Clinical and genotypic characteristics of patients with Nonaka distal myopathy at a specialized clinic in Salvador, BA

Case presentation: Distal myopathy of the Nonaka type is a rare genetic disorder, with an estimated prevalence of 1 in 1,000,000. It is progressive and inherited autosomally recessively, caused by mutations in the GNE gene. This gene encodes the enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, vital for sialic acid biosynthesis. The disease typically manifests in the third decade of life with predominant distal muscle weakness. We describe five patients from four distinct families diagnosed with GNE myopathy at a specialized clinic in Salvador, BA. The group comprises three women and two men, averaging 38.6 years old. All had distal lower limb muscle weakness starting at around 25 years old, yet the average time to genetic diagnosis was 9.6 years. All five patients showed foot drop as a primary clinical feature from anterior leg compartment weakness. Two patients had consanguineous parents. One initially presented with dropped head syndrome, an atypical late manifestation, currently using a cervical collar. This patient is the only one in this series with respiratory involvement, experiencing respiratory effort and dyspnea. Genetic analysis revealed the following GNE mutations: c.829C> T (p.Arg277Trp) in homozygosity, c.766G> A (p.Asp256Asn) in heterozygosity, and G> A in homozygosity. The c.829C> T variant is present in three patients and is one of the most common pathogenic variants associated with this disease. The c.766G> A (p.Asp256Asn) variant, present in one patient, is documented in the literature and considered probably pathogenic. Muscle biopsies from four patients showed autophagic vacuoles and cytoplasmic inclusions consistent with the disease. Three patients use wheelchairs, with a mean onset of 5.6 years after molecular diagnosis. All patients are currently receiving multidisciplinary outpatient care following their confirmed diagnosis. Discussion: This case series is crucial for advancing scientific understanding of the genotype-phenotype correlation of this disease. One case presents atypically with the onset of dropped head syndrome, a manifestation typically seen only in advanced stages due to the progressive distal-to-proximal muscle involvement affecting the neck flexors. The usual clinical presentation is distal leg weakness, evident as foot drop, followed by slow progression to upper musculature. Respiratory involvement, rare in literature, occurs in advanced stages. All identified mutations have been previously documented. Most mutations are seen across multiple families or within a single family with several cases, impacting symptom onset, presentation, severity, and disease progression. Final comments: Understanding clinical-genotypic aspects of Nonaka distal myopathy is crucial for comprehending disease behavior. As a rare condition with limited global research, this series can enhance knowledge through investigating genotypic and phenotypic characteristics.