WITHDRAWN: Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.pjnns.2018.02.008. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients.

INTRODUCTION: Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively. METHODS: Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases. RESULTS: The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) - DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (< 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles-188 bp and 196 bp without common interruptions. CONCLUSION: The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1).

Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals.

Hereditary spastic paraplaegias are a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. The most common forms of hereditary spastic paraplaegia are SPG4 and SPG3A caused by sequence variants in the SPAST and ATL1 genes, as well as by deletions and duplications not detected by standard techniques. In this study, we used the multiplex ligation-dependent probe amplification (MLPA) analysis for screening 93 patients (52 familial and 41 isolated cases). As a result, we identified 11 different deletions and 1 duplication in the SPAST gene and a single exon deletion in the ATL1 gene. These results indicate that micro-rearrangements in the SPAST gene are a fairly frequent cause of hereditary spastic paraplaegia and that MLPA is a useful and efficient technique to detect a considerable proportion of the mutations in the most common forms of hereditary spastic paraplaegias.

Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings.

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

The occurrence of spinocerebellar ataxias caused by dynamic mutations in Polish patients.

BACKGROUND AND PURPOSE: Autosomal dominant spinocerebellar ataxias (SCAs) belong to a group of neurodegenerative disorders usually of adult age at onset. Predominant clinical features are progressive ataxia, dysarthria, as well as pyramidal signs and polyneuropathy. Molecular analysis allows particular types of SCA to be distinguished. Genetic tests are applied in 10 types of SCA resulting from dynamic mutations: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17 and DRPLA. MATERIAL AND METHODS: DNA samples from 1598 patients with ataxia symptoms were analysed to establish the number of CAG/CTG repeats in respective genes excluding SCA10. RESULTS: We diagnosed 224 cases of SCA1 (120 families) and 49 cases of SCA2 (23 families). Moreover, presymptomatic testing was done in 85 individuals from SCA1 families and for 21 cases from SCA2 families. An increased number of CTG repeats in the SCA8 gene was observed in 14 families and in 3 families a rare type of SCA, SCA17, was detected. CONCLUSIONS: Our data suggest that frequencies of some types of SCA in Poland are different from those in other European countries, with irregular distribution within the country. The most frequent types are SCA1 and SCA2. A striking feature of the Polish population is the lack of SCA3 - the most frequent type in Western Europe.

[Detection of rare mutations in the dystrophin gene]. / Wykrywanie rzadkich mutacji w genie dystrofiny.

INTRODUCTION: Duchenne/Becker muscular dystrophies (DMD/BMD) are allelic X-linked, recessive proximal muscle disorders, caused by mutations in the dystrophin gene located in Xp21. DMD occurs with the incidence 1:3500, BMD with the incidence of 1:18,500 new-born males. Approximately about 60% of mutations in the dystrophin gene are deletions, 10%--duplications and 30%--point mutations. AIM: The aim of the study was detection of the mutations: rare deletions, duplications and point mutations in the dystrophin gene in patients diagnosed as DMD/BMD in whom the presence of the most common deletions had previously been excluded. MATERIALS AND METHODS: Molecular analysis was performed using DNA samples isolated from 105 DMD and 10 BMD patients. Detection of rare deletions and duplications was carried out by Multiplex Ligation-dependent Probe Amplification (MLPA). Point mutations were identified by analysis of single strand conformation polymorphism (SSCP) and DNA sequencing. RESULTS: 38 Different mutations were detected: 10 rare deletions, 14 duplications and 14 point mutations and microdeletions. Majority of the detected rare deletions (7 out of 10) and point mutations (11 out of 14) are novel mutations. CONCLUSIONS: Application of MLPA technique allows the detection of small, rare deletions and duplications. Identification of the nature and localization of the mutations may, in the future, help to apply appropriate therapeutic approaches in DMD patients.

Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington's disease and without mutation in the IT15 gene.

BACKGROUND AND PURPOSE: The aim of this study was to perform DNA analysis in patients with clinical diagnosis of Huntington's disease (HD) after molecular exclusion of HD and further molecular examinations for other neurodegenerative diseases such as Huntington's disease-like 2 (HDL-2; gene JPH3), dentatorubral pallidoluysian atrophy (DRPLA; gene ATN1) and spinocerebellar ataxia type 17 (SCA17; gene TBP). MATERIAL AND METHODS: The material comprised 224 DNA samples isolated from peripheral blood from patients suspected of HD and 100 DNA samples from unaffected controls. The control group was used to determine the normal range of the number of CAG/CTG repeats in genes JPH3, ATN1 and TBP in the Polish population. Molecular analysis was carried out by PCR reaction, embracing microsatellite repeats in genes JPH3, ATN1 and TBP with specific, fluorescently labelled primers. PCR products were separated in polyacrylamide gels. The normal ranges of the number of repeats established for the control group in genes JPH3, ATN1 and TBP were 7-19, 9-27 and 29-45, respectively. RESULTS: Molecular analysis of DNA from 224 individuals suspected of HD (117 women and 107 men) revealed one case of dynamic mutation - 55 CAG repeats - in the TBP locus (SCA17). No cases of DRPLA or HDL-2 were detected. The range of CAG/CTG repeats for the JPH3 gene in the patient group was 11-19, with the most common alleles containing 14 and 16 repeats. For the ATN1 gene in patients the range of 8-27 repeats was established and the most frequent allele with 16 triplets was present. CONCLUSIONS: The study on 244 patients referred with the clinical diagnosis of HD and without mutation of the IT15 gene revealed one case of SCA17 but did not disclose the presence of two other diseases with a similar clinical manifestation: DRPLA and HDL2.

