A small number of infants have a variant of PKU in which a restricted PA diet does not prevent neurologic involvement. In some such infants, a dystonic extrapyramidal rigidity (“stiff-baby syndrome”) has appeared as early as the neonatal period, and, according to Allen and coworkers, it responds to biopterin. Such infants have normal levels of PA hydroxylase in the liver. The defect is a failure to synthesize the active cofactor tetrahydrobiopterin, because of either an insufficiency of dihydropteridine reductase or an inability to synthesize biopterin (see “Biopterin Deficiency”). The urinary metabolites of catecholamines and serotonin are reduced and are not responsive to low-PA diets. There is some evidence that the underlying neurotransmitter fault can be corrected by l-dopa and by 5-hydroxytryptophan (Scriver and Clow).
This is a rare, predominantly dermatologic aminoacidopathy, that exists in three types, each with an underlying mutation (FAH, TAT, and HPD), and in more than one-half of the infants there is developmental delay. The protein product of these genes pertain to the breakdown of tyrosine. Also, as in some other aminoacidopathies, there may be self-mutilation and incoordination of limb movements. Language defects are prominent. Toward the end of the first or second year of life, lacrimation, photophobia, and redness of the eyes (because of corneal erosions) appear. Neovascularization of the corneas and opacification follow. Palmar and plantar keratosis with hyperhidrosis and pain are frequently present as a result of an inflammatory reaction to deposits of crystalline tyrosine (also the cause of the corneal changes). Elevated tyrosine in the blood (>0.18 mM) and urine is diagnostic. The most severe form (type 1) is caused by a mutation in the gene (FAH) that codes for fumarylacetoacetate hydrolase, the final enzymatic step in tyrosine metabolism, a deficiency of which results in the accumulation of tyrosine and its metabolites.
A low-tyrosine and low-PA diet, optimized to allow growth and development, has resulted in rapid amelioration of symptoms but must be started early. Retinoids given orally improve the skin lesions. Neonatal tyrosinemia can cause liver failure and early death. This disease can be distinguished from the Cross syndrome (albinism with mental retardation, growth impairment, spastic weakness, and alkalosis) and from the Waardenburg ocular albinism syndrome (white forelock, hypertelorism, deafness). For a detailed discussion of the albinism syndromes, see the article by Oetting and King.
This disease causes a progressive infantile encephalopathy; it is of special interest because tyrosine is the precursor of l-dopa and the other catecholamines. Levels of these chemical substances in the brain are greatly reduced. As a result, the encephalopathy takes the form mainly of fluctuating extrapyramidal signs in combination with ocular and vegetative symptoms. l-Dopa causes some improvement in the motor symptoms (see Hoffmann et al). This disease has similarities to juvenile dopa-responsive dystonia, which is exquisitely sensitive to l-dopa treatment (as discussed in Chap. 38) and to the deficiency of l-amino decarboxylase, described above, which also causes low levels of catecholamines and a movement disorder.