OOA (Old Order Amish)
MEN (General Swiss-German Mennonite)
DGM (Dutch-German Mennonite)
HUT (Hutterite)

Inheritance: autosomal recessive
Genes: PAH

Phenylalanine hydroxylase deficiency

Mental retardation
Sparse hair
Developmental retardation


Clinical Characteristics

General description (for patients):

This is an uncommon but potentially serious cause of mental retardation of varying degrees. It is usually detected at birth through state-mandated screening programs, and is treatable if discovered early.  Untreated patients usually have a light pigmentation and a ‘mousey’ odor to their urine. Later, various degrees of developmental retardation are evident together with walking and sitting problems. All of these symptoms can be prevented to a major extent by a special diet in which phenylalanine is eliminated. There is considerable variation in the degree of developmental retardation among some untreated individuals but normal mentality is rare. Untreated females with minimal symptoms who become pregnant, however, may have children with intrauterine growth retardation and brain damage. It has been recommended that even carrier mothers (who do not have the disease PKU), and who are on low phenylalanine diets should avoid becoming pregnant as control of blood phenylalanine is variable and a significant number of offspring have some demonstrable neurological defect.

 Medical description: 

The classic type of PKU is due to a deficiency of phenylalanine hydroxylase as a result of a large number of allelic mutations in the PAH gene. As a result, the rate limiting step in phenylalanine metabolism, hydroxylation of phenylalanine to tyrosine, is impaired and blood phenylalanine is elevated. Heterozygous mothers are able to metabolize their dietary phenylalanine, and that of the fetus, normally Hence intrauterine development usually proceeds normally but it has been recommended that the maternal phenylalanine levels be strictly monitored. Postnatally, however, homozygote levels of phenylalanine toxic to the CNS result in significant physical and neurologic impairment. Homozygous women of child-bearing age who are on low phenylalanine diets even should be discouraged from becoming pregnant as a significant number of their children have cognitive and behavioral abnormalities, likely as a result of fluctuating maternal blood phenylalanine levels. There is evidence, however, that strict control of blood phenylalanine levels beginning prior to conception may be beneficial. Massive screening programs mandated by states that require newborn heel sticks have revealed several other classes of PKU, some of which are milder than the classic type presented here.


This is an autosomal recessive disorder caused by a mutation in the PAH gene encoding the enzyme phenylalanine hydroxylase. The locus (12q24.1) is on chromosome 12. Heterozyotes are phenotypically normal but loading doses of phenylalanine are removed from the plasma more slowly than in normals. A large number of allelic variants have been identified and compound heterozygosity is common. At least four PAH mutations in plain people are  known. The phenotype has been found in Old Order Mennonites and Amish in Pennsylvania, Mennonites, Old Order Amish, and Hutterites, and perhaps occurs among all plain peoples, reflecting its generally worldwide distribution. There is evidence that this PKU (type I) is a conformational disease, i.e., the hydroxylase protein product is destabilized by abnormal folding. PKU can also result from a deficiency in dihydropteridine reductase deficiency (type II) (see +261630) which may respond to tetrahydrobiopterin (BH4), a PAH cofactor, with lowering of blood phenylalanine levels. These usually have a milder disease and many have missense mutations.


This is a treatable disorder if a low phenylalanine diet is applied vigorously but it must be initiated early in infancy. Since tyrosine is normally made from phenylalanine, it may need to be supplemented when phenylalanine is severely restricted. A number of commercial low phenylalanine diets are available.


Outlook is generally good if the diet is initiated early although some studies have noted that such treatment does not always lead to normalization of overall IQ. Similarly, offspring of homozygous mothers with good control of blood phenylalanine may have mild neurologic deficits and pregnancy in such women should be discouraged.

Ancillary treatments and support:

No treatment beyond diet and possibly BH4 supplimentation in some patients has been reported to be of benefit.

Specialists and specialty centers:


Neurologist, pediatrician, nutritionist.


Scriver, C.R.:  The PAH gene, phenylketonuria, and a paradigm shift.  Hum. Mutat. 28: 831-845, 2007.  PubMed ID: 17443661

Rouse, B., Azen, C., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., and Shifrin, H.:  Maternal phenylketonuria collaborative study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae.  Am. J. Med. Genet. 69: 89-95, 1997.  PubMed ID: 9066890

Scriver, C.R., and Clow, C.L.:  Phenylketonuria: epitome of human biochemical genetics.  New Eng. J. Med. 303: 1336-1342 and 1394-1400, 1980.  PubMed ID: 7001231

Gersting, S.W., Kenter, K.F., Staudigl, M., Messing, D.D., Danecka, M.K., Lagier, F.B., Sommerhoff, C.P., Roscher, A.A., and Muntau, A.C.:  Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability.  Am. J. Hum. Genet. 83: 5-17, 2008.  PubMed ID: 18538294


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