Hyperprolinemia is an inherited metabolic condition where the body cannot properly break down the amino acid proline, leading to its excess accumulation in the blood. Proline is a component used by the body to build proteins, and this rare disorder occurs when that breakdown process is impaired.
Genetic Causes and Types
Hyperprolinemia results from a deficiency in one of two enzymes that break down proline, and the condition is categorized into two types based on which enzyme is affected. Each type is inherited in an autosomal recessive pattern, meaning a child must inherit a non-working gene from each parent. Individuals who inherit only one copy of the gene are carriers but do not show signs of the disorder.
Type I hyperprolinemia is caused by a deficiency of the enzyme proline dehydrogenase, which performs the first step in proline breakdown. Mutations in the PRODH gene disrupt this enzyme’s function, causing proline to accumulate to levels three to ten times higher than normal.
Type II hyperprolinemia stems from a deficiency of the enzyme pyrroline-5-carboxylate dehydrogenase, which handles the second step in the breakdown pathway. Mutations in the ALDH4A1 gene cause this deficiency, leading to a buildup of both proline and a related substance called pyrroline-5-carboxylate. In this type, blood proline levels can be ten to fifteen times higher than normal.
Clinical Presentation and Symptoms
The signs and symptoms associated with hyperprolinemia differ significantly between the two types. The buildup of proline and related compounds can interfere with normal bodily functions, particularly in the central nervous system.
For individuals diagnosed with Type I hyperprolinemia, the condition is considered a benign biochemical finding, and the vast majority of people have no symptoms. While some reports have noted potential associations with neurological issues, such as seizures or intellectual disability, a direct causal link has not been firmly established. Most individuals lead healthy lives without any medical complications related to their proline levels.
In contrast, Type II hyperprolinemia is more likely to be associated with observable symptoms, primarily affecting the neurological system. Individuals with this type may experience seizures, developmental delays, or intellectual disabilities that can vary in severity. The accumulation of pyrroline-5-carboxylate, in addition to high proline levels, is thought to contribute to these neurological effects.
Diagnosis and Screening
The identification of hyperprolinemia often begins with newborn screening, where a small blood sample from a baby’s heel is tested for various conditions. An elevated proline level on this screen indicates the need for further investigation but does not confirm a diagnosis.
Follow-up testing begins with a plasma amino acid analysis, a more precise blood test to confirm high proline levels. To distinguish between Type I and Type II, a urine test is performed to detect pyrroline-5-carboxylate, which is only elevated in the urine of individuals with Type II.
For a definitive diagnosis, genetic testing is used to examine the PRODH and ALDH4A1 genes to identify the specific mutations responsible for the enzyme deficiency. Pinpointing the exact genetic cause provides a conclusive diagnosis, clarifies the type, and helps in counseling families about the inheritance pattern.
Management and Medical Care
Since Type I hyperprolinemia is asymptomatic, no specific medical treatment is required, and individuals can expect to live a normal life. Ongoing monitoring is often minimal once the diagnosis is confirmed.
For individuals with Type II, management focuses on reducing high proline levels and addressing any associated neurological symptoms. The primary strategy is a low-protein diet to limit the intake of proline. A metabolic specialist and a dietitian guide this diet to ensure it is nutritionally complete.
In cases where neurological symptoms such as seizures occur, they are managed with standard medical treatments like anticonvulsant medications. Pyridoxine, also known as vitamin B6, can also be effective in managing seizures for some individuals. The overall care plan is coordinated by a team of specialists to address both the metabolic and neurological aspects of the disorder.