The classical form of PKU presents with a diverse brain pathology, including microcephaly, epilepsy, profound intellectual changes, but also behavioral problems [3]. Tremor and motor system abnormalities such as hemiplegia and paraplegia may also be encountered [2], while excessive phenylalanine can also cause changes on the skin (eczema, decreased skin and hair pigmentation and a musty body odor) [3]. Psychiatric symptoms in the form of depression, anxiety, and development of phobias may appear in later life [3].

• Weakness

  In addition, BH4 administration can help lower phenylalanine blood levels in patients whose PAH has a weak BH4 affinity. Hyperphenylalaninemias lead to mental retardation due to an imbalance of amino acids crossing the blood brain barrier. [studentreader.com]

  There are some differences in the results of our study on the developmental skills with other studies which may be due to low sample size in our study or possible weaknesses in the related test. [ijp.tums.pub]

  The pattern of deficits was similar in both groups, with relative weaknesses in working memory and attention. [ncbi.nlm.nih.gov]

• Epilepsy

  with epilepsy and global developmental delay/intellectual disability. [go.gale.com]

  The classical form of PKU presents with a diverse brain pathology, including microcephaly, epilepsy, profound intellectual changes, but also behavioral problems. [symptoma.com]

  Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels. Epilepsia. 2007; 48(6):1143-50. [thefreelibrary.com]

  Microcephaly or small head size Increased activity in the child or behavioural problems Mental retardation and developmental delays Jerky movements of the legs and arms Tremors Abnormal movements of the hands and arms Seizures or epilepsy like features [news-medical.net]

  Epilepsy is not a prominent feature of primary autism. Neuropediatrics 2004; 35 (4) 207-210 44 Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. [thieme-connect.com]

• Small Head

  Microcephaly or small head size Increased activity in the child or behavioural problems Mental retardation and developmental delays Jerky movements of the legs and arms Tremors Abnormal movements of the hands and arms Seizures or epilepsy like features [news-medical.net]

  They have small heads, small bodies, and poorly developed teeth. Skin rashes may also result. These children often have an unpleasant musty or mousy odor from the excess by-products of unprocessed phenylalanine. [drgreene.com]

  This can lead to various problems in the baby, including: intellectual disabilities heart defects delayed growth low birth weight an abnormally small head These signs aren’t immediately noticeable in a newborn, but a doctor will perform tests to check [healthline.com]

• Osteoporosis

  […] following: late diagnosis (beyond the neonatal period), toddlers and adults (the available DXA software was suitable for those with 5-18 years of age), history of recent fracture (within three months preceding the study), positive family history for osteoporosis [endometabol.com]

• Eczema

  PKU-like symptoms include eczema and fair hair and skin coloring. Causes Genetic defects in phenylalanine hydroxylase cause most cases of hyperphenylalaninemia. [emedicine.medscape.com]

  Diseases The presence of excess phenylalanine in the blood (as in phenylketonuria) SYMPTOMS At phenylalanine levels near 20 mg/dl (1200 mmol/l), phenylketonuria (pku)-like symptoms may emerge, including more pronounced developmental abnormalities,eczema [yogavanahill.com]

  […] phenylketonuria–PKU or hyperphenylalaninemia, type 1 is an AR condition characterized by a deficiency in phenylalanine hydroxylase, which if not recognized early–urine has a 'mousy' odor—and treated by restricting dietary phenylalanine, results in tremors, seizures, eczema [medical-dictionary.thefreedictionary.com]

  Classical phenylketonuria is caused by a severe deficiency of phenylalanine hydroxylase and presents in infancy with developmental delay; seizures; skin hypopigmentation; eczema; and demyelination in the central nervous system. [icd9data.com]

  Classical phenylketonuria is caused by a severe deficiency of phenylalanine hydroxylase and presents in infancy with developmental delay; SEIZURES; skin HYPOPIGMENTATION; ECZEMA; and demyelination in the central nervous system. [medvik.cz]

• Fair Complexion

  Treatment Untreated PKU patients develop moderate to profound mental retardation and have a characteristic "mousy" odor, fair complexion, abnormal gait and stance, and dermatitis. [medschool.lsuhsc.edu]

• Seizure

  We describe an 8-year-old girl with delay, seizures, and dystonia with mild hyperphenylalaninemia detected in late childhood. [wwww.unboundmedicine.com]

  […] classic manifestations of phenylketonuria (PKA; see this term) and that later on is clinically differentiated by neurologic symptoms such as microcephaly, intellectual disability, central hypotonia, delayed motor development, peripheral spasticity and seizures [orpha.net]

  The symptoms of hyperphenylalaninemia include impaired cognitive function, seizures, and behavioral and developmental abnormalities that may become apparent within months of birth. Read More [britannica.com]

  Treatment with dopamine and serotonin precursors, L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, was associated with improvement in temperament and motor tone and less frequent seizures. [ncbi.nlm.nih.gov]

  This can cause mental retardation, behavioral and movement problems, seizures, and delayed development. [icd9data.com]

