A number sign (#) is used with this entry because of evidence that hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is caused by compound heterozygous mutation in the LARS2 gene (604544) on chromosome 3p21.

Biallelic mutation in the LARS2 gene can also cause Perrault syndrome-4 (PRLTS4; 615300), which shows some overlapping features.

Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) is an autosomal recessive multisystem disorder characterized by the onset of hydrops in utero. The severity of the hydrops and the disorder in general is highly variable. At birth, affected infants usually show poor growth, lactic acidosis, pulmonary hypertension with hypoxic respiratory insufficiency, and sideroblastic anemia. More variable features may include hepatosplenomegaly or cholestasis, hypoglycemia, pancreatic insufficiency, and micropenis or hypospadias. Death in infancy may occur. Those who survive tend to have resolution of lactic acidosis and anemia, but may show developmental delay and sensorineural deafness (summary by Riley et al., 2020).

Riley et al. (2016) reported a female infant, born of unrelated Pakistani parents, with a lethal multisystem disorder resulting in death at 5 days of age. The pregnancy was complicated by oligohydramnios, fetal growth restriction, hydrops, and anemia, with antenatal scans showing fetal pericardial effusion, ascites, and scalp edema. The infant was delivered prematurely at 29 weeks by emergency cesarean section, and intubated and ventilated from birth. There were multisystem complications, including severe metabolic acidosis with increased lactate, hyaline membrane disease, mild cardiac defects associated with tachyarrhythmias, pulmonary hypertension, thrombocytopenia, and anemia. Bone marrow aspirate showed ringed sideroblasts, and liver samples showed extramedullary hematopoiesis with dyserythropoiesis. Other features included liver dysfunction with disordered coagulation, refractory seizures, and abnormal EEG consistent with diffuse cerebral dysfunction. Head ultrasound was normal; additional imaging was not performed. Immunoblotting showed decreased complex I protein levels in patient muscle (57% of controls), with even larger decreases in patient liver (25% of controls), although activity levels were not sufficiently decreased to be diagnostic for a mitochondrial respiratory chain disorder.

Riley et al. (2020) reported 3 male infants from 2 unrelated families, patient 1 of Japanese/Caucasian origin and patients 2a and 2b of Middle Eastern origin, with HLASA. Hydrops was detected prenatally in all cases, although the severity was variable. The 2 sibs were delivered at 32 to 33 weeks' gestation due to fetal distress. After birth, all patients had lactic acidosis, respiratory insufficiency and failure associated with pulmonary hypoplasia and hypertension, and sideroblastic anemia, confirmed by bone marrow aspirate in 2 patients. All also had gonadal dysgenesis manifest as hypospadias, micropenis, or undescended testes, and liver involvement with cholestasis or hepatosplenomegaly. Two had hypoglycemia and 1 had exocrine pancreatic insufficiency. Patient 2a died on day 1 of life, but the other 2 children survived to ages 18 and 8 months, respectively, at the time of the report. The surviving boys had developmental delay and sensorineural deafness; 1 required tube feeding.

The transmission pattern of HLASA in the family reported by Riley et al. (2016) was consistent with autosomal recessive inheritance.

In a female infant with lethal HLASA, Riley et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene: T522N (604544.0001) and A430V (604544.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in E. coli showed that the A430V variant resulted in an 18-fold loss of catalytic activity, whereas the T522N variant resulted in a 9-fold reduction compared to wildtype. Immunoblot analysis showed normal levels of LARS2 in patient muscle, but about a 50% decrease in patient liver. Levels of mitochondrial complex proteins, particularly complex I, were decreased in patient liver and less so in patient muscle, but not in patient fibroblasts. There was no defect in mitochondrial protein synthesis in patient fibroblasts or induced myotubes, suggesting that the variants only affect tissue with higher energy demands, such as heart and brain.

In 3 boys from 2 unrelated families (families 1 and 2) with HLASA, Riley et al. (2020) identified compound heterozygous missense mutations in the LARS2 gene (604544.0011-604544.0014). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None was present in the gnomAD database. In vitro functional expression studies of these recombinant variants showed that all resulted in decreased LARS2 aminoacylation activity compared to controls, although some had more severe effects on enzyme activity than others. The authors postulated that the degree of impaired enzyme activity correlates with the severity of the phenotype, such that HLASA-associated LARS2 mutations have a more detrimental effect compared to Perrault syndrome-4 (PRLTS4; 615300)-associated mutations. However, there is a phenotypic spectrum with overlapping clinical features between the 2 disorders.