A number sign (#) is used with this entry because of evidence that hyperuricemia, pulmonary hypertension, renal failure, and alkalosis syndrome (HUPRAS) is caused by homozygous mutation in the SARS2 gene (612804), which encodes mitochondrial seryl-tRNA synthetase, on chromosome 19q13.

HUPRA syndrome is a severe autosomal recessive multisystem disorder characterized by onset in infancy of progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, pulmonary hypertension, hypotonia, and delayed development. Affected individuals are born prematurely (summary by Belostotsky et al., 2011).

Belostotsky et al. (2011) reported in detail 3 patients from 2 unrelated Palestinian families from the same village. All were born premature (27-34 weeks' gestation) and presented in infancy with failure to thrive. Laboratory studies showed renal failure associated with multiple electrolyte abnormalities, including hyperuricemia, hyponatremia, and hypomagnesemia, and all developed hypochloremic metabolic alkalosis. Renal biopsy of 1 patient showed dedifferentiated, atrophic tubules with thick basement membrane or denuded tubules; ultrastructural studies showed that the tubular epithelial cells contained markedly enlarged mitochondria with paracrystalline lesions, consistent with a mitochondrial cytopathy. All also developed pulmonary hypertension with evidence of ventricular hypertrophy. Additional features included anemia, thrombocytopenia, and leukopenia, diabetes mellitus, hypotonia, and global developmental delay. The disorder was progressive, and all 3 patients died before age 14 months.

Rivera et al. (2013) reported 2 Spanish sibs with HUPRAS. The older sib had anemia from the age of 5 months, and progressive renal failure with hyperuricemia and metabolic hypochloremic alkalosis from the age of 11 months. At age 15 months, physical examination showed mild hypotonia and motor delay. Renal biopsy at age 24 months showed interstitial fibrosis, tubular atrophy, and enlarged mitochondria in the proximal tubules. Muscle biopsy showed variation in fiber size. The patient developed failure to thrive, hypertension, and progressive renal failure, and she died at age 26 months from multiorgan failure. Hypertrophic cardiomyopathy was identified postmortem. Her younger brother was diagnosed with anemia at age 2 months, hyperuricemia at age 3 months, and failure to thrive at age 7 months. He had renal insufficiency with urea levels comparatively higher than creatinine values and hypochloremic alkalosis. At 15 months he had normal cognitive development and mild motor delay. Peritoneal dialysis was started due to high creatinine levels. A renal biopsy at age 17 months showed interstitial fibrosis, tubular damage, and abnormal appearing mitochondria. Respiratory chain enzyme testing in cultured skin fibroblasts showed mildly reduced function of complexes I and IV. At age 16 months, pulmonary hypertension and right ventricular hypertrophy were diagnosed. He died at age 21 months from pulmonary hemorrhage, refractory pulmonary hypertension, and cardiac failure in the setting of pneumonia.

HUPRA syndrome is an autosomal recessive disorder (Belostotsky et al., 2011).

In an infant boy, born of nonconsanguineous Palestinian parents, with HUPRA syndrome, Belostotsky et al. (2011) identified a homozygous mutation in the SARS2 gene (D390G; 612804.0001). Within the extended family, in an infant girl with HUPRA syndrome, born of first-cousin Palestinian parents, the authors identified homozygosity for the same D390G mutation. A third infant with a similar disorder from an unrelated Palestinian family from the same village was also found to carry the same homozygous mutation.

In 2 Spanish sibs with HUPRA syndrome, Rivera et al. (2013) identified a homozygous missense mutation in the SARS2 gene (R402H; 613845.0002). The mutation, which was identified by direct gene sequencing, segregated with the disorder in the family. Respiratory chain enzyme testing was normal in muscle tissue from both sibs, but in one of the sibs, testing showed mildly reduced function of complexes I and IV in cultured skin fibroblasts.