Dr. Ron’s Research Review – June 27, 2018


This week’s research review focuses on phenylalanine and aspartame.

The dopamine pathway is as follows.
L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine
Dopamine → norepinephrine → epinephrine

Excess phenylalanine concentrations, however, are associated with decreased concentrations of catecholamine, serotonin, and dopamine. (Choudhary and Pretorius, 2017)


The genetic disorder phenylketonuria (PKU) is the inability to metabolize phenylalanine because of a lack of the enzyme phenylalanine hydroxylase, which converted phenylalanine into L-tyrosine with molecular oxygen (O2) and tetrahydrobiopterin as cofactors.
Adult-onset phenylketonuria with rapidly progressive neural symptoms and parkinsonism has been described.(Tufekcioglu et al., 2016) (Daelman et al., 2014)


Aspartame is metabolized into phenylalanine (50%), aspartic acid (40%), and methanol (10%) by gut enzymes (esterase and peptidase). (Choudhary and Pretorius, 2017)


Dr. Ron




Revisiting the safety of aspartame.
            (Choudhary and Pretorius, 2017)  Download
Aspartame is a synthetic dipeptide artificial sweetener, frequently used in foods, medications, and beverages, notably carbonated and powdered soft drinks. Since 1981, when aspartame was first approved by the US Food and Drug Administration, researchers have debated both its recommended safe dosage (40 mg/kg/d) and its general safety to organ systems. This review examines papers published between 2000 and 2016 on both the safe dosage and higher-than-recommended dosages and presents a concise synthesis of current trends. Data on the safe aspartame dosage are controversial, and the literature suggests there are potential side effects associated with aspartame consumption. Since aspartame consumption is on the rise, the safety of this sweetener should be revisited. Most of the literature available on the safety of aspartame is included in this review. Safety studies are based primarily on animal models, as data from human studies are limited. The existing animal studies and the limited human studies suggest that aspartame and its metabolites, whether consumed in quantities significantly higher than the recommended safe dosage or within recommended safe levels, may disrupt the oxidant/antioxidant balance, induce oxidative stress, and damage cell membrane integrity, potentially affecting a variety of cells and tissues and causing a deregulation of cellular function, ultimately leading to systemic inflammation.

Progressive neuropsychiatric manifestations of phenylketonuria in adulthood.
            (Daelman et al., 2014)  Download
INTRODUCTION:  Neuropsychiatric signs and MRI abnormalities can occur in patients with phenylketonuria in adulthood. We describe clinical and radiological features of phenylketonuric patients and we discuss the advantage of continuing diet in adulthood. METHOD:  We report late onset neuropsychiatric symptoms of four phenylketonuric patients (33-45years) diagnosed in infancy and report the case of a patient (33years) diagnosed with phenylketonuria because of late onset neurological signs. We describe clinical and radiological features of these 5 patients, and their evolution under diet and propose a review of the literature. RESULTS:  The main neurological abnormalities in phenylketonuric patients diagnosed in infancy are: brisk reflexes, spastic paraparesis, psychiatric signs that appear 10.5years after the diet arrest. A leukoencephalopathy was present in 93% of cases and 91.7% improve clinically after poor phenylalanine diet reintroduction. In 4 patients, neurological abnormalities (spastic paraparesis, dementia, Parkinsonism) led to the late diagnosis. Two of them had a leukoencephalopathy on brain MRI. Patients had high levels of phenylalanine (above 1500μmol/L) when neuropsychiatric signs occurred. Improvement after diet suggests that hyperphenylalaninemia has a direct toxic effect on the brain. DISCUSSION/CONCLUSION:  The long-term follow-up of phenylketonuric patients is mandatory to depict and treat neurological complications in time. Diet reintroduction is efficacious in most cases.

Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism.
            (Tufekcioglu et al., 2016)  Download
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder due to mutations in the phenylalanine hydroxylase (PAH) gene, which converts phenylalanine (PHE) to tyrosine. Although it is principally a childhood disorder, in rare cases, the first signs of PKU may develop in late adulthood resembling common neurological diseases. Here we report a 59-year-old, previously normal functioning man who was admitted with blurred vision, cognitive problems, and gait difficulty that began 8 months before. He had brisk reflexes and left side dominant parkinsonism. His Mini-Mental State Examination (MMSE) score was 25/30, and neuropsychological evaluation revealed a dysexecutive syndrome with simultanagnosia and constructional apraxia. His Clinical Dementia Rating score (CDR) was 1. Cranial MRI revealed bilateral diffuse hyperintense lesions in parietal and occipital white matter in T2, fluid-attenuated inversion recovery, and diffusion weighted images. Diagnostic workup for rapidly progressive dementias was all normal except PHE level which was found to be highly elevated (1075 μmol/L, normal 39-240 μmol/L) with normal tyrosine level (61.20 μmol/L, normal 35-100 μmol/L). Three months after PHE-restricted diet, his cognitive impairment and signs of parkinsonism significantly improved, with MRI scan unchanged. This case demonstrates that late-onset PKU is a rare, treatable cause of rapidly progressive dementia and parkinsonism with certain constellations such as consanguinity and white matter abnormalities (WMAs) in imaging.



Choudhary, AK and E Pretorius (2017), ‘Revisiting the safety of aspartame.’, Nutr Rev, 75 (9), 718-30. PubMed: 28938797
Daelman, L, F Sedel, and A Tourbah (2014), ‘Progressive neuropsychiatric manifestations of phenylketonuria in adulthood.’, Rev Neurol (Paris), 170 (4), 280-87. PubMed: 24726436
Tufekcioglu, Z, et al. (2016), ‘Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism.’, Neurocase, 22 (3), 273-75. PubMed: 26962957