J. Mladenovic

Survival and mortality of myotonic dystrophy type 1 (Steinert's disease) in the population of Belgrade

The purpose of this investigation was to determine survival and mortality in patients with myotonic dystrophy type 1 (DM1) in the Belgrade population within the period from 1983 to 2002. Data of a number of diagnosed DM1 patients with their demographic, clinical and genetic characteristics were gathered from hospital records in all neurologic institutions in Belgrade for the period 1983–2002. Death certificates were reviewed to determine the cause of death. Survival analysis by life table method and Cox proportional hazard model was performed. Within the observed period, in the population of Belgrade, 15 fatal outcomes among 101 patients with DM1 were registered. Average DM1 mortality rate was 0.5/1 000 000 (95% CI 0.3–0.8), and standardized mortality ratio (SMR) was 5.3. A significant inverse correlation was found between age at onset of DM1 and CTG repeats (P = 0.023). The cumulative probability of 15‐year survival for DM1 patients in Belgrade was 49 ± 5% (48 ± 2% for males and 50 ± 7% for females). Younger age at onset was a significant unfavorable prognostic factor (hazard ratio = 4.2; P = 0.012).

Epidemiology of myotonic dystrophy type 1 (Steinert disease) in Belgrade (Serbia)

The aim of this study was to estimate the incidence and prevalence of myotonic dystrophy type 1 (DM1) in Belgrade during the period 1983-2002. The patients who had DM1 were ascertained through hospital records from all neurological departments in Belgrade during 1983-2002. The molecular genetic analysis was performed in all patents included in the study. We identified 101 DM1 patients (52 males and 49 females). The average annual incidence rate of DM1 in Belgrade for the period observed was 2.0/1,000,000 (95% confidence interval (CI), 0.3-8.3), 2.1/1,000,000 (95% CI, 0.3-8.3) for males and 2.0/1,000,000 (95% CI, 0.3-8.3) for females. The highest age-specific DM1 incidence was registered in the age group 20-49: 3.4/1,000,000 (95% CI, 0.5-7.6), 4.0/1,000,000 (95% CI, 1.1-10.2) in males and 2.5/1,000,000 (95% CI, 0.5-7.6) in females. In the population of Belgrade, a cumulative probability of acquiring DM1 was 1 per 8621 for men and 1 per 9259 for women (1 per 8940 of the population for both sexes). The prevalence of DM1 in Belgrade on 31 December 2002 was 5.3/100,000 (95% CI, 4.2-6.6).

Mutational analysis of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in Serbian Charcot-Marie-Tooth patients

We report the results of mutational analysis in the following genes: GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE in 57 Charcot‐Marie‐Tooth (CMT) patients of Serbian origin without the PMP22 duplication. We found 10 different mutations in 14 CMT patients: 6 mutations in GJB1, 3 in MPZ, and 1 in PMP22. Five of six GJB1 mutations are reported for the first time, and the most frequent one appears to be a founder mutation in the Serbian population. No mutations were found in EGR2 or LITAF. Thus, GJB1 mutation analysis should be done in patients without the PMP22 duplication and male‐to‐male transmission of CMT.

Haplotype analysis of the DM1 locus in the Serbian population

Objectives – Analysis of the CTG‐repeat number and three biallelic markers, Alu(+/−), HinfI(+/−), and TaqI(+/−), in the DMPK gene in healthy and myotonic dystrophy type 1 (DM1) Serbian individuals. Also, the consideration of haplotypes in the light of the proposed models of CTG‐repeat evolution and origin of the DM1 mutation.

Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

Abstract Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation- dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70<FSIQ ≤85), while seven (18.92%) were intellectually impaired (FSIQ <70). The FSIQ was not associated with proximal and distal mutations when boundaries were set at exons 30 and 45. However, FSIQ was statistically significantly associated with mutation location when we assumed their functional consequence on dystrophin isoforms and when mutations in the 5’-untranslated region (5’UTR) of Dp140 (exons 45-50) were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients.

Epidemiology of Charcot-Marie-Tooth Disease in the Population of Belgrade, Serbia

Background: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). Methods: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. Results: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5–14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 ± 7.8% (44.9 ± 31.8% for males and 98.2 ± 1.8% for females). Conclusions: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries.

Childhood cerebral X-linked adrenoleukodystrophy more than 5 years after hematopoietic cell transplantation: the first case from Serbia and southeastern Europe.

