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Hyperprolinemia type 2(HYRPRO2)

MedGen UID:
419175
Concept ID:
C2931835
Disease or Syndrome
Synonyms: 1-PYRROLINE-5-CARBOXYLATE DEHYDROGENASE DEFICIENCY; Deficiency of pyrroline-5-carboxylate reductase; Delta-1-pyrroline-5-carboxylate dehydrogenase deficiency; Hyperprolinemia, Type II; HYRPRO2
SNOMED CT: Deficiency of pyrroline-5-carboxylate reductase (124177001); Hyperprolinemia type 2 (717181004); Hyperprolinemia type II (717181004); delta'-Pyrroline-5-carboxylate dehydrogenase deficiency (124177001); Pyrroline-5-carboxylate reductase deficiency (124177001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ALDH4A1 (1p36.13)
 
Monarch Initiative: MONDO:0009401
OMIM®: 239510
Orphanet: ORPHA79101

Definition

Hyperprolinemia type II results in proline levels in the blood between 10 and 15 times higher than normal, and high levels of a related compound called pyrroline-5-carboxylate. This form of the disorder is more likely than type I to involve seizures or intellectual disability that vary in severity.

Hyperprolinemia can also occur with other conditions, such as malnutrition or liver disease. In particular, individuals with conditions that cause elevated levels of a chemical called lactic acid in the blood (lactic acidosis) may have hyperprolinemia as well, because lactic acid stops (inhibits) the breakdown of proline.

Hyperprolinemia is an excess of a particular protein building block (amino acid), called proline, in the blood. This condition generally occurs when proline is not broken down properly by the body. There are two forms of hyperprolinemia, called type I and type II.

People with hyperprolinemia type I often do not show any symptoms, although they have proline levels in their blood between 3 and 10 times the normal level. Some individuals with hyperprolinemia type I exhibit seizures, intellectual disability, or other neurological or psychiatric problems. [from MedlinePlus Genetics]

Clinical features

From HPO
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Hydroxyprolinuria
MedGen UID:
215298
Concept ID:
C0948585
Finding
An increased concentration of 4-hydroxy-L-proline in the urine.
Prolinuria
MedGen UID:
1830245
Concept ID:
C5779510
Finding
Level of proline in the urine anove the upper limit of normal.
Elevated urinary pyrroline hydroxycarboxylic acid level
MedGen UID:
1053893
Concept ID:
CN377452
Finding
The amount of pyrroline hydroxycarboxylic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hyperprolinemia
MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
An increased concentration of proline in the blood.
Elevated circulating 1-pyrroline-5-carboxylic acid concentration
MedGen UID:
1053393
Concept ID:
CN377523
Finding
The concentration of delta-1-pyrroline-5-carboxylate in the blood circulation is above the upper limit of normal.
Reduced tissue delta-1-pyrroline-5-carboxylate dehydrogenase activity
MedGen UID:
1054238
Concept ID:
CN377524
Finding
Concentration or activity of delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDH; EC 1.5.1.12) below the lower limit of normal. P5CDH can be measured in multiple tissues including leukocytes and cultured fibroblasts. P5CDH is a mitochondrial matrix NAD(+)-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperprolinemia type 2
Follow this link to review classifications for Hyperprolinemia type 2 in Orphanet.

Professional guidelines

PubMed

Lachman A
J Child Adolesc Ment Health 2014;26(2):109-24. doi: 10.2989/17280583.2014.924416. PMID: 25391710

Recent clinical studies

Etiology

Sager G, Türkyilmaz A, Günbey HP, Taş İ, Ozhelvaci F, Akin Y
Eur J Paediatr Neurol 2023 May;44:51-56. Epub 2023 Apr 28 doi: 10.1016/j.ejpn.2023.04.002. PMID: 37141741
Lachman A
J Child Adolesc Ment Health 2014;26(2):109-24. doi: 10.2989/17280583.2014.924416. PMID: 25391710
Di Rosa G, Nicotera AG, Lenzo P, Spanò M, Tortorella G
Psychiatr Genet 2014 Aug;24(4):172-5. doi: 10.1097/YPG.0000000000000037. PMID: 24842239
Clelland JD, Read LL, Drouet V, Kaon A, Kelly A, Duff KE, Nadrich RH, Rajparia A, Clelland CL
Schizophr Res 2014 Jun;156(1):15-22. Epub 2014 Apr 29 doi: 10.1016/j.schres.2014.03.017. PMID: 24787057Free PMC Article
Clelland CL, Read LL, Baraldi AN, Bart CP, Pappas CA, Panek LJ, Nadrich RH, Clelland JD
Schizophr Res 2011 Sep;131(1-3):139-45. Epub 2011 Jun 8 doi: 10.1016/j.schres.2011.05.006. PMID: 21645996Free PMC Article