• Tremor

  ' phenylketonuria–PKU or hyperphenylalaninemia, type 1 is an AR condition characterized by a deficiency in phenylalanine hydroxylase, which if not recognized early–urine has a 'mousy' odor—and treated by restricting dietary phenylalanine, results in tremors [medical-dictionary.thefreedictionary.com]

  The recessive form presents with hyperphenylalaninemia within the first six months of life, significant developmental delay, truncal hypotonia, hypertonia of the extremities, tremors, seizures, and, at times, autonomic dysfunction. [invitae.com]

  Tremor and motor system abnormalities such as hemiplegia and paraplegia may also be encountered, while excessive phenylalanine can also cause changes on the skin (eczema, decreased skin and hair pigmentation and a musty body odor). [symptoma.com]

  Untreated PKU can also eventually cause: delayed development behavioral and emotional problems neurological problems, such as tremors and seizures PKU is a genetic condition, so it can’t be prevented. [healthline.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 [nlm.nih.gov]

• Clumsiness

  Clinical-neurologic examination revealed a mild rest and intention tremor in one subject with non-PKU hyperphenylalaninemia and a clumsy diadochokinesis in another. One control subject presented a mild rest and intention tremor. [nature.com]

Severe neurological damage in early childhood must consider HPA in the differential diagnosis and a meticulous physical examination is necessary to assess clinical signs and symptoms. Patient history may be an equally important diagnostic tool, with a focus on family history and onset of symptoms. To confirm HPA, however, levels of phenylalanine in blood should be measured and on the basis of its values, the diagnosis of PKU (> 1000 µmol/L) or non-PKU HPA (120-1000 µmol/L) can be made [3] [5]. Additionally, a BH4 loading test may be used to confirm BH4-associated HPA [3]. Subsequent genetic testing to determine the exact mutation responsible for the disease may be performed as well [3].

Restriction of dietary intake of phenylalanine was considered as the mainstay of therapy in patients across all subtypes, but individuals with milder forms may be monitored for a period of time and assess whether a need for a dietary restriction is necessary [1]. The introduction of BH4 into therapy has shown marked improvements in treatment and is now recommended for patients in whom BH4 deficiency is reduced [8] [9]. It is important to emphasize that treatment must be life-long in order to maintain circulating levels of phenylalanine within physiological limits, but the issue of adherence to therapy has been documented and presents a significant challenge for the patient and for the physician [3].

The prognosis significantly varies on the subtype. Timely and adequate life-long therapy does have a significant effect on the quality of the patient's life. The introduction of screening during a neonatal period in many countries has led to early recognition and therapy, thus reducing the burden of the disease even in those with severe deficiencies, but if patients are left untreated, severe brain damage and intellectual disability may occur [3].

HPA is considered to be an autosomal recessive disease and two main genetic events have emerged as underlying causes [3] [4]:

• PAH deficiency - PAH is responsible for a conversion of phenylalanine to tyrosine and its deficiency leads to accumulation of phenylalanine in the circulation [2]. So far, more than 500 mutations involving the PAH gene situated on chromosome 12 have been described [3].
• BH4 deficiency - BH4 is a cofactor required for a hydroxylation of various aromatic amino acids, including phenylalanine and its role in a conversion of phenylalanine to tyrosine is well established [4].

It is important to mention that HPA may be considered as a multifactorial disease, as isolated PAH and BH4 deficiencies may not be as dangerous without a constant dietary intake of phenylalanine, which further increases the circulating concentrations of this amino acid [3].

Significant variations of HPA prevalence and incidence have been observed across different parts of the world. Incidence rates range from 1 in 2,600, 1 in 4,500 and 1 in 15,000 live births in Turkey, Ireland, and France, respectively [3] [5], to 1 in 143,000 and 1 in 200,000 live births in Japan and Finland [5]. Consequently, estimated carrier rates are much higher in countries of high vs low incidence (1 in 26-33 individuals vs 1 in 50-200) [5]. Additionally, marked variations in BH4 deficient cases were detected, as studies show that only 1-2% of Caucasians have this genetic defect, compared to 15% and 19% in Turkey and Taiwan, while 66% of patients from Saudi Arabia were diagnosed with BH4 deficiency in the setting of elevated phenylalanine levels [4]. It is still unknown why such differences across the world exist.

HPA starts with genetic mutations that impair normal conversion of phenylalanine to tyrosine. Under physiological conditions, phenylalanine is an essential amino acid used for a synthesis of proteins and excess levels are converted to tyrosine (in the presence of oxygen) through the activity of PAH and by a support of BH4 [7], a cofactor necessary for this chemical reaction. In the setting of genetic mutations that either cause deficiency of PAH or BH4, phenylalanine is not converted to tyrosine at a desirable rate, causing this amino acid to accumulate and induce toxic effects to the brain and other parts of the central nervous system [3]. The exact mechanism for brain damage is not known, but it is suspected that the large amino acid transport affects protein synthesis, neurotransmitter function and the activity of dopamine [3] [4].

