An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.

Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk.

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10-2.37), 2.09 (CI: 1.43-3.07), 2.87 (CI: 1.76-4.70) and 3.88 (CI: 1.72-8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18-2.46), 2.29 (CI: 1.55-3.38) and 6.21 (CI: 2.67-14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.

Germline mutations of inhibins in early-onset ovarian epithelial tumors.

To identify novel genetic bases of early-onset epithelial ovarian tumors, we used the trio exome sequencing strategy in a patient without familial history of cancer who presented metastatic serous ovarian adenocarcinomas at 21 years of age. We identified a single de novo mutation (c.1157A>G/p.Asn386Ser) within the INHBA gene encoding the ßA-subunit of inhibins/activins, which play a key role in ovarian development. In vitro, this mutation alters the ratio of secreted activins and inhibins. In a second patient with early-onset serous borderline papillary cystadenoma, we identified an unreported germline mutation (c.179G>T/p.Arg60Leu) of the INHA gene encoding the α-subunit, the partner of the ßA-subunit. This mutation also alters the secreted activin/inhibin ratio, by disrupting both inhibin A and inhibin B biosynthesis. In a cohort of 62 cases, we detected an additional unreported germline mutation of the INHBA gene (c.839G>A/p.Gly280Glu). Our results strongly suggest that inhibin mutations contribute to the genetic determinism of epithelial ovarian tumors.