Ten novelHMGCLmutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria

Abstract

3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and L-leucine catabolism. The clinical acute symptoms include vomiting, convulsions, metabolic acidosis, hypoketotic hypoglycaemia and lethargy. To date, 33 mutations in 100 patients have been reported in the HMGCL gene. In this study 10 new mutations in 24 patients are described. They include: 5 missense mutations: c.109G>A, c.425C>T, c.521G>A, c.575T>C and c.598A>T, 2 nonsense mutations: c.242G>A and c.559G>T, one small deletion: c.853delC, and 2 mutations in intron regions: c.497+4A>G and c.750+1G>A. Two prevalent mutations were detected, 109G>T (E37X) in 38% of disease alleles analyzed and c.504_505delCT in 10% of them. Although patients are mainly of European origin (71%) and mostly Spanish (54%), the group is ethnically diverse and includes, for the first time, patients from Pakistan, Palestine and Ecuador. We also present a simple, efficient method to express the enzyme and we analyze the possible functional effects of missense mutations. The finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes."

Favourable Outcome in Two Pregnancies in a Patient with 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency

“…Genetic analysis demonstrated a donor splice site mutation, c.876 + G > C. To date, there are no data on the clinical phenotype of this mutation. As stated by Menao et al (2009), it is generally difficult to establish a genotype-phenotype correlation in patients with HMG-CoA lyase deficiency. Further, there is no specific clinical or laboratory parameter that can predict the severity of the disease, especially in pregnancy.…”

“…1). So far, 43 mutations in 124 patients have been reported in the HMGCL gene (Menao et al 2009). Common clinical features of the disease at first presentation are hypoketotic hypoglycemia, acidosis, vomiting, and a reduced level of consciousness.…”

HMG–CoA Lyase Deficiency

“…Position refers to the numbering of the HL cDNA sequence in Mitchell et al, 1993. ht, heterozygous The second most frequent mutation is the c.109G>T (Mediterranean mutation) (55 alleles, 31 patients: 24 homozygous, 6 double heterozygous, 1 heterozygous with an allele unknown), found mostly in the Iberian Peninsula (13 patients in Portugal, 11 in Spain and 3 in brazilianportugueses). It has also been described two cases in Morocco and another in Turkey (Pié et al, 1997;Casale et al, 1998;Cardoso et al, 2004;Puisac et al, 2005;Menao et al, 2009). It has been hypothesized that in Portugal and Spain the genetic hit was introduced during the Arabian invasions of the Iberian Peninsula in the eighth century.…”

Recurrent mutation in the HMGCL gene in a family segregating HMG-CoA lyase deficiency

“…The enzyme HMGCL is encoded by the gene HMGCL located on chromosome 1p36.11. The HMGCL gene produces two isoforms; isoform A is expressed in mitochondria and isoform B is found in peroxisomes (Menao et al, 2009). HMGCLD is rare in Europe and Japan, but a common inherited disease in Saudi Arabia and Portugal (Cardoso et al, 2004;Ozand et al, 1992;Funghini et al, 2001).…”

“…HMGCLD is rare in Europe and Japan, but a common inherited disease in Saudi Arabia and Portugal (Cardoso et al, 2004;Ozand et al, 1992;Funghini et al, 2001). HMG CoA lyase deficiency has been extensively studied and over 30 mutations in the HMGCL gene have been reported (Cardoso et al, 2004;Menao et al, 2009). In Saudi Arabia, 89% of patients have a missense mutation in exon 2 (122G>A; R41Q) (Ozand et al, 1991(Ozand et al, , 1992.…”