Early Dietary Treated Patients With Phenylketonuria Can Achieve Normal Growth and Mental Development.

Phenylketonurias Clinical Trial

Official title:

Early Dietary Treated Patients With Phenylketonuria Can Achieve Normal Growth and Mental Development.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04302194
• Other study ID #: Phenylketonuria
• Status: Not yet recruiting
• Start date: May 1, 2020
• Est. completion date: October 2021

Study information

• Verified date: March 2020
• Source: Assiut University
• Contact: Monica Dobs
• Phone: 01220777433
• Email: monicaibrahim9111[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The study aim is to follow up body growth(body weight by kg, length by cm, head circumference, abdominal circumference, and body mass index ) and mental development of infants on phenylalanine restricted diet in comparison with normal matchable infants.

Description:

Phenylketonuria is rare genetic disease caused by mutation in gene of phenylalanine (Phe) hydroxylase that converts Phenylalanine into tyrosine. The absence of this enzyme leads to elevation and accumulation of Phenylalanine and, increased phenylketones in urine (hence PKU), and also leads to decrease myelin formation, dopamine, norepinephrine, and serotonin production.

Phenylketonuria worldwide affects about 1 in 12,000 babies.

In Egypt the incidence rate reported 1 : 3000 (0.03%), The actual prevalence of PKU in this study were 1/3000. This is higher than that reported by Temtamy25, who found in a pilot study on 15,000 newborns in 3 governorates in Egypt that the incidence of PKU was 1/ 7500 . The latest consensus in Egypt showed that at least one million babies are born every year.

Phenylalanine hydroxylase deficiency (PAH deficiency) causes a spectrum of disorders, including classic phenylketonuria (PKU).

A rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency, which occurs when the PAH enzyme is normal, and a defect is found in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4).

Elevations of phenylalanine in the plasma depend on the degree of enzyme deficiency. In patients with severe PAH deficiency (previously referred to classic phenylketonuria ), plasma phenylalanine levels on unrestricted diet usually exceed 20 mg/dL (>1,200 μmol/L). In affected infants with plasma concentrations >20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate) that are excreted in the urine, giving rise to the term phenylketonuria (PKU).

If left untreated and not detected early , irreversible damage may occur due to the accumulation of Phenylalanine and its metabolites in the body and will affect the growth and development of patients .

Without treatment most children develop profound and irreversible intellectual disability, seizures, hyperactive behavior with autistic features, psychiatric symptoms, eczema, musty body odor, and light pigmentation.

Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by heel prick, typically performed 2-7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding. PKU is commonly included in the newborn screening panel of many countries and Egypt , with varied detection techniques. Most babies are screened for PKU soon after birth.

If left untreated and not detected early , irreversible damage may occur due to the accumulation of Phenylalanine and its metabolites in the body and will affect the growth and development of patients .

Without treatment most children develop profound and irreversible intellectual disability, seizures, hyperactive behavior with autistic features, psychiatric symptoms, eczema, musty body odor and light pigmentation.

Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by heel prick, typically performed 2-7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding. PKU is commonly included in the newborn screening panel of many countries and Egypt , with varied detection techniques. Most babies are screened for PKU soon after birth.

Treatment is with a diet low in foods that contain phenylalanine and special supplements. Babies should use a special formula with a small amount of breast milk. The diet should begin as soon as possible after birth and be continued for life. People who are diagnosed early and maintain a strict diet can have normal health and a normal life .

The target of the treatment is to reach optimal health ranges of phenylalanine (or "target ranges") are between 120 and 360 µmol/L or equivalently 2 to 6 mg/dL, and aimed to be achieved during at least the first 10 years, to allow the brain to develop normally.

The dietary restriction in phenylketonuria should be only in protein diet (phenylalanine),while fat and carbohydrate diet don't need to be restricted.

Lifelong treatment will provide the best effect on growth and development, prevents neurocognitive impairment and abnormal executive functioning and helps maintaining mental health.

Anthropometric measures are important for evaluating the growth development and nutritional status of infants with phenylketonuria.

The dietary restriction in phenylketonuria should be only in protein diet (phenylalanine),while fat and carbohydrate diet don't need to be restricted.

Lifelong treatment will provide the best effect on growth and development, prevents neurocognitive impairment and abnormal executive functioning and helps maintaining mental health.

Anthropometric measures are important for evaluating the growth development and nutritional status of infants with phenylketonuria.

Intelligence and mental development in PKU PKU results, in untreated patients, a profound intellectual disability and more subtle cognitive deficits in individuals who were treated early and continuously. The assessment of intellectual functioning in PKU has been an important target outcome variable since the implementation of neonatal PKU screening programs in the 1960s . Research on intellectual functioning in individuals with PKU has played a significant role in guiding treatment recommendations and improving outcomes.

