What Is Hyperprolinemia Type I?

Introduction to hyperprolinemia type 1

Definition and Overview

Hyperprolinemia Type I arises due to an insufficiency of proline oxidase (POX), alternatively referred to as proline dehydrogenase (PRODH). The genetic blueprint for POX, coded by the PRODH gene, is situated on chromosome 22. Notably, this chromosomal locus experiences deletion in a congenital malformation syndrome recognized as velo-cardio-facial syndrome. 

The exact prevalence of hyperprolinemia type 1 is not well-established due to its rarity, but the disorder has been reported in various populations. Early diagnosis and appropriate management are crucial to prevent or mitigate the potential cognitive and neurological effects associated with proline accumulation.¹

Genetic basis

Hyperprolinemia Type 1 is primarily caused by genetic mutations affecting the PRODH gene located on chromosome 22. This gene encodes the enzyme proline oxidase (POX) or proline dehydrogenase (PRODH), which is crucial for the breakdown of proline, an amino acid involved in various physiological processes. The PRODH gene mutations result in reduced or absent activity of the POX enzyme, leading to the accumulation of proline in the bloodstream and tissues. This accumulation can have detrimental effects on brain function, contributing to the cognitive and neurological symptoms observed in individuals with Hyperprolinemia Type 1.²

Biochemical mechanisms

Role of proline in metabolism

Prolidase-catalyzed reactions yield proline as a product, impacting the functioning of transcription factors. Notably, proline was identified as a modulator hindering the hydroxylation of specific proline residues within the oxygen-dependent degradation (ODD) domain of HIF-1α. This obstruction prevents the ubiquitination and subsequent proteasomal degradation of HIF-1α. Intriguingly, RKO cells employing proline via proline oxidase (POX) display diminished HIF-1α expression due to proline's influence. Conversely, fibroblasts, characterized by low POX expression, exhibit elevated HIF-1α levels. Notably, the elevation of HIF-1α in fibroblasts seems unrelated to the metabolites of proline. This induction occurs in the absence of glutamine (Gln), which is converted to glutamate (Glu) and α-ketoglutarate (α-KG) in fibroblasts. Deprivation of Gln precipitates a reduction in α-KG levels, rendering cells more responsive to proline's stabilizing effect on HIF-1α. Given that proline upregulates the HIF-1α transcription factor responsible for activating pro-survival genes, the augmented degradation of proline by POX might contribute to a pro-apoptotic cellular phenotype.³

Enzymatic dysfunction in hyperprolinemia type 1

Hyperprolinemia Type 1 stems from a critical enzymatic dysfunction involving the proline oxidase (POX) or proline dehydrogenase (PRODH) enzyme. PRODH, encoded by the PRODH gene located on chromosome 22, is responsible for the conversion of proline into pyrroline-5-carboxylate, a crucial step in proline catabolism. In individuals with Hyperprolinemia Type 1, mutations in the PRODH gene lead to reduced or absent PRODH activity, resulting in the accumulation of proline in various tissues and biological fluids. This disruption in the proline catabolic pathway directly contributes to the elevated proline levels observed in affected individuals. The inability to effectively break down proline disrupts its equilibrium, impacting various metabolic processes and potentially leading to the observed cognitive and neurological symptoms. The exact mechanisms by which proline accumulation contributes to these effects are not fully elucidated, but studies have indicated its influence on signalling pathways and protein modifications.

Accumulation of proline and its consequences

The consequences of proline accumulation in Hyperprolinemia Type 1 can have significant impacts on physiological processes, particularly in the central nervous system. The elevated proline levels are proposed to disrupt cellular homeostasis and potentially interfere with signalling pathways, resulting in cognitive and neurological symptoms observed in affected individuals. One notable consequence is the possible interference with the oxygen-dependent degradation (ODD) domain of hypoxia-inducible factor-1α (HIF-1α). Proline's inhibitory effect on the hydroxylation of specific proline residues within this domain can lead to the stabilization of HIF-1α, a transcription factor involved in cellular responses to hypoxia. This stabilization can subsequently induce the expression of pro-survival genes, which might contribute to the observed pro-apoptotic phenotype of cells.⁴

Clinical presentation

Symptoms and early signs

Hyperprolinemia Type 1 is characterized by a spectrum of symptoms that can exhibit varying degrees of severity among individuals affected. The early signs of Hyperprolinemia Type 1 often manifest during infancy or childhood.

• Hypotonia: Reduced muscle tone (hypotonia) can contribute to motor difficulties and delayed developmental milestones.
• Gastrointestinal Symptoms: Some individuals may experience gastrointestinal issues such as vomiting and feeding difficulties.
• Facial Features: While not universally present, certain facial features like a broad nasal bridge and a flat midface have been reported in individuals with Hyperprolinemia Type 1.
• Hyperprolinuria: Elevated proline levels can lead to hyperprolinuria, where excessive proline is excreted in the urine. Hyperprolinuria can sometimes be an early indication of the disorder.

Neurological and cognitive impact

Individuals with Hyperprolinemia Type 1 may exhibit neurological deficits such as intellectual disabilities, developmental delays, and speech impairments. These cognitive and motor delays can significantly impact overall functioning. Seizures, particularly absence seizures, have been reported in some individuals with Hyperprolinemia Type 1. The frequency and intensity of these seizures can differ. Behavioural abnormalities, including attention deficits, hyperactivity, and autistic-like behaviours, may be present in affected individuals.

Variability in severity

The variability in severity is thought to be influenced by several factors, including the degree of enzyme deficiency, the accumulation of toxic metabolites, and the interactions with other genetic and environmental factors. Genetic modifiers, epigenetic changes, and individual differences in metabolic pathways may contribute to the differences in symptom expression among affected individuals.⁵

Diagnosis

Newborn screening

Newborn screening is a vital public health initiative aimed at identifying certain congenital conditions in newborns shortly after birth. Hyperprolinemia type 1 is one of the disorders that can be included in newborn screening programs due to its potential impact on an infant's health. However, the inclusion of hyperprolinemia in specific newborn screening panels can vary based on regional or national guidelines. Newborn screening assessments involve analyzing amino acids within whole blood samples gathered on specialized filter paper.

Laboratory tests: prolinate levels

Individuals experiencing uncontrolled seizures, developmental delay, or unexplained encephalopathy should consider undergoing blood amino acid analysis. In the case of hyperprolinemia type 1, elevated blood proline levels typically range from fivefold to tenfold higher than the established normal range of 51–271 μmol/L.

Genetic testing

Genetic testing can help confirm the diagnosis by identifying mutations in the PRODH or P5CDH genes. Targeted sequencing or whole-exome sequencing approaches may be used to identify these mutations.

Treatment and management

Dietary modifications

Dietary management is often considered in cases of hyperprolinemia type 1 to help mitigate the accumulation of proline and its metabolites, which can contribute to neurological and psychiatric symptoms. A primary approach is to limit proline intake through dietary modifications. This often involves reducing consumption of proline-rich foods such as dairy products, meat, poultry, fish, and certain grains. While reducing proline intake, it's important to ensure a balanced and adequate intake of other essential nutrients. Consultation with a registered dietitian or a medical professional is recommended to ensure the individual's nutritional needs are met.

Vitamin and mineral supplementation

Antioxidants like vitamin E, vitamin C, and glutathione have the potential to be effective in mitigating oxidative stress. Vitamin B6 may enhance the activity of enzymes involved in proline degradation. It can potentially aid in the conversion of proline to its metabolites, helping to reduce proline buildup.

Pharmacological interventions

Pharmacological interventions aim to address the metabolic imbalance caused by proline accumulation in hyperprolinemia type 1. These interventions are designed to either enhance proline metabolism or alleviate the associated neurological and psychiatric symptoms. Some studies have explored the potential of neuroprotective agents to counteract the impact of proline accumulation on the nervous system. These agents could potentially mitigate the neurological and psychiatric symptoms seen in Hyperprolinemia type 1. Pharmacological chaperones can stabilize misfolded or dysfunctional proteins. It helps to enhance the activity of the defective proline dehydrogenase enzyme.

