{
 "topic": "Phenylketonuria (Pku)",
 "slug": "phenylketonuria-pku",
 "category_id": 15229,
 "passage_count": 14,
 "source_chars": 13269,
 "enough_material": true,
 "references": [
  {
   "title": "Pediatric Environmental Health",
   "author": "American Academy of Pediatrics Council on Environmental Health,Ruth A. Etzel,Sophie J. Balk",
   "pages": [
    53
   ]
  },
  {
   "title": "Zitelli and Davis' Atlas of Pediatric Physical Diagnosis: Expert Consult - Online",
   "author": null,
   "pages": [
    56
   ]
  },
  {
   "title": "Pediatric Board Study Guide",
   "author": null,
   "pages": [
    165,
    1036
   ]
  },
  {
   "title": "AAP Developmental and Behavioral Pediatrics",
   "author": "AAP Section on Developmental and Behavioral Pediatrics,Robert G. Voigt,Michelle M. Macias ,Scott M. Myers ,Carl D Tapia",
   "pages": [
    74,
    684
   ]
  },
  {
   "title": "Cover",
   "author": "Vitalsource Download",
   "pages": [
    1956,
    1960,
    1968
   ]
  },
  {
   "title": "MedStudy Pediatrics Core 11th Edition 2024-2025",
   "author": null,
   "pages": [
    989
   ]
  },
  {
   "title": "Gomella's Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs, Eighth Edition",
   "author": "Tricia Lacy Gomella, Fabien G. Eyal and Fayez Bany-Mohammed",
   "pages": [
    963
   ]
  },
  {
   "title": "Netters Pediatrics (Florin \u0422., Ludwig St.)",
   "author": null,
   "pages": [
    798
   ]
  }
 ],
 "passages": [
  {
   "source": "Pediatric Environmental Health, p. 53",
   "text": "clinical perspective, phenylketonuria (PKU) is defined as a genetic disease. Specifically, it is an autosomal recessive trait; nearly all cases are associated with mutations in the gene encoding phenylalanine hydroxylase, which has been mapped to human chromosome 12q24.1.2 The devastating neurodevelopmental effects of PKU are caused _by the environment_ . Among children with the PKU genotype, excessive intake and accumulation of phenylalanine, an essential amino acid usually metabolized by phenylalanine hydroxylase, induces the disease. Children with PKU who are identified early and treated with restrictive diets develop normally.3 In this example, there are 2 factors (one genetic and one environmental) necessary for the development of PKU. For the disease to develop, one must have both the genetic disposition and exposure to phenylalanine. PKU is viewed as a genetic disease because exposure to phenylalanine is nearly universal, and PKU mutations are rare. Consider, however, if the converse were true\u2014 ie, if"
  },
  {
   "source": "Zitelli and Davis' Atlas of Pediatric Physical Diagnosis: Expert Consult - Online, p. 56",
   "text": "**Phenylketonuria.** A common disorder of transamination is _phenylketonuria_ (PKU), in which the transamination of phenylalanine to tyrosine is impaired. PKU is a relatively common autosomal recessive disorder of protein metabolism (affecting 1 in 10,000 to 1 in 15,000), and is most commonly diagnosed by newborn screening. Affected patients follow a diet restricted in phenylalanine (containing just enough natural protein from fruits, vegetables, and limited starches to meet essential phenylalanine needs for growth and maintenance), supplemented with a medical food \u201cformula\u201d containing tyrosine and other essential amino acids and nutrients, and specially formulated low-phenylalanine foods. If untreated, the disorder results in mental retardation, eczematous skin changes, a \u201cmousy\u201d odor, and other changes. Well-treated patients may have mild tremor, but physical examination is otherwise normal. Although cognitive outcomes are normal in most diet-adherent patients, some patients experience mild to moderate"
  },
  {
   "source": "Pediatric Board Study Guide, p. 165",
