The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

Mastrangelo, Mario; Chiarotti, Flavia; Berillo, Luana; Caputi, Caterina; Carducci, Claudia; Biasi, C. Di; Manti, Filippo; Nardecchia, Francesca; Leuzzi, Vincenzo

doi:10.1016/j.ymgme.2015.08.005

Cited by 30 publications

(24 citation statements)

References 33 publications

(60 reference statements)

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“…Of the 643 articles retrieved from the initial search, 83 met criteria for inclusion in this review (Figure ). Patients had been maintained on a Phe‐restricted diet during early childhood, although this did not necessarily equate to strict treatment; overall adherence to diet throughout their lifetime was not consistently reported and was variable between studies.…”

Section: Resultsmentioning

confidence: 99%

“…However, another study reported abnormalities despite the fact that all patients had adhered to dietary treatment since birth . Additionally, the severity of brain abnormalities were generally associated with historical Phe levels, while there appeared to be no relationship with Phe concentration at the time of MRI evaluation . Furthermore, there was no significant correlations between the volumes of different brain structures and current or historical Phe levels…”

Section: Neuroimagingmentioning

confidence: 96%

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The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

Burlina

Lachmann

Manara

et al. 2019

J of Inher Metab Disea

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Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long‐term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine‐restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early‐treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early‐treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU‐specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

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Section: Resultsmentioning

confidence: 99%

Section: Neuroimagingmentioning

confidence: 96%

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

Burlina

Lachmann

Manara

et al. 2019

J of Inher Metab Disea

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“…White matter changes seem to be reversible with adherence to a strict low-phenylalanine diet. Patient age and quality of dietary control were shown to have independent cumulative effects on the outcome of patients with white matter alterations (71). Over time, ventriculomegaly and secondary atrophy may develop.…”

Section: Phenylketonuria: Omim 261600mentioning

confidence: 99%

Neuroimaging Findings of Organic Acidemias and Aminoacidopathies

Reddy¹,

Calloni²,

Vernon³

et al. 2018

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Although individual cases of inherited metabolic disorders are rare, overall they account for a substantial number of disorders affecting the central nervous system. Organic acidemias and aminoacidopathies include a variety of inborn errors of metabolism that are caused by defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. These defects can lead to the abnormal accumulation of organic acids and amino acids in multiple organs, including the brain. Early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurologic impairments or death. Neuroimaging findings can be nonspecific, and metabolism- and genetics-based laboratory investigations are needed to confirm the diagnosis. However, neuroimaging has a key role in guiding the diagnostic workup. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. RSNA, 2018.

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“…Unexplained phenotypic variability concerns many dimensional aspects of the outcome of the PAH defect in adulthood: (1) an undetermined, but relatively high, percentage of patients with ECTPKU have an IQ score lower than expected (as compared with healthy controls or unaffected relatives)4–6; (2) a clinically relevant neuropsychological impairment is found in about 25% of ECTPKU subjects6; (3) about 90% of adults with ECTPKU show variable white matter alterations on brain MRI7; (4) 20%–40% of subjects with ECTPKU suffer from minor neurological symptoms (tremor, brisk lower limb reflexes, mild motor impairment)8 9; (5) an undetermined, but probably low, percentage of subjects with ECTPKU experience a decline of IQ score after diet discontinuation in late adolescence or early adulthood; (6) about 0.4% of early treated subjects with PKU who have discontinued the diet experience severe neurological deterioration that may be reversed by metabolic control restoration10; (7) exceptional PKU cases suffer in adulthood from visual impairment after diet discontinuation that can be reversed by re-initiating the diet11 (Leuzzi, unpublished case).…”

Section: Introductionmentioning

confidence: 99%

Predictability and inconsistencies of cognitive outcome in patients with phenylketonuria and personalised therapy: the challenge for the future guidelines

et al. 2019

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Phenylketonuria (PKU) is a prototypical model of a neurodevelopmental metabolic disease that follows a cascade of pathological events affecting brain maturation and functioning. Neonatal screening and early treatment have eradicated the classical PKU phenotype in patients with early and continuously treated phenylketonuria (ECTPKU). However, effort is required to optimise the treatment of the disease to minimise the risk of lifelong neurological, cognitive and behavioural impairment, and to solve issues on the variability in clinical outcome that are rather not understood and has yet hampered a more personalised approach to its treatment. The aim of the present review is to focus on the inconsistencies in the clinical outcome of adult patients with ECTPKU unexplained by the biochemical markers adopted for the monitoring of the disease to date. The interindividual variability of clinical outcome in late as well as in early treated patients under similar biochemical control suggests the existence of disease-independent determinants influencing the individual vulnerability to the neurotoxic effect of phenylalanine. This is further supported by the low predictive power of blood phenylalanine on the clinical outcome from the second decade of life onwards. In conclusion, individual vulnerability to the metabolic alterations of PKU contributes to the prognosis of PKU, also in patients with ECTPKU. The biological factors constitutive of this vulnerability are unknown (but have not been the object of many studies so far) and should be the target of further research as prerequisite for a personalised treatment aimed at avoiding burden and costs of overtreatment and clinical consequences and risks of undertreatment in patients with PKU.

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The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

Cited by 30 publications

References 33 publications

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

Neuroimaging Findings of Organic Acidemias and Aminoacidopathies

Predictability and inconsistencies of cognitive outcome in patients with phenylketonuria and personalised therapy: the challenge for the future guidelines

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