ERRORS OF THE PROLINE AND SERINE METABOLISM

HYPERPROLINAEMIA

• Hyperprolinaemia is inherited as an autosomal recessive pattern.

• There are two forms of hyperprolinaemia: I and II.

• Type I is an inherited deficiency of the first enzyme in the proline catabolic pathway, known as proline oxidase enzyme .

• Type II is an inherited deficiency of a second enzyme in the proline catabolic pathway named P5C dehydrogenase.

• Mutations in the ALDH4A1 (located chromosome 1p36) and PRODH (located on chromosome 22q11) genes cause hyperprolinaemia.

PRODH: TYPE I HYPERPROLINAEMIA• PRODH encodes the proline oxidase (POX) enzyme located in the inner-mitochondrial

membrane that has a role in the proline degradation pathway.

• 16 PRODH missense mutations have been linked to type I hyperprolinaemia; the alleles affected influences the severity of the disorder.

• Mild hyperprolinaemia (<30% reduction in POX activity): R185Q, L289M, A455S and A472T.

• Moderate hyperprolinaemia (30-70% reduction in POX activity): Q19P, R185W, A167V, V427M, D426N and R431H.

• Severe hyperprolinaemia (>70% reduction in POX activity): P406L, T466M, L441P, R453C and Q521E.

• Studies are looking to see if there is a relation between PRODH genotype and POX activity to plasma proline levels.

• Patients with hyperprolinaemia I have been found to have;

• Homozygous for a deletion (removing the entire PRODH gene): proline of 2,246μM.

• Homozygous for most severe missense mutation (L441P): proline of 1,255μM and 800μM.

• Compound heterozygote with PRODH deletion and missense allele: proline of 538μM.

• Studies have shown an association between variations in the PRODH gene and psychiatric disorders such as schizophrenia while others have found no significant association.

• Jacquet et al (2004) found hyperprolinaemia to be a significant risk factor for developing a schizoaffective disorder.

ALDH4A1: TYPE II HYPERPROLINAEMIA • ALDH4A1 encodes the pyrroline-5-carboxylate dehydrogenase (P5DCh) enzyme that is

located in the mitochondrial matrix and is NAD dependent.

• P5DCh is involved in the proline degradation pathway (the second step).

• Four mutant alleles have been identified causing this type II hyperprolinaemia:

• 1 base pair deletion at nucleotide 21

• 1 base pair insertion of thymine following nucleotide 1563 – frameshift

• Missense mutation (S352L)

• Missense mutation (P16L)

CONGENITAL MICROCEPHALY• Congenital Microcephaly is a common disorder that is displayed in patients who express the inborn error of serine metabolism, 3-

phosphoglycerate dehydrogenase (3-PGDH).

• Deficiency of 3-PGDH, which catalyses the first step in the biosynthetic pathway of serine, can give rise to congenital microcephaly.

• The gene PHGDH is located on chromosome 1q12.

• As of 2009 only two missense mutations have been identified that cause 3-PGDH deficiency; pV425M and V490M.

• However Tabatabaie et al (2009) describes 5 mutations found in individuals with the enzyme deficiency;

• One frameshift mutation (p.G238fsX)

• Four missense mutations (p.R135W, p.V261M, p.A373T and p.G377S)

• It was found that the missense mutations

associated with this enzyme deficiency either

effects substrate binding or causes low residual

enzyme activity.

The N-methyl-D-aspartate (NMDA) is a glutamate receptor that is involved in the development of the nervous system, in brain plasticity and in neurodegeneration.

5,10-methylenetetrahydrofolate

SERINE DEFICIENCY• Serine deficiencies are a series of inborn metabolic errors that affect the synthesis of this

amino acid

• Serine deficiency could happen due to a defect in any of the three enzymes involved in its synthesis. The most frequent defect is 3-phosphoglycerate dehydrogenase (PHGDH) deficiency that is also the most serious

EXAMPLES OF INBORN ERRORSCongenital microcephaly is an example of a serine deficient metabolic error. This is where a delay in the psychomotor development can be displayed in the first few months of life, followed by refractory seizures, cataracts, spastic tetraparesis (weakness of all four limbs) and nystagmus (rapid involuntary movements of the eyes) in some patients.