Brumm and Grant conducted a literature review examining the relationship between intellectual outcome and treatment parameters including initiation of treatment, duration of treatment, and blood phenylalanine (Phe) levels from infancy through adulthood. While current PKU treatment practices have eliminated severe neurological and cognitive impairment, evidence suggests that intellectual functioning, although typically within the average range when PKU is treated early and continuously, may not be maximized under the current definition of well-controlled PKU, which is based on blood Phe levels.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: October 2021
• Est. primary completion date: May 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 1 Month to 3 Years

Eligibility

Inclusion Criteria:

1. Infants with hyperphenylalaninemia on special formula and diet

2. Infants of both sexes

3. Age since birth till three years

4. Type of feeding : diet restriction of phenylalanine

5. Controls: normal healthy children match with cases in the same social class, age and sex

Exclusion Criteria:

1. Age greater than three years

2. Patients diagnosed with PKU and not regular in feeding for special diet and formula.

3. PKU patients not diagnosed since birth

Related Conditions & MeSH terms

• Phenylketonurias

Intervention

Dietary Supplement:
• phenylalanine restricted diet
Infants with hyperphenylalaninemia on special formula and diet

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assiut University

References & Publications (13)

Belanger-Quintana A, Martínez-Pardo M. Physical development in patients with phenylketonuria on dietary treatment: a retrospective study. Mol Genet Metab. 2011 Dec;104(4):480-4. doi: 10.1016/j.ymgme.2011.08.002. Epub 2011 Aug 10. — View Citation

Blau N. Genetics of Phenylketonuria: Then and Now. Hum Mutat. 2016 Jun;37(6):508-15. doi: 10.1002/humu.22980. Epub 2016 Mar 18. Review. — View Citation

Brumm VL, Grant ML. The role of intelligence in phenylketonuria: a review of research and management. Mol Genet Metab. 2010;99 Suppl 1:S18-21. doi: 10.1016/j.ymgme.2009.10.015. Review. — View Citation

Burgard P. Development of intelligence in early treated phenylketonuria. Eur J Pediatr. 2000 Oct;159 Suppl 2:S74-9. Review. — View Citation

Cleary M, Trefz F, Muntau AC, Feillet F, van Spronsen FJ, Burlina A, Bélanger-Quintana A, Gizewska M, Gasteyger C, Bettiol E, Blau N, MacDonald A. Fluctuations in phenylalanine concentrations in phenylketonuria: a review of possible relationships with outcomes. Mol Genet Metab. 2013 Dec;110(4):418-23. doi: 10.1016/j.ymgme.2013.09.001. Epub 2013 Sep 9. Review. — View Citation

Dokoupil K, Gokmen-Ozel H, Lammardo AM, Motzfeldt K, Robert M, Rocha JC, van Rijn M, Ahring K, Bélanger-Quintana A, MacDonald A. Optimising growth in phenylketonuria: current state of the clinical evidence base. Clin Nutr. 2012 Feb;31(1):16-21. doi: 10.1016/j.clnu.2011.09.001. Epub 2011 Sep 29. Review. — View Citation

Evans S, Daly A, MacDonald J, Pinto A, MacDonald A. Fifteen years of using a second stage protein substitute for weaning in phenylketonuria: a retrospective study. J Hum Nutr Diet. 2018 Jun;31(3):349-356. doi: 10.1111/jhn.12510. Epub 2017 Sep 21. — View Citation

Evans S, Daly A, MacDonald J, Preece MA, Santra S, Vijay S, Chakrapani A, MacDonald A. The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge. Ann Nutr Metab. 2014;65(1):42-8. doi: 10.1159/000363391. Epub 2014 Sep 4. — View Citation

Jani R, Coakley K, Douglas T, Singh R. Protein intake and physical activity are associated with body composition in individuals with phenylalanine hydroxylase deficiency. Mol Genet Metab. 2017 Jun;121(2):104-110. doi: 10.1016/j.ymgme.2017.04.012. Epub 2017 Apr 28. — View Citation

MacDonald A, Gokmen-Ozel H, van Rijn M, Burgard P. The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis. 2010 Dec;33(6):665-70. doi: 10.1007/s10545-010-9073-y. Epub 2010 Apr 7. Review. — View Citation

Meli C, Bianca S. Dietary control of phenylketonuria. Lancet. 2002 Dec 21-28;360(9350):2075-6. — View Citation

Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency. Genet Med. 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. Review. — View Citation

Rocha JC, van Rijn M, van Dam E, Ahring K, Bélanger-Quintana A, Dokoupil K, Gokmen Ozel H, Lammardo AM, Robert M, Heidenborg C, MacDonald A. Weight Management in Phenylketonuria: What Should Be Monitored. Ann Nutr Metab. 2016;68(1):60-5. doi: 10.1159/000442304. Epub 2015 Nov 25. Review. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Normal growth in early dietary treated patients with Phenylketonuria to assessed by body mass index in kg/m^2	Normal growth in early dietary treated patients with Phenylketonuria to assessed by body mass index in kg/m^2	one year
Primary	Normal growth in Early dietary treated patients with Phenylketonuria to assessed by head circumference in centimeters	Normal growth in Early dietary treated patients with Phenylketonuria to assessed by head circumference in centimeters	one year
Primary	Normal growth in Early dietary treated patients with Phenylketonuria to assessed by abdominal circumference in centimeters	Normal growth in Early dietary treated patients with Phenylketonuria to assessed by abdominal circumference in centimeters	one year
Primary	Mental development in early dietary treated patients with Phenylketonuria to assessed by using Emerging Pattern Of Behavior of infants	Mental development in early dietary treated patients with Phenylketonuria to assessed by using Emerging Pattern Of Behavior of infants	one year
Primary	Comparison between early dietary treated patients with Phenylketonuria with normal matchable infants regarding normal growth and mental development	Comparison between early dietary treated patients with Phenylketonuria with normal matchable infants regarding normal growth and mental development	one year