Screening for premutation in the FMR1 gene in male patients suspected of spinocerebellar ataxia.

BACKGROUND AND PURPOSE: The aim of this study was to determine the molecular basis of the disorder in patients suspected of spinocerebellar ataxias (SCAs) and search for premutation in the FMR1 gene causing FXTAS among patients in whom 9 SCA types were previously excluded. MATERIAL AND METHODS: DNA obtained from 1385 patients suspected of SCA and 516 controls were used for molecular tests. DNA analysis was carried out by PCR reaction with specific primers. PCR products were separated in denaturing polyacrylamide gels in an ABIPrism 377 sequencer. Amplification of polymorphic regions embracing trinucleotide repeats was performed in the following genes: ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN80S (SCA8), PPP2R2B (SCA12), TBP (SCA17), ATN1 (DRPLA). Afterwards, a search for FXTAS caused by premutation in the FMR1 gene was performed. Two hundred and sixty-nine subjects selected from the study group with 9 excluded types of SCAs were tested; a subgroup of 178 males aged 50 years was sorted out. RESULTS: Molecular analysis in 1385 individuals revealed SCA1 in 225, SCA2 in 56, SCA8 in 33, SCA17 in 4 subjects. SCA3, SCA6, SCA7, SCA12, and DRPLA were not detected. Within the subgroup aged>or=50 years with ataxia in whom 9 types of SCAs were excluded only one case of FXTAS was detected, which is 1/178 (0.56%), and within the group of males>or=70 years (n=19) one case was also found (5.26%). CONCLUSIONS: The low frequency of FXTAS in the studied material probably results from the fact that the syndrome is much more common in elderly persons (penetrance of the pathogenic premutation gene is higher among elderly individuals).

[A study on the occurrence of the deletion 22q11.2 in patients affected with a psychiatric disease]. / Badania nad wystepowaniem delecji 22q11.2 u osób z choroba psychiczna.

AIM: The aim of the study was an estimation of the rate of deletion 22q11.2 among psychiatric patients and an attempt at the assessment of the degree in which this rate is influenced by the coexistence of dysmorphic features and congenital defects. METHODS: Cytogenetic examination was performed in 255 patients with psychosis. Patients were divided into two groups. Group I was composed of 61 patients with psychosis and at least two phenotypic features characteristic of 22q11.2 deletion syndrome (22q11DS), group II was composed of 194 patients with psychosis without phenotypic features of 22q11DS. Banding and fluorescence in situ hybridization (FISH) techniques were applied. RESULTS: 22q11.2 deletion was found in 3/61 patients of group I (4.9%) and in 3/255 among all psychiatric patients (1.2%). This incidence was significantly higher than in the general population (p < 0.001). The frequency of the deletion was even higher among psychiatric patients revealing phenotypic features of 22q11DS: 3/61 (4.9%) (p < 0.0001). In all the cases with the deletion, the phenotype features were characteristic of 22q11DS. Three other psychiatric patients had sex chromosomes' aberrations: 47, XYY, 47, XXY and 47, XXX. Moreover one case of balanced translocation t(2;10) (q10; q10) was detected. Conclusions. (1) 22q11.2 deletion was found to be 40 times more common among psychiatric patients than in the general population; sex chromosome aberrations are also significantly more common than in the general population. (2) The presence of dysmorphic features and some congenital defects in psychiatric patients increases the rate of deletion 22q11.2 significantly.

Reliability and validity of the International Cooperative Ataxia Rating Scale: a study in 156 spinocerebellar ataxia patients.

To evaluate the efficacy of treatments in spinocerebellar ataxias (SCAs), appropriate clinical scales are required. This study evaluated metric properties of the International Cooperative Ataxia Rating Scale (ICARS) in 156 SCA patients and 8 controls. ICARS was found to be a reliable scale satisfying accepted criteria for interrater reliability, test-retest reliability, and internal consistency. Although validity testing was limited, we found evidence of validity of ICARS when ataxia disease stages and Barthel index were used as external criteria. On the other hand, our study revealed two major problems associated with the use of ICARS. First, the redundant and overlapping nature of several items gave rise to a considerable number of contradictory ratings. Second, a factorial analysis showed that the rating results were determined by four different factors that did not coincide with the ICARS subscales, thus questioning the justification of ICARS subscore analysis in clinical trials.

