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Hyperprolinemia

MedGen UID:
75690
Concept ID:
C0268528
Disease or Syndrome
Synonym: Proline hydrogenase deficiency
SNOMED CT: Hyperprolinemia (59655002)
 
HPO: HP:0008358
Monarch Initiative: MONDO:0023419

Definition

An increased concentration of proline in the blood. [from HPO]

Conditions with this feature

Proline dehydrogenase deficiency
MedGen UID:
120645
Concept ID:
C0268529
Disease or Syndrome
Phang et al. (2001) noted that prospective studies of HPI probands identified through newborn screening as well as reports of several families have suggested that it is a metabolic disorder not clearly associated with clinical manifestations. Phang et al. (2001) concluded that HPI is a relatively benign condition in most individuals under most circumstances. However, other reports have suggested that some patients have a severe phenotype with neurologic manifestations, including epilepsy and mental retardation (Jacquet et al., 2003). Genetic Heterogeneity of Hyperprolinemia See also hyperprolinemia type II (HYRPRO2; 239510), which is caused by mutation in the gene encoding pyrroline-5-carboxylate dehydrogenase (P5CDH, ALDH4A1; 606811) on chromosome 1p36.
Schizophrenia 4
MedGen UID:
371517
Concept ID:
C1833247
Disease or Syndrome
A schizophrenia that has material basis in an autosomal dominant mutation of PRODH on chromosome 22q11.21.
Hyperprolinemia type 2
MedGen UID:
419175
Concept ID:
C2931835
Disease or Syndrome
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.\n\nHyperprolinemia 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.\n\nHyperprolinemia 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.\n\nPeople 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.
Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
MedGen UID:
816734
Concept ID:
C3810404
Disease or Syndrome
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills.
Lipoyl transferase 1 deficiency
MedGen UID:
904073
Concept ID:
C4225379
Disease or Syndrome
Lipoyl transferase 1 deficiency is a very rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.
Combined oxidative phosphorylation defect type 21
MedGen UID:
1638633
Concept ID:
C4706316
Disease or Syndrome
Combined oxidative phosphorylation deficiency-21 (COXPD21) is an autosomal recessive disorder characterized either by onset within the first months of life of severe hypotonia, failure to thrive, epilepsy and early death or by onset after 6 months of life with a milder course and longer survival (summary by Zheng et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Mitochondrial complex 1 deficiency, nuclear type 35
MedGen UID:
1745427
Concept ID:
C5436576
Disease or Syndrome
Mitochondrial complex 4 deficiency, nuclear type 3
MedGen UID:
1764816
Concept ID:
C5436682
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 3 (MC4DN3) is an autosomal recessive multisystem metabolic disorder with a highly variable phenotype. Some patients present with encephalomyopathic features in early infancy, whereas others may present later in infancy or the first years of life after normal early development. Affected individuals show hypotonia, failure to thrive, and developmental delay or regression with poor eye contact and loss of motor skills with ataxia. Additional features observed in some patients include proximal renal tubulopathy, macrocytic anemia, sensorineural hearing loss, nystagmus, and hypertrophic cardiomyopathy, consistent with systemic involvement. Brain imaging in most patients shows lesions consistent with Leigh syndrome (see 256000). Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV. Most patients die in infancy (summary by Valnot et al., 2000 and Antonicka et al., 2003). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 20
MedGen UID:
1771040
Concept ID:
C5436726
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 20 (MC4DN20) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and global developmental delay. Additional features include elevated liver enzymes, increased serum lactate, metabolic acidosis, and pulmonary arterial hypertension (PAH), which may result in cardiorespiratory failure and early death. Patient tissues show variably decreased levels and activity of mitochondrial respiratory complex IV (Baertling et al., 2017). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 1 deficiency, nuclear type 36
MedGen UID:
1773965
Concept ID:
C5436935
Disease or Syndrome
Mitochondrial complex I deficiency nuclear type 36 (MC1DN36) is an autosomal recessive metabolic disorder characterized by global developmental delay, hypotonia, and failure to thrive apparent from infancy or early childhood. Affected individuals usually do not acquire ambulation, show progressive spasticity, and have impaired intellectual development with absent speech. More variable features may include pale optic discs, poor eye contact, seizures, and congenital heart defects. Laboratory studies show increased serum lactate; metabolic acidosis may occur during stress or infection. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Patient tissue showed isolated mitochondrial complex I deficiency. Death may occur in childhood (Alahmad et al., 2020). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Mitochondrial complex IV deficiency, nuclear type 22
MedGen UID:
1786100
Concept ID:
C5543491
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 22 (MC4DN22) is an autosomal recessive metabolic disorder characterized by neonatal hypertrophic cardiomyopathy, encephalopathy, and severe lactic acidosis with fatal outcome (Wintjes et al., 2021). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A
MedGen UID:
1841116
Concept ID:
C5830480
Disease or Syndrome
Mitochondrial complex V deficiency nuclear type 4A (MC5DN4A) is an autosomal dominant metabolic disorder characterized by poor feeding and failure to thrive in early infancy. Laboratory studies show increased serum lactate, alanine, and ammonia, suggesting mitochondrial dysfunction. Some affected individuals show spontaneous resolution of these symptoms in early childhood and have subsequent normal growth and development, whereas others show developmental delay with impaired intellectual development and movement abnormalities, including dystonia, ataxia, or spasticity; these neurologic deficits are persistent (Lines et al., 2021, Zech et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, nuclear types, see MC5DN1 (604273).
Combined oxidative phosphorylation deficiency 58
MedGen UID:
1841277
Concept ID:
C5830641
Disease or Syndrome
Combined oxidative phosphorylation deficiency-58 (COXPD58) is an autosomal recessive disorder characterized by a wide range of clinical presentations including neonatal lactic acidosis, epileptic encephalopathy, developmental delay and impaired intellectual development with nonspecific changes on brain MRI, or mitochondrial myopathy with a treatable neuromuscular transmission defect (Van Haute et al., 2023). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Professional guidelines

