Metabolic control and clinical outcome in adolescents with phenylketonuria.

The main neurological, cognitive, and behavioural consequences of phenylketonuria have been eradicated thanks to new-born screening and Phe-restricted diet therapy. However, the effects of high phenylalanine levels during adolescence and adulthood on neurocognitive functions remain a concern. This systematic review aimed at collecting clinical data suggesting the safest metabolic target for early treated PKU during the second decade of life. Twenty studies met the inclusion criteria for full-text review. Relevant studies included papers that (a) examined the relationship between metabolic control and neurocognitive functions during adolescence or (b) investigated the impact of metabolic control in adolescence on adult outcomes. Most studies showed a positive correlation between metabolic control during adolescence and neurocognitive outcomes across ages. This was true both for IQ and executive functions, although data on executive functions were less clear, and it remains to be established whether they are more vulnerable to Phe than IQ. Taken together present evidence confirm brain vulnerability to Phe during adolescence and suggests that low average Phe levels and low Phe fluctuations should be maintained throughout life. While results are fully compatible with current European recommendations, clinical and methodological limitations coupled with remarkable interindividual variability prevented a clear identification of a safe threshold for Phe blood levels during adolescence.

Neuroimaging in early-treated phenylketonuria patients and clinical outcome: A systematic review.

Lacking direct neuropathological data, neuroimaging exploration has become the most powerful tool to give insight into pathophysiological alterations of early-treated PKU (ETPKU) patients. We conducted a systematic review of neuroimaging studies in ETPKU patients to explore 1) the occurrence of consistent neuroimaging alterations; 2) the relationship between them and neurological and cognitive disorders; 3) the contribution of neuroimaging in the insight of neuropathological background of ETPKU subjects; 4) whether brain neuroimaging may provide additional information in the monitoring of the disease course. Thirty-eight studies met the inclusion criteria for the full-text review, including morphological T1/T2 sequences, diffusion brain imaging (DWI/DTI) studies, brain MRI volumetric, functional neuroimaging studies, neurotransmission and brain energetic imaging studies. Non-progressive brain white matter changes were the most frequent and precocious alterations. As confirmed in hundreds of young adults with ETPKU, they affect over 90% of ETPKU patients. Consistent correlations are emerging between microstructural alteration (as detected by DWI/DTI) and metabolic control, which have also been confirmed in a few interventional trials. Volumetric studies detected later and less consistent cortical and subcortical grey matter alterations, which seem to be influenced by the patient's age and metabolic control. The few functional neuroimaging studies so far showed preliminary but interesting data about cortical activation patterns, skill performance, and brain connectivity. Further research is mandatory in these more complex areas. Recurrent methodological limitations include restricted sample sizes concerning the clinical variability of the disease, large age-range, variable measures of metabolic control, and prevalence of cross-sectional rather than longitudinal interventional studies.

Neurodevelopmental Impairment As the Main Phenotypic Hallmark Associated with the Translocation t(7;10)(7p22.3;q26.11).

Reported here is a novel patient carrying an unbalanced t (10q26.11-q26.3; 7p22.3) and presenting with a severe intellectual disability with autistic features, abnormalities of muscle tone, and a drug-responsive epilepsy. The prominence of neurological and neurodevelopmental abnormalities in the clinical phenotype highlights a possible pathogenic role for different genes in the involved regions. Hypothetical mechanisms may include a possible gene dosage effect for DOCK1 and/or haploinsufficiency of PRKAR1B SUN1, ADAP1 , and GPER1 .

Missense PDSS1 mutations in CoenzymeQ10 synthesis cause optic atrophy and sensorineural deafness.

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency).