Publications (32)182.24 Total impact
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Article: Czech family confirms the link between FBLN5 and Charcot-Marie-Tooth type 1 neuropathy.
Brain 01/2013; · 9.46 Impact Factor -
Article: Clinical, In Silico, and Experimental Evidence for Pathogenicity of Two Novel Splice Site Mutations in the SH3TC2 Gene.
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ABSTRACT: Charcot-Marie-Tooth (CMT) neuropathy is the most common inherited neuromuscular disorder. CMT is genetically very heterogeneous. Mutations in the SH3TC2 gene cause Charcot-Marie-Tooth neuropathy type 4C (CMT4C), a demyelinating form with autosomal recessive inheritance. In this study, two novel splice site mutations in the SH3TC2 gene have been studied (c.279G → A, c.3676-8G → A). Mutation c.279G → A was detected on one allele in two unrelated families with CMT4C in combination with a known pathogenic mutation (c.2860 C →T in one family, c.505T → C in the other) on the second allele of SH3TC2 gene. Variant c.3676-8G → A was detected in two patients from unrelated families on one allele of the SH3TC2 gene in combination with c.2860C →T mutation on the other allele. Several in silico tests were performed and exon trap experiments were undertaken in order to prove the effect of both mutations on proper splicing of SH3TC2. Fragments of SH3TC2 were subcloned into pET01 exon trap vector (Mobitec) and transfected into COS-7 cells. Aberrant splicing was predicted in silico for both mutations, which was confirmed by exon trap analysis. For c.279G → A mutation, 19 bases from intron 3 are retained in cDNA. The mutation c.3676-8G→ A produces a novel splice acceptor site for exon 17 and complex changes in splicing were observed. We present evidence that mutations c.279G → A and c.3676-8G →A in the SH3TC2 gene cause aberrant splicing and are therefore pathogenic and causal for CMT4C.Journal of neurogenetics 09/2012; · 0.73 Impact Factor -
Article: DFNB35 due to a novel mutation in the ESRRB gene in a Czech consanguineous family.
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ABSTRACT: Non-syndromic hearing loss (NSHL) is a genetically heterogeneous disorder with mostly autosomal recessive inheritance. So far 40 genes and the same amount of loci with as yet unknown genes were described with autosomal recessive NSHL. A consanguineous Czech family with a child with NSHL was genotyped using SNP array and homozygous regions were compared with previously reported DFNB loci. GRXCR1 and ESRRB genes associated with autosomal recessive NSHL were located in two of the eight homozygous regions detected by SNP array genotyping. Mutation p.R291L in a homozygous state was found in the deaf child, the parents were heterozygous. The entire coding region of the ESRRB gene was sequenced in additional 39 patients of Czech origin with early NSHL and only two variants, p.V413I and p.P386S, were found in homozygous state, but are considered to be polymorphisms. Homozygosity mapping is a powerful method for identification of genes in heterogeneous recessive diseases. This is the first report of DFNB35 mutations in the Czech Republic and it seems to be a rare cause of NSHL. Additional mutations in ESRRB gene were reported in Pakistan, Tunisia and Turkey.International journal of pediatric otorhinolaryngology 08/2012; 76(11):1681-4. · 0.85 Impact Factor -
Article: Charcot-Marie-Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype--usefulness of human mapping chip linkage analysis in a Czech family.
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ABSTRACT: Charcot-Marie-Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 - missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient's healthy father.Neuromuscular Disorders 04/2012; 22(8):742-6. · 2.80 Impact Factor -
Article: Four novel point mutations in the PMP22 gene with phenotypes of HNPP and Dejerine-Sottas neuropathy.
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ABSTRACT: We report four novel point mutations in the PMP22 gene with two different phenotypes: mutation p.Ser79Thr arose de novo in a patient with the Dejerine-Sottas neuropathy (DSN) phenotype; and mutations c.78+5 G>A, c.320-1 G>C, and p.Trp140Stop segregated with HNPP in 5 families.Our findings show that point mutations in PMP22 may be more likely in HNPP patients than in CMT1 patients after exclusion of CMT1A/HNPP.Muscle & Nerve 11/2011; 44(5):819-22. · 2.37 Impact Factor -
Article: [Heterozygous carriers of Slavic mutation 657del5 of NBN gene in patients with colorectal cancer].
