Hanna Drac

Infantile Chronic Peripheral Neuropathy with Giant Axons

SummaryAn 8-year-old boy with a slowly progressive motor neuropathy is described. The first signs appeared at the age of 3 years. Histological examination of the sural nerve showed the presence of numerous segmental axonal swellings and features of demyelination as well as remyelination. These enlargements were filled with irregularly orientated 10 nm filaments. The case resembled the previously described cases of giant axonal neuropathy but differed from them in absence of kinky hair.

Familial inclusion body myopathy with desmin storage

Abstract We report two adult familial cases of inclusion body myopathy (IBM) with desmin storage in skeletal muscle. Clinically, both patients presented late-onset, progressive, symmetrical, both proximal and distal muscle weakness. Muscle biopsy findings were identical in both cases and consisted of marked variability in fiber size, increased number of central nuclei and vacuolation involving 10% of fibers. Single or multiple vacuoles were located subsarcolemmally or in the center, and were rimmed by basophilic material. At the ultrastructural level, tubulofilamentous nuclear and cytoplasmic inclusions of 16–21 nm in diameter were frequently observed. In addition, large subsarcolemmal and central deposits composed of electron-dense granular material were present in many fibers. Immunocytochemistry revealed staining for desmin, vimentin and ubiquitin within both inclusions and vacuolated fibers. Possible structural and functional associations between these two types of muscle changes remain unclear. They may either represent two coexistent disease processes or merely reflect an abnormal form of muscle fiber degradation, with unidentifiable specificity.

Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene†

Charcot-Marie-Tooth disease (CMT) is a heterogenous group of disorders of peripheral nervous system with a prevalence of 1:2,500. The frequency of axonal form of Charcot-Marie-Tooth disease (CMT2) remains unknown. To date 17 loci in autosomal dominant (14) and in autosomal recessive (3) CMT2 have been mapped [Bernard et al., 2006; Zuchner and Vance, 2006]. Among 11 genes identified in AD-CMT2, the Mitofusin 2 gene has been shown to be mutated in 11% of CMT2 cases [Verhoeven et al., 2006]. SomeAD-CMT2 forms are characterizedby specific clinical features, whereas to distinguish between other types linkage analysis is necessary. The firstMPZmutation in the hypertrophic form of CMT disease was reported in 1993 [Hayasaka et al., 1993]. The congenital hypomyelination neuropathy (CHN) was a second phenotype which was shown to be associated with mutations in the MPZ gene [Warner et al., 1996; Szigeti et al., 2003; Kochanski et al., 2004]. Interestingly, CMT2 disease associated with mutations in the myelin protein zero gene (MPZ) was not recognized until 1997. In 1997, a novel mutation in the MPZ gene was identified in a large CMT2 Sardinian family consisting of five generations [Marrosu et al., 1998]. In this study we report on two affected patients from a CMT2 family, in which a novel p.Pro105Thr mutation in the MPZ gene has been found. The family consists of three generations (Fig. 1). The proband (III:2) had been admitted to Neurology Department at age 54 due to clumsy gait and sensory loss in the distal parts of the upper and lower limbs since the age of 46.Onneurological examination hehadweakness of the distal muscles of the lower limbs and hypertrophy of calf muscles. Achilles tendon reflexes were bilaterally absent. A sensory loss within all modalities was prominent in the lower limbs distally and extended proximally to the knees. The patient showed marked ataxia when walking with closed eyes. There was a prominent steppage gait and he was unable to walk on his heels and toes. Audiometry showed left-sided severe sensorineural hearing loss of 20 progressing to 60 dB hearing level (HL) in the high frequencies. The brother of the proband (III:1), a 60-year-old man, first noticed foot drop at age 54. The disease was progressing within the next years, leading to marked wasting of the calf muscles. He complained of pains and paraesthesia in the lower limbs. On neurological examination at the age of 60 years he had pes cavus deformity, weakness, and wasting of the distal muscles of the lower limbs. Tendon reflexes in the lower limbs were absent. There was hypesthesia in the distal parts of the lower limbs. Similar to his brother he had marked ataxia when walking with closed eyes. In spite of denying any

A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease

Charcot–Marie–Tooth disease (CMT) caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene is characterized by a spectrum of phenotypes. Recurrent nonsense mutations (Q163X and S194X) showing regional distribution segregate with an early onset, severe course of recessive CMT disease with early loss of ambulancy. Missense mutations in GDAP1 have been reported in sporadic CMT cases with variable course of disease, among them the recurrent L239F missense GDAP1 mutation occurring in the European population. Finally, some GDAP1 mutations are associated with a mild form of CMT inherited as an autosomal dominant trait. In this study, we characterize the CMT phenotype in one Polish family with recessive trait of inheritance at the clinical, electrophysiological, morphological, cellular, and genetic level associated with a new Gly327Asp mutation in the GDAP1 gene. In spite of the nature of Gly327Asp mutation (missense), the CMT phenotype associated with this variant may be characterized as an early onset, severe axonal neuropathy, with severe skeletal deformities. The mutation lies within the transmembrane domain of GDAP1 and interferes with the mitochondrial targeting of the protein, similar to the loss of the domain in the previously reported Q163X and S194X mutations. We conclude that the loss of mitochondrial targeting is associated with a severe course of disease. Our study shows that clinical outcome of CMT disease caused by mutations in the GDAP1 gene cannot be predicted solely on the basis of genetic results (missense/nonsense mutations).

A novel Met116Thr mutation in the GDAP1 gene in a Polish family with the axonal recessive Charcot-Marie-Tooth type 4 disease

Mutations in the gene coding for ganglioside-induced differentiation-associated protein-1 (GDAP1), which maps to chromosome 8q21, have been described in families with autosomal recessive Charcot-Marie-Tooth disease (CMT4A). Interestingly, some mutations in the GDAP1 gene have been reported in the demyelinating form of CMT1 disease, whereas others were found in patients with the axonal type of CMT disease. So far, 23 mutations in the GDAP1 gene have been reported in patients of different ethnic origins. In this study we report a novel mutation Met116Thr in the GDAP1 gene identified in a three generation Polish family with axonal CMT4.

Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models

Abstract  Recent studies have shown that mutations in neurofilament light subunit gene (NEFL) cause Charcot‐Marie‐Tooth (CMT) disease. Since the first description of the Gln333Pro mutation in the NEFL gene, 10 pathogenic mutations in the NEFL gene have been reported in patients affected with CMT disease. We report a novel I214M amino acid substitution in the NEFL gene in two unrelated patients affected with CMT. Because the I214M amino acid substitution in the NEFL protein was not detected in a CMT affected brother of the proband, its pathogenic effect became unclear. In order to determine whether this amino acid substitution is a benign polymorphism or causative of the disease, we performed a functional analysis of the mutant I214M neurofilament protein (NFL). Transfections of the mutant protein in cultured cells revealed an increased tendency to form highly compacted filamentous structures but no other alterations of neurofilament assembly or transport were observed. Furthermore, the sibling of one of the patients was also affected with CMT but did not have the I214M substitution. These data suggest that this I214M substitution in the NEFL gene was not a direct cause of the disease but could be a polymorphism or possibly a modifier of the CMT phenotype.

A patient with both Charcot-Marie-Tooth disease (CMT 1A) and mild spinal muscular atrophy (SMA 3).

In the present study, we report a single Polish SMA family in which the 17p11.2-p12 duplication causative for the Charcot-Marie-Tooth type 1A disease (CMT1A) was found in addition to a deletion of exons 7 and 8 of the SMN1 gene. A patient harboring both SMA and CMT1A mutations manifested with SMA3 phenotype and foot deformity. Her electrophysiological testing showed chronic neurogenic changes in proximal muscles that are typical for SMA, but also slowed conduction velocity in motor and sensory fibers that is typical for demyelinating neuropathy.

A novel mutation, Thr65Ala, in the MPZ gene in a patient with Charcot-Marie-Tooth type 1B disease with focally folded myelin.

Charcot-Marie-Tooth type 1B disease is a demyelinating neuropathy caused by mutations in the Myelin Protein Zero gene. It is inherited in an autosomal dominant fashion. So far only a few patients with a focally folded myelin phenotype on nerve biopsy have been shown to have mutations in the Myelin Protein Zero gene. In this report we describe a Polish patient with Charcot-Marie-Tooth type 1B disease. Sural nerve biopsy demonstrated focally folded myelin. Molecular genetic analysis of the coding region of the Myelin Protein Zero gene revealed a novel mutation, Thr65Ala, in exon 2 of the Myelin Protein Zero gene.

Phenomenon of Schwann cell apoptosis in a case of congenital hypomyelinating neuropathy with basal lamina onion bulb formation

We analyzed a sural nerve biopsy of a child with congenital hypomyelinating neuropathy. A lack of normally myelinated fibres, abnormal architecture of premyelin fibres and basal lamina onion bulbs were identified. The most prominent pathological finding was the appearance of significant death of Schwann cells with apoptotic morphology. This new finding may suggest that abnormal premyelin fibres are susceptible to death and that their disappearance is responsible for empty basal lamina onion bulb formation.

Dysmyelinating and demyelinating Charcot–Marie–Tooth disease associated with two myelin protein zero gene mutations

Mutations in the myelin protein zero (MPZ) gene are the third most frequent cause of hereditary motor and sensory neuropathies (HMSN), also called Charcot–Marie–Tooth disorders (CMT). Only in case of recurrent mutations occurring in the MPZ gene is it possible to draw phenotype–genotype correlations essential for establishing the prognosis and outcomes of CMT1. We have surveyed a cohort of 67 Polish patients from CMT families with demyelinating neuropathy for mutations in the MPZ gene. In this study, we report two CMT families in which the Ile135Thr and Pro132Leu mutations have been identified for the MPZ gene. These MPZ gene mutations had not been identified hitherto in the Polish population. The Pro132Leu mutation segregates with a severe early-onset dysmyelinating–hypomyelinating neuropathy, whereas the Ile135Thr substitution is associated with the classical phenotype of CMT1. To the best of our knowledge, we present here, for the first time, morphological data obtained in two sural nerve biopsies pointing to a hypomyelination–dysmyelination process in a family harboring the Pro132Leu mutation in the MPZ gene.