PubMed

Sun A, Teschner W, Yel L
Expert Rev Clin Immunol 2013 Jun;9(6):577-87. doi: 10.1586/eci.13.39. PMID: 23730887
Guilmatre A, Legallic S, Steel G, Willis A, Di Rosa G, Goldenberg A, Drouin-Garraud V, Guet A, Mignot C, Des Portes V, Valayannopoulos V, Van Maldergem L, Hoffman JD, Izzi C, Espil-Taris C, Orcesi S, Bonafé L, Le Galloudec E, Maurey H, Ioos C, Afenjar A, Blanchet P, Echenne B, Roubertie A, Frebourg T, Valle D, Campion D
Hum Mutat 2010 Aug;31(8):961-5. doi: 10.1002/humu.21296. PMID: 20524212
Kuhara T
J Chromatogr B Analyt Technol Biomed Life Sci 2007 Aug;855(1):42-50. Epub 2007 Mar 31 doi: 10.1016/j.jchromb.2007.03.031. PMID: 17467347

Recent clinical studies

Etiology

Namavar Y, Duineveld DJ, Both GIA, Fiksinski AM, Vorstman JAS, Verhoeven-Duif NM, Zinkstok JR
Am J Med Genet B Neuropsychiatr Genet 2021 Jul;186(5):289-317. Epub 2021 Jul 24 doi: 10.1002/ajmg.b.32869. PMID: 34302426
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
Plecko B
Handb Clin Neurol 2013;113:1811-7. doi: 10.1016/B978-0-444-59565-2.00050-2. PMID: 23622403
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
Jacquet H, Demily C, Houy E, Hecketsweiler B, Bou J, Raux G, Lerond J, Allio G, Haouzir S, Tillaux A, Bellegou C, Fouldrin G, Delamillieure P, Ménard JF, Dollfus S, D'Amato T, Petit M, Thibaut F, Frébourg T, Campion D
Mol Psychiatry 2005 May;10(5):479-85. doi: 10.1038/sj.mp.4001597. PMID: 15494707