Monitoring progress

Regular monitoring of individuals with hyperprolinemia type 1 is essential to assess the effectiveness of interventions, track symptom management, and ensure overall health. Regular blood tests are performed to measure proline levels. Monitoring the reduction in elevated proline levels can indicate the success of dietary modifications, supplementation, or other interventions. Regular clinical evaluations by medical professionals can help assess neurological, developmental, and psychiatric symptoms. Tracking improvements or changes in symptoms over time is crucial.⁶

Research and future directions

Advances in understanding pathophysiology

Studies have delved into the molecular mechanisms underlying PRODH and P5CDH deficiencies. These enzymes play a crucial role in proline catabolism, and their dysfunction leads to the accumulation of proline and its metabolites. Elevated proline levels disrupt metabolic pathways, potentially impacting neurotransmitter metabolism, energy production and oxidative stress regulation. Advances in neuroimaging techniques have allowed researchers to explore the impact of proline accumulation on brain structure and function. These insights contribute to understanding the neurological symptoms associated with Hyperprolinemia Type-1, including developmental delay, seizures, and movement disorders. Advances in genomics and molecular genetics have enabled the identification of specific mutations in the PRODH and P5CDH genes, enhancing our understanding of the genetic basis of the disorder.

Therapeutic innovations

Research is underway to explore gene therapy approaches that aim to correct the genetic mutations responsible for PRODH and P5CDH enzyme deficiencies. These innovative therapies could potentially restore normal enzyme function and reduce proline accumulation. Enzyme replacement therapy (ERT) is being investigated as a potential avenue. ERT involves administering functional PRODH or P5CDH enzymes to compensate for the deficiency, thus reducing proline levels. Researchers are exploring small molecule compounds that can modulate proline metabolism and mitigate the accumulation of proline and its metabolites. These compounds could help restore metabolic balance. Given the neurological symptoms associated with HPI, therapies targeting neuroprotection are being studied. These agents aim to preserve nerve cells and minimize the impact of proline accumulation on the nervous system. 

Potential gene therapies

Gene therapy in hyperprolinemia type 1 involves introducing functional copies of the PRODH or P5CDH genes into the patient's cells. This can be achieved using various delivery methods, such as viral vectors or non-viral delivery systems. By providing the correct genetic instructions, these therapies aim to restore the normal function of the deficient enzymes and thereby reduce proline accumulation.

Summary

Hyperprolinemia Type 1 is primarily caused by genetic mutations affecting the PRODH gene located on chromosome 22. This gene encodes the enzyme proline oxidase (POX) or proline dehydrogenase (PRODH), which is crucial for the breakdown of proline, an amino acid involved in various physiological processes. The PRODH gene mutations result in reduced or absent activity of the POX enzyme, leading to the accumulation of proline in the bloodstream and tissues. This accumulation can have detrimental effects on brain function, contributing to the cognitive and neurological symptoms observed in individuals with Hyperprolinemia Type 1.  

Individuals with Hyperprolinemia Type 1 may exhibit neurological deficits such as intellectual disabilities, developmental delays, and speech impairments. These cognitive and motor delays can significantly impact overall functioning. The variability in severity is thought to be influenced by several factors, including the degree of enzyme deficiency, the accumulation of toxic metabolites, and the interactions with other genetic and environmental factors. Newborn screening is a vital public health initiative aimed at identifying certain congenital conditions in newborns shortly after birth. Hyperprolinemia type 1 is one of the disorders that can be included in newborn screening programs due to its potential impact on an infant's health. Hyperprolinemia type 1, elevated blood proline levels typically range from fivefold to tenfold higher than the established normal range of 51–271 μmol/L. Genetic testing can help confirm the diagnosis by identifying mutations in the PRODH or P5CDH genes. Targeted sequencing or whole-exome sequencing approaches may be used to identify these mutations.  Pharmacological chaperones can stabilize misfolded or dysfunctional proteins. It helps to enhance the activity of the defective proline dehydrogenase enzyme. Regular monitoring of individuals with hyperprolinemia type 1 is essential to assess the effectiveness of interventions, track symptom management, and ensure overall health. Regular blood tests are performed to measure proline levels. Monitoring the reduction in elevated proline levels can indicate the success of dietary modifications, supplementation, or other interventions.