Ribose-5-phosphate isomerase deficiency

Last updated
Ribose-5-phosphate isomerase deficiency
Other namesRPI deficiency [1]

Ribose-5-phosphate isomerase deficiency (RPID) is a rare human disorder caused by mutations in ribose-5-phosphate isomerase, an enzyme of the pentose phosphate pathway. With only four diagnosed patients over a 27-year period, RPI deficiency is the second rarest disease known as of now, being beaten only by Fields Condition affecting two known individuals, Catherine and Kirstie Fields. [2] [3]

Contents

Mechanism

In the search for an explanation for this rarity, it has been found that the patient has a seldom-seen allelic combination. [2] One allele is a nonfunctional null allele, while the other encodes for a partially active enzyme. Furthermore, the partially functional allele has expression deficits that depend on the cell type in which it is expressed. Therefore, some of the patient's cells have a considerable amount of RPI activity, whereas others do not.[ citation needed ]

The molecular cause of the pathology is not fully understood. One hypothesis is that ribose-5-phosphate may be insufficient for RNA synthesis. Another possibility is that the accumulation of D-ribitol and D-arabitol may be toxic. [4] However, Klussman et al. [5] evaluated the toxicity of polyols on a rat neurochip model and concluded that the accumulation of polyols has likely only a secondary effect on brain dysfunction, if any at all.

In rat prefrontal cortex, mitochondrial superoxide production was elevated with the addition of ribitol, but not with arabitol. Furthermore, the activity of three antioxidant enzymes was increased under the influence of ribitol, while arabitol showed no such effect. Neither polyol had any impact on the glutathione content in the rat prefrontal cortex. Additionally, neither polyol influenced the oxidation levels of proteins or lipids. [6]

Paradoxically, downregulation of ribose-5-phosphate isomerase in Drosophila melanogaster leads to a fitter phenotype: enhanced tolerance to oxidative stress and extended lifespan. [7] Artificial downregulation of RPI has been therefore suggested as a treatment against disease caused by polyglutamine neutroxicity (such as Huntington's disease) but also to counteract normal ageing.

Diagnosis

Symptoms include optic atrophy, nystagmus, cerebellar ataxia, seizures, spasticity, psychomotor retardation, leukoencephalopathy and global developmental delay. [8]

RPI can be diagnosed by gene sequencing or increased polyol levels in blood or urine. Patients also present highly elevated polyols in the brain, which can be revealed by proton magnetic resonance spectroscopy.

Treatment

There are no current treatment or prognosis for ribose-5-phosphate isomerase deficiency.

History

The first patient was a male born in 1984 to healthy, unrelated parents. [9] Early in life, the patient had psychomotor retardation and developed epilepsy at age 4. From age 7, a slow neurological regression occurred with prominent cerebellar ataxis, some spasticity, optic atrophy, and a mild sensorimotor neuropathy with no observed organomegaly dysfunction of internal organs. MRI scans at age 11 and 14 revealed extensive abnormalities of the cerebral white matter and elevated levels of D-ribitol and D-arabitol. [9]

In 1999 van der Knaap and colleagues [10] [4] reviewed this case of the then 14-year-old boy and characterised the associated symptoms of RPI deficiency as the following: developmental delay, insidious psychomotor regression, epilepsy, leukoencephalopathy and abnormal polyol metabolism. Later, Naik and colleagues [11] reported a second case, an 18-year-old man with seizures, psychomotor regression and diffuse white matter abnormality. A third case was reported in 2018 by Sklower Brooks and colleagues, a child with neonatal onset leukoencephalopathy and psychomotor delays. [12] A fourth case was reported in 2019 by Kaur and colleagues [13] with progressive leukoencephalopathy and elevated urine polyols arabitol and ribitol.

Related Research Articles

A rare disease is a disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financial incentives from governments or other agencies. Orphan drugs are medications targeting orphan diseases.

In biochemistry, isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:

<span class="mw-page-title-main">Pentose phosphate pathway</span> Series of interconnected biochemical reactions

The pentose phosphate pathway is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by Bernard Horecker and co-workers.

<span class="mw-page-title-main">Ribulose</span> Monosaccharide with five carbon atoms and a ketone functional group

Ribulose is a ketopentose — a monosaccharide containing five carbon atoms, and including a ketone functional group. It has chemical formula C5H10O5. Two enantiomers are possible, d-ribulose and l-ribulose. d-Ribulose is the diastereomer of d-xylulose.

<span class="mw-page-title-main">Glucose-6-phosphate isomerase</span> Mammalian protein found in Homo sapiens

Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia, and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

<span class="mw-page-title-main">Transketolase</span> Enzyme involved in metabolic pathways

Transketolase is an enzyme that, in humans, is encoded by the TKT gene. It participates in both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. Transketolase catalyzes two important reactions, which operate in opposite directions in these two pathways. In the first reaction of the non-oxidative pentose phosphate pathway, the cofactor thiamine diphosphate accepts a 2-carbon fragment from a 5-carbon ketose (D-xylulose-5-P), then transfers this fragment to a 5-carbon aldose (D-ribose-5-P) to form a 7-carbon ketose (sedoheptulose-7-P). The abstraction of two carbons from D-xylulose-5-P yields the 3-carbon aldose glyceraldehyde-3-P. In the Calvin cycle, transketolase catalyzes the reverse reaction, the conversion of sedoheptulose-7-P and glyceraldehyde-3-P to pentoses, the aldose D-ribose-5-P and the ketose D-xylulose-5-P.

<span class="mw-page-title-main">2-Hydroxyglutaric aciduria</span> Medical condition

2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.

<span class="mw-page-title-main">Triosephosphate isomerase deficiency</span> Medical condition

Triosephosphate isomerase deficiency is a rare autosomal recessive metabolic disorder which was initially described in 1965.

<span class="mw-page-title-main">Ribulose 5-phosphate</span> Chemical compound

Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.

<span class="mw-page-title-main">Transaldolase</span> Enzyme family

Transaldolase is an enzyme of the non-oxidative phase of the pentose phosphate pathway. In humans, transaldolase is encoded by the TALDO1 gene.

<span class="mw-page-title-main">Ribose 5-phosphate</span> Chemical compound

Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate.

<span class="mw-page-title-main">Erythrose 4-phosphate</span> Chemical compound

Erythrose 4-phosphate is a phosphate of the simple sugar erythrose. It is an intermediate in the pentose phosphate pathway and the Calvin cycle.

<span class="mw-page-title-main">6-phosphogluconolactonase</span> Cytosolic enzyme

6-Phosphogluconolactonase (EC 3.1.1.31, 6PGL, PGLS, systematic name 6-phospho-D-glucono-1,5-lactone lactonohydrolase) is a cytosolic enzyme found in all organisms that catalyzes the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconic acid in the oxidative phase of the pentose phosphate pathway:

<span class="mw-page-title-main">Ribose-5-phosphate isomerase</span>

Ribose-5-phosphate isomerase (Rpi) encoded by the RPIA gene is an enzyme that catalyzes the conversion between ribose-5-phosphate (R5P) and ribulose-5-phosphate (Ru5P). It is a member of a larger class of isomerases which catalyze the interconversion of chemical isomers. It plays a vital role in biochemical metabolism in both the pentose phosphate pathway and the Calvin cycle. The systematic name of this enzyme class is D-ribose-5-phosphate aldose-ketose-isomerase.

<span class="mw-page-title-main">MLC1</span> Protein-coding gene in the species Homo sapiens

Membrane protein MLC1 is a protein that in humans is encoded by the MLC1 gene.

<span class="mw-page-title-main">D2HGDH</span> Protein-coding gene in the species Homo sapiens

D-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the D2HGDH gene.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

<span class="mw-page-title-main">Transaldolase deficiency</span> Medical condition

Transaldolase deficiency is a disease characterised by abnormally low levels of the transaldolase enzyme. It is a metabolic enzyme involved in the pentose phosphate pathway. It is caused by mutation in the transaldolase gene (TALDO1). It was first described by Verhoeven et al. in 2001.

Megalencephalic leukoencephalopathy with subcortical cysts is a form of hereditary CNS demyelinating disease. It belongs to a group of disorders called leukodystrophies. It is characterized by early-onset enlargement of the head (macrocephaly) as well as delayed-onset neurological deterioration to include spasticity, epilepsy, and lack of muscular coordination. MLC does not appear to be a disease that is fatal at birth or early in life despite its symptoms, although the number of patients throughout history known to have the disease is fairly limited.