We report the clinical course, brain magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy findings in a boy with childhood cerebral X-linked adrenoleukodystrophy whose neurological disease keeps progressing more than 5 years after conventional hematopoietic cell transplantation with full donor-derived engraftment accomplishment. The described clinical and radiological findings follow all phases of this childhood cerebral X-linked adrenoleukodystrophy: from the clinically asymptomatic pretransplant stage to the present day. This is the first patient not only from Serbia but from the entire area of Southeastern Europe who underwent hematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy. The presented disease course and the posttransplant outcome in the only case of transplanted adrenoleukodystrophy from Serbia enhances the overwhelming appeal for better X-linked adrenoleukodystrophy screening, earlier disease detection, and contributes to the well-known anticipation of the refined hematopoietic cell transplantation eligibility criteria in future adrenoleukodystrophy treatment.

Is the 31 CAG repeat allele of the spinocerebellar ataxia 1 (SCA1) gene locus non-specifically associated with trinucleotide expansion diseases?

A number of human hereditary neuromuscular and neurodegenerative disorders are caused by the expansion of trinucleotide repeats within certain genes. The molecular mechanisms that underlie these expansions are not yet known. We have analyzed six trinucleotide repeat-containing loci [spinocerebellar ataxias (SCA1, SCA3, SCA8), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington chorea (HD) and fragile X syndrome (FRAXA)] in myotonic dystrophy type 1 (DM1) patients (n = 52). As controls, we analyzed two groups of subjects: healthy control subjects (n =133), and a group of patients with non-triplet neuromuscular diseases (n = 68) caused by point mutations, deletions or duplications (spinal muscular atrophy, Charcot–Marie–Tooth disease, type 1A, hereditary neuropathy with liability to pressure palsies, and Duchenne and Becker muscular dystrophy). Allele frequency distributions for all tested loci were similar in these three groups with the exception of the SCA1 locus. In DM1 patients, the SCA1 allele with 31 CAG repeats account for 40.4% of all chromosomes tested, which is significantly higher than in two other groups (11.3% in healthy controls and 6.6% in the group of non-triplet diseased patients;P < 0.001, Fishers exact test). This is consistent with our previous findings in HD patients. The absence of this association in non-triplet diseases as well as in healthy controls could indicate a possible role of this SCA1 allele with 31 repeats in triplet diseases. Here we discuss a possible role of the SCA1 region in pathological trinucleotide repeat expansions.

Epidemiology of myotonic dystrophy type 1 in the population of central Serbia

The objective of this epidemiological survey was to estimate the frequency and distribution of Myotonic dystrophy type 1 (MD1) (Steinerts disease) in central Serbia, during the period 1983-2002. The data on the number of diagnosed MD1 patients were obtained using the analysis of hospital records, which were examined in all the relevant neurological institutions in central Serbia in the mentioned period. Incidence rate and prevalence were used for the data analysis. In the study period in central Serbia, 154 patients (78 males and 76 females) with MD1 were identified. The average annual incidence rate of MD1 was 1.3 (95% CI-confidence interval 0.1-7.2) per 1,000,000 population, 1.4/1,000,000 (95% CI 0.1-7.2) for males, 1.3/1,000,000 (95% CI 0.1-7.2) for females. The trend of MD1 incidence rates in the observed period in central Serbia had a tendency of the statistically significant decrease, according to the linear model, in both male (y = 0.205 - 0.0066x, p = 0.021) and female populations (y = 0.1788 - 0.0048x, p = 0.032). The prevalence of MD1 on December 31, 2002 in central Serbia was 3.8/100,000 (95% IP 3.2-4.6), 3.7/100,000 (95% IP 3.3 - 4.8) for males, 3.3/100,000 (95% IP 3.0 - 4.4) for females.

An Algorithm for Genetic Testing of Serbian Patients with Demyelinating Charcot-Marie-Tooth

Charcot-Marie Tooth (CMT) is a clinically and genetically heterogeneous group of diseases with rough genotype-phenotype correlation, so the final diagnosis requires extensive clinical and electrophysiological examination, family data, and gene mutation analysis. Although there is a common pattern of genetic basis of CMT, there could be some population differences that should be taken into account to facilitate analyses. Here we present the algorithm for genetic testing in Serbian patients with demyelinating CMT, based on their genetic specificities: in cases of no PMP22 duplication, and if -X-linked CMT (CMTX) is not contraindicated by pattern of inheritance (male-to-male transmission), one should test for c.94A>G GJB founder mutation, first. Also, when a patient is of Romani ethnicity, or if there is an autosomal recessive inheritance in a family and unclear ethnicity, c.442C>T mutation in NDRG1 should be tested.