The cardinal clinical feature is mental retardation. The patients are asymptomatic until the initiation of dietary phenylalanine. Currently the overt phenylketonuria is rare with the advent of widespread screening at birth. If missed the symptoms are insidious until early infancy, with delayed milestones. The children also suffer from the other neurological diseases such as epilepsy. There is also be a “mosy” smell in urine due to the metabolite phenylacetic acid.

• Progressive Intellectual Disability 

  Left untreated, the disorder can cause brain damage and progressive intellectual disability as a result of the accumulation of phenylalanine and its breakdown products. [yourdictionary.com]

  Progressive intellectual disability results if PKU is not treated from early infancy. With treatment, children with PKU can grow and develop normally. [betterhealth.vic.gov.au]

  Left untreated, the disorder can cause brain damage and progressive intellectual disability as a result of the accumulation of phenylalanine and its breakdown products. phen′yl·ke′to·nu′ric adj. & n. phenylketonuria (PKU) [fen′əlkē′tōnyoo͡r′ē·ə, fē′nəl [medical-dictionary.thefreedictionary.com]

• Pediatric Disease

  Focuses on the core aspects of pediatric health and disease. Emphasizes the pathophysiologic aspects of pediatric disease and the psychosocial dynamics of illness. [web.archive.org]

  Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 103. Kumar V, Abbas AK, Aster JC. Genetic and pediatric diseases. In: Kumar V, Abbas AK, Aster JC, eds. Robins Basic Pathology. 10th ed. [medlineplus.gov]

• Pallor

  An ischaemic attack in the hands manifests as intense pallor of the fingers and the patient complains of impaired sensation ("numb fingers”). [czytelniamedyczna.pl]

  A Raynaud phenomenon attack is sudden with the development of cold digits and the demarcation of "white" areas also known as skin pallor or white attack. Instead of white attack, there may be cyanotic skin changes, otherwise known as a blue attack. [ncbi.nlm.nih.gov]

  […] vasospasm of the fingers and toes and usually occurs in response to stress or cold exposure. [1] The phenomenon is named for Maurice Raynaud, who, as a medical student, defined the first case in 1862 as "episodic, symmetric, acral vasospasm characterized by pallor [emedicine.medscape.com]

• Problems at School

  Some children, even when treated, have problems with school work and may need extra help. If treatment is not started until several weeks after birth, delays or learning problems may occur. The level of delay varies from child to child. [newbornscreening.info]

• Collapse

  Collapse all Expand all Contexte La phénylcétonurie est une maladie héréditaire traitée par une restriction alimentaire de l'acide aminé phénylalanine. [cochranelibrary.com]

• Vomiting

  Clinical description In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty [orpha.net]

  This 2-year-old boy was first hospitalized for bilious vomiting and moderate back pain. Laboratory values included a lipase level of 1.142 U/L, a phenylalanine level of 10mg/dL, and computed tomography revealed Balthazar grade E pancreatitis. [ncbi.nlm.nih.gov]

  • Other symptoms include:  Eczema  Recurrent vomiting  Jerking movements in arms and legs  Tremors  Mood disorders  Microcephaly, 6. [slideshare.net]

• Nausea

  Symptoms include intellectual disability, seizures, nausea, vomiting, an eczema-like rash, and a mousy or musty body odor. The diagnosis is based on a blood test. Children who are diagnosed and treated early should develop normally. [msdmanuals.com]

  The most common adverse events reported in the Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal [fda.gov]

  ADVERSE REACTIONS The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reaction lasting at least 14 days, pruritus, nausea [investors.biomarin.com]

  Occasionally, because of the severity of the nausea and vomiting and lack of appetite associated with early pregnancy, women with PKU are hospitalized for nutrition. Usually, intravenous (I.V.) nutrition is administered. [web.archive.org]

• Diarrhea

  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 [ncbi.nlm.nih.gov]

  Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea [fda.gov]

  hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing, rash, urticaria, pruritus, and gastrointestinal symptoms (vomiting, nausea, diarrhea [investors.biomarin.com]

  Low levels can cause mental and physical sluggishness, loss of appetite, anemia, rashes, and diarrhea. If these symptoms are suspected, the parent should be contacted and arrangements made for a physician evaluation. POTENTIAL EMERGENCIES: None. [medhelp.org]

