolved without GPB discontinuation. Patients/families preferred GPB for its lower volume, greater palatability and easier administration. GPB appeared to improve biochemical measures and clinical outcomes. The causes are multi-factorial and are likely to include prolonged action of GPB and its good tolerability, even at higher doses, facilitating tighter control of ammonia.
ABSTRACT
Isolated remethylation defects are rare inherited diseases caused by a defective remethylation of homocysteine to methionine, preventing various essential methylation reactions to occur. Patients present with a systemic phenotype, which can especially affect the central and peripheral nervous systems leading to epileptic encephalopathy, developmental delay and peripheral neuropathy. Respiratory failure has been described in some cases, caused by both central and peripheral neurological involvement. In published cases, the genetic diagnosis and initiation of appropriate therapy were rapidly performed following respiratory failure and led to a rapid recovery of respiratory insufficiency within days. Here, we present two infantile-onset cases of isolated remethylation defects, cobalamine (Cbl)G and methylenetetrahydrofolate reductase (MTHFR) deficiencies, which were diagnosed after several months of respiratory failure. Disease modifying therapy based on hydroxocobalamin and betaine was initiated and shows a progressive improvement and enabled weaning off respiratory support after 21 and 17 months in CblG and MTHFR patients respectively. We show that prolonged respiratory failure responds to conventional therapy in isolated remethylation defects, but can require a sustained period of time before observing a full response to therapy.
ABSTRACT
Long-term management of urea cycle disorders (UCDs) often involves unlicensed oral sodium benzoate (NaBz) which has a high volume and unpleasant taste. A more palatable treatment is licenced and available (glycerol phenylbutyrate [GPB], Ravicti) but guidance on how to transition patients from NaBz is lacking. A retrospective analysis of clinical and biochemical data was performed for eight children who transitioned from treatment with a single ammonia scavenger, NaBz, to GPB at a single metabolic centre; UCDs included arginosuccinic aciduria (ASA) (n = 5), citrullinaemia type 1 (n = 2) and carbamoyl phosphate synthetase I deficiency (CPS1) (n = 1). Patients transitioned either by gradual transition over 1-2 weeks (n = 3) or direct replacement of NaBz with GPB (n = 5). Median initial dose of GPB was 8.5 mL/m2/day based on published product information; doses were revisited subsequently in clinic and titrated individually (range 4.5-11 mL/m2/day). Pre-transition and post-transition mean ammonia levels were 37 µmol/L (SD 28 µmol/L) and 29 µmol/L (SD 22 µmol/L), respectively (p = 0.09), and mean glutamine levels were 664 µmol/L (SD 225 µmol/L) and 598 µmol/L (SD 185 µmol/L), respectively (p = 0.24). There were no reductions in levels of branched chain amino acids. No related adverse drug reactions were reported. Patients preferred GPB because of its lower volume and greater palatability. Direct replacement of NaBz with GPB maintained metabolic control and was simple for the health service and patients to manage. A more cautious approach with additional monitoring would be warranted in brittle patients and patients whose ammonia levels are difficult to control.
ABSTRACT
Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype. Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients' results on biochemical and genetic investigations and on in-depth phenotyping are presented. Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort. Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.