Lipoyltransferase 1 Deficiency

A number sign (#) is used with this entry because of evidence that lipoyltransferase-1 deficiency (LIPT1D) is caused by compound heterozygous mutation in the LIPT1 gene (610284) on chromosome 2q11.

Clinical Features

Soreze et al. (2013) reported a boy, born of unrelated French parents, who presented at age 15 months with delayed psychomotor development and hypotonia. At age 18 months, he had acute metabolic decompensation associated with gastroenteritis. Symptoms included increased serum lactate, metabolic acidosis, abnormal liver enzymes, and psychomotor regression manifest as severe hypotonia, dystonia, loss of head control, and coma. After a few days, he had spastic tetraparesis and extrapyramidal signs as well as inability to speak, but he was otherwise fully conscious and alert. Brain imaging showed cerebellar atrophy, cortical atrophy, bilateral thalamic abnormalities, bifrontal white matter abnormalities, and delayed myelination. The findings were consistent with a clinical diagnosis of Leigh syndrome (256000). Laboratory studies showed increased glutamine and proline and were consistent with decreased activities of the pyruvate dehydrogenase complex (PDHC) and alpha-ketoglutarate dehydrogenase (KGDH), as demonstrated in patient fibroblasts. Branched-chain alpha-keto acid dehydrogenase (BCKDH) activity was also decreased. Glycine was not increased. Carbon dioxide production by the Krebs cycle and mitochondrial respiratory chain activity were decreased with pyruvate as a substrate compared to controls.

Tort et al. (2014) reported a female infant, born of unrelated parents, who presented with sudden clinical deterioration and bradycardia on the second day of life. She had moderate jaundice, hypoactivity, and weak cry, and a perinatal infection was suspected. Physical examination showed generalized hypertonia and dystonic movements of the hands and feet. She developed pulmonary hypertension and further clinical deterioration, resulting in cardiorespiratory arrest and death at age 9 days. Laboratory studies showed severe lactic acidosis, liver dysfunction, and increased 2-ketoglutarate. There was no evidence of increased glycine. Overall PDHC activity was decreased compared to controls, but partial reactions catalyzed by the E1 (PDHA1, 300502 and PDHB, 179060) and E3 (DLD; 238331) subunits were normal; E2 (DLAT; 608770) activity was not measured, but sequence analysis of DLAT was normal. Muscle samples from the patient showed normal mitochondrial respiratory chain activities.

Inheritance

The transmission pattern of LIPT1 deficiency in the family reported by Soreze et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy with early-onset encephalopathy due to LIPT1 deficiency, Soreze et al. (2013) identified compound heterozygous mutations in the LIPT1 gene (S292X, 610284.0001 and T179A, 610284.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Immunoblot analysis of patient fibroblasts showed absence of the LIPT1 protein and absence of the expected lipoylated E2 proteins of KGDH, PDHC, and BCKDH.

In a female infant with fatal LIPT1 deficiency, Tort et al. (2014) identified compound heterozygous missense mutations in the LIPT1 gene (S71F, 610284.0003 and R98G, 610284.0004). Immunostaining analysis of patient cells showed decreased levels of lipoylated E2-PDH and E2-KGDH. There was normal lipoylation of the H protein (GCSH; 238330) of the glycine cleavage system (GCS) and normal activity of the GCS, suggesting that the LIPT1 mutations caused a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis.