Pathophysiology in PKU

Development of the unmanaged PKU brain

It is well known that unmanaged PKU will most likely cause severe mental retardation, delayed mental development, seizures, tremors, spasticity, difficulties in executive functioning, behavioral issues, irritability, and eczema in childhood.^32-36 What is not well understood is the exact mechanism by which it occurs. While gray matter atrophy and reduced dendritic arborization have been observed, MRI studies have revealed another notable neuropathological finding: diffuse white matter abnormalities.³⁷ These include delayed or defective myelination, status spongiosis, demyelination, and gliosis.¹⁰ Additional studies have observed abnormal cerebrospinal fluid neurotransmitter concentrations.¹⁹

IQ loss correlates with concurrent serum Phe levels

An extensive meta-analysis has quantified the correlation between serum Phe levels during critical childhood development and IQ.³⁸ A meta-analysis of 40 studies focused on Phe elevation and neurological and dietary outcomes. The analysis showed that each 100- µmol/L increase in lifetime blood Phe predicts an average 1.9- to 4.1-point decrease in IQ over a range of blood Phe from 394 µmol/L to 666 µmol/L. Concurrent Phe levels were shown to correlate significantly with both IQ and white matter abnormalities.²⁰

Correlations between Phe Level and IQ³⁸

• Phe levels during critical period from 0–12 years of age
  • Phe ↑ 100 µmol/L → IQ ↓ 1.3–3.1 points
• Lifetime blood Phe levels:
  • Phe ↑ 100 µmol/L → IQ ↓ 1.9–4.1 points

Cortical atrophy and white matter abnormalities in PKU

These symptoms vary in presentation according to the age of treatment onset with cortical atrophy and white matter spongiosis more common in late-treated adults.³⁹ The clinical spectrum is likely due to a combination of these brain abnormalities, with the rate and extent of presentation dependent on an array of individual parameters such as PAH mutation, diet control, tetrahydrobiopterin expression, metabolic characteristics, and blood-brain transport kinetics.

Gray matter abnormalities now discovered in PKU

More recently, significant gray matter volume changes in PKU patients have been discovered that are associated with lower IQ and older age at the time of PKU diagnosis. On one hand, significant gray matter decreases were observed in the motor and premotor cortex and the thalamus of 27 PKU patients compared with 27 matched controls.⁴⁰ Conversely, a relative increase in gray matter volume was noted in the ventral part of the striatum. Of note, no significant group differences were discovered for global white matter volume, although a larger global white matter volume in regions that are sensitive to metabolic decompensation in PKU was associated with higher recent Phe levels in early-treated patients as opposed to late-treated patients (Phe-restricted diet began at 2 months vs a mean age of 8 years, respectively). More insight into the effects of PKU on variations in both gray and white matter anatomy is needed.

Intracerebral Phe concentration predicts neuropathophysiology

While a patient’s blood Phe level offers an easily accessible and convenient indication of clinical risk, an arguably better indicator for neuropathological potential is brain concentration. This is due to the fact that the primary symptomatology presents in the central nervous system. For this reason, recent imaging studies have focused particular attention on the correlation between brain Phe concentration, blood Phe concentration, and neuropathological presentation.¹⁸