   "text": "**Fig. 5.6** Clinical manifestations of phenylketonuria ![](/tmp/pdf-images/pdf-0164-30.png) **----- Start of picture text -----**<br> Intellectual disability Fair skin, hair,<br>Developmental delay and blue eyes<br>Microcephaly<br>Seizures Eye abnormalities<br>Light sensitivity<br>Eczema<br>**----- End of picture text -----**<br> [Figure OCR, page 164, figure 1] Fair skir and blue Eye abr Light se 5 Metabolic Disorders 155 ## **Dietary treatment** - Newborn screening can detect PKU in nearly 100% of cases; thus, cognitive deficits can be prevented by treatment with dietary restriction of phenylalanine often with tyrosine supplementation - Breastfeeding should continue and monitored by PKU specialty clinic - Phenylalanine-free medical formula as soon as possible after birth - The diet requires careful monitoring by a nutritionist experienced in PKU and followed by metabolic disease clinic - Aspartame (sugar substitute containing phenylalanine) must also be avoided"
  },
  {
   "source": "AAP Developmental and Behavioral Pediatrics, p. 74",
   "text": "Phenylketonuria (PKU) was a common cause of intellectual disability prior to the advent of newborn screening. With early identification, appropriate dietary management, and strict adherence to treatment, patients with PKU now have normal cognitive outcomes. Similarly, newborn screening for congenital hypothyroidism and for congenital hearing loss has significantly decreased the number of children in the population with potentially preventable developmental delays. Since many primary pediatric health care professionals are no longer familiar with the untreated phenotypes of these diseases, it is important to verify that the newborn screen was done and the state in which testing was done. **54** American Academy of Pediatrics Developmental and Behavioral Pediatrics ## **Assessment of Hearing and Vision**"
  },
  {
   "source": "Cover, p. 1960",
   "text": "## **130 Hyperphenylalaninemias and Phenylketonuria** Bernd Christian Schwahn ## **INTRODUCTION** Hyperphenylalaninemia causes chronic toxic encephalopathy, depending on the timing, extent, and length of exposure to increased phenylalanine concentrations. Severe hyperphenylalaninemia leading to phenylketonuria (PKU) has a distinct role in the field of inherited metabolic disorders: PKU is the first genetic disease that could be treated exclusively by dietary manipulation and that could be entirely prevented by universal newborn screening and presymptomatic dietary intervention. This has had a huge impact on pediatric medicine, on the evolution of neonatal screening, and on the concept of gene-environment interaction. Genetic defects associated with hyperphenylalaninemia can be regarded as a strong risk factor for neurodisability, but the clinical outcome is more determined by the quality of metabolic treatment than by genetic variability. ## **PATHOGENESIS AND EPIDEMIOLOGY**"
  },
  {
   "source": "MedStudy Pediatrics Core 11th Edition 2024-2025, p. 989",
   "text": "Phenylalanine hydroxylase BH, == BH, BH, = tetrahydrobiopterin BH, = dihydrobiopterin, Figure 23-2: Phenylketonuria caused by phenylalanine hydroxylase deficiency Clinical findings vary, depending on when treatment is initiated and on the degree of metabolic control. Phe in high amounts is toxic to the CNS. Those who remain untreated have severe intellectual disability with IQs of < 30. The damage becomes irreversible by 8 weeks of age. Infants with PKU appear normal at birth, but early symptoms occur in > 50% of those affected. The most common presentations in infants include vomiting, irrita- bility, an eczematous rash, and a peculiar odor\u2014\u201cmousy,\u201d \u201cwolflike,\u201d or musty in character\u2014that is due to the phen- ylacetic acid in the urine. Nearly all of those affected are fair haired and fair skinned, compared to their unaffected relatives, EEGs are abnormal. Diagnosis, made by demonstrating an elevated serum concentration of Phe, must occur in the neonatal period"
  },
  {
   "source": "Cover, p. 1968",
   "text": "- F\u00f8lling I. The discovery of phenylketonuria. _Acta Paediatr Suppl_ . 1994;407:410. - Lindegren M, Krishnaswami S, Fonnesbeck C, et al. Adjuvant treatment for phenylketonuria (PKU). Comparative effectiveness review No. 56. Rockville, MD: Agency for Healthcare Research and Quality; Feb 2012; AHRQ Publication No 12-EHC035-EF. - Ney DM, Blank RD, Hansen KE. Advances in the nutritional and pharmacological management of phenylketonuria. _Curr Opin Clin Nutr Metab Care_ . 2014;17:61-68. - Singh RH, Cunningham AC, Mofidi S, et al. Updated, web-based nutrition management guideline for PKU: an evidence and consensus based approach. _Mol Genet Metab_ . 2016;118:72-83. - Van Spronsen FJ, van Wegberg AMJ, Ahring K, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. _Lancet Diabetes Endocrinol_ . 2017;5:743-756. - Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. _Genet Med_ . 2014;16:188-"
