Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. METHODS: Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. RESULTS: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. CONCLUSIONS: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.

Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy.

The Warburg micro syndrome (WARBM) is a genetically heterogeneous syndrome linked to at least 4 loci. At the clinical level, WARBM is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, severe mental retardation, and hypogonadism. In some families additional clinical features have been reported. The presence of uncommon clinical features (peripheral neuropathy, cardiomyopathy) may result in misdirected molecular diagnostics. Using the next generation sequencing approach (NGS), we were able to diagnose WARBM1 syndrome by detection of a new mutation within the RAB3GAP1 gene. We have detected some DNA variants which may be responsible for cardiomyopathy. We did not find any obvious pathogenic mutation within a set of genes known to be responsible for hereditary motor and sensory neuropathy (HMSN). We conclude that: (i) in clinically delineated syndromes, a classical single-gene oriented approach may be not conclusive especially in the presence of rare clinical features, (ii) peripheral neuropathy and cardiomyopathy are rare additional symptoms coexisting with WARBM1, (iii) a pleiotropic effect of a single point mutation is sufficient to be causative for WARBM1 and (iv) more WARBM-affected patients should be reported to delineate a complete phenotype.

Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy.

Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1) kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2), with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.

The impact of assisted reproductive technologies on the genome and epigenome of the newborn.

The question of genetic alterations resulting from assisted reproductive technologies (ART) in humans is examined within the organization of the human genome. Increased rates of birth defects have been reported among children conceived using ART; however, questions remain and controversy exists regarding how "infertility" predisposes to birth defects. ART has been shown to be associated with an increased number of chromosomal alterations especially in the X chromosome. There is increased risk for embryonal tumors among ART conceived children, as well as, imprinting disorders (Beckwith-Wiedemann and Angelman Syndromes). Genetic studies of children conceived using ART reveal a larger (genome-wide) scale of methylation defects that encompass hundreds of genes. Genes involved in carcinogenesis and developmental pathways appear altered and may impact on later development of chronic illness, although these data are very preliminary. ART may create novel mutations by different chromosomal and molecular mechanisms; however, these techniques also enable propagation of pre-existing mutations that are associated with impaired fertility. While older maternal age is often associated with female infertility and chromosomal aneuploidy, sperm from older men have more new gene mutations. The prevalence of birth defects is increased when ART is used for conception. These data are summarized by large meta-analyses or from multi-year national registries. Whether the increased number of birth defects is due to ART procedures themselves or are a consequence of the impaired fertility of the parents is discussed. Long-term evaluation of children conceived using ART and/or ovarian hyper-stimulation is needed to determine whether alterations during embryonic development may increase the prevalence of chronic diseases in adulthood.

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

OBJECTIVE: Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. METHODS: We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. RESULTS: In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. CONCLUSIONS: With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling.

Charcot-Marie-Tooth type 1A disease caused by a novel Ser112Arg mutation in the PMP22 gene, coexisting with a slowly progressive hearing impairment.

Among 57 mutations in the peripheral myelin protein 22 gene (PMP22) identified so far in patients affected by Charcot-Marie-Tooth disease (CMT), only 8 have been shown to segregate with a mixed phenotype of CMT and hearing impairment. In this study, we report a new Ser112Arg mutation in the PMP22 gene, identified in a patient with early-onset CMT and slowly progressive hearing impairment beginning in the second decade of life. We suggest that the Ser112Arg mutation in the PMP22 gene might have a causative role in the early-onset CMT with hearing impairment. Thus, our study extends the spectrum of CMT phenotypes putatively associated with PMP22 gene mutations.

Screening of the 17p11.2--p12 region in a large cohort of patients with Charcot-Marie-Tooth (CMT) disease or hereditary neuropathy with liability to pressure palsies (HNPP).

