Are Neuropsychological Impairments in Children with Early-Treated Phenylketonuria (PKU) Related to White Matter Abnormalities or Elevated Phenylalanine Levels?

Abstract

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.

Dietary Habits and Metabolic Control in Adolescents and Young Adults with Phenylketonuria: Self-Imposed Protein Restriction May Be Harmful

“…Despite early dietary treatment, MRI findings revealed typical white matter lesions of PKU as previously reported (Bick et al 1993;Cleary and Walter 2001;Moller et al 2003;Anderson et al 2007;Leuzzi et al 2007;Ding et al 2008;Anderson and Leuzzi 2010) in many, but not all patients. In an attempt to quantify the white matter lesions, an adapted Scheltens score was used (Scheltens et al 1993).…”

“…Although major disabilities can be prevented by early protein restriction, more subtle deficits are common (Bick et al 1993;Huijbregts et al 2002;Anderson et al 2007;Gentile et al 2010), even in patients with good metabolic control. These health problems may be more pronounced in those patients who do not adhere to dietary recommendations and requirements.…”

Desenvolvimento infantil na fenilcetonúria: atuação fonoaudiológica

“…Isso demonstra a grande preocupação da literatura com relação ao acompanhamento do desenvolvimento cognitivo destes indivíduos, uma vez que o aumento do nível da fenilalanina é tóxico para o sistema nervoso central e traz sequelas globais para o desenvolvimento, inclusive deficiência intelectual, alterações neuropsicolinguísticas e comportamentais [7][8][9][10][11][12][13][14][17][18][19][20][21] . A literatura apresenta a influência da fenilalanina e tirosina que em excesso interfere na síntese proteica cerebral, na formação da mielina, nos neurotransmissores, prejudicando, particularmente, as via dopaminérgicas das regiões do córtex pré-frontal e podem apresentar também alterações na substância branca cerebral 1,[22][23][24][25][26] . Desta forma, as funções executivas podem estar comprometidas de maneira diversa.…”

“…A literatura refere que indivíduos com PKU apresentam com frequência atraso do desenvolvimento da linguagem oral, influenciado pela alteração na aquisição da linguagem receptiva, com redução do uso de estratégias de organização semântica, atraso na velocidade de respostas e na aprendizagem de novas informações verbais, proporcionando déficits no desempenho semântico, pragmático e sintático [17][18][19][20][21] . Estes estudos também apontam os reflexos do transtorno de atenção, concentração e memória para a aprendizagem da linguagem 17,19,24,26 . Apesar da ocorrência de distúrbios da linguagem e comunicação em indivíduos com PKU, há poucos estudos na literatura que investigaram especificamente estas habilidades.…”

“…Uma vez que estas crianças são de risco para alterações no desenvolvimento linguístico [17][18][19][20][21]24 e cognitivo [1][2][3][4][5][6][7]10,12,13,[19][20][21][22][23][24][25][26][27] , o fonoaudiólogo pode atuar nesses programas de modo a prevenir, habilitar e reabilitar os distúrbios da comunicação, contribuindo para o trabalho em equipe promovendo saúde nesta população.…”