<span class="mw-page-title-main">Transaldolase 1</span> Protein-coding gene in the species Homo sapiens

Transaldolase 1 is a protein that in humans is encoded by the TALDO1 gene.

References

  1. ↑ "OMIM Entry - # 608611 - Ribose 5-Phosphate Isomerase Deficiency". omim.org. Retrieved 16 March 2019.
  2. ↑ Dalling, Robert (2017-02-10). "These twins are 'trapped' in their living room as work plans stall". WalesOnline. Retrieved 2021-07-31.
  3. 1 2 Huck JH, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS (April 2004). "Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics. 74 (4): 745–51. doi:10.1086/383204. PMC   1181951 . PMID   14988808.
  4. ↑ Klusmann, A.; Fleischer, W.; Waldhaus, A.; Siebler, M.; Mayatepek, E. (December 2005). "Influence of D ‐arabitol and ribitol on neuronal network activity". Journal of Inherited Metabolic Disease. 28 (6): 1181–1183. doi:10.1007/s10545-005-0073-2. ISSN   0141-8955.
  5. ↑ Stone, V.; Kudo, K.Y.; August, P.M.; Marcelino, T.B.; Matté, C. (October 2014). "Polyols accumulated in ribose‐5‐phosphate isomerase deficiency increase mitochondrial superoxide production and improve antioxidant defenses in rats' prefrontal cortex". International Journal of Developmental Neuroscience. 37 (1): 21–25. doi:10.1016/j.ijdevneu.2014.06.009. ISSN   0736-5748.
  6. ↑ Wang, Ching‐Tzu; Chen, Yi‐Chun; Wang, Yi‐Yun; Huang, Ming‐Hao; Yen, Tzu‐Li; Li, Hsun; Liang, Cyong‐Jhih; Sang, Tzu‐Kang; Ciou, Shih‐Ci; Yuh, Chiou‐Hwa; Wang, Chao‐Yung; Brummel, Theodore J.; Wang, Horng‐Dar (February 2012). "Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila". Aging Cell. 11 (1): 93–103. doi:10.1111/j.1474-9726.2011.00762.x. ISSN   1474-9718. PMC   3257417 . PMID   22040003.
  7. ↑ "Ribose 5-Phosphate Isomerase Deficiency disease: Malacards - Research Articles, Drugs, Genes, Clinical Trials". www.malacards.org. Retrieved 2018-03-05.
  8. 1 2 Huck, Jojanneke H. J.; Verhoeven, Nanda M.; Struys, Eduard A.; Salomons, Gajja S.; Jakobs, Cornelis; van der Knaap, Marjo S. (April 2004). "Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy". American Journal of Human Genetics. 74 (4): 745–751. doi:10.1086/383204. ISSN   0002-9297. PMC   1181951 . PMID   14988808.
  9. ↑ van der Knaap MS, Wevers RA, Struys EA, Verhoeven NM, Pouwels PJ, Engelke UF, Feikema W, Valk J, Jakobs C (December 1999). "Leukoencephalopathy associated with a disturbance in the metabolism of polyols". Annals of Neurology. 46 (6): 925–8. doi:10.1002/1531-8249(199912)46:6<925::aid-ana18>3.0.co;2-j. PMID   10589548. S2CID   43743595.
  10. ↑ Naik N, Shah A, Wamelink MC, van der Knaap MS, Hingwala D (September 2017). "Rare case of ribose 5 phosphate isomerase deficiency with slowly progressive leukoencephalopathy". Neurology. 89 (11): 1195–1196. doi:10.1212/WNL.0000000000004361. PMID   28801340. S2CID   9554949.
  11. ↑ Brooks SS, Anderson S, Bhise V, Botti C (October 2018). "Further Delineation of Ribose-5-phosphate Isomerase Deficiency: Report of a Third Case". Journal of Child Neurology. 33 (12): 784–787. doi:10.1177/0883073818789316. PMID   30088433. S2CID   51936427.
  12. ↑ Kaur, Parneet; Wamelink, Mirjam M.C.; Van Der Knaap, Marjo S.; Girisha, Katta Mohan; Shukla, Anju (2019-08-01). "Confirmation of a Rare Genetic Leukoencephalopathy due to a Novel Bi-allelic Variant in RPIA". European Journal of Medical Genetics. 62 (8): 103708. doi:10.1016/j.ejmg.2019.103708. ISSN   1769-7212. PMID   31247379. S2CID   195760193.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.