Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Abstract

Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population. The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history. We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant

“…Here we report a patient diagnosed with Leigh‐like syndrome, characterized by persistent lactic acidosis, seizures, spastic quadriplegia, and neuroradiological abnormalities (Table S1). Whole exome sequencing identified homozygous nonsense variants in two genes, PDHX and TIMMDC1 , where recessive LoF mutations are a known cause of Leigh syndrome (Ivanov et al, ; Kremer et al, ). These were a reported pathogenic variant in the PDH subunit gene PDHX (GRCh37 chr11:35016549C>T; NM_003477.2:c.1336C>T; NP_003468.2:p.(Arg446*); Ivanov et al, ) and an uncharacterized variant in the OXPHOS complex I (CI) assembly factor gene TIMMDC1 (GRCh37 chr3:119236128C>T; NM_016589.3:c.673C>T; NP_057673.2:p.(Arg225*)).…”

“…Whole exome sequencing identified homozygous nonsense variants in two genes, PDHX and TIMMDC1 , where recessive LoF mutations are a known cause of Leigh syndrome (Ivanov et al, ; Kremer et al, ). These were a reported pathogenic variant in the PDH subunit gene PDHX (GRCh37 chr11:35016549C>T; NM_003477.2:c.1336C>T; NP_003468.2:p.(Arg446*); Ivanov et al, ) and an uncharacterized variant in the OXPHOS complex I (CI) assembly factor gene TIMMDC1 (GRCh37 chr3:119236128C>T; NM_016589.3:c.673C>T; NP_057673.2:p.(Arg225*)). The TIMMDC1 p.(Arg225*) mutation was a strong candidate disease‐causing variant that could potentially be classified as pathogenic or likely pathogenic by the ACMG guidelines (PVS1, PM2, and PP3).…”

Remembering MUDPILES: A Case of Unexplained Metabolic Acidosis

“…Thus, her suspected ethnic background does provide a clue to diagnosis. In fact, this mutation is seen in #60% of Roma patients with PDH deficiency, 11 so the mutation testing in these patients could start with sequencing the PDHX gene. Her presentation in childhood (rather than in infancy) as a girl with severe intellectual disability, spasticity, and growth retardation is typical for this gene change.…”

“…Her presentation in childhood (rather than in infancy) as a girl with severe intellectual disability, spasticity, and growth retardation is typical for this gene change. 11…”

A uniqueLAMB3splice-site mutation with founder effect from the Balkans causes lethal epidermolysis bullosa in several European countries

“…Homozygous recessive mutations are more common in children born to blood relatives . Geographically or socially isolated groups like the Amish, Icelandic, French‐Canadian from Quebec or Roma communities have an increased risk of harbouring founder effects. Additionally, the mutation was also detectable in Western or Southern European countries in migrating individuals who were not even aware of their connection to the Roma community.…”