  },
  {
   "source": "MedStudy Pediatrics Core 11th Edition 2024-2025, p. 989",
   "text": "orders are typically single-gene deficiencies. Systemic manifestations are typical because of the large amount of small-molecule metabolites in the circulation, frequently resulting in intellectual disability. These disorders fall into the intoxication classification of disorders. Presentation can be either acute or chronic, depending on the disorder. Phenylalanine-Tyrosine Disorders Classic Phenylketonuria (PKU) PKU is an AR disorder in which phenylalanine cannot be converted to tyrosine. The enzyme defect is in phenylala- nine hydroxylase (PAH), hence the other name for PKU is phenylalanine hydroxylase deficiency (PAH deficiency). \u00a9 2023 MedStudy INTOXICATIONS This results in high levels of phenylalanine (Phe) in the blood and large amounts of phenylpyruvic acid in the urine. PKU occurs in 1/10,000 to 1/20,000 births. See Figure 23-2, Protein from diet WA or endogenous \\ Phenylalanine <> Tyrosine Phenylalanine hydroxylase BH, == BH, BH, = tetrahydrobiopterin BH, = dihydrobiopterin,"
  },
  {
   "source": "Gomella's Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs, Eighth Edition, p. 963",
   "text": "- **B. A child of a mother with phenylketonuria** is an obligate heterozygote for the disease, and the PKU allele is frequent in the general population (1:20); the child has a 1 in 80 risk of being affected. Thus, measurement of phenylalanine levels after enteral feedings are established is mandatory. Although institutional practices vary, many geneticists recommend early quantitative amino acid analysis rather than routine newborn screening in this scenario. Newborns of affected mothers with insufficient treatment may manifest with **microcephaly** , **congenital heart disease** , and **intellectual disability** (even if the infant is not homozygous for PKU). - **XII. Diagnosis**"
  },
  {
   "source": "AAP Developmental and Behavioral Pediatrics, p. 684",
   "text": "Phenylketonuria (PKU), 53 Phenytoin teratogenic effect, 46 Phoneme, 348, 348 _t_ Phonological and articulation disorder, 353 Phonological production deficit, 357 _t_ Phonological-syntactic deficit, 356, 357 _t_ PHQ-2. _See_ Patient Health Questionnaire-2 (PHQ-2) PHQ-9. _See_ Patient Health Questionnaire-9 (PHQ-9) Physical examination biological influences on child development, 50\u201353 developmental evaluation, 178\u2013179 social and emotional development, 233 Pica, 112, 113 Pictorial Pediatric Symptom Checklist, 234 _t_ Picture Exchange Communication System (PECS), 363, 441, 446 Pincer grasp, 170 Pivot response training (PRT), 441, 443 _t_ PKU. _See_ Phenylketonuria (PKU) Placebo effect, 586 Play autism spectrum disorder (PLAY), 442 _t,_ 445 representational, 310 _t_ symbolic, 310 _t_ vision impairment, 273 PLAY. _See_ Play and Language for Autistic Youngsters (PLAY) Play and Language for Autistic Youngsters (PLAY), 442 _t,_ 445 Play audiometry, 257 Plomin, Robert, 6 Pober, Barbara, 330 Pointing, 350 POSI. _See_"
  },
  {
   "source": "Cover, p. 1956",
   "text": "**Phenylketonuria** Screening for phenylketonuria (PKU) has been implemented in most developed countries since the late 1960s. The initial test first reported in 1963 was the \u201cGuthrie test,\u201d a bacterial-inhibition assay. Alternative methods that were subsequently developed include fluorimetry and colorimetry. More recently, PKU screening has been done by tandem mass spectrometry (MS), where this is available. Screening in the United States may take place after 24 hours, but elsewhere, testing after at least 48 hours is more typical. Patients under good control of phenylalanine levels by 3 to 4 weeks along with maintenance of good average control have good neuropsychological outcomes. There are still minor deficits, in particular in those with poor dietary compliance, and maternal PKU remains a persistent problem."
