In the past, BH4 deficiency was termed "atypical PKU" or "malignant PKU". Neither term applies any longer. Today, the term "atypical PKU" designates a mild form of PAH deficiency (non-PKU HPA) and the term "malignant PKU" should not be used because, in most cases, a BH4 deficiency is no longer lethal.
 

The BH4 deficiencies are a very heterogeneous group of diseases and different clinical and biochemical criteria define and characterize the variants. The primary enzyme defect, its severity, outcome of the BH4 challenge, reactivity with the antibodies against the protein, and responses to therapy are some of the criteria used to define a specific defect. Although a wide range of metabolic defects may exist, the term "typical" (severe, general) or "atypical" (mild, peripheral, partial) will be used clinically according to the actual need to treat, or not to treat. Accordingly, the following nomenclature applies:

1. Phenylalanine hydroxylase (PAH) deficiency (PKU)

1. Classical PKU (OMIM# 261600); Phe >1200 umol/l
2. Mild PKU; Phe = ~600-1200 umol/l
3. Mild HPA (MHPA); Phe = ~120-600 umol/l
4. BH4-responsive HPA/PKU; Phe = ~360-1700 umol/l

2. Tetrahydrobiopterin deficiencies

with hyperphenylalaninemia

1. GTP cyclohydrolase I (GTPCH) deficiency, autosomal recessive(OMIM# 233910); Phe (P) = 90-1200 umol/l
2. 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (OMIM# 261640); Phe (P) = 240-2500 umol/l
3. Dihydropteridine reductase (DHPR) deficiency (OMIM# 261630); Phe (P) = 180-2500 umol/l
4. Pterin-4a-carbinolamine dehydratase (PCD) deficiency; "Primapterinuria" (OMIM# 264070); Phe (P) = 180-1200 umol/l

without hyperphenylalaninemia

1. Dopa-responsive dystonia (DRD) due to atosomal dominant GTPCH deficiency (OMIM# 600225): Phe (P) <120 umol/l
2. Sepiapterin reductase (SR) deficiency (OMIM# 182125): Phe (P) <120 umol/l

Literature

1. Blau N, Thöny B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001: 1275-1776.
2. N. Blau and M. Blaskovics, Hyperphenylalaninemia, in Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases, ed. N. Blau, M. Duran, and M. Blaskovics (London: Chapman & Hall, 1996), 65-78.
3. N. Blau, I. Barnes, and J. L. Dhondt, International database of tetrahydrobiopterin deficiencies, J Inherit Metab Dis 19 (1996): 8-14.
4. Bonafé L, Thöny B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 2001;69:269-277.