Introduction
Hyperprolinemia is a rare autosomal recessive genetic disorder that results in a pathologic accumulation of the amino acid proline and its metabolic byproducts in various parts of the body. This is due to the aberration in the enzyme that breaks down the proline. The condition is primarily an amino acid metabolic disorder. The condition may present with symptoms of varying severity ranging from no symptoms to serious clinical manifestations. This amino acid and its metabolic byproducts build up can even result in brain damage with significant neurological indications.
What Are the Types of Hyperprolinemia?
Based on the involved mutated gene and their encoded enzyme, hyperprolinemia is categorized into two types:
- Hyperprolinemia type I (HP-I).
- Hyperprolinemia type II (HP-II).
Who Is Susceptible to Hyperprolinemia?
Hyperprolinemia type I is a rare congenital disorder that presents a clinical prevalence of one in 310,000 to 700,000 individuals with no gender, race, or ethnic predilection. Hyperprolinemia type II is also a rare condition with no gender predilection. The type I variant has been observed to accumulate lesser amounts of amino acid and its byproducts than the type II variant.
What Causes Hyperprolinemia?
Hyperprolinemia type I is caused due to a microdeletion mutation in the POX (PRODH) gene present in the long arm of chromosome 22 (22q11 region). The gene encodes the enzyme proline oxidase, which begins the proline degradation process converting proline into pyrroline-5-carboxylate. The degree of the mutation of the gene also determines the severity of the presentation. The varying PRODH gene mutations lead to three different variations in POX enzymatic activity leading to mild, moderate, or severe reductions. The degree of reduction in the enzymatic activity does not correlate with the clinical severity.
Hyperprolinemia type II is caused due to mutations in the ALDH4A1 gene, which is present on the short arm of chromosome 1 (1p36). The gene encloses the enzyme 1-pyrroline-5-carboxylate dehydrogenase, which breaks down the pyrroline-5-carboxylate into glutamate amino acid. Type I has 2 to 10 times higher amounts of proline and its byproducts in the body, while type II shows an excess in the range of 10 to 15 times. Hyperprolinemia can also occur in adjunct to other conditions like malnutrition or liver disorders or even in other conditions that cause lactic acidosis. Lactic acidosis is characterized by elevated levels of lactic acid in the blood and is an inhibitor of the proline breakdown process.
What Are the Signs and Symptoms of Hyperprolinemia?
Hyperprolinemia does not usually show symptoms, especially in the milder sub-types, whereas severe sub-type may present with symptoms like
- Intellectual disability.
- Epilepsy.
- Schizophrenia.
- Renal disorders.
- Abnormal ECG (electrocardiogram) readings.
- Hypotonia (low muscle tone).
- Developmental delays.
- Aggressive behaviors.
- Hyperactivity.
- Repetitive movements (stereotypy).
How to Diagnose Hyperprolinemia?
The normal proline level is around 450 units. Hyperprolinemia type I is diagnosed through laboratory studies after a preliminary diagnosis by the clinician.
Laboratory Reports of Hyperprolinemia Type I:
- Proline levels in serum: 1900 to 2000 units which relates to about a 2 to 10-fold increase. This is around 0.8 to 4.0 mmol/L of proline.
- No excretion of P5C in urine.
Laboratory Reports of Hyperprolinemia Type II:
- Proline levels in excess of 2000 units.
- Elevated excretion of P5C in the urine.
The presence of P5C in the urine is a differentiating factor between the types of hyperprolinemia. The diagnosis is usually made by exclusion, where in the absence of an accurate diagnosis, an amino acid assay is ordered which reveals the characteristic laboratory studies of hyperprolinemia.
How to Treat Hyperprolinemia?
Proline is a non-essential amino acid that can be produced by the body. Externally, proline is found in foods containing collagen, like bone broth, chicken wings (with the skin), pork rinds, gelatin, meat, fish, and dairy foods. Due to the non-essential nature of the amino acid, its accumulation cannot be prevented by dietary restrictions.
Hyerprolinemia type I does not cause serious symptoms and hence does not warrant aggressive treatment modalities. Overall, the condition is treated symptomatically, and the treatment regime is tailored according to the patient’s clinical presentation.
Although no specific treatment is available against the disease, it is recommended that the patients are provided with high doses of vitamin B6, vitamin E, and vitamin C.
What Is the Prognosis of Hyperprolinemia?
Even with the lack of any accurate treatment protocol, the symptoms are well managed. The condition needs to be diagnosed accurately in order to identify the root cause of the presenting symptoms. Patients with neurological manifestations have been observed to be free of fever or seizure episodes in the later stages of life. The patient is expected to have a good prognosis with long-term vitamin supplementation.
What Is the Differential Diagnosis of Hyperprolinemia?
- Lactic acidosis.
- Phenylketonuria.
- Urea cycle disorders.
- Glycine encephalopathy.
- Citrullinemia.
- Homocystinuria.
- Hyperphenylalaninemia.
Complications of Hyperprolinemia:
- Neurological deficits.
- Intellectual disabilities.
- Delayed wound healing.
- Lack of antioxidative reactions.
- Improper immune responses.
Conclusion
The end result of the proline breakdown process is the production of another amino acid-glutamate. This amino acid plays an important role in maintaining the requirement of various amino acids for protein synthesis and also for intracellular energy transfer. Since hyperprolinemia is an autosomal recessive condition, it requires both the maternal and paternal copies of the mutated gene in all the cells. Individuals with a single copy of the mutated PRODH or ALDH4A1 gene usually have normal levels of proline in the blood. Due to its inheritable nature, parents with symptomatic or diagnosed hyperprolinemia may consider genetic counseling before family planning. A genetic study can inform the probability of the condition being transferred to the offspring. Pre-natal genetic counseling, either by peripheral blood analysis or amniocentesis, can identify the condition in the womb. Early diagnosis prepares the parents from being unwantedly alarmed by the presenting symptoms. If the infant is started on supplementation quite early in life, the chances of clinical presentation decrease. The pediatrician should be kept in the loop before and after the birth. Regular follow-ups and long-term vitamin supplementation go a long way in preventing neurological or developmental deficits.