  },
  {
   "source": "Netters Pediatrics (Florin \u0422., Ludwig St.), p. 798",
   "text": "## PHENYLKETONURIA Classic PKU results from deficient phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Rare cases may be caused by deficiency of the cofactor tetrahydrobiopterin or by defects in biopterin synthesis that require additional treatment with various neurotransmitters. Untreated patients present with progressive brain disease that manifests as acquired microcephaly, developmental delays, seizures, behavioral problems, and intellectual disabilities. A fair complexion, eczema, and a mousy or musty odor (caused by increased levels of phenylacetic acid) have also been noted. Classic PKU is associated with persistently elevated phenylalanine levels above 20 mg/dL with normal or low tyrosine and characteristic urinary derivatives. In variants with persistent hyperphenylalaninemia, phenylalanine levels range from 4 to 10 mg/dL. Patients with classic PKU and other variants with elevated phenylalanine require phenylalanine-restricted diets to maintain"
  },
  {
   "source": "Pediatric Board Study Guide, p. 1036",
   "text": "Last-minute review\u2014Metabolic disorders Most likely answer<br>Child presents with a musty odor, eczema, fair skin Phenylketonuria (PKU)<br>and hair, and intellectual disability<br>Newborn with positive PKU on newborn screening. Start a low-protein diet and a phenylalanine-free medical<br>What is the next best step? formula as soon as possible. Then confirm with genetic<br>testing<br>What is the major consequence of delaying dietary Irreversible intellectual disability in most children<br>restriction in children with PKU?<br>Black pigments in the diapers, unusually dark urine Alkaptonuria<br>few days after birth; when older, develops blue<br>discolorations in the ear cartilage and palpable<br>calcifications in the discolored areas, arthritic<br>symptoms in the spine, hip and knee<br>Child with an intellectual disability, normal aorta, Homocystinuria (in Marfan syndrome the lens is dislocated<br>pectus excavatum, increased risk of clotting, along upward and no intellectual disability)<br>with downward"
  },
  {
   "source": "2021_Fleisher_&_Ludwig's_Textbook_of_Pediatric_Emergency_Medicine.epub",
   "text": "Phenylketonuria is a disorder of amino acid metabolism associated with a deficiency of phenylalanine dehydroxylase and dihydropteridine reductase, which forces use of minor metabolic pathways of phenylalanine, resulting in the buildup of phenylacetic acid. It is the buildup of phenylacetic acid in sweat and urine that causes the characteristic aroma described as musty, mousy, horsey, wolflike, barny, or stale sweaty locker-room towels. Clinical features of untreated phenylketonuria include white-blond hair, blue eyes, fair complexion, eczema, microcephaly, hypertonicity, seizures, and progressive mental deterioration. Although neonatal screening detects most of these cases, the observation of a characteristic odor in an infant should prompt immediate appropriate laboratory studies, which may include a urine ferric chloride test in the ED. Prompt diagnosis and dietary restriction of phenylalanine promote normal development."
  }
 ]
}