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Phenylketonuria: blood brain and... Body (van Spronsen)

Phenylketonuria: blood brain and... Body (van Spronsen)

We all know that phenylalanine is increased in the blood and that – somehow – this results in brain dysfunction. One of the unanswered questions remains whether there are problems in organs outside the brain.

Skin has been mentioned various times, but in 2012 no new details have been published on this organ system. In 2012, some small number of papers have called our attention to other issues outside the brain in PKU, bones and kidney, as well as the metabolic syndrome.

High protein intake is associated with kidney dysfunction and metabolic syndrome at later ages.  Both are associated with hypertension. Decreased bone density measurement is associated with PKU and some other inborn errors of metabolism, although it is not completely clear what the relation is.

In this small review I would like to call your attention to three papers, one of them concerning renal dysfunction might prove to be very important (Hennermann et al 2012). The others are about metabolic syndrome (Rocha et al 2012) and bone density (de Groot et al 2012).

The first paper is from the Berlin group studying renal dysfunction in PKU patients (Hennermann et al 2012). In this paper they investigated some 67 PKU adult patients.  It is the first paper calling our attention to hypertension and kidney dysfunction in PKU with a possible relation to dietary protein intake. The last point has been an issue for years as some countries/centers advise more total protein (especially more amino acid mixture) than others. There has been some evidence that higher intake – especially more amino acid mixture – results in better growth and/or more stable phenylalanine concentrations, but the question always was whether this would cause renal problems in the longer term. The paper of Hennermann et al suggests that there is a relationship between kidney function and protein intake. However, the population did not receive that high amounts of total protein, so that other causes need to be taken into consideration as well in future studies. One of the causes, already mentioned by Hennermann et al is that the amino acids given with the amino acid mixture can be given in too large quantities at one ‘meal’.

The paper of Rocha et al started with the idea that metabolic syndrome could be found at a higher prevalence than in controls. This appeared not to be the case. Obviously the diet with a risk of receiving more protein (especially by amino acid mixtures), more fat and carbohydrates (due to the low natural protein food regimen) did not result in such problems. Even so, the paper shows that triglycerides can be increased. Increased triglycerides and cholesterol have been shown in other diseases such as glycogen storage disease type I. Notwithstanding such increased levels, neither patient group manifests evidence of increased risk of heart disease. Such findings not only raise questions about PKU and its treatment but also – maybe more importantly – calls scientists to carefully consider the pathophysiology of ‘general diseases’ in normal populations.

The paper by de Groot et al shows that bone density in PKU is not simply a problem of adulthood. In contrast, decreased bone density is already present at early age and does not increase with age. The paper studied – as many other papers have – the relation with laboratory measures in relation to PKU dietary intake but did not find a clear-cut reason for the decreased bone density. It is still unclear what the exact mechanism is, but knowing now that the problem begins in young children and does not increase significantly with age, the cause should be looked for at earlier ages rather than at adult ages. For that reason future studies may take into account data on earlier years regarding dietary intake, supplements, vitamins, bone turnover measures etc.


Hennermann JB, Roloff S, Gellermann J, Vollmer I, Windt E, Vetter B, Plöckinger U, Mönch E, Querfeld U. Chronic kidney disease in adolescent and adult patients with phenylketonuria. J Inherit Metab Dis. 2013;36:747-756.

de Groot MJ, Hoeksma M, van Rijn M, Slart RH, van Spronsen FJ. Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients. Mol Genet Metab. 2012;105:566-70.

Rocha JC, van Spronsen FJ, Almeida MF, Soares G, Quelhas D, Ramos E, Guimarães JT, Borges N. Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome. Mol Genet Metab. 2012;107:659-63.

Francjan Van Spronsen

Pediatrician metabolic diseases, Associate Professor Pediatrics
Beatrix Children's Hospital
University of Groningen
Groningen, Netherlands