Diagnosis

Eltoum A, O'Rourke D, Sharif F
BMJ Case Rep 2022 Jan 17;15(1) doi: 10.1136/bcr-2020-240941. PMID: 35039335Free PMC Article
Priyadharshini Christy J, George Priya Doss C
Front Biosci (Landmark Ed) 2015 Jan 1;20(2):335-76. doi: 10.2741/4313. PMID: 25553455
Plecko B
Handb Clin Neurol 2013;113:1811-7. doi: 10.1016/B978-0-444-59565-2.00050-2. PMID: 23622403
Plecko B, Stöckler S
Can J Neurol Sci 2009 Aug;36 Suppl 2:S73-7. PMID: 19760909
Kuhara T
J Chromatogr B Analyt Technol Biomed Life Sci 2007 Aug;855(1):42-50. Epub 2007 Mar 31 doi: 10.1016/j.jchromb.2007.03.031. PMID: 17467347

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
Sun A, Teschner W, Yel L
Expert Rev Clin Immunol 2013 Jun;9(6):577-87. doi: 10.1586/eci.13.39. PMID: 23730887
Plecko B
Handb Clin Neurol 2013;113:1811-7. doi: 10.1016/B978-0-444-59565-2.00050-2. PMID: 23622403
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

Prognosis

Eltoum A, O'Rourke D, Sharif F
BMJ Case Rep 2022 Jan 17;15(1) doi: 10.1136/bcr-2020-240941. PMID: 35039335Free PMC Article
Priyadharshini Christy J, George Priya Doss C
Front Biosci (Landmark Ed) 2015 Jan 1;20(2):335-76. doi: 10.2741/4313. PMID: 25553455
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
Guilmatre A, Legallic S, Steel G, Willis A, Di Rosa G, Goldenberg A, Drouin-Garraud V, Guet A, Mignot C, Des Portes V, Valayannopoulos V, Van Maldergem L, Hoffman JD, Izzi C, Espil-Taris C, Orcesi S, Bonafé L, Le Galloudec E, Maurey H, Ioos C, Afenjar A, Blanchet P, Echenne B, Roubertie A, Frebourg T, Valle D, Campion D
Hum Mutat 2010 Aug;31(8):961-5. doi: 10.1002/humu.21296. PMID: 20524212

Clinical prediction guides

Namavar Y, Duineveld DJ, Both GIA, Fiksinski AM, Vorstman JAS, Verhoeven-Duif NM, Zinkstok JR
Am J Med Genet B Neuropsychiatr Genet 2021 Jul;186(5):289-317. Epub 2021 Jul 24 doi: 10.1002/ajmg.b.32869. PMID: 34302426
Priyadharshini Christy J, George Priya Doss C
Front Biosci (Landmark Ed) 2015 Jan 1;20(2):335-76. doi: 10.2741/4313. PMID: 25553455
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
Guilmatre A, Legallic S, Steel G, Willis A, Di Rosa G, Goldenberg A, Drouin-Garraud V, Guet A, Mignot C, Des Portes V, Valayannopoulos V, Van Maldergem L, Hoffman JD, Izzi C, Espil-Taris C, Orcesi S, Bonafé L, Le Galloudec E, Maurey H, Ioos C, Afenjar A, Blanchet P, Echenne B, Roubertie A, Frebourg T, Valle D, Campion D
Hum Mutat 2010 Aug;31(8):961-5. doi: 10.1002/humu.21296. PMID: 20524212

Recent systematic reviews

Namavar Y, Duineveld DJ, Both GIA, Fiksinski AM, Vorstman JAS, Verhoeven-Duif NM, Zinkstok JR
Am J Med Genet B Neuropsychiatr Genet 2021 Jul;186(5):289-317. Epub 2021 Jul 24 doi: 10.1002/ajmg.b.32869. PMID: 34302426

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