Within the last decade, numerous methods have been applied to detect the most common mutation in patients affected with Charcot-Marie-Tooth (CMT) disease, i.e. submicroscopic duplication in the 17p11.2--p12 region. In 1993, another neuropathy - known as hereditary neuropathy with liability to pressure palsies (HNPP) - has been shown to be caused by a 17p11.2--p12 deletion. Historically, Southern blot analysis was the first approach to identify CMT1A duplication or HNPP deletion. This time- and labor-consuming method requires prior selection of DNA samples. In fact, only CMT patients affected with the demyelinating form of CMT1 have been screened for CMT1A duplication. After the 17p11.2--p12 duplication was identified in the CMT1 families, subsequent studies revealed additional axonal features in the patients harboring the 17p11.2--p12 duplication. Thus it seems reasonable to test all patients affected with CMT for the presence of the 17p11.2--p12 duplication. To evaluate the utility of real-time polymerase chain reaction (Q-PCR) and restriction fragment length polymorphism PCR (RFLP-PCR), we screened a large group of 179 families with the diagnosis of CMT/HNPP for the presence of the 17p11.2--p12 duplication/deletion. Due to a high frequency of CMT1A duplication in familial cases of CMT, we propose (in contrast to the previous studies) to perform Q-PCR analysis in all patients diagnosed with CMT.

Mild form of Charcot-Marie-Tooth type 1X disease caused by a novel Cys179Gly mutation in the GJB1/Cx32 gene.

Charcot-Marie-Tooth type 1X (CMT1X) disease is inherited as an X-linked dominant trait. Female CMT1X patients are usually mildly affected or even asymptomatic carriers of mutations in the GJB1 gene coding for a gap junction protein called connexin-32 (Cx32). In this report, a five-generation CMT1X family is described from which the new mutation in the GJB1 gene Cys179Gly was identified. The Cys179Gly mutation is located in the highly conservative domain of the Cx32 protein. Previous functional studies performed in the oocyte system have shown that point mutations in the highly conserved Cx32 cysteine residues result in a complete loss of function of the gap junction. However, despite severe biochemical defects, the Cys179Gly mutation segregates with a mild CMT1X phenotype. This study further documents a discrepancy between biochemical effects of GJB1 mutations and the CMT1X phenotype.

Charcot-Marie-Tooth disorders with an autosomal recessive mode of inheritance.

In recent years, 13 loci and 10 genes have been identified in Charcot-Marie-Tooth disorders with a recessive mode of inheritance (AR-CMT). Accordingly, the entity of AR-CMT has been divided into subgroups on the basis of genetic linkage. Mutations in the MTMR2, MTMR13, GDAP1, PRX, CTDPI, KIAA1985 and NDRG1 genes have been shown to be associated with specific CMT phenotypes. In AR-CMT disorders associated with mutations in the LMNA and MED25 genes the number of patients is still too low to achieve reliable phenotype-genotype correlations. In the present review, we summarize molecular, electrophysiological, neuropathological and clinical aspects of AR-CMT disorders.

Charcot-Marie-Tooth disease type 4C4 caused by a novel Pro153Leu substitution in the GDAP1 gene.

Charcot-Marie-Tooth type 4C4 disease (CMT4C4) is an early onset, autosomal recessive neuropathy with hoarseness caused by mutations in the GDAP1 gene which maps to the 8q13 region. To date, only 24 mutations in the GDAP1 gene have been reported. Neuropathological findings of sural nerve biopsies have been published for a limited number of CMT4C4 patients. Herein, a novel Pro153Leu mutation in the GDAP1 gene identified in a consanguineous Polish family is described and longitudinal clinical and electrophysiological studies as well as morphological findings are presented.

Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene.

Mutations in the ganglioside -induced differentiation-associated protein 1 (GDAP1) gene are common a cause of the Charcot-Marie-Tooth (CMT4A) disease with autosomal recessive mode of inheritance. To date more than twenty mutations in the GDAP1 gene have been reported in patients suffering from the demyelinating, axonal or mixed form of Charcot-Marie-Tooth disease. Only in a few CMT4A affected patients sural nerve biopsy findings have been provided. We report a homozygous Leu239Phe mutation in the GDAP1 gene in a 39-year-old female with a severe form of mixed axonal and demyelinating Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth type 4F disease caused by S399fsx410 mutation in the PRX gene.