Diagnosis

Motte J, Fisse AL, Grüter T, Schneider R, Breuer T, Lücke T, Krueger S, Nguyen HP, Gold R, Ayzenberg I, Ellrichmann G
BMC Neurol 2019 Dec 29;19(1):345. doi: 10.1186/s12883-019-1583-0. PMID: 31884946Free PMC Article
Lachman A
J Child Adolesc Ment Health 2014;26(2):109-24. doi: 10.2989/17280583.2014.924416. PMID: 25391710
Mitsubuchi H, Nakamura K, Matsumoto S, Endo F
Pediatr Int 2014 Aug;56(4):492-6. doi: 10.1111/ped.12420. PMID: 24931297Free PMC Article
van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L, Wevers R, Morava E
J Inherit Metab Dis 2014 May;37(3):383-90. Epub 2013 Oct 31 doi: 10.1007/s10545-013-9660-9. PMID: 24173411
Jang MA, Kim BC, Ki CS, Lee SY, Kim JW, Choi TY, Lee DH, Song J, Lee YW, Park HD
Ann Clin Lab Sci 2013 Winter;43(1):31-6. PMID: 23462603

Therapy

van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L, Wevers R, Morava E
J Inherit Metab Dis 2014 May;37(3):383-90. Epub 2013 Oct 31 doi: 10.1007/s10545-013-9660-9. PMID: 24173411
Clelland CL, Read LL, Baraldi AN, Bart CP, Pappas CA, Panek LJ, Nadrich RH, Clelland JD
Schizophr Res 2011 Sep;131(1-3):139-45. Epub 2011 Jun 8 doi: 10.1016/j.schres.2011.05.006. PMID: 21645996Free PMC Article
Wyse AT, Netto CA
Metab Brain Dis 2011 Sep;26(3):159-72. Epub 2011 Jun 4 doi: 10.1007/s11011-011-9246-x. PMID: 21643764
Ferreira AG, Stefanello FM, Cunha AA, da Cunha MJ, Pereira TC, Bonan CD, Bogo MR, Netto CA, Wyse AT
Metab Brain Dis 2011 Jun;26(2):141-7. Epub 2011 Apr 21 doi: 10.1007/s11011-011-9243-0. PMID: 21509571
Wang HS, Kuo MF
Chang Gung Med J 2007 Sep-Oct;30(5):396-401. PMID: 18062169

Prognosis

Motte J, Fisse AL, Grüter T, Schneider R, Breuer T, Lücke T, Krueger S, Nguyen HP, Gold R, Ayzenberg I, Ellrichmann G
BMC Neurol 2019 Dec 29;19(1):345. doi: 10.1186/s12883-019-1583-0. PMID: 31884946Free PMC Article
Di Rosa G, Nicotera AG, Lenzo P, Spanò M, Tortorella G
Psychiatr Genet 2014 Aug;24(4):172-5. doi: 10.1097/YPG.0000000000000037. PMID: 24842239
van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L, Wevers R, Morava E
J Inherit Metab Dis 2014 May;37(3):383-90. Epub 2013 Oct 31 doi: 10.1007/s10545-013-9660-9. PMID: 24173411

Clinical prediction guides

van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L, Wevers R, Morava E
J Inherit Metab Dis 2014 May;37(3):383-90. Epub 2013 Oct 31 doi: 10.1007/s10545-013-9660-9. PMID: 24173411
Jang MA, Kim BC, Ki CS, Lee SY, Kim JW, Choi TY, Lee DH, Song J, Lee YW, Park HD
Ann Clin Lab Sci 2013 Winter;43(1):31-6. PMID: 23462603
Clelland CL, Read LL, Baraldi AN, Bart CP, Pappas CA, Panek LJ, Nadrich RH, Clelland JD
Schizophr Res 2011 Sep;131(1-3):139-45. Epub 2011 Jun 8 doi: 10.1016/j.schres.2011.05.006. PMID: 21645996Free PMC Article
Ferreira AG, Stefanello FM, Cunha AA, da Cunha MJ, Pereira TC, Bonan CD, Bogo MR, Netto CA, Wyse AT
Metab Brain Dis 2011 Jun;26(2):141-7. Epub 2011 Apr 21 doi: 10.1007/s11011-011-9243-0. PMID: 21509571

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