HUPRA Syndrome: A Comprehensive Review
Introduction
HUPRA syndrome (Hyperuricemia, Pulmonary hypertension, Renal failure in infancy, and Alkalosis) is an ultrarare autosomal recessive mitochondrial disease first described in 2011. The condition is characterized by a distinctive constellation of clinical features that reflect severe mitochondrial dysfunction affecting multiple organ systems. With fewer than ten cases reported worldwide as of 2025, HUPRA syndrome represents one of the rarest known mitochondrial disorders with an estimated prevalence of less than one in a million.[1][2][3]
Etiology and Pathophysiology
Genetic Basis
HUPRA syndrome is caused by mutations in the SARS2 gene, located on chromosome 19 (19q13.2), which encodes the mitochondrial seryl-tRNA synthetase (SerRS). This enzyme plays a critical role in mitochondrial protein synthesis by catalyzing the attachment of serine to its cognate tRNA, enabling proper translation of mitochondrial-encoded genes essential for respiratory chain function.[4][5][6][7][1]
The pathogenic mechanism involves impaired mitochondrial protein synthesis due to defective SerRS activity. This leads to dysfunction of the mitochondrial respiratory chain complexes, particularly complexes I, III, and IV, resulting in compromised cellular energy production. The enzyme normally functions as a homodimer, with each subunit containing an N-terminal tRNA-binding domain and a C-terminal catalytic domain.[2][7][8][4]
Molecular Pathogenesis
Studies have demonstrated that SARS2 mutations cause selective degradation of mitochondrial tRNA-Ser(AGY), which is the primary driver of disease pathogenesis. This degradation leads to impaired mitochondrial translation and comprehensive mitochondrial dysfunction, affecting tissues with high energy demands such as the kidneys, heart, lungs, and brain.[9][2]
The condition follows an autosomal recessive inheritance pattern, with most reported cases involving homozygous mutations, though compound heterozygous mutations have also been identified.[10][4]
Clinical Presentation
Core Clinical Features
The acronym HUPRA encompasses the four cardinal manifestations of the syndrome:[5][1]
· Hyperuricemia: Elevated serum uric acid levels, typically >400 μmol/L
· Pulmonary hypertension: Primary pulmonary arterial hypertension with elevated pulmonary artery systolic pressure
· Renal failure: Progressive kidney dysfunction beginning in infancy
· Alkalosis: Metabolic alkalosis with hypochloremic changes
Additional Clinical Manifestations
Beyond the core features, patients typically present with:[2][4][5]
· Prematurity: Most affected infants are born preterm
· Failure to thrive: Poor growth and feeding difficulties
· Global developmental delay: Significant neurodevelopmental impairment
· Hypotonia: Decreased muscle tone
· Ventricular hypertrophy: Cardiac involvement with right heart strain
· Elevated serum lactate: Reflecting mitochondrial dysfunction
· Electrolyte abnormalities: Including hyponatremia, hypomagnesemia, and hypochloremia
· Pancytopenia: Reduced blood cell counts in some cases
Atypical Presentations
Recent case reports have described patients with atypical features, including metabolic acidosis rather than alkalosis, absence of pulmonary hypertension, and predominant renal involvement with bilateral kidney atrophy. These variations may correlate with specific mutations and their residual enzymatic activity.[3][4]
Diagnosis
Laboratory Investigations
Diagnostic workup typically reveals:[4][2]
· Markedly elevated serum uric acid (>400 μmol/L)
· Elevated blood urea nitrogen and creatinine
· Metabolic alkalosis with decreased CO2 combining power
· Hyponatremia and hypochloremia
· Elevated serum lactate
· Anemia and potential leukopenia
· Elevated cardiac biomarkers (NT-proBNP, CK-MB, troponin T)
Imaging Studies
· Echocardiography: Documents pulmonary hypertension with elevated pulmonary artery systolic pressure, right heart enlargement, and tricuspid regurgitation[2]
· Renal ultrasound: May show bilateral kidney atrophy in advanced cases[4]
· CT chest: Can reveal pulmonary artery enlargement and right heart strain[2]
Histopathological Findings
Renal biopsy demonstrates characteristic features including:[4]
· Interstitial fibrosis
· Tubular atrophy
· Markedly enlarged mitochondria in tubular epithelial cells
· Absence of significant glomerular lesions
Genetic Testing