Fortunately, many countries have introduced mandatory screening for PAH deficiency in regular practice and testing during newborn period is now becoming a part of regular practice [3] [10]. This strategy is, by far, the most important method to prevent brain damage and symptoms associated with this condition, while screening of relatives at risk for HPA can also be a valid preventive strategy [3].

Hyperphenylalaninemia (HPA) is an autosomal recessive metabolic disease that primarily arises due to deficiency of phenylalanine hydroxylase (PAH) [1], a hepatic enzyme that normally converts phenylalanine to tyrosine. As a result, accumulation of phenylalanine in the circulation occurs [2]. So far, more than 500 different mutations have been identified in the PAH gene located on chromosome 12 [3], while deficiency of tetrahydrobiopterin (BH4), a cofactor essential for proper functioning of PAH, has also been proposed as a cause of HPA [4]. The overall incidence rates are estimated at 1 in 15,000 individuals, but significant differences exist across the world [3]. In Turkey and Ireland, HPA is diagnosed in 1 in 2,600 and 4,500 live births, respectively, whereas a rate of 1 in 143,000 live births was established in Japan [5]. HPA has three distinct phenotypes, which are formed on the basis of severity of HPA and tolerance of phenylalanine from food [3]:

• Phenylketonuria (PKU) - Considered as the most severe subtype of HPA, PKU is confirmed in the setting of near complete or complete PAH deficiency and plasma phenylalanine values are > 1000 μmol/L. Although neonates with PAH deficiency do not show any physical signs of HPA, apart from a lower birth weight and smaller head circumference [3], numerous neurological deficits may be encountered in childhood, such as epilepsy, encephalopathy, hydrocephalus and severe intellectual impairment if left untreated [2].
• Non-PKU HPA and variant PKU - Non-PKU HPA is defined by phenylalanine values between 120-1000 μmol/L and is characterized by a milder and somewhat delayed clinical presentation in childhood and adolescence compared to PKU, while variant PKU possesses similar clinical features as non-PKU HPA [3].

To make the diagnosis, levels of phenylalanine in blood, as well as an activity of BH4 cofactor through a procedure known as BH4 loading test are evaluated in order to assess the severity of a deficiency, while genetic testing to determine the exact mutation on chromosome 12 may be performed to confirm the diagnosis [3]. At this moment, therapy consists of restriction of daily phenylalanine intake through food and BH4 supplementation, which has emerged as a very important treatment strategy [6]. It may be used only in individuals who develop HPA due to BH4 deficiency, in addition to PAH deficiency, with numbers varying from 66% in Saudi Arabia, 15% in Turkey and only 1-2% of Caucasian patients [4]. Despite the fact that mandatory screening for HPA and PKU has been implemented in various countries, these conditions pose a significant burden, partly because of the need for a life-long dietary regimen in many patients, but also because unrecognized patients may develop severely debilitating neurological symptoms that have a detrimental impact on their daily life [3].

Hyperphenylalaninemia (HPA) is a genetic disorder characterized by excess levels of phenylalanine in the body. Phenylalanine is an essential amino acid, meaning that it must be supplied from a diet (the body is not able to synthesize it internally) and it is used for formation of various proteins. Once the necessary amounts are used up, it is normally converted to tyrosine through the activity of an enzyme called phenylalanine hydroxylase (PAH), with the help of a cofactor, tetrahydrobiopterin (BT4) and several other enzymes. In the setting of various genetic mutations that cause insufficient production of PAH and/or BT4, accumulation of phenylalanine in the circulation occurs, resulting in HPA. Based on the amount of this amino acid in the blood, HPA may be further classified into phenylketonuria (PKU), non-PKU HPA and variant HPA. PKU is the most severe form of HPA that is characterized by severe brain damage and symptoms such as intellectual disability, seizures, tremor and motor abnormalities, while non-PKU HPA has a somewhat milder clinical presentation. The reason why neurological symptoms are the hallmark of HPA is because phenylalanine is considered to be toxic for the brain when present in high concentrations, but the exact mechanism of damage remains unknown. To make the diagnosis, it is necessary to evaluate phenylalanine levels in the blood, while genetic testing to confirm the exact mutation may be performed as well. PKU is established when levels are > 1000 µmol/L, while non-PKU HPA is diagnosed when a concentration between 120-1000 µmol/L is observed. Dietary restriction of phenylalanine is the most important therapeutic measure, which implies a reduction of food high in proteins (meat, fish, eggs, cheese), but the introduction of BT4 supplementation has shown to be of significant benefit for patients in whom BT4 deficiency is the cause of HPA. Fortunately, numerous countries over the world have implemented screening of newborn babies for HPA, so that early initiation of treatment can prevent the occurrence of symptoms that may be severely debilitating for the patient and the family. Having in mind the fact that HPA is transmitted through an autosomal recessive pattern of inheritance, meaning that each parent is a carrier of a single mutated gene, but is not ill and if both genes are transferred to their child, their presence will cause a disease. For this reason, screening of families in whom cases of HPA have been confirmed may also be an effective preventive strategy.

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