HUPRA syndrome

Overview

HUPRA syndrome is a rare and fatal autosomal recessive mitochondrial disorder characterized by a combination of Hyperuricemia, Pulmonary hypertension, Renal failure in infancy, and Alkalosis-from which the acronym HUPRA is derived. The condition primarily affects the kidneys and lungs, leading to early-onset renal failure and respiratory complications. HUPRA syndrome is considered a mitochondrial disease due to its association with defects in mitochondrial protein synthesis.

Causes

HUPRA syndrome is caused by mutations in the SARS2 gene, which encodes the mitochondrial seryl-tRNA synthetase enzyme. This enzyme plays a vital role in protein translation within mitochondria. Mutations in SARS2 impair mitochondrial protein synthesis, particularly affecting tissues with high energy demands such as the kidneys and lungs. The condition is inherited in an autosomal recessive pattern, meaning a child must inherit two defective copies of the gene—one from each parent—to develop the disorder.

Symptoms

Symptoms of HUPRA syndrome typically present in the first months of life and may include:

• Severe hyperuricemia (high levels of uric acid in the blood)

• Failure to thrive and poor weight gain

• Respiratory distress and pulmonary hypertension

• Progressive renal failure

• Metabolic alkalosis (elevated blood pH due to excess bicarbonate)

• Hypotonia (reduced muscle tone) and neurological delays in some cases

The disease course is aggressive, and complications develop quickly due to organ dysfunction.

Diagnosis

Diagnosis of HUPRA syndrome is based on clinical presentation, biochemical findings, and genetic testing. Key diagnostic steps include:

• Blood tests showing hyperuricemia, elevated creatinine, and metabolic alkalosis

• Echocardiography to detect pulmonary hypertension

• Renal ultrasound or biopsy to assess kidney damage

• Mitochondrial functional studies (in specialized cases)

• Genetic testing confirming mutations in the SARS2 gene

Early genetic diagnosis is important for family counseling and understanding recurrence risks.

Treatment

There is no curative treatment for HUPRA syndrome. Management is supportive and focuses on delaying progression and addressing complications. Treatment options may include:

• Medications to manage hyperuricemia (e.g., allopurinol)

• Diuretics and oxygen therapy for pulmonary hypertension

• Dialysis or peritoneal dialysis for end-stage renal failure

• Nutritional support and hydration management

• Multidisciplinary care including nephrology, pulmonology, and palliative care

Experimental therapies and mitochondrial disease research are ongoing, but options are currently limited.

Prognosis

The prognosis for individuals with HUPRA syndrome is very poor. Most affected children succumb to the disease in early childhood due to progressive renal failure and severe pulmonary complications. The rapid deterioration of organ function despite supportive care limits long-term survival. Early diagnosis and supportive measures may help improve comfort and extend life expectancy modestly, but the syndrome remains a fatal condition with no effective cure.