Phosphoglycerate Kinase Deficiency: Overview

This assignment delves into the intricacies of Phosphoglycerate Kinase Deficiency, a rare genetic disorder impacting energy production within cells. It comprehensively examines the condition's clinical manifestations, diagnostic procedures, available treatments, and ongoing research efforts aimed at developing more effective therapeutic strategies.

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Overview
Phosphoglycerate kinase deficiency is an inherited metabolic disorder that rarely
occurs in humans, marked by the deficiency of the enzyme phosphoglycerate kinase (PGK).
It is a group of metabolic muscle diseases interfering with the carbohydrate metabolism
within the body, and eventually the production of energy for normal body functioning. The
enzyme is accountable for breaking down of glycogen molecule within the body. PGK is a
valuable enzyme involved in the glycolytic pathway that carries out the catalysis of the
conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate and generation ATP. PGK is
in competition with the enzyme diphosphoglycerate mutase (DPGM) for the substrate 1,3
DPG in the reaction.
The alternative routing of glycolytic intermediates is known as the ‘energy clutch’ of
glycolysis. When glycolysis takes place, the simple sugar molecules are broken down to give
rise to energy in the form of ATP. It is to be noted that the enzyme is ubiquitous as its
expression is found in all tissues with the exception of testes. The deficiency is an inborn
error that is inherited in an X-linked manner. The gene whose mutation leads to this
deficiency is Xq13, present on the X chromosome. Different mutations have been identified
though the factors for clinical manifestations are still unknown (1).
Mutations taking place in the PGK1 gene leads to a reduction of the activity of
phosphoglycerate kinase, thereby disrupting the production of energy. Th ultimate result is
cell death or cell damage. There is little information on the reasons for this abnormality to
preferentially impact brain cells in some people and red blood cells in others. Symptoms of
this disorder include haemolytic anaemia that is lower levels of circulating red blood cells,
the impaired condition of speech and writing, impaired condition of intellectual ability, pain

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and stiffness due to exercise, spleen enlargement and hemiplegia or paralysis of the body on
one side (2).
Research
Present research on phosphoglycerate kinase deficiency is going on across the globe
with a special focus on the invention of a better diagnosis method that would permit early-
stage identification of at-risk individuals. Animal models are being developed that would
help in understanding the disease in a better manner. Development of gene therapies and
enzyme replacement therapies are also on the ist of objectives for further research (3).
Diagnosis
The three primary features of phosphoglycerate kinase deficiency are an intellectual
disability, hemolytic anaemia and muscle problems. A person suffering from this disease
might be affected by more than one of the mentioned characteristics; however, all the three
signs are rare to be present in one individual. It is to be noted that most of the patients
suffering this condition are affected to a moderate level. The disorder is completely expressed
in males only while heterozygous females suffer from mild haemolytic anaemia with no signs
of intellectual disability or myopathy. Myopathy along with muscle plain, cramps and
stiffness are indicated in young male and adolescents. Myoglobinuria is seen in cases of
severe episodes (4). The diagnosis is done based on physical examination, and laboratory
results confirm the same. Biochemical studies involve an indication of low muscle PGK
enzyme activity and low erythrocyte (below 25% and 23% respectively). The differential
diagnosis must include other causative factors for hereditary nonspherocytic hemolytic
anaemia. Molecular prenatal diagnosis is usually done for an index case. Diagnosis of the
disease is possible at birth if enzymatic testing is carried out.

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Treatment
Treatment of PGK deficiency commonly takes into consideration iron supplements
together with blood transfusions depending on the severity of the patient condition. A
splenectomy is an option for patients who have enlargement of the spleen, and this method
has been proved to be effective for some cases. It is very important that an individual avoids
strenuous exercise when there is an indication of muscle breakdown and under such
conditions, special care is required to be taken. The neurologic crisis demands complete rest
so that life-threatening situations do not arise. When there is severe neurological
deterioration, bone marrow transplant is an option (5). Genetic counselling has been indicated
to show some benefits for the patients as well as their families. Other treatment options are
supportive (6).
Policy
The Australian Research Council has constantly been supporting the research on
different significant topics in relation to metabolism, which includes PGK deficiency. As per
the Australian Research Council (ARC) Medical Research Policy funding is being allocated
for future research. This funding is either directly or in collaboration with the National Health
and Medical Research Council (NHMRC). The policy requires research to be done on aspects
of therapeutic approaches and bioengineering, which are essential aspects of PGK deficiency
research (7).

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References
1. Tamai M, Kawano T, Saito R, Sakurai K, Saito Y, Yamada H et al. Phosphoglycerate
kinase deficiency due to a novel mutation (c. 1180A>G) manifesting as chronic hemolytic
anemia in a Japanese boy. International Journal of Hematology. 2014;100(4):393-397.
2. Chiarelli L, Morera S, Bianchi P, Fermo E, Zanella A, Galizzi A et al. Molecular
Insights on Pathogenic Effects of Mutations Causing Phosphoglycerate Kinase Deficiency.
PLoS ONE. 2012;7(2):e32065.
3. Lopez-Manzaneda S, Torres R, Olivier E, Garcia-Torralba A, Sanchez-Dominguez R,
Alberquilla O, Mountford J, Ramirez JC, Bueren JA, Segovia JC. Modelling pyruvate kinase
deficiency in human progenitors using crispr/cas9. Haematologica 2017 Jun 26;102: 446-446.
4. Pey AL, Maggi M, Valentini G. Insights into human phosphoglycerate kinase 1
deficiency as a conformational disease from biochemical, biophysical, and in vitro expression
analyses. Journal of inherited metabolic disease. 2014 Nov 1;37(6):909-16.
5. Garcia-Gomez M, Calabria A, Garcia-Bravo M, Benedicenti F, Kosinski P, López-
Manzaneda S, Hill C, del Mar Mañu-Pereira M, Martín MA, Orman I, Vives-Corrons JL.
Safe and efficient gene therapy for pyruvate kinase deficiency. Molecular Therapy. 2016 Jul
1;24(7):1187-98.
6. Saudubray JM, Baumgartner MR, Walter J, editors. Inborn metabolic diseases:
diagnosis and treatment. Springer; 2016 Nov 10.
7. ARC Medical Research Policy | Australian Research Council [Internet]. Arc.gov.au.
2017 [cited 16 September 2017]. Available from: http://www.arc.gov.au/arc-medical-
research-policy