Clinical Applications Of ～1H Magnetic Resonance Spectroscopy In Untreated Patients Of Hyperphenylalaninemia

ObjectiveHyperphenylalaninemia (HPA) is an autosomal recessive metabolic genetic disease. Untreated patients have high occurrences of severe mental retardation and seizure. ¹H magnetic resonance spectroscopy (¹HMRS) is a novel method to detect brain neurological metabolites including phenylalanine (Phe) etc. Measuring the brain phenylalanine concentration with ¹H magnetic resonance spectroscopy in HPA patients, this study investigated the correlation between blood Phe and brain Phe concentrations, the characteristics of blood-brain phenylalanine metabolism and its impacts on mental retardation. The feasibility to quantify blood-brain Phe concentration in patients non-invasively employing ¹HMRS has great clinical significance in HPA patients diagnose and treatments.Methods and Subjects33 patients diagnosed with HPA by the clinical standard of blood Phe concentrations above 0.12mmol/L (mM) were studied, including 18 males and 15 females (age ranging from 33 days to 13 years old, m=2.42±3.07 yrs). They were further categorized into 30 cases of Phenylketonuria (PKU), 2 cases of Tetrahydrobiopterin deficiency (BH₄D) and 1 case of BH₄ responsive phenylalanine hydroxylase (PAH) according to BH₄ loading tests. In addition, 8 cases have epilepsy (5 males and 3 females) history, including 6 cases of PKU and 2 cases of BH₄D. MRI and ¹HMRS were performed in all patients. Blood Phe concentrations were measured and developmental quotient (DQ) or intelligence quotients (IQ) were evaluated. Data were collected and studied to evaluate the neurological and neuropsychological impairment or white matter changes with MRI imaging in all the 22 patients elder than 6 months.Results1. The brain Phe concentration measured by ¹HMRS (shown as Phe/Cr ratio) was ranged from 0.0640 to 0.6296mM (mean=0.1606±0.1117 mM) while the blood Phe concentration was from 0.3804 to 2.5140mM (mean =1.4088±0.5130raM) in all the 33 cases of HPA patients.2. There was a positve linear correlation (r=0.6103 (p＜0.01) ) between the blood Phe and brain Phe concentrations.3. Variable mental retardation and. intelligence impairment were observed in 25 cases patients in this study. Two of them diagnosed with BH₄D had extreme severe mental retardation (DQ＜25) and 5 of the 8 cases HPA patients with seizure history (including 2 cases of BH₄D) were diagnosed as severe mental retardation. 4. There was a non-significant correlation between the blood-brain Phe concentration to the mental retardation (r_blood =-0.1015, r_brain=-0.1127 (p＞0.05)). There was a negative correlation between blood-brain Phe concentration to the mental retardation (r_blood=-0.5045, r_brain=-0.6471 (p＜0.01) ) in 22 case of the HPA patients elder than 4 months.5. The MHR data showed variable brain white matter damagein all the 22 cases of the HPA patients elder than 6 months which could be graded to: 13 cases Gradeâ… damage, 5 cases Gradeâ…¡damage and 4 cases of Gradeâ…¢damage. There was a negative correlation between the brain white matter impairment degree and the intelligence (r =-0.5738 (p＜0.05) ) while the brain Phe concentration had non-correlation with the MRI white matter impairment grading ( r=0.2375 (p＞0.05)).6. The history of seizure had a high correlation with intelligence quotient development comparing with many other factors and the brain Phe concentration had more significant correlation with mental development than the blood Phe concentration.Conclusions¹HMRS is a novel non-invasive method to detect the brain metabolites beside Phe concentration in HPA patients. In this study, data suggested that the blood Phe concentration and the brain Phe concentration fit a linear correlation as the blood Phe concentration could correspondingly represent the Phe concentration in brain. There was a negative correlation between the Phe concentration and the mental intelligence in 22 case of the HPA patients elder than 4 months. And the brain Phe concentration could more accurately illustrate the impairment of brain damage in HPA patients. The grade of the white matter impairment could reflect the degree of mental damage substantially. BH₄D patients had lower DQ comparing with PKU patients. The history of seizure had a high correlation with mental retardation. The feasibility to quantify blood-brain Phe concentration in patients non-invasively with ¹HMRS has great clinical significance for understanding the mechanism of HPA patient's mental retardation, providing proper objective standards for better diagnosing and treating in HPA patients.