Introduction

Pyruvate Kinase Deficiency (PKD) is the most common enzyme-related glycolytic defect that results in red blood cell haemolysis. This process results in premature cell death when erythrocytes reach the spleen. The study of PKD`s epidemiology is crucial due to its clinical heterogeneity, which leads to varying degrees of haemolysis among affected individuals. Understanding demographic factors influencing this condition can help improve diagnosis and treatment strategies.

This article will explore various epidemiological aspects of PKD, including:

• genetic predisposition
• prevalence
• demographic factors

Epidemiological aspects of PKD

PKD is classified as a rare genetic disorder, and it is caused by homozygous or compound heterozygous mutations in the PKLR gene. Its estimated prevalence in Western populations is 3.2-8.5 individuals per million.¹ Furthermore, over 350 variants in the PKLR gene have been reported, with most being missense substitutions,¹ alterations that cause a single amino acid in the protein.²

A study involving 362 patients found that the most frequently observed amino acid variant was p.Arg510Gln, both overall and in Northern and Central Europe and North America. However, this variant was absent in Asia, where the p.Glu241Ter mutation was the most prevalent.¹ These findings confirm that mutation frequencies vary significantly across different geographical regions. The challenge in accurately determining prevalence rates is exacerbated by underdiagnosed cases due to mild symptoms and misdiagnosis.³ PKD is typically diagnosed during infancy or childhood, although symptom severity varies, and as mentioned earlier, milder forms may go undiagnosed until adulthood, of which many individuals with mild PKD may never be diagnosed.⁴

A systematic literature review was conducted to assess the prevalence of PKD.⁵ After screening 1,390 references, 34 studies were deemed relevant, with four considered high-quality for prevalence estimation. Two studies, based on known population sizes, estimated diagnosed PK deficiency prevalence at 3.2 and 8.5 per million, while another study estimated 6.5 per million by screening jaundiced newborns.⁵ A final study, using mutant allele frequencies, suggested the total prevalence (diagnosed and undiagnosed) could reach 51 per million. These findings indicate that clinically diagnosed PK deficiency in Western populations likely ranges from 3.2 to 8.5 per million, with potential underdiagnosis leading to higher true prevalence.⁵

To address these challenges, an international panel of experts has developed standardised diagnostic and management guidelines, which aim to improve early detection and optimise treatment strategies, agreeing on recommendations across diagnostics, therapies, special populations among other topics, this will allow to facilitate the best practices.⁶

There is no strong evidence to suggest gender-based differences in PKD prevalence. However, genetic factors play a significant role in its occurrence within certain communities. For instance, specific mutations have been found characteristic of Pennsylvania Amish and Romani communities³ could be explained by the high consanguinity (relationship between individuals who are related by blood) in the population, contributing to increased disease frequency.⁷ PKD case clusters have also been found in Brasil, where genetic mutations of PKD were analysed in ten Brasilian patients, identifying ten PKLR gene variants, including three novel ones. Screening of a non-affected population found a 0.1% allele frequency for one common variant, while another was absent.⁸

Moreover, in Tunisia a study analysing 253 patients with unexplained haemolytic anaemia identified six PKLR mutations, including four novel variants.⁹ Genotype-phenotype correlations for the new missense mutations were explored using three-dimensional structure analysis. The findings provided valuable insights into PK deficiency in Tunisia and highlight the need for neonatal screening to identify affected individuals early for proper medical follow-up.⁹

A retrospective analysis of cross‐sectional data from two separate data sources, attempting to estimate the lifetime prevalence of select conditions based on reported medical history showed that patients with PK deficiency that had never been blood transfused had higher rates of select comorbidities, including osteoporosis, pulmonary hypertension and liver cirrhosis, compared to individuals without PK deficiency¹⁰; however, more research is required, in different populations, and the impact of transfusion frequency or spleen removal (splenectomy) on the prevalence of these comorbidities.

To bridge the knowledge gaps in PKD epidemiology, the Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry was established as a global observational study. The Peak Registry consists of an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency, and the aim is to enroll up to 500 participants across 20 countries over 7 years, and between 2 and 9 years.¹¹ The Peak Registry will provide data to improve the understanding of PK, including key epidemiological factors such as geographical distribution as well as a longitudinal follow-up to improve the understanding and care for patients in the future.

Summary

This review highlights the key epidemiological aspects of pyruvate kinase deficiency (PKD), emphasising its rarity, genetic diversity, and the challenge of underdiagnosis. While PKD affects individuals worldwide, genetic variations differ across populations, with certain communities showing a higher prevalence due to inherited mutations. The condition often remains undiagnosed, particularly in mild cases, which complicates accurate prevalence estimates.

Future research should focus on identifying undiagnosed cases, understanding the long-term impact of treatments such as blood transfusions and splenectomy, and exploring genetic variations to develop more targeted therapies. Additionally, the association between PKD and other health conditions requires further investigation in order to improve patient care.

Continued surveillance, global collaboration, and patient registries are essential for advancing PKD research and improving diagnosis and treatment. Initiatives like the Pyruvate Kinase Deficiency Global Longitudinal (PEAK) Registry provide valuable data that can enhance disease management and patient outcomes. Greater awareness and genetic screening will help ensure earlier detection and better support for individuals living with PKD.