PROLINE METABOLISM• Proline concentration is directly related to the balance of enzymatic activities of proline

dehydrogenase and Delta-1-pyrroline-5-carboxylate (P5C) reductase

• P5C plays a pivotal role in maintaining the concentration of proline in body fluids and inborn errors of P5C metabolism lead to the disturbance of proline metabolism

PROLINE DEHYDROGENASE DEFICIENCY• Proline Dehydrogenase Deficiency is the cause of hyperprolinemia 1 (HPA1)

• HPA1 sufferers often have no symptoms but have 3-10 times the normal proline levels in their blood

• Some individuals exhibit seizures, intellectual disability or other neurological disorders or psychiatric problems

DELTA-1-PYRROLINE-5-CARBOXYLATE (P5C) DEFICIENCY• Proline levels in the blood are usually 10-15 times higher than normal

• More likely than type 1 to involve seizures or intellectual disability

• Hyperprolinemia can also occur with other conditions such as malnutrition or liver disease

PROLINE HYPERPROLINEMA TYPE 1 - DIAGNOSIS

• This rare disorder is asymptomatic and therefore not often tested for

• Recent work has suggested that it can be associated with a subset of schizophrenic patients, also patients with mental retardation and other neurological problems

• Expectant 3-10 times the normal level of proline in the blood

TESTING• P5-C is not present therefore direct amino acid analysis can not be done

• Direct enzyme assay is also not possible

• High proline levels can be detected as a non specific test

• Mutation analysis

HYPERPROLINEMIA TYPE 2 - DIAGNOSIS• Relatively benign

• Likely disposition to recurrent seizures (B6 antagonist)

• A high level of lactic acid may be indicative of Hyperprolinemia type 2

• Expectant 10-15 times the normal level of proline in the blood

TESTING• Testing for a presence of P5-C because a deficiency in pyrroline-5-carboxylate

dehydrogenase does not convert the P5-C into glutamate

• Several specific assays will quantify the activity of the reaction of P5-C to ortho-aminobenzaldehyde

• P5-C-dehydrogenase activity can be measured in skin fibroblasts

TREATMENT FOR PROLINE DISORDERS OF METABOLISM• Most treatments are applied to the symptoms

• In cases where psychiatric disorders are linked certain medicines may obscure a true serum proline level (such as valproic acid)

NEW STUDY • One trial in the USA is beginning soon to look at therapeutic vitamin D supplements in

hyperprolinemia-associated schizophrenia

• The study hopes to have been completed by august 2017

More details : http://clinicaltrials.gov/ct2/show/NCT02197286?term=%22hyperprolinemia%22&rank=1

SERINE3-PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY - DIAGNOSIS

• Where microcephaly; impaired development of physical reactions, movement and speech; and recurrent seizures occur, this deficiency may be tested for

THE TEST• Plasma amino acids must be measured in the fasting state

• In CSF, serine is always decreased

• Diagnosis is confirmed when activity of 3-phosphoglycerate dehydrogenase is deficient

• Prenatal diagnosis is only possible with mutation analysis

TREATMENT FOR SERINE DISORDER OF METABOLISM• Currently treated with L-serine and frequently paired with glycine

• Results can be variable

• In cases of linked epilepsy, anti-epileptic drugs may be administered

REFERENCES Bender, H.U., Almashanu, S., Steel, G., Hu, C.A., Lin, W.W., Willis, A., Pulver, A. and Valle, D. (2005) Functional

Consequences of PRODH Missense Mutation. The American Journal of Human Genetics. 76:3, pp.409-20.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196393/

Coskun, T., Aydin, H.I., Kilic, M., Dursun, A., Haliloglu, G., Topaloglu, H., Karli-Oguz, K. And de Koning, T.J. (2009) 3-phosphoglycerate dehydrogenase deficiency: a case report of a treatable cause for seizures. The Turkish Journal of Paediatrics. 51:6, pp.587-92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20196394

De Rosa, G., Pustorino, G., Spano, M., Campion, D., Calabro, M., Aguennouz, M., Caccamo, D., Legallic, S., Sgro, D.L., Bonsignore, M. and Tortorella, G. (2008) Type I hyperprolinemia and proline dehydrogenase (PRODH) mutations in four Italian children with epilepsy and mental retardation. Psychiatric Genetics. 18:1, pp.40-2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18197084