  Gastrointestinal complications include gastric distress, nausea, and diarrhea. These are usually mild and self limited and may be avoided in many by taking the medicine with food. [clinicaladvisor.com]

• Failure to Thrive

  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 [ncbi.nlm.nih.gov]

  Affected infants experience vomiting, dehydration, weak muscle tone (hypotonia), excessive tiredness (lethargy), and failure to gain weight and grow at the expected rate (failure to thrive). [web.archive.org]

• Eczema

  Clinical features in the untreated patient include intellectual disability, defects in executive functioning, seizures, and eczema. Caused by a deficiency of hepatic phenylalanine hydroxylase activity. [bestpractice.bmj.com]

  Clinical description In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty [orpha.net]

• Skin Rash

  An early clue to the disease is light coloring of the skin, eczema (an itchy skin rash), and a musty odor. Diagnosis Screening tests are now mandatory for all babies born in the U.S. and Canada. [healthcentral.com]

  Other symptoms may include: Delayed mental and social skills Head size much smaller than normal Hyperactivity Jerking movements of the arms or legs Mental disability Seizures Skin rashes Tremors If PKU is untreated, or if foods containing phenylalanine [medlineplus.gov]

  If a Phe-restricted diet is followed, babies will develop normally – if not, babies are at risk for mental retardation, delayed social skills, hyperactivity, seizures, skin rashes, and other medical problems. [newenglandconsortium.org]

• Blonde Hair

  This may explain why persons with phenylketonuria generally have blond hair, blue eyes, and fair skin. Phenylketonuria is transmitted by an autosomal recessive gene, which is present in about 1 in every 60 people. [britannica.com]

  hair Irritability, restlessness, hyperactivity Diagnosis Phenylketonuria is diagnosed by a blood test, usually as part of the routine screening tests given to a newborn within the first few days of life. [rarediseases.about.com]

  As a result, children with PKU often will have pale skin, blond hair and blue eyes. Dry skin; eczema; and a "musty" odor resulting from the buildup of phenylalanine in hair, skin and urine are also common. [drugs.com]

  It has been shown that almost 90% of affected people have light coloration such as blond hair and blue eyes. Signs also include skeletal changes such as a small head, short stature, and flat feet. [web.archive.org]

• Flushing

  […] include beta-blockers (widely used for angina, high blood pressure, and anxiety), migraine remedies containing ergotamine or methysergide, bleomycin and other chemotherapy agents (for cancer treatment), clonidine (for high blood pressure, migraine or flushing [dermnetnz.org]

  AND PRECAUTIONS Anaphylaxis Signs and symptoms of anaphylaxis reported include syncope, hypotension, hypoxia, dyspnea, wheezing, chest discomfort/chest tightness, tachycardia, angioedema (swelling of face, lips, eyes, tongue), throat tightness, skin flushing [investors.biomarin.com]

  Pharmacotherapy often fails to bring about the desired effect and is costly, while also being cumbersome for the patients, who have to take their medications 3-4 times a day and often experience headaches, flushed skin, low blood pressure and gastroesophageal [czytelniamedyczna.pl]

• Seizure

  Clinical features in the untreated patient include intellectual disability, defects in executive functioning, seizures, and eczema. Caused by a deficiency of hepatic phenylalanine hydroxylase activity. [bestpractice.bmj.com]

  Here we report an adult patient who developed generalized seizures later in life, despite strict dietary control, and whose seizures were aggravated by levetiracetam (LEV). [ncbi.nlm.nih.gov]

  ˌfe-nᵊl-ˌkē-tᵊn-ˈu̇r-ē-ə, ˌfē-, -ˈyu̇r- \ Definition of phenylketonuria : an inherited metabolic disorder caused by an enzyme deficiency resulting in accumulation of phenylalanine and its metabolites in the blood causing usually severe intellectual disability and seizures [merriam-webster.com]

  Excessive phenylalanine is generally thought responsible for the brain damage that underlies the severe mental retardation and seizure disorder of PKU. In untreated infants, cognitive delay becomes evident within 6 months and is progressive. [epilepsy.com]