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ABSTRACT: Nijmegen breakage syndrome (NBS) is one of the chromosomal instability syndromes due to DNA repair disorder. The syndrome is autosomal recessive determined, in homozygotes is characterized by many disorders including high predisposition to lymphoreticular malignancy in childhood and adolescence. Laboratory findings represent low level of immunoglobulins, B and T lymphocytes, increased sensitivity to the mutagens, especially hyperradiosensitivity and increased chromosomal instability. Heterozygotes show also elevated radiosensitivity and have an increased cancer risk in adult age. There is no predilection of the malignancy. Colorectal cancer was found often among the relatives of patients with NBS. Majority of the NBS patients are of the Central and Eastern European origin and carry the common founder mutation 657del5 in the NBN gene. The formation of second malignancy both in homozygotes and heterozygotes can be prevented by excluding any radiation. The aim of study is estimation of frequency of 657del5 heterozygotes among patients with colorectal cancer. Within a group of 161 patients with colorectal cancer 5 heterozygotes with 657del5 mutation were registered, e.g. 5-times higher incidence than expected. The elemental prevention in patients with proved positivity of Slavic mutation in NBN gene is to exclude any radiation.Casopís lékar̆ů c̆eských 01/2011; 150(2):97-9. -
Article: Utility of Charcot-Marie-Tooth Neuropathy Score in children with type 1A disease.
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ABSTRACT: The aim of this study was to evaluate the utility of the Charcot-Marie-Tooth Neuropathy Score (CMTNS) for evaluation of disease severity in young children with Charcot-Marie-Tooth type 1A. Current validated scoring scales for Charcot-Marie-Tooth are the CMTNS and the Neuropathy Impairment Score (NIS). Both work well for adult patients, and usually also for children over 10 years of age. There is no validation of scales for young children. Children with genetically proven Charcot-Marie-Tooth type 1A disease (n = 20, aged 3 to 10 years) were examined clinically, followed by electrophysiologic examination, and were scored under the CMTNS scale. The clinical symptoms were mild; the two most frequent symptoms were difficulty in heel walking and lower limb areflexia. The score was maximally abnormal in four of the nine categories. Categories for sensation, sensory symptoms, and motor symptoms of the arms were normal in all cases. The score was below 8 for all tested children. To conclude, the CMTNS in children aged 10 years and younger has limited sensitivity; out of nine categories, only four are useful. Thus, evaluation of disease severity and progression in young children with Charcot-Marie-Tooth disease remains limited, and there is need for other, effective scoring systems.Pediatric Neurology 12/2010; 43(6):407-10. · 1.52 Impact Factor -
Article: Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.
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ABSTRACT: Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.The American Journal of Human Genetics 10/2010; 87(4):513-22. · 10.60 Impact Factor -
Article: Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without Enlarged Vestibular Aqueduct (EVA).
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ABSTRACT: Mutations in SLC26A4 cause Pendred syndrome (PS) - hearing loss with goitre - or DFNB4 - non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2-negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral - 19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings.Annals of Human Genetics 07/2010; 74(4):299-307. · 2.57 Impact Factor -
Article: Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability.
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ABSTRACT: Genomic rearrangements involving the peripheral myelin protein gene (PMP22) in human chromosome 17p12 are associated with neuropathy: duplications cause Charcot-Marie-Tooth disease type 1A (CMT1A), whereas deletions lead to hereditary neuropathy with liability to pressure palsies (HNPP). Our previous studies showed that >99% of these rearrangements are recurrent and mediated by nonallelic homologous recombination (NAHR). Rare copy number variations (CNVs) generated by nonrecurrent rearrangements also exist in 17p12, but their underlying mechanisms are not well understood. We investigated 21 subjects with rare CNVs associated with CMT1A or HNPP by oligonucleotide-based comparative genomic hybridization microarrays and breakpoint sequence analyses, and we identified 17 unique CNVs, including two genomic deletions, ten genomic duplications, two complex rearrangements, and three small exonic deletions. Each of these CNVs includes either the entire PMP22 gene, or exon(s) only, or ultraconserved potential regulatory sequences upstream of PMP22, further supporting the contention that PMP22 is the critical gene mediating the neuropathy phenotypes associated with 17p12 rearrangements. Breakpoint sequence analysis reveals that, different from the predominant NAHR mechanism in recurrent rearrangement, various molecular mechanisms, including nonhomologous end joining, Alu-Alu-mediated recombination, and replication-based mechanisms (e.g., FoSTeS and/or MMBIR), can generate nonrecurrent 17p12 rearrangements associated with neuropathy. We document a multitude of ways in which gene function can be altered by CNVs. Given the characteristics, including small size, structural complexity, and location outside of coding regions, of selected rare CNVs, their identification remains a challenge for genome analysis. Rare CNVs may potentially represent an important portion of "missing heritability" for human diseases.The American Journal of Human Genetics 06/2010; 86(6):892-903. · 10.60 Impact Factor -
Article: L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.
