Cerebral folate deficiency: a treatable cause of late deterioration in epilepsy with developmental delay.

A 25-year-old woman with childhood-onset refractory epilepsy and developmental delay experienced a gradually progressive marked deterioration in mobility and seizure control, with language regression. Investigation identified a homozygous deletion within the contactin-associated protein-like 2 gene (CNTNAP2), underlying her early presentation, but also cerebral folate deficiency that most likely contributed to her later deterioration. Following antiseizure medication adjustment and treatment with folinic acid, she stabilised with improved seizure control and limited improvement in language and motor function; she has remained neurologically stable for more than a decade. That the previously observed neurological decline was halted by folinic acid replacement supports this being due to cerebral folate deficiency. Metabolic conditions are less well recognised in adults and can be under-diagnosed. They are potentially treatable and should be considered even in the presence of another cause, particularly when the presentation is not fully compatible.

Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder.

Cerebral folate deficiency (CFD) syndrome is a rare treatable neurometabolic disorder with low levels of the active form of folaten in cerebrospinal fluid (CSF) arising from different causes such as FOLR1 gene mutations or autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus. It is characterized by late infantile onset refractory seizures, ataxia, movement disorder, and unexplained global developmental delay. Here, we report a patient diagnosed with autistic spectrum disorder, followed by refractory myoclonic-atonic seizures, ataxia, and loss of motor skills over time. A homozygous missense (c.665A > G) mutation in FOLR1 gene and extremely low CSF 5-methyltetrahydrofolate level led to the diagnosis of CFD. Although she was initiated on combined oral and intravenous high doses of folinic acid treatment at 6 years of age, mild improvement was achieved in terms of epileptic seizures and motor skills. It is important that CFD should be kept in mind in cases with refractory myoclonic-atonic seizure and folinic acid treatment should be started as soon as possible.

A novel miniature transposon-like element discovered in the coding sequence of a gene that encodes for 5-formyltetrahydrofolate in wheat.

BACKGROUND: Transposable elements (TEs) comprise over 80% of the wheat genome and usually possess unique features for specific super-families and families. However, the role of TEs in wheat evolution and reshaping the wheat genome remains largely unclear. RESULTS: In this study, we discovered a miniature (307 bp in length) TE-like sequence in exon 6 of a gene that encodes for 5-formyltetrahydrofolate, in two accessions of wild emmer wheat (T. turgidum ssp. dicoccoides) and has interfered with the gene translation by creating a shorter reading frame as a result of a stop codon. The sequence that was termed Mariam, does not show any structural similarity to known TEs. It does not possess terminal inverted repeats (TIRs) that would allow us to assign this element to one of the TIR DNA super-families, and it does not possess characteristic features of SINE, such as a Pol-III promotor or a poly-A tail. In-silico analysis of five publicly available genome drafts of Triticum and Aegilops species revealed that Mariam element appears in a very low copy number (1-3 insertions) in diploid wheat species and ~ 12 insertions in tetraploid and hexaploidy wheat species. In addition, Mariam element was found to be unique to wheat, as it was not found in other plant genomes. The dynamic nature of Mariam in the wheat genome was assessed by site-specific PCR analysis and revealed that it retained activity in wild emmer populations in a population-specific manner. CONCLUSIONS: This study provides additional insight into the evolutionary impact of TEs in wheat.