The authors report the long-term prospective follow-up of two unrelated females with congenital hypomyelinating neuropathy (CHN) and review previously reported cases. The authors' first patient presented with neonatal hypotonia and extremely slow nerve conduction velocities. Sural nerve biopsy revealed profound hypomyelination, without inflammation or evidence of myelin breakdown. She is now 9 years of age, and her motor function has continued to improve. Follow-up nerve-conduction velocities are unchanged. The authors' second patient presented at 5 months with hypotonia. Nerve-conduction velocities were extremely slow, and sural nerve biopsy revealed severe hypomyelination, with no inflammation or evidence of myelin breakdown. She is now 5 years of age and has also demonstrated improved motor function. Repeated nerve-conduction velocities are unchanged. Both patients have normal cognitive development. Molecular genetic analysis in Patient 2 disclosed a point mutation in the myelin protein zero gene; this same point mutation has been reported in three other patients diagnosed with Dejerine-Sottas syndrome (DSS) but has never been reported in a patient with CHN. Although CHN is a distinct clinical entity, it may share similar genetic features with DSS.
"Gabreels-Festen et al., 1996; Kirschner et al., 1996; Meijerink et al., 1996; Rouger et al., 1996; Warner et al., 1996; Bort et al., 1997; Komiyama et al., 1997; Phillips et al., 1999; Hattori et al., 2003; Lee et al., 2004; Bai et al., 2006; Mandich et al., 2009; Baets et al., 2011 c.292C4T p.Arg98Trp 1 1 This report c.293G4A p.Arg98His* 2 2 Hayasaka et al., 1993b; Gabreels-Festen et al., 1996; Kirschner et al., 1996; Meijerink et al., 1996; Rouger et al., 1996; Lagueny et al., 1999; Ohnishi et al., 1999; Mersiyanova et al., 2000; Young et al., 2001; Watanabe et al., 2002; Shy et al., 2004; Lee et al., 2005; Mandich et al., 2009 "
"Presenting symptoms in the neonate can be severe and often include hypotonia and respiratory insufficiency (Phillips et al., 1999; Smit et al., 2008). In other patients, clinical presentation consists of early foot deformities, delay in early motor milestones, distal sensory loss and weakness with progressive gait difficulties (Plante-Bordeneuve and Said, 2002; Wilmshurst et al., 2003; Burns et al., 2009). "
[Show abstract][Hide abstract] 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.
"The occurrence of UCM is in agreement with the known function of P0 as a homophilic adhesion molecule, but the functional significance of FFM in P0 mutations is unexplained. CHN was reported in a minority of P0 mutations, suggesting a disturbed myelin formation (Warner et al. 1996; Tachi et al. 1998; Mandich et al. 1999; Phillips et al. 1999). "
[Show abstract][Hide abstract] ABSTRACT: Dejerine-Sottas syndrome (DSS) is an early onset demyelinating motor and sensory neuropathy with motor nerve conduction velocities below 12 m s(-1). The phenotype is genetically heterogeneous, and autosomal dominant (AD) as well as autosomal recessive (AR) inheritance is described. Nerve pathology is highly variable. It is generally presumed that clinical course is severe, leading to wheelchair dependency at an early age. In this study we documented the clinical and pathological features in 25 patients with a DSS and we evaluated the clinical course. In our series 14 patients had an AD mutation and six were probably affected by an AR disorder. In three patients inheritance mode was unknown and two patients obviously suffered from an acquired disorder. The clinical course in all patients was documented. Nine of the 25 patients showed a moderate handicap in adult life; walking distance was still at least 1 km. Age at last investigation of the ambulant patients ranged from 22 to 62 years (mean 38.6 years), and ambulant patients were found in all genetic subgroups. We conclude that DSS, although in general denoting a more serious neuropathy than CMT1, does not imply a severe disability or wheelchair dependency in adult life.
Journal of Anatomy 05/2002; 200(4):341-56. DOI:10.1046/j.1469-7580.2002.00043.x · 2.10 Impact Factor
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