Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these “unusual” PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

IQ: 74), while neurological assessment did not show any abnormalities.

Detected through affected/PKU child
Supplemental Case 2 is a Danish woman of normal intelligence and without a history of seizures, who has completed one year of business school. At the age of 20 years, she gave birth to a child with microcephaly, and was then found to have a plasma Phe concentration of 980 µmol/l herself with subsequent measurements up to 1,550 µmol/l. Genetic analysis showed compound heterozygosity for the PAH variants c.1222C>T/p.R408W and c.1315+1G>A/p.IVS12+1G>A. She started a Phe-restricted diet at the time of her second pregnancy, but this was discontinued and changed for large neutral amino acid treatment after four years. At later age, neuropsychological assessment by the WAIS showed an IQ within the normal range.
Cases 3 and 4 are two unrelated women from Serbia with comparable stories. At the age of 18y and 21y, they gave birth to a child who was diagnosed with PKU in newborn screening (case 3), and a child with signs of the maternal PKU syndrome (case 4), and these mothers

Mental/neurological deterioration at later age
Supplemental Case 6 is a male from the USA who had completed 2 years of vocational college and had been working as a plumber and a warehouse keeper. Since his 40s, he had suffered from generalized tonic-clonic and partial complex seizures. At age 48, he began to have episodes of confusion, speech problems, a change in gait, swallowing difficulties, dizziness, tinnitus, and memory loss. MRI performed at 50 years of age showed minor microvascular changes, which increased over the years. At age 57 years, he presented with an acute change in mental status, which was responsive to steroid therapy, and a picture of leukoencephalopathy on MRI. Further investigations because of his history of seizures and a sibling, who had been diagnosed with PKU at the age of 14 years, showed a plasma Phe concentration of 1,080 µmol/l. DNA sequencing revealed a compound heterozygosity for the c.1222C>T/p.R408W and c.745C>T/p.L249F PAH variants. Dietary treatment had never been applied. Neurological examination at 57 years of age showed a well oriented but anxious person, who sometimes forgets directions or appointments and has some difficulty in word finding. Physical examination showed a pupil asymmetry, mild postural and kinetic tremor, and spastic paraplegia.
Supplemental Cases 7A (male) and B (female) are two siblings originating from Sudan who presented at the age of 18 years when arriving in the UK with some neurocognitive impairment and a family history of a cousin diagnosed with PKU. There was no history of seizures. They were shown to have plasma Phe concentrations of 1,600 and 1,500 µmol/l, respectively, and dietary treatment in both was promptly initiated. Both cases have attended a special needs school with a life skills course, are independent for activities of daily living, and are employable doing simple jobs such as stacking shelves. The female sibling is comparatively higher functioning; she comes into clinic by herself, has an understanding of the diet and can convey her medical concerns. In addition, both have learned to speak English besides Arabic, since coming to the UK.
Supplemental Cases 8A and B are male twins originating from Israel, who both had shown an unremarkable neonatal screening result. Case 8A presented at the age of 3y9m with a developmental delay and seizure disorder and concomitant Tourette's syndrome and attention deficit hyperactivity disorder. Biochemical investigation then showed plasma Phe concentrations up to 1,440 µmol/l and cerebral MRI showed mild abnormalities. Following the diagnosis of PKU, a Phe-restricted diet was instituted on which seizures disappeared. In addition, his twin brother with developmental delay and behavioral-emotional difficulties without additional psychiatric abnormalities nor seizures was investigated and found to have plasma Phe concentrations up to 1,400 µmol/l as well. Similar to his brother, a Phe-restricted diet was initiated immediately. At age 9 and 12 years, both brothers showed intellectual functioning within the normal range.