Genetic spectrum of hereditary neuropathies with onset in the first year of life

Abstract

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.

Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

“…Data from recent studies in large cohorts of CMT patients indicated that molecular diagnosis could be established in ϳ 50-70% of them [Baets et al, 2011;Saporta et al, 2011]. These results strongly indicate that an important number of additional CMT genes remains to be discovered.…”

NEFL N98S mutation: another cause of dominant intermediate Charcot–Marie–Tooth disease with heterogeneous early-onset phenotype

“…As a whole, NEFL mutations represent between 0.8 and 2 % of all patients with CMT [15,18,[22][23][24][25]. NEFL-associated CMT is a highly variable disorder that comprises more than 18 disease-causing mutations, targeting the head or rod protein domains, with highly variable phenotypic expression, N98S (N97 in the old nomenclature) being reported in five pedigrees with severe early-onset disease phenotype [15,19,26,27].…”

Autosomal recessive demyelinating or axonal Charcot–Marie–Tooth neuropathy

“…This finding has been considered as the pathological hallmark of CMT4B1 and CMT4B2. However, similar focally folded myelin sheaths were found, although to a lesser extent, in FGD4, PRX, MPZ, and SH3TC2 associated CMT [38][39][40]. Secondary axonal loss is usually observed in CMT4B1.…”