Neurological, behavioural defects an intrinsic manifestation of ADA deficiency
Published Date: 6/7/17Download Full Text Article
medwireNews: Neurological and behavioural impairments are not uncommon in patients with adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID), report Italian researchers who propose aberrant adenosine metabolism in the brain as the underlying cause.
The study, which involved investigations in ADA-SCID patients and in a mouse model of the disorder, also showed that enzyme replacement therapy (ERT) does little to correct these defects, indicating a need for ADA delivery into the brain.
Of 21 children with ADA-SCID included in the study, five were untreated at the initial evaluation, while 16 had received polyethylene glycol-modified (PEG)-ADA therapy. Stratifying the treated children by age (< vs > 3 years) also grouped them by length of PEG-ADA treatment, with younger and older patients receiving ERT for an average of 1.1 and 12.6 years, respectively.
The investigators report in Scientific Reports that one child each in the untreated and older treated groups showed severe motor dysfunction, while one young and two older treated children had mild symptoms.
Abnormal electroencephalography (EEG) findings were also prevalent, observed in 66% of the three untreated participants who underwent EEG, as well as in all three younger and half of the older treated children with available EEG results.
And magnetic resonance imaging of the brain revealed white matter alterations in 40% of untreated participants and in a similar proportion (38%) of the younger treated patients, but the occurrence of such changes was lower in the older treated group, at 17%. The enlargement of ventricles and subarachnoid spaces was seen in 80%, 38% and 17% of children, respectively.
In light of these results, Alessandro Aiuti, from IRCCS San Raffaele Scientific Institute in Milan, and co-workers observe that “[d]espite partially reducing these manifestations, PEG-ADA treatment cannot completely prevent their onset or resolve pre-existing defects.”
The researchers also found evidence of impaired neuropsychological development, with all seven of the younger treated children who underwent assessment showing mental development scores lower than the population average (within 2 standard deviations). Similarly, the total intelligence quotient of all six of the older treated group who underwent verbal and performance testing was “well below” the population mean.
Experiments in a mouse model of Ada deficiency reinforced these findings. Although the homozygous Ada-mutated mice did not show any defects in sensory or motor development relative to their control littermates, they were significantly less active as shown by the reduced distance travelled in the open field test.
The Ada-deficient mice also displayed anxiety-like behaviour in the dark and light box test, not only heading to the dark (safe) compartment significantly quicker than controls, but also spending significantly more time there, pointing to alterations in explorative behaviour.
Of note, PEG-ADA treatment did not improve the performance of Ada-deficient mice in either test, although it did correct the ventriculomegaly commonly seen in untreated mice, suggesting that the behavioural defects are cell intrinsic or molecular in nature whereas the ventriculomegaly is an extrinsic metabolic defect, observe Aiuti et al.
Further investigation suggested that these neurological and behavioural manifestations could be due to aberrant adenosine receptor signalling, specifically via Adora2a, which is one of four adenosine receptors.
On the hot plate test, Ada-mutated mice exhibited reduced pain perception relative to wild-type controls, licking their hind paws significantly later. This mirrors the phenotype seen in mice lacking Adora2a, which are known to be hypoalgesic, the researchers explain.
Furthermore, the levels of Adora2a were significantly lower in homozygous Ada-deficient mice than in controls, remaining low even after administration of PEG-ADA.
These results indicate that prolonged exposure to high concentrations of adenosine can lead to increased degradation of Adora2a, which is not rescued by metabolic detoxification via ERT in the brain, the study authors comment.
In conclusion, they say that “[f]urther studies will have to be performed to assess if a genotype-phenotype correlation exists between the ADA mutation and severity of the neurological phenotype” and also to assess whether “certain Adora polymorphisms may lead to a different neurological outcome or may serve as prognostic markers to predict long-term outcome.”
The team continues: “In ADA-SCID patients carrying highly sensitive adenosine receptor subtypes or with poor outcome after treatment, adenosine receptor antagonists already available in clinical practice might be suitable to ameliorate their phenotype.”
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