Definitive diagnosis requires identification of pathogenic mutations in the SARS2 gene through:
· Whole exome sequencing
· Targeted SARS2 gene sequencing
· Functional studies demonstrating reduced respiratory chain activity in cultured fibroblasts or muscle tissue[2][4]
Differential Diagnosis
HUPRA syndrome should be considered in the differential diagnosis of:
· Other mitochondrial respiratory chain disorders
· Primary hyperuricemia syndromes
· Congenital nephropathies with tubulopathy
· Primary pulmonary hypertension in infancy
· Metabolic alkalosis syndromes
Management
Supportive Care
Currently, no curative treatment exists for HUPRA syndrome. Management focuses on supportive care and symptom control:[3][2]
Pulmonary Hypertension Management:
· Sildenafil (phosphodiesterase-5 inhibitor)
· Bosentan (endothelin receptor antagonist)
· Oxygen supplementation
· Diuretics (furosemide) for fluid management
Mitochondrial Support Therapy:
· Coenzyme Q10
· L-carnitine
· B-vitamins (B1, B2, B6)
· Mecobalamin (vitamin B12)
· Acetylcysteine
Renal Management:
· Monitoring of electrolyte balance
· Management of acid-base disorders
· Eventual renal replacement therapy consideration
Infection Prevention:
· Prompt treatment of respiratory and urinary tract infections
· Prophylactic measures given immunodeficiency tendencies
Emerging Therapeutic Approaches
Research is ongoing into potential therapeutic strategies targeting mitochondrial dysfunction, including:
· Enhancement of healthy mitochondrial proliferation
· Mitochondrial replacement therapy
· Gene therapy approaches
· Antioxidant strategies
Prognosis
The prognosis for HUPRA syndrome remains poor, with most patients dying in early infancy. Key prognostic factors include:[4][2]
· Survival: Most homozygous mutation cases survive an average of 17 months, with a range of 10-26 months[4]
· Compound heterozygous cases may have milder phenotypes and longer survival (up to 70 months reported)[4]
· Cause of death: Typically multiorgan failure, pulmonary hypertension complications, or sepsis[2][4]
· Better outcomes have been reported with prompt supportive care and mitochondrial support therapy[2]
Epidemiology and Prevention
Prevalence and Demographics
· Global prevalence: <1 in 1,000,000 individuals[3]
· Geographic clustering: Initial cases were identified in a Palestinian village, with one in fifteen inhabitants found to be carriers[1]
· No gender predilection has been reported
· Consanguinity increases risk due to autosomal recessive inheritance
Genetic Counseling
Families with affected children should receive comprehensive genetic counseling addressing:
· Recurrence risk: 25% for each subsequent pregnancy when both parents are carriers
· Carrier screening for family members
· Prenatal diagnosis options through genetic testing
· Family planning considerations
Research Directions
Current research efforts focus on:[11][5]
· Expanding the phenotypic spectrum through additional case identification
· Developing genotype-phenotype correlations
· Investigating therapeutic targets for mitochondrial dysfunction
· Creating cellular and animal models for drug development
· Establishing natural history studies for clinical trial design
Conclusion
HUPRA syndrome represents a devastating mitochondrial disorder with characteristic clinical features of hyperuricemia, pulmonary hypertension, renal failure, and alkalosis. The identification of SARS2 mutations as the underlying cause has enhanced our understanding of mitochondrial seryl-tRNA synthetase function and its critical role in cellular energy metabolism. While the prognosis remains poor, early recognition and supportive care may improve quality of life and potentially extend survival. Continued research into mitochondrial biology and therapeutic interventions offers hope for future treatment developments for this ultrarare condition.
The disorder serves as an important example of how defects in a single mitochondrial enzyme can cause multisystem disease, highlighting the critical importance of mitochondrial function in human health and development. Healthcare providers should maintain awareness of this condition when evaluating infants with unexplained multisystem dysfunction, particularly those presenting with the characteristic constellation of hyperuricemia, pulmonary hypertension, and progressive renal failure.
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