Relationship between age and white matter integrity in children with phenylketonuria

Wesonga, Erika; Shimony, Joshua S.; Rutlin, Jerrel; Grange, Dorothy K.; White, Desirée A.

doi:10.1016/j.ymgmr.2016.03.003

Cited by 12 publications

(13 citation statements)

References 47 publications

(65 reference statements)

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“…Finally, decreased MD values have been previously shown to correlate with increased age [ 8 , 11 , 12 ] in PKU children, which further supports the results shown in this work. MD and RD are thought to be a good marker of myelin structure and, in healthy populations, decreased RD and MD values are usually associated to a better WM microstructure [ 2 , 40 , 60 , 61 ].…”

Section: Discussionsupporting

confidence: 91%

“…White et al [ 8 ] showed MD restriction values in the anterior part of the CC (genu and rostral body). Wesonga et al [ 12 ] demonstrated significant abnormal diffusion values in the genu and splenium of the CC. In contrast, we found decreased of MD values but also RD decreased values in the body and splenium of the CC.…”

Section: Discussionmentioning

confidence: 99%

“…Non-significant differences in FA compared to control group. Wesonga et al 2016 [ 12 ] ETPKU paediatric patients (mean age 12.2 years) ( n = 31). Control group (mean age = 12 years) ( n = 51).…”

Section: Methodsmentioning

confidence: 99%

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White matter microstructural damage in early treated phenylketonuric patients

González

Polo²,

Ripollés

et al. 2018

Orphanet J Rare Dis

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BackgroundDespite dietary intervention, individuals with early treated phenylketonuria (ETPKU) could present neurocognitive deficits and white matter (WM) abnormalities. The aim of the present study was to evaluate the microstructural integrity of WM pathways across the whole brain in a cohort of paediatric ETPKU patients compared with healthy controls (HCs), by collecting DTI-MRI (diffusion tensor magnetic resonance imaging) data and diffusion values (mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA)).MethodsDTI-MRI data and diffusion values (MD, RD, FA) from WM tracts across the whole brain were analized using Tract Based Spatial Statistics (TBSS), in 15 paediatrics TPKU patients (median age: 12 years) and compared with 11 HCs. Areas showing abnormal values in the patient group were correlated (Pearson) with age, lifetime Phe values, last year median and mean Phe, concurrent Phe values in plasma, urine neurotransmitters status biomarkers, and with a processing speed task.ResultsETPKU showed bilaterally decreased MD values compared with HCs in the body and splenium of the corpus callosum, superior longitudinal fasciculus, corona radiata and in the posterior limb of the internal capsule. RD values followed a similar pattern, although decreased RD values in PKU patients were also found in the anterior limb of the internal capsule and in the cerebral peduncle. Decreased MD and RD values within the aforementioned regions had significant negative correlations with age, last year median and mean Phe and concurrent Phe values. No correlations were found with monoamines in urine or processing speed task.ConclusionsETPKU patients showed MD and RD values significantly decreased across the whole brain when compared with HCs, and this damage was associated with high Phe values and the age of patients. Despite this microstructural damage, no affectation in processing speed was observed in patients with good metabolic control. DTI-MRI sequences could be used as a technique to quantify WM damage that is difficult to be detect in T1 or T2-weighted images, but also to quantify damage of WM through the follow up of patients with poor metabolic control in prospective studies.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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White matter microstructural damage in early treated phenylketonuric patients

González

Polo²,

Ripollés

et al. 2018

Orphanet J Rare Dis

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“…The white matter pathology observed in PKU patients is diffuse throughout the brain and worsens with age, and it seems to participate in the decline of executive functions due to non-adherence to the treatment (Hawks et al, 2019). To illustrate, the microstructural development of white matter is progressively impaired in PKU children (Wesonga, Shimony, Rutlin, Grange, & White, 2016), affecting inferior executive abilities in PKU patients at different ages (Antenor-Dorsey et al, 2013).…”

Section: Cn S Demyelinati On In Pkumentioning

confidence: 99%

White matter disturbances in phenylketonuria: Possible underlying mechanisms

Ferreira

Rodrigues

Streck

et al. 2020

J of Neuroscience Research

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White matter pathologies, as well as intellectual disability, microcephaly, and other central nervous system injuries, are clinical traits commonly ascribed to classic phenylketonuria (PKU). PKU is an inherited metabolic disease elicited by the deficiency of phenylalanine hydroxylase. Accumulation of l‐phenylalanine (Phe) and its metabolites is found in tissues and body fluids in phenylketonuric patients. In order to mitigate the clinical findings, rigorous dietary Phe restriction constitutes the core of therapeutic management in PKU. Myelination is the process whereby the oligodendrocytes wrap myelin sheaths around the axons, supporting the conduction of action potentials. White matter injuries are implicated in the brain damage related to PKU, especially in untreated or poorly treated patients. The present review summarizes evidence toward putative mechanisms driving the white matter pathology in PKU patients.

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“…Whether the observed retinal changes relate to WML burden remains speculative as MRI scans were not available in any of the OCT studies (38)(39)(40), including ours. However, WMLs have repeatedly been described in ETPKU patients with the underlying molecular mechanisms remaining elusive (17)(18)(19)(59)(60)(61)(62)(63). Intramyelinic edema is primarily thought to be responsible for reversible WMLs (17), but impairment of microstructural development has also been described (59).…”

Section: Discussionmentioning

confidence: 99%

Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency

et al. 2021

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In phenylalanine hydroxylase (PAH) deficiency, an easily feasible method to access the progression of neurodegeneration is warranted to contribute to current discussions on treatment indications and targets. The objective of the present study was to investigate whether optical coherence tomography (OCT) measures as markers of neurodegeneration differ between patients with PAH deficiency and healthy controls (HCs) according to phenotype and metabolic control. In this single-center cross-sectional study, 92 patients with different phenotypes of PAH deficiency [PAH deficiency not requiring treatment, early treated phenylketonuria (ETPKU), and late-diagnosed phenylketonuria (PKU)] compared with 76 HCs were examined using spectral-domain OCT. Indices of phenylalanine elevation and variability were correlated with OCT parameters. Late-diagnosed PKU patients showed reduced peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIPL) volume. Adult ETPKU patients were found to have lower GCIPL volume (p = 0.016), which correlated with the indices of phenylalanine control. In pediatric ETPKU patients with poor metabolic control, pRNFL was significantly reduced (p = 0.004). Patients with PAH deficiency not requiring treatment did not exhibit retinal degeneration. Inner nuclear layer (INL) was significantly increased in the pediatric ETPKU patients, driven by those with current poor metabolic control (p = 0.006). Our data provide evidence of retinal neuroaxonal degeneration and INL swelling, depending on the phenotype, current age, and metabolic control. These findings suggest that OCT is suitable to investigate neurodegeneration in PKU and we propose OCT as a sensitive, reliable, safe, low-burden, and low-cost examination for future multicenter studies.

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Relationship between age and white matter integrity in children with phenylketonuria

Cited by 12 publications

References 47 publications

White matter microstructural damage in early treated phenylketonuric patients

White matter microstructural damage in early treated phenylketonuric patients

White matter disturbances in phenylketonuria: Possible underlying mechanisms

Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency

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