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ABSTRACT: Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.Neurogenetics 03/2010; 11(3):357-66. · 3.35 Impact Factor -
Article: Six new gap junction beta 1 gene mutations and their phenotypic expression in Czech patients with Charcot-Marie-Tooth disease.
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ABSTRACT: X-linked Charcot-Marie-Tooth (CMTX) disease is a hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 gene (GJB1 codes for connexin 32). In this study we report six novel mutations p.Met1Arg, p.Leu9Phe, p.Ser17Tyr, p.Val63Phe, p.Val170Ile, and p.Leu212Phe in GJB1 and their phenotypic expression. These mutations affect both intracellular and extracellular parts of the GJB1 protein. The screened patients had previously excluded the duplication/deletion on 17p11.2 and the male-to-male transfer in the pedigree. Except p.Val170Ile, all reported mutations segregated with the CMT phenotype in the families and caused CMTX1 neuropathy. Mutations were not found in 200 control DNA samples. Additionally, we performed in silico analysis of the novel mutations with the program PANTHER. The PANTHER scored five mutations, all but p.Val170Ile, as likely deleterious and supported the pathogenicity of the found mutations. These results provided evidence that these five mutations are causative for CMTX1.Genetic Testing and Molecular Biomarkers 02/2010; 14(1):3-7. · 1.11 Impact Factor -
Article: GJB2 mutations in patients with nonsyndromic hearing loss from Croatia.
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ABSTRACT: The aim of the study was to determine (1) the frequency and type of mutations in the coding region of the GJB2 gene (sequencing), (2) the frequency of splice site mutation IVS1 + 1G > A in the GJB2 gene (multiplex ligation-dependent probe amplification analysis), (3) possible copy number changes in the GJB2, GJB3, GJB6, and WFS1 genes (multiplex ligation-dependent probe amplification analysis), and (4) the frequency of del(GJB6-D13S1830) in the GJB6 gene in 58 unrelated patients with nonsyndromic hearing loss from Croatia. About 44.8% of our patients presented with mutation in the GJB2 gene. We identified seven sequence variations. Six of them had previously been reported as disease related (35delG, W24X, V37I, L90P, 313del14, and IVS1 + 1G > A), and we report here for the first time one novel variant, -24A > C. We detected the greatest frequency of 35delG allele compared to the other alleles (35.3%). Allelic frequencies of other common mutations accounted for 2.6-0.9% of analyzed chromosomes. Neither GJB6 deletion nor copy number changes in the GJB2, GJB3, GJB6, and WFS1 genes were found. The 35delG/35delG genotype was associated with severe to profound hearing loss in 94% of 35delG homozygotes. High mutation rate (44%) indicates that testing of the GJB2 gene will clarify the genetic cause in almost half of the cases of recessive nonsyndromic hearing loss in Croatia.Genetic Testing and Molecular Biomarkers 10/2009; 13(5):693-9. · 1.11 Impact Factor -
Article: Emery-Dreifuss muscular dystrophy: a novel mutation in the LMNA gene.
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ABSTRACT: Described here is the phenotypical expression of a novel LMNA mutation c.1157 G>T in a Czech patient with an early-onset form of Emery-Dreifuss muscular dystrophy. The mutation predicts aberrant splicing. Now 21 years old, the patient has had slowly progressing muscle dystrophy since the age of one and early contractures of elbows. He is the only family member affected. Even though the dystrophy typically affects the heart as well, in the present case these signs are not yet expressed.Pediatric Neurology 08/2009; 41(2):127-30. · 1.52 Impact Factor -
Article: Mutations in the LMNA gene do not cause axonal CMT in Czech patients.
