Acyl-CoA dehydrogenase 9 deficiency is considered as a rare neuromuscular syndrome with an autosomal recessive transmission. The ACAD9 protein presents two essential functions, i.e., the limiting step enzyme of the fatty acid β-oxidation pathway and one of the complex’s compounds involved in the respiratory chain complex I assembly. Thus, loss-of-function mutations are known to convey mitochondrial cytopathologies. A patient with a mild and late-onset phenotype, suffering from exercise intolerance and hypertrophic cardiomyopathy, was diagnosed as a compound heterozygote of the ACAD9 gene. The first c.1240C> T p.Arg414Cys variant has been previously reported and is known to be responsible for ACAD9 deficiency. However, the second c.1636G> A p.Val546Met variant has never been described. The goal was to investigate the eventual pathogenicity of this new genetic variant. For this purpose, molecular cloning was generated to express the ACAD9 gene with the V546M variant in a cell line (ACAD9mut) and compared to cells expressing the wild-type ACAD9. Then, the mitochondrial respiration, ATP production, the mitochondrial network, and the oxidative phosphorylation’s composition were investigated to reveal the effects of the V546M variant. While avoiding to affect the amount of the respiratory chain’s complexes, the new ACAD9 variant was entirely responsible for reducing over 50% of the mitochondrial complex I activity.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons. ALS is mostly sporadic, but there are familial forms. In more than half of the familial forms, a pathogenic variant is found in one of the following genes: C9ORF72, SOD1, TDP-43, FUS, and VCP. SOD1 is the 2nd most common gene involved in genetic forms of ALS. Genotype–phenotype relationships are occasionally established in genetic forms of ALS associated with SOD1 mutations pathogenic variants. The c.281G > T (p.[G93V]) variant in SOD1 is associated with a rarely described and unexplained anticipation phenomenon. We report a large family from Martinique in whom ALS is associated with a c.281G > T (p.[G93V]) pathogenic variant in SOD1 and a statistically suggested anticipation. A whole-exome study and detection of CNVs (CoDESeq) from 3 affected members of this family revealed the presence of variants of uncertain signification (VUS) in other ALS genes. VUS in DCTN1 and NEFH were present in patients of the 2nd generation, and CNVs involving UBQLN2 and C21orf2 were found in the youngest case of the family.

Background: 4q21 microdeletion syndrome is an emergent non‐recurrent genomic disorder characterized by facial dysmorphy, progressive growth retardation, severe intellectual deficit, and absent or severely delayed speech. Deletions occur in clusters along 4q interstitial or terminal regions. 4q chromosomal aberrations are variable in type, size, and breakpoint. Genotype–phenotype correlation is a challenging task. The recurrent antenatal feature associated a posteriori with this syndrome is intrauterine growth retardation. There are very few precise antenatal descriptions of this syndrome.Methods: We report here the first antenatal history of one of the largest deletion of this region.Results: Our case harbored a 16.9 Mb deletion encompassing 135 protein coding genes including 20 OMIM morbid genes involved in neurological and cognitive abilities. Those breakpoints overlap two clusters of described microdeletion syndromes of cytogenetic band 4q13 and 4q21.Conclusion: From the end of the second trimester, set of call signs associated with this syndrome can be completed by: excess of amniotic fluid, mild growth retardation, short long bones, bony anomalies of the extremities, and bulging cheeks. So, emphasis should be placed on the examination of the extremities, and the face during the routine targeted prenatal ultrasound.

Background: Huntington's Disease‐like 2 (HDL2), caused by a CAG repeat expansion in JPH3 , closely resembles HD. All reported HDL2 patients to date have some African ancestry. While both disorders exist in the Caribbean, their relative frequency and clinical characteristics remain largely unknown. Objectives: To characterize HD and HDL2 patients in Martinique. Methods: We retrospectively analyzed all HD and HDL2 patients evaluated over 20 years at a single neurology center in Martinique, collecting longitudinal clinical features, UHDRS scores, and repeat lengths. Results: In Martinique, combined HD and HDL2 minimum prevalence was 7.77/100,000. We ascertained 24 HD individuals, from 16 pedigrees, and 18 HDL2 individuals, from two pedigrees, one being the most extensive HDL2 pedigree yet reported. Because most HDL2 patients belong to a single large pedigree, the data must be interpreted with caution as familial clustering may introduce bias. HDL2 cases were predominantly male (83% vs. 45% in HD). Motor symptoms were the most frequent initial manifestation in both. Repeat length negatively correlated with estimated onset age in both diseases. Longitudinal motor (UHDRS‐TMS) and functional capacity (UHDRS‐TFC) scores in HDL2 revealed progressive worsening similar to HD. Inter‐ and intra‐familial clinical and genetic heterogeneity was obvious in both diseases. Anticipation was not exclusively reserved to paternal transmissions in HDL2. Conclusions: HDL2 is nearly as prevalent as HD in Martinique. The study reinforces the similarities between HD and HDL2 in genotype–phenotype correlation and disease course, while highlighting heterogeneity and germline instability in HDL2. Interpretation is limited by the small number of HDL2 families.

The likely pathogenic variant c.407A>T p.Asp136Val of the LMNA gene has been recently described in a young woman presenting with atypical progeroid syndrome, associated with severe aortic valve stenosis. We further describe the cardiovascular involvement associated with the syndrome in her family. We identified seven members with a general presentation suggestive of progeroid syndrome. All of them presented heart conduction abnormalities: degenerative cardiac diseases such as coronary artery disease (two subjects) and aortic stenosis (three subjects) occurred in the 3rd–5th decade, and a young patient developed a severe dilated cardiomyopathy, leading to death at 15 years of age. The likely pathogenic variant was found in all the patients who consented to carry out the genetic test. This diverse family cardiologic phenotype emphasizes the complex molecular background at play in lamin-involved cardiac diseases, and the need for early and thorough cardiac evaluations in patients with laminopathic progeroid syndromes.