• Hyperactivity

  In treated patients, clinical signs vary based on treatment and diet compliance, and may include psychiatric disorders such as attention deficit-hyperactivity disorder and depression. [orpha.net]

  Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. [ncbi.nlm.nih.gov]

• Profound Intellectual Disability

  Most untreated individuals with PKU have profound intellectual disability. After the discovery of PKU, routine testing of institutionalized patients with intellectual disability identified a 1% incidence of PKU in this group. [emedicine.medscape.com]

• Global Developmental Delay

  Hereby, we describe a three- year old male child who presented with generalized edema and global developmental delay. Investigations revealed PKU along with FSGS. [ncbi.nlm.nih.gov]

  Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. [owlcation.com]

  The international survey of women with PKU, the results of which were published in 1980, documented an increased risk of spontaneous miscarriage (24%), intrauterine growth retardation (40%), microcephaly (73%), global developmental delays (92%), and congenital [pediatrics.aappublications.org]

• Cognitive Disorder

  Abstract Phenylketonuria is one of the most important congenital disorders and an autosomal recessive metabolic disease that can cause irreversible brain damages, mental retardation, and cognitive disorders if left untreated. [ncbi.nlm.nih.gov]

Screening is usually done in the first week of life. This is done by checking the phenylalanine and tyrosine levels. Blood levels are typically high (>20g/dl), but the wide variability in the phenylalanine levels over a 24 hour period may necessitate repeat sampling [6].

Laboratory studies

The most useful method is via tandem-mass spectrometry, as this method can also measure other amino acid levels such as tyrosine. Any abnormal levels will require immediate action and appropriate referral

Imaging

There is white matter injury apparent on phenylketonuria patients. The severity of the injury is related to the treatment status. There are new techniques that may be able to estimate the phenylalanine level on magnetic resonance spectroscopy.

Genetic testing

Molecular analysis may be used to identify mutations on the enzyme locus and predict enzyme activity in some cases. All patients with a diagnosis of phenylketonuria require genetic counselling.

• Brain MRI Abnormal

  MRI Abnormalities Related to Status Epilepticus. 38 Morana G...Piccardo A 29465492 2018 42 Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. 38 Hayes J...Costello JF 29077933 2018 43 p53 expression and subcellular [malacards.org]

  In more recent studies, it has been shown that brain MRI abnormalities and electrophysiologic testing abnormalities referable to the central nervous system are observed in adults who are on unrestricted Phe intake. [pediatrics.aappublications.org]

• Phenylalanine Increased

  Increase in the excretion of phenylalanine metabolites was found in patients who were considered to have good blood phenylalanine control. [doi.org]

  Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. [nature.com]

Management of patients with phenylketonuria should be provided by an experienced team of nutritionists, social workers, psychologists, metabolic specialists, and pediatricians [7].

Dietary

The mainstay of therapy is dietary restriction of phenylalanine. This requires use of feeds that are deficient in phenylalanine, (with tyrosine supplementation) but supply adequate nutrition. These substitutes have to meet the requirement for development and optimal growth. Phenylalanine level are followed closely from initially one to two times a week and once a month in the older children and adults (but this is subject to local guidelines). Normal levels being the desired targets. Compliance may be an issue in older children and adults due to the poor taste of these substitutes and supplements. The diet restriction are for life for optimal outcomes.

There are currently a number of other strategies are being developed especially for patients who cannot adhere to the strict diet. It has been noted that ingestion of large amounts of neutral amino acids maybe beneficial by competing with phenylalanine at the blood brain barrier [8].

Pharmacotherapy

Patients with residual activity may benefit from administration of tetrahydrobiopterin (BH4) cofactor [9]. Upcoming treatments include Phenylalanine ammonia lyase, which is injectable. It is currently in the testing phase, but the optimism is guarded currently and more testing will be required.

The prognosis is excellent if the condition is identified early and the correct management is instituted and maintained strictly. There is a direct relationship between the phenylalanine levels and IQ levels especially in the early years when there is brain development. If left untreated the intellectual disability can be substantial.