[Spinocerebellar ataxias type 1 and 2: comparison of clinical, electrophysiological and magnetic resonance evaluation]. / Ataksja rdzeniowo-mózdzkowa typu 1 i 2 - porównanie oceny klinicznej, elektrofizjologicznej i rezonansu magnetycznego.

BACKGROUND AND PURPOSE: Spinocerebellar ataxias type 1 (SCA1) and type 2 (SCA2) belong to neurodegenerative disorders of autosomal dominant inheritance, genetically and clinically heterogeneous, caused by the expansion of CAG trinucleotides. Trunk and limb ataxia, dysarthria, dysphagia, gaze palsy, sensory and motor axonal neuropathy are the dominant features in both entities. The aim of the study was to evaluate the differences between genotype and phenotype based on clinical and electrophysiological assessment of the visual, auditory pathways, and EEG alterations in comparison with the cerebellar and brain atrophy in MRI. MATERIAL AND METHODS: 44 patients with SCA1 and 24 cases with SCA2 confirmed molecularly were examined neurologically and using the International Cooperative Ataxia Rating Scale (ICARS). A correlation of clinical symptoms and signs, and CAG repeat numbers with EEG, visual (VEP) and brainstem auditory (BAEP) evoked potentials, and MRI alterations were evaluated. RESULTS: A statistically significant negative correlation between the age of disease onset and number of CAG repeats in both types of SCA was found. Examined patients with SCA2 were younger, with longer disease duration and more pronounced cerebellar and brain atrophy in MRI. We found a significant correlation between ICARS and CAG repeats in this group. The dysphagia, pyramidal tract involvement and depressive reaction were significantly frequent in SCA1 patients. However in SCA2 patients, the peripheral nerve damage and extrapyramidal signs were more prominent. The amplitude of P100 visual evoked potentials was significantly lower in SCA1 patients and negatively correlated with CAG repeats. CONCLUSIONS: These results provide further evidence for the phenotypic differences of genetically defined SCA1 and SCA2 patients, expressed by more frequent involvement of the pyramidal tract and depression reaction in SCA1, in contrast to peripheral nerve involvement and extrapyramidal signs in the clinical feature of SCA2 phenotype. Furthermore, atrophy of the brain and cerebellum revealed in MRI was more pronounced than electrophysiological functional alterations, especially in SCA2. The decreased amplitude of P100 VEP in SCA1 patients was the only electrophysiological parameter differentiating between both groups of patients.

[MELAS--mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome--two cases confirmed by biochemical and molecular investigations. Differential diagnosis of stroke causes]. / Zespól MELAS--mitochondrialna encefalomiopatia z kwasica mleczanowa i epizodami udaropodobnymi: przypadki potwierdzone biochemicznie i molekularnie oraz diagnostyka róznicowa przyczyn udarów.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a maternally inherited multisystem disease caused by mutations of the mitochondrial DNA. The characteristic clinical features are: encephalopathy manifesting as dementia and seizures, stroke-like episodes at young age (usually < 40), lactic acidosis and myopathy with ragged-red fibres. Other frequent manifestations include: sensorineural deafness, diabetes, hypoparathyroidism, peripheral neuropathy and cardiomyopathy. We present two patients with MELAS who were diagnosed 4 and 9 years respectively following the onset of the disease despite the characteristic clinical pictures. The differential diagnostics of inborn and acquired disorders causing stroke is included. We regard that mitochondrial diseases are still insufficiently known and are frequently misdiagnosed. The knowledge is indispensable for establishing diagnosis and accurate genetic counselling. Although there is no specific therapy for mitochondrial diseases to date, coenzyme Q and various vitamins as well as moderate degree exercise might be recommended.

[Clinical and genetic study of juvenile form of Huntington's disease]. / Badania kliniczne i genetyczne w mlodzienczej postaci choroby Huntingtona.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by high instability and extension of CAG sequences within the coding region of IT15 gene. It affects both sexes and age at onset of the disease may be different but usually occurs in midlife. The term Juvenile Huntington's disease is generally applied to 10% of the cases with onset before 20. We present clinical features and results of DNA analysis in 16 patients from 14 families aged 9 to 36. The age of onset was between 5 to 20 years; duration of the disease was from 2 to 16 years. In 10 cases the mutated gene was transmitted by the affected father; only in two cases by the mother. In all cases anticipation manifested by earlier onset of the disease in subsequent generations and expansion of CAG repeats was documented. The number of CAG repeats was between 50 and 92 (mean 67.3). Progressive mental deterioration, declining school performance, hyperactivity and emotional disturbances were the first symptoms of juvenile HD. Neuropsychological assessment showed mean IQ in Wechsler test 59.6 and Mini-Mental State Examination scores 22.8. Rigidity and bradykinesia were predominant features in the cases with juvenile onset, the remaining ones developed choreatic movements. Three persons had epileptic seizures; two (both females) revealed behaviour and psychiatric disturbances. Amplitudes of somatosensory evoked potentials, visual evoked potentials and brainstem auditory evoked potentials were markedly reduced. MRI of the brain showed atrophy of heads of the caudate nuclei, putamen and globus pallidus.