Last updated:
July 12, 2021
Years published: 1988, 1989, 2003, 2021
NORD gratefully acknowledges Tara Gallagher and Mariano Flores, NORD Editorial Interns from the University of Notre Dame, and Shirou Matsumoto, MD, PhD, Department of Pediatrics, Faculty of Medical Sciences, Kumamoto University, Japan, for assistance in the preparation of this report.
Summary
Hyperprolinemia type I (HPI) is an inherited metabolic disorder of proline metabolism, which is characterized by abnormally high levels of proline, hydroxyproline and glycine in the blood and the urine. The high level of blood proline is the result of a deficiency of the enzyme proline oxidase, also called POX or proline dehydrogenase (PRODH), which is essential to the normal breakdown (metabolism) of proline. There are often no clinical manifestations of HPI.
Introduction
There are two types of hyperprolinemia: type I (HPI) and type II (HPII). Each type is caused by an autosomal recessive inborn error of the proline metabolic pathway. Proline is abundant in nature and readily found in a variety of foods.
HPII is another form of hyperprolinemia caused by a deficiency of a different enzyme, Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase, leading to high blood proline levels. Patients with HPII have higher plasma levels of proline than do people with HPI and it is associated with neurological problems such as seizures and intellectual disability.
HPI does not usually cause symptoms, but patients with intellectual disability and/or generalized epilepsy have been reported. A relationship between adult schizophrenia or schizoaffective disorders and HPI has been discussed. Kidney (renal) symptoms have been reported in some affected people. Other symptoms include abnormal EEG readings, generalized low muscle tone (hypotonia), global developmental delay, aggressive behavior, hyperactivity and repetitive movements (stereotypy).
Hyperprolinemia has been reported in patients with a microdeletion of the POX (PRODH) gene in the chromosome 22q11 region. Various mutations have been reported. This gene is involved in the initial steps of breaking down proline. The PRODH mutations have been divided into three groups: those leading to mild (<30%); moderate (30–70%); and severe (>70%) reductions of POX enzyme activity. Serum proline level seems to correlate with the severity of POX enzyme deficiency but not to be related with clinical severity.
HPI is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
HPI is a very rare disorder that is present at birth. It affects males and females in equal numbers. There appears to be no differences across ethnicities. The prevalence is unknown, but current studies of different populations suggest rates of 1 in 310,000 to 1 in 700,000.
HPI is diagnosed biochemically based on a high plasma proline level without urinary excretion of P5C. In contrast, the presence of P5C in the urine is indicative of HPII.
The normal level of proline is approximately 450 units, but people with HPI may have levels of 1,900 to 2,000 units. These high levels of proline are often 2 to 10 fold, around 0.8-4.0 mmol/L of proline. Often, the diagnosis is made by exclusion. After failure to arrive at a diagnosis by other means, a blood proline level is ordered and this confirms the diagnosis.
Newborn screening can also be used to test the blood proline levels and compare them to the standard. A pilot study for HPI newborn screening is currently underway in California and China.
Treatment
Proline is common in food, and attempts to control blood proline levels by restrictive dieting have not succeeded. Because the medical consequences of HPI appear to be modest or inconsequential, many physicians do not take an aggressive approach toward treatment.
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TEXTBOOKS
Phang JM, Yeh GC, Scriver CR. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 7th ed. McGraw-Hill Companies. New York, NY; 1995:1125-26; 1343-44.
JOURNAL ARTICLES
Ersoy M. Yılmaz S & Ceylaner S. Antioxidant therapy in a patient with hyperprolinemia type 1 presenting with mild neuromotor retardation and speech disturbance. Indian J Pediatr. 2021 88: 601. https://doi.org/10.1007/s12098-021-03744-2
Knezevic C, Ness M, Kratz L, et al. Elevated creatine in a patient on IVIG-therapy. Clinica Chimica Acta. 2018;486:94-97.
Duarte M, Afonso, J, Moreira A, et al. Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations. Brain Dev. 2017;39(6):539-541.
Huang X, Zhang Y, Hong, F, et al. Screening for amino acid metabolic disorders of newborns in Zhejiang province:prevalence, outcome and follow-up. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2017;46(3):233-239.
Mitsubuchi H, Nakamura K, Matsumoto S, Endo F. Biochemical and clinical features of hereditary hyperprolinemia. Pediatr Int. 2014 Aug;56(4):492-6. doi: 10.1111/ped.12420.
Clelland C, Read L, Baraldi A, et al. Evidence for association of hyperprolinemia with schizophrenia and a measure of clinical outcome. Schizophrenia Research. 2011;131(1-3):139-45.
Wu G, Bazer F, Burghardt R, et al, Proline and hydroxyproline metabolism: implications for animal and human nutrition, Amino Acids. 2011 April ; 40(4): 1053–1063.
Ferreira AGK, Lima DD, Delwing D et al. Proline impairs energy metabolism in cerebral cortex of young rats. Metab Brain Dis, 2010; 25: 161–168. https://doi.org/10.1007/s11011-010-9193-y
Guilmatre A, Legallic S, Steel G, et al. Type I hyperprolinemia: genotype/phenotype correlations, Human Mutation 2010; 31 (8): 961–965.
Mitsubuchi H, Nakamura K, Matsumoto S and Endo F. Inborn errors of protein metabolism. The Journal of Nutrition 2008;138;2016S–2020S.
Raux G, Bumsel E, Hecketsweiler B, et al, Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome, Human Molecular Genetics, 2007; 16(1): 83–91.
Jacquet H, Raux G, Thibaut F, et al. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet. 2002;11:2243-49.
Humberclaude V, Rivier F, Roubertie A, et al. Is hyperprolinemia type I actually a benign trait? Report of a case with severe neurologic involvement and vigabatrin intolerance. J Child Neurol. 2001;16:622-23.
Goodman BK, Rutberg J, Lin WW, et al. Hyperprolinemia in patients with deletion (22)(q11.2) syndrome. J Inherit Metab Dis. 2000;23:847-48.
Shivananda, Christopher R, Kumar P. Type I hyperprolinemia. Indian J Pediatr. 2000;67:541-43.
Oyanagi K, Tsuchiyama A, Itakura Y, et al. Clinical, biochemical and enzymatic studies in type I hyperprolinemia associated with chromosomal activity. Tohoku J Exp Med. 1987;151:465-75.
INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 239500. Last Edit Date: 07/09/2016.
https://www.omim.org/entry/239500 Accessed June 16, 2021.
Prolinemia. Baby’s First Test. https://www.babysfirsttest.org/newborn-screening/conditions/prolinemia Accessed June 16, 2021.
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