De Koning, T.J., Duran, M., Dorland, L., Gooskens, R., Van Schaftingen, E., Jaeken, J., Blau, N., Berger, R. and Poll-The, B.T. (1998) Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency. Annals of Neurology. 44:2, pp.261-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9708551

Geraghty, M.T., Vaughn, D., Nicholson, A.J., Lin, W.W., Jimenez-Sanchez, G., Obie, C., Flynn, P., Valle, D. and Hu, C.A. (1998) Mutations in the Δ1-Pyrroline 5-Carboxylate Dehydrogenase Gene Cause Type II Hyperprolinemia. Human Molecular Genetics. 7:9, pp.1411-15. Available from: http://hmg.oxfordjournals.org/content/7/9/1411

Jacquet, H., Raux, G., Thibaut, F., Hecketsweiler, B., Huoy, E., Demilly, C., Haouzir, S., Allio, G., Fouldrin, G., Drouin, V., Bou, J., Petit, M., Campion, D. and Frebourg, T. (2002) PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Human Molecular Genetics. 11:19, pp.2243-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12217952/

Jacquet, H., Berthelot, J., Bonnemains, C., Simard, G., Saugier-Veber, P., Raux. G., Campion, D., Bonneaux, D. and Frebourg, T. (2003) The severe form of type I hyperprolinaemia results from homozygous inactivation of the PRODH gene. Journal of Medical Genetics. 40:1, e7.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/12525555

Jacquet, H., Demily, C., Huoy, E., Hecketsweiler, B., Bou, J., Raux, G., Lerond, J., Allio, G., Haouzir, S., Tillaux, A., Bellegou, C., Fouldrin, G., Dellamillieure, P., Menard, J.F., Dollfus, F., D’Amato, T., Petit, M., Thibaut, F., Frebourg, T. and Campion, D. (2004) Hyperprolinemia is a risk factor for schizoaffective disorder. Molecular Psychiatry. 10:5, pp.479-85. DOI: 10.1038/sj.mp.4001597

Jaeken, J. (2009) 3-Phosphoglycerate Dehydrogenase Deficiency. Encyclopedia of Molecular Mechanisms of Disease. Pp.1638-39.

DOI: 10.1007/978-3-540-29676-8_1610

Mitsubuchi, H., Nakamura, K., Matsumoto, S. and Endo, F. (2014) Biochemical and clinical features of hereditary hyperprolinemia. Pediatrics International. 56:4, pp.492–496. DOI: 10.1111/ped.12420

Tabatabaie, L., de Koning, T.J., Geboers, A.J., van den Berg., I.E., Berger, R. and Klomp, L.W. (2009) Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Human Mutations. 30:5, pp.749-56.

Available from: http://www.ncbi.nlm.nih.gov/pubmed/19235232

Genetics Home Reference, 2014. Hyperprolinemia. [Online] Available at: http://ghr.nlm.nih.gov/condition/hyperprolinemia[Accessed 27 October 2007].

Hospital Maternoinfantil, 2012. Serine Deficiency. [Online] Available at: http://www.guiametabolica.org/sites/default/files/Triptico_DefSerina_EN_0.pdf[Accessed 2012].

Koning, T. J., 2006. Treatment with amino acids in serine deficiency disorders. Journal of Inherited Metabolic Disease, 3(2), pp. 347-351.

Koning, T. & Jaeken, J., 1999. Continuing education in neurometabolic disorders--serine deficiency disorders.. Neuropediatrics, 1(30), pp. 1-4.

Malaria Parasite Metabolic Pathways, 2014. Glycine and Serine Metabolism. [Online] Available at: http://mpmp.huji.ac.il/maps/glycineSerinemetpath.html

[Accessed 29 September 2014].

Mitsubuchi, H., Nakamura, K., Matsumoto, S. & Endo, F., 2008. Inborn Errors of Proline Metabolism. The Journal of Nutrition, pp. 855-860.

Clelland, C. & Katz, R., ~2012. Novel methods for the diagnosis and treatment of hyperprolinemia-related mental disorders including Schizophrenia. [Online] Available at: http://innovation.columbia.edu/technologies/cu12071_novel-methods-for-the-diagnosis-and-treatment-of-hyperprolinemia-related-mental-disorders-including-schizophrenia[Accessed 1 10 2015].