Caracterización fenotípica y molecular de las neuropatías hereditarias en la infancia y la adolescencia

Resumen

BACKGROUND: Most polyneuropathies in childhood are genetically determined, with an estimated 70-90% of all neuropathies. Inherited peripheral neuropathies (IPN) include Charcot-Marie-Tooth disease and complex hereditary syndromes, whether they are neurodegenerative diseases or inborn errors of metabolism in which polyneuropathy is one of their characteristics. Medical literature is scarce on studies of IPN in the pediatric population, which may be attributable to the short supply of national and international database programs and uniform pediatric evaluation scales for general application. OBJECTIVES: The main objective is the genetic and phenotypic characterization of a series of IPN patients under 20 years of age, including the search for new causative genes. The secondary objectives are the following: to determine the variability of the severity of the different types of IPN and to estimate the sensitivity of the CMTPedS scale as a measure of progression in the different IPN. METHODS: This is a 3-year longitudinal descriptive study of a hospital-based series prospectively recruited and assessed between September 2017 and September 2020 in the Neuromuscular Diseases and Child Neurology Unit of the Hospital Universitario y Politécnico La Fe (Valencia, Spain). Only patients who were under 20 years of age at the start of the study and had a definitive diagnosis of peripheral neuropathy of genetic origin were included, even if the causal genetic defect was not known, both in index cases and in secondary cases (either parent or affected sibling). Patients were studied from the clinical, neurophysiological, neuroimaging, disability (with the CMTPedS scale) and genetic perspective following the protocols reflected in this thesis. The research group on inherited neuropathies at The Children's Hospital at Westmead (NSW, Australia) contributed with patients with pure motor IPN for the study on the utility of the CMTPedS scale in pure motor forms. The inclusion and exclusion criteria that patients from these two centers had to meet were the same. RESULTS: A total of 110 patients with IPN who were under 20 years old at onset were studied. Most belonged to the cohort of patients referred to Hospital Universitario y Politécnico La Fe, while 8 of them were contributed by The Children's Hospital at Westmead. Of the 102 patients from the Hospital Universitario y Politécnico La Fe, three presented such a unique phenotype and shared the same TRMT5 genotype that they were described in an extensive separate study (Argente-Escrig et al., 2022). Thus, 99 patients were reflected in the study Argente-Escrig et al., 2021a. Of these 99 (59 male), 14 presented with distal hereditary motor neuropathy (dHMN) and 85 had a sensorimotor form with 2/3 of the demyelinating subtype (Argente-Escrig et al., 2021a). Genetic diagnosis was achieved in 79.5% of families, with a detection rate of mutations in demyelinating forms (88.7%) and axonal forms (89.5%), significantly higher than in dHMN families (18.2%). CMT1A was the most frequent subtype (n = 37), followed by those with heterozygous mutations in the GDAP1 (n = 9) or GJB1 (n = 8) genes. Mutations in another 15 genes were identified, including a new pathogenic variant in the ATP1A1 gene (Argente-Escrig et al., 2021a). The cohort of 22 dHMN patients (13 female) from 19 families came from the two teaching hospitals (Argente-Escrig et al., 2021b). 14 people were symptomatic in the first year of life. Intellectual disability was present in 6 individuals and upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, most frequently in BICD2 (BICD2-4, DYNC1H1-2, MFN2-2, GARS1-1). A new pathogenic variant in the GARS1 gene was identified (Argente-Escrig et al., 2021b). The CMTpedS detected significant disease progression in all sensorimotor genetic subtypes (Argente-Escrig et al., 2021a), at a rate of 1.84 (±3.7) over 1 year (p < 0.0005, n = 62) and a rate of 3.6 (± 4.4: p < 0.0005, n = 45) at 2 years. Significant worsening was also detected for CMT1A at 1 year (1.7 ± 3.6, p < 0.05) and at 2 years (4.2 ± 4.3, p < 0.0005). In the dHMN, the CMTPedS total score over 1 year deteriorated, on average, 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within 1 year of follow-up (Argente-Escrig et al., 2021b). Finally, neuropathies associated with two different genes are phenotyped in depth: FGD4 and TRMT5. The two sibling patients who were carriers of the pathogenic variants c.514delG (p.Ala172Glnfs*28) and c.2211dupA (Ala738Serfs*5) in the FGD4 gene had their onset in adolescence and showed a very mild phenotype in contrast to what was previously published (Argente -Escrig et al., 2019). The p.Ala738Serfs*5 truncated protein may have partially conserved FGD4 activity since the main functional domains are preserved. Recessive mutations in the TRMT5 gene in three patients from three different families were associated with a phenotype not previously described (Argente-Escrig et al., 2022). They presented with global developmental delay, predominantly sensory demyelinating neuropathy of congenital or infantile onset, pyramidal signs, mild cerebellar ataxia, and no biochemical profile consistent with OXPHOS deficiency. The routine pathological analysis of muscle and nerve in these patients was apparently normal while the ultrastructural study was clearly abnormal. CONCLUSIONS: Our pediatric series presents differentiating characteristics with other cohorts by the higher proportion of heterozygous carriers in the GDAP1 gene. Pyramidal tract and cognitive involvement are frequent in the pure motor forms in the pediatric population. The progression of the sensorimotor forms was confirmed at two years of follow-up measured with the CMTPedS, and as a novelty it was detected that the CMTPedS is sensitive to change also in the first year of follow-up. The present data support the CMTPedS scale as a measure of disability sensitive to progression at one year also in motor forms, and our study suggests that a scale modelled on CMTPedS might be useful for pediatric patients with motor forms. The in-depth phenotyping and exhaustive genetic analysis carried out help us to understand the pathogenic mechanisms associated with the different variants and their influence on the final phenotype. Ultrastructural muscle and nerve specimens may point to a mitochondrial etiology in cases where routine histopathologic imaging appears normal.