RESUMEN
BACKGROUND: Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithal RNF216 mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism. CASE PRESENTATION: Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before. CONCLUSIONS: We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype-phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with RNF216 mutations.
Asunto(s)
Ataxia Cerebelosa , Síndrome de Klinefelter , Humanos , Ataxia Cerebelosa/genética , Ataxia , Mutación , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Frontotemporal lobar degeneration (FTLD) describes a group of progressive brain disorders. The expansion of a noncoding GGGGCC (G4C2) hexanucleotide repeat in the C9orf72 gene is a major cause of both familial FTLD and amyotrophic lateral sclerosis. The aim of this study was to determine the prevalence of C9orf72 G4C2-repeat expansion in a Turkish population with FTLD and to determine its effects on the phenotype. The G4C2 expansion in the C9orf72 gene was analyzed in 100 cases of FTLD without mutations of the MAPT, PGRN, CHMP2B, VCP, TARDBP, and FUS genes and 100 age-matched healthy controls by using repeat-primed polymerase chain reaction and fragment length analysis techniques. A possible pathogenic repeat (≥30) was found in one of the familial cases (1/33), but none of the sporadic cases. The difference in the allele length between the cases and controls was statistically significant (p < 0.01). Intermediate (20-30) repeats were detected in 4% of our cases. Patients with psychotic symptoms appear to be enriched for intermediate and possibly pathogenic repeats. To determine whether the intermediate and ≥30-repeat allele carriers shared the C9orf72 risk haplotype, we examined rs4879515 and rs3849942 in all samples and family members of patients with possibly pathogenic alleles. We identified at least one risk allele for each single-nucleotide polymorphism in all intermediate and possibly pathogenic repeat carriers. We observed that ≥8 unit repeats were strongly correlated with the tagging risk alleles for both single-nucleotide polymorphisms (p < 0.001). To our knowledge, this is the first study to evaluate C9orf72 G4C2 repeats in Turkish patients with FTLD. The present findings suggest that pathogenic expansions of the C9orf72 repeat are uncommon in Turkish patients with FTLD, but intermediate repeats may be a risk factor for FTLD and act as a genetic modifying factor for psychotic symptoms.