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ABSTRACT: The LMNA gene was sequenced in 98 Czech patients from 94 unrelated families with early-onset axonal Charcot-Marie-Tooth (CMT) disease consistent with both autosomal recessive inheritance and sporadic cases. Biallelic pathogenic mutations were not found in any patient in this group. One patient carried the c.1870C>T mutation that is predicted to result in the amino-acid substitution, p. Arg624Cys, on one allele, but the second causative mutation was not detected. LMNA mutation is not likely to be associated with the disease in this family. To exclude larger deletions/duplications in the LMNA gene not detectable by sequencing, 48 patients from this group were also analyzed with multiplex ligation-dependent probe amplification. No rearrangements in the LMNA gene were detected. We conclude that mutations in the LMNA gene are absent from a large group of Czech patients with axonal autosomal recessive CMT disease. Consequently, LMNA mutation screening does not seem to be relevant for axonal CMT DNA diagnostics. A similar situation may apply to other European populations.Journal of Human Genetics 05/2009; 54(6):365-8. · 2.57 Impact Factor -
Article: Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.
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ABSTRACT: Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 x 10(-3) and 1 x 10(-4). This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.European journal of human genetics: EJHG 12/2008; 17(4):517-24. · 3.56 Impact Factor -
Article: Abnormal corticospinal tract modulation of the soleus H reflex in patients with pure spastic paraparesis.
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ABSTRACT: Central motor conduction time (CMCT) is usually abnormally prolonged in leg muscles of patients with pure hereditary spastic paraparesis (PHSP). One consequence of such abnormality should be an abnormal timing in the modulation of segmental reflexes, which might be more relevant for the pathophysiology of spasticity-related gait disturbances than just the CMCT delay. We examined the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex in 13 control subjects and 11 PHSP patients using a conditioning (TMS) and test (H reflex) paradigm. Interstimulus interval (ISI) was 0-100 ms in steps of 10 ms. The amplitude of the H reflex at each interval was expressed as percentage of the control H reflex and the conditioned curves were compared between control subjects and patients. In control subjects, TMS-induced facilitation of the H reflex with two well-defined phases: early (ISIs 10 and 20 ms) and late (ISIs 70-90 ms). In patients, the early phase of facilitation was significantly reduced, while there was facilitation at 40 ms that was not present in control subjects. However, neither the characteristics of the MEP nor the differential modulation of the H reflex correlated significantly with clinical measures of motor dysfunction. Our results indicate an abnormal effect of TMS on the H reflex in PHSP patients. This suggests that the excitability of interneurons and soleus motoneurons is not modified in tune with the arrival of descending inputs. Desynchronization of the descending volley may contribute to both the lack of early facilitation and the presence of abnormal facilitatory phases.Neuroscience Letters 06/2008; 437(1):15-9. · 2.11 Impact Factor -
Article: Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.
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ABSTRACT: Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.Brain 06/2008; 131(Pt 5):1217-27. · 9.46 Impact Factor -
Article: Cancer risk of heterozygotes with the NBN founder mutation.
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ABSTRACT: The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk. Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided. Thirteen of the 344 blood relatives had confirmed cases of any type of cancer; 11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P = .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004). The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes.CancerSpectrum Knowledge Environment 01/2008; 99(24):1875-80. · 14.07 Impact Factor -
Article: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
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ABSTRACT: To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.Archives of Neurology 06/2007; 64(5):706-13. · 7.58 Impact Factor
Top co-authors
Top Journals
- Brain (4)
- Archives of Neurology (2)
- Genetic Testing (2)
- Muscle & Nerve (2)
- The American Journal of Human Genetics (2)
Institutions
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2002–2013
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University Hospital Motol
Praha, Hlavni mesto Praha, Czech Republic
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2004–2012
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Charles University in Prague
- • Klinika dětské neurologie (2. LF)
- • 1. lékařská fakulta
- • 2. lékařská fakulta
Praha, Hlavni mesto Praha, Czech Republic
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2004–2010
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University of Antwerp
- VIB Department of Molecular Genetics
Antwerpen, VLG, Belgium
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2006
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Vlaams Instituut voor Biotechnologie
- Genetics and Molecular Techniques
Gent, VLG, Belgium
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