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Mol Genet Metab. 2013;110 Suppl:S66-70. doi: 10.1016/j.ymgme.2013.10.006. Epub 2013 Oct 12.

Man made disease: clinical manifestations of low phenylalanine levels in an inadequately treated phenylketonuria patient and mouse study.

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Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.



Phenylalanine (Phe) deficiency and its clinical manifestations have been previously described mostly as sporadic case reports dating back to the 1960's and 1970's. In these reports, low plasma Phe levels were associated with listlessness, eczematous eruptions and failure to gain weight, most often in infants in their first year of life.


Herein we describe a 9 month old female patient with known phenylketonuria, who presented with an unusual constellation of symptoms, including severe erythema and desquamation, alopecia, keratomalacia, corneal perforation, failure to thrive and prolonged diarrhea. The diagnostic possibilities of acrodermatitis enteropathica and vitamin deficiencies were ruled out, and further investigation into her medical history led to the conclusion that during the weeks preceding the hospitalization, the patient's diet consisted of the phenylalanine-free medical formula alone, without the addition of a standard infant formula or food as recommended. Subsequently, dietary control of the blood phenylalanine levels brought swift and marked resolution of the dermatological lesions, with renewal of hair growth.


Following this experience, and due to the relative paucity of data regarding the clinical manifestations of low serum phenylalanine levels in humans and their putative pathogenetic mechanisms, we sought to further investigate the effects of a phenylalanine-free diet in a mouse study.


For this purpose, twenty mice were randomly allocated to receive either a phenylalanine-deficient diet (n=10) or a normal diet (n=10). Weight was measured weekly, and laboratory tests were obtained including complete blood count, electrolyte studies, and phenylalanine and tyrosine levels. Finally, necropsies and histopathological examinations of different tissues were performed in selected mice, either early after diet initiation, late after diet initiation or following re-introduction of normal diets. The study was then repeated in additional two groups of mice, for a period of up to thirteen weeks, with a total of 63 mice.


Gross lesions noted on necropsy in the Phe-deficient mice included scruffy coat, tendency toward weight loss, a reduction in thymic mass, and most notably severe gastric dilation, all of which were not seen in the controls. Histologic findings included thymic depletion, hepatocellular vacuolation, and exocrine pancreatic atrophy. No histopathological lesions were evident in the brain, nor were significant lesions in the eyes.


Diagnosis of the iatrogenic condition of phenylalanine deficiency, which manifests in gastrointestinal, dermatological and ocular findings, requires a high index of suspicion. Mice fed a phenylalanine-deficient diet display to some extent similar organ involvement, although no eye abnormalities were evident.


Phenylalanine deficiency; Phenylketonuria

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