Deficiency of the hepatic enzyme phenylalanine hydroxylase causes accumulation of phenylalanine and its metabolites. Phenylalanine hydroxylase is required for the conversion of the amino acid phenylalanine to tyrosine with tetrahydrobiopterin (deficiency of tetrahydrobiopterin accounts for about 2% of phenylketonuria) being used as a co-factor necessary for the activity of phenylalanine hydroxylase.

The incidence of this condition is approximately 1 in every 13,550 to 19,000 births and is less common in individuals of African descent. Information from intellectual disability clinics show 0.04-1% of the patients are affected by phenylketonuria.

The enzyme accounts for about two thirds of the disposal of the amino acid with the rest being used protein synthesis [2]. The tyrosine levels are usually normal to low. The extent of the deficiency depends on the enzyme activity, complete deficiency causes phenylketonuria, with residual enzyme activity causing mild phenylketonuria.

In total enzyme deficiency usual results in serum levels of phenylalanine above 20mg/dl. Residual activity lead to levels to of about 10 to 20mg/dl [3].
The mechanism of mental retardation of is not known, but a number of theories have been proposed including, oxidative stress, affecting neuronal development. Other theories postulate metabolites of phenylalanine (phenylacetate and phenylpyruvate) which may inhibit neuronal growth [4].

Individuals with a strong family history of this enzyme deficiency need be tested and get counselled (genetic) before conceiving. [10]

Phenylketonuria is an inborn error in the metabolism of the aromatic amino acid phenylalanine. It is caused by the deficiency of a liver enzyme that causes accumulation of the amino acid. The enzyme is called phenylalanine hydroxylase. If not identified early can lead to mental retardation [1].
It has autosomal recessive mode of inheritance, with mutations in the gene coding for phenylalanine hydroxylase located on chromosome 12. More than 400 mutations have been identified.

Definition: Phenylketonuria is a genetic disease that is caused by a deficiency in an enzyme that breaks down a dietary protein building block (amino acid) called phenylalanine. Lack of this enzyme means that body cannot break this amino acid down and it accumulates with the body causing symptoms, mostly to the brain.

Cause: It is caused by a deletion in the gene that gives the instruction for making the enzyme. This deletion is passed down from parents (who are carriers and sufferers) to their children.

Symptoms: Patients with phenylketonuria suffer from mental retardation due to the high levels of the phenylalanine hindering brain development, especially in the younger years when the brain is growing. The bones may also be affected. Patients may have delayed milestones, such as sitting, walking and speech development. They may also suffer from seizures and have behavioral problems.

Diagnosis: It is diagnosed by a blood test that is done during the first week of life.

Treatment and follow-up: Treatment involves many people, but the mainstay of treatment is total restriction of food that contain the amino acid phenylalanine. This is done by giving medical substitutes that contain all the other necessary proteins and nutrients required for optimal growth and deployment. If the diet is followed the patients are expected to have normal intellect and lives. Anybody diagnosed will require genetic testing and counselling before they can have a baby. Regular testing of the phenylalanine is required to monitor progress of the patients.

1. Santos LL, Castro-Magalhaes M, Fonseca CG, et al. PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet. Nov 2008;72:774-9.
2. Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis. Feb 2007;30(1):29-34.
3. Guldberg P, Henriksen KF, Sipila I, Guttler F, de la Chapelle A. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet. Dec 1995;32(12):976-8.
4. Ounap K, Lillevali H, Metspalu A, Lipping-Sitska M. Development of the phenylketonuria screening programme in Estonia. J Med Screen. 1998;5(1):22-3.
5. Bodamer OA. Screening for phenylketonuria. In: Phenylketonuria: Special Issue: Annales Nestle, English ed, Lentze MJ (Ed), S Karger Pub, 2010. Vol Vol 68, No 2, p.53.
6. Cerone R, Schiaffino MC, Di Stefano S, Veneselli E. Phenylketonuria: diet for life or not? Acta Paediatr 1999; 88:664.
7. Lambruschini N, Pérez-Dueñas B, Vilaseca MA, et al. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 2005; 86 Suppl 1:S54.
8. Abadie V, Berthelot J, Feillet F, et al. [Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. Arch Pediatr 2005; 12:594.
9. Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab 2002; 3:123.
10. Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, et al. Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study. Pediatrics. Jun 2013;131(6):e1881-8.