Charcot-Marie-Tooth type 4F disease (CMT4F) is an autosomal recessive neuropathy caused by mutations in the PRX gene. To date, only seven mutations have been identified in the PRX gene. In this study, the authors report a novel S399fsX410 mutation in the PRX gene and its effects at the protein level, which was identified in an 8-year-old patient with early-onset CMT disease.

Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene.

A recessive demyelinating subtype of Charcot-Marie-Tooth disease called CMT4 is a heterogeneous group of disorders. A relatively frequent form of recessive CMT (CMT4 A) has been mapped to the chromosome 8 q21 and shown to be caused by mutations in the ganglioside-induced differentiation protein 1 (GDAP1) gene. Twenty mutations in the GDAP1 gene have been reported in patients suffering from the axonal and demyelinating forms of CMT disease. In this study we report two novel mutations in the GDAP1 gene in a patient suffering from CMT2 disease and whose parents were asymptomatic carriers of a Ser130Cys and 3'-splice site (311-1G > A) mutation, respectively.

Mild early onset axonal Charcot-Marie-Tooth disease not linked to other axonal Charcot-Marie-Tooth loci.

Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2) is a heterogeneous group of disorders with seven chromosomal loci mapped in the uncomplicated forms of CMT2. The authors report clinical, electrophysiologic, and genetic analysis of a Polish CMT2 family. Nine known CMT2 gene loci and one MPZ gene locus have been excluded. The authors' findings suggest that this family represents a novel form of CMT2 disease.

Mutations in the Myelin Protein Zero result in a spectrum of Charcot-Marie-Tooth phenotypes.

Initially the Myelin Protein Zero gene was shown to be mutated in the demyelinating form of Charcot-Marie-Tooth disease (CMT1). The vast majority of the mutations in the Myelin Protein Zero gene have been detected in the Charcot-Marie-Tooth (1B) disease, however, some of them were found in patients suffering from congenital hypomyelinating neuropathy and axonal type Charcot-Marie-Tooth disease. In this study, a Charcot-Marie-Tooth disease phenotype diversity associated with different mutations in the MPZ gene, is described.

A novel MPZ gene mutation in congenital neuropathy with hypomyelination.

Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.

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.

Focally folded myelin in Charcot-Marie-Tooth type 1B disease is associated with Asn131Lys mutation in myelin protein zero gene: short report.

Charcot-Marie-Tooth disease type 1B (CMT1B) is a demyelinating neuropathy inherited as an autosomal dominant trait. The majority of CMT1B cases are caused by mutations in the myelin protein zero (P0) gene (MPZ). Only a few mutations in MPZ gene have been reported to be associated with focally folded myelin sheaths. We have studied five patients from one family with five generations, affected by CMT1B disease. The morphological studies of sural nerve biopsy performed in the proband revealed fibers with focally folded myelin. DNA sequencing analysis showed the Asn131Lys mutation in the MPZ gene in three members of the affected family.

DNA damage induced by lithotripter generated shock waves: short report.

The side effects of shock waves on biological tissues have been intensively investigated in past years. In contrast to the morphological studies, only a little information exists up to now about molecular effects of shock waves at the DNA level. To study the shock wave effects on DNA in water solution, 100, 500, 1,000, 1,500 wave shocks, generated with a experimental lithotripter, were applied at 18 kV and 20 kV, corresponding to the positive pressure peaks of 16 and 30 MPa and negative ones of 5 and 9 MPa. The DNA damage was evaluated in two "submarine" electrophoresis approaches. In the first - standard DNA electrophoresis - no DNA damage was detected, confirming previously described results. In the second electrophoresis, performed under changed conditions, sever double strand DNA damage was found. Our results strongly suggest that shock waves applied at the therapeutical level of energy may generate the double strand DNA damage.