Hydrops, Lactic Acidosis, And Sideroblastic Anemia

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. One such patient has been reported.

Clinical Features

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.

Inheritance

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

Molecular Genetics

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.