Resumo A síndrome de tremor-ataxia associada ao X-frágil (FXTAS) é uma causa de distúrbios do movimento e de declínio cognitivo que provavelmente tem sido subdiagnosticada, especialmente se a sua prevalência for realmente similar às da paralisia supranuclear progressiva e esclerose lateral amiotrófica. Relatamos um caso de um homem de 74 anos que se apresentou com tremor de ação, ataxia de marcha e esquecimento. Havia história familiar de tremor e de demência e um de seus netos era mentalmente deficiente. A avaliação neuropsicológica demonstrou uma síndrome frontal. A ressonância magnética (RM) revelou hiperintensidade de ambos os pedúnculos cerebelares médios, um critério maior para o diagnóstico de FXTAS. Os testes genéticos confirmaram a presença da pré-mutação do gene FMR1, com uma repetição (CGG)90. O diagnóstico de FXTAS é importante para o aconselhamento genético porque as filhas dos indivíduos afetados tem alto risco de ter uma criança com síndrome do X-frágil. A presença de tremores e declínio cognitivo deve levantar a hipótese diagnóstica de FXTAS, que poderá ser reforçada pela RM e confirmada pela presença da pré-mutação do gene FMR1.

Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS) is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG)90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

Chromosomal rearrangements involving partial deletion of the short arm of chromosome 4 and partial duplication of the short arm of chromosome 8 have been described both in Pitt-Rogers-Danks syndrome (PRDS) and Wolf-Hirschhorn syndrome (WHS), the former being considered a milder phenotype of the latter. We describe a patient with partial deletion of chromosome 4 and partial duplication of chromosome 8 documented by array-comparative genomic hybridization (Array-CGH). In addition to the typical features of PRDS, the patient exhibited some clinical signs (genital hypoplasia, radioulnar synostosis and mesomelic limb shortness) infrequently, or never previously, reported in PRDS. These findings broaden the spectrum of anomalies generally associated with these syndromes.

The loss-of-function mutation of the FMR1 gene due to expansion of the 5' UTR CGG repeat causes the fragile X syndrome, the most frequent form of inherited mental retardation. On the other hand, the FMR1 premutation, which is transcriptionally active and produces the protein, confers an increased risk for premature ovarian failure (POF) to carrier females. Among 41 unrelated Brazilian women with idiopathic POF, we found three carriers of premutations (CGG expansionse > 59 repeats) and two carriers of high-intermediate alleles (50-55 repeats). Two premutations and two intermediate alleles were detected among the 16 familial POF cases, and one premutated woman, among the 25 sporadic cases. The premutation frequency among the familial cases (12.5%) differed significantly from that found in a control group of 96 unrelated Brazilian women aged > 47 years, who had not experience POF and in which no premutations or high-intermediate alleles were detected. In the search for factors influencing the probability of a premutation carrier presenting POF, another 20 unrelated premutated women with POF, from fragile X families, were included in the study. The analysis of the FMR1-linked loci DXS548 and FRAXAC1 did not indicate any association of a particular haplotype with the occurrence of POF. An effect of X-inactivation skewing was not apparent in blood cells, and POF-associated premutations showed a wide range of repeat sizes, from 59, the smallest known to expand to full mutations upon transmission to offspring, to approximately 200.

In order to investigate the stability of the FMR1 (Fragile X Mental Retardation 1) alleles from the normal population, when maternally inherited, we analyzed 75 mother-to-son transmissions. Sixty-eight alleles fell within the common range with 20-40 CGG repeats, and seven alleles were intermediate, with 41-48 repeats. No change was observed either in the length or in the structure of these repeats upon transmission. Fifty-three alleles were ascertained in different families, and their size distribution was similar to those described for European and European-derived populations, with three peaks of frequency: 66% of the alleles with (CGG)29, (CGG)30 or (CGG)31, 7.5% with (CGG)20, and 5.7% with (CGG)23. Regarding the AGG interspersion pattern, 69.8% had two AGG repeats, 20.8% had one, 5.7% had three and 3.8% had none. The most common patterns were 10+9+9 (30.2%), 9+9+9 (18.9%), 10+9 (7.5%), and 10+9+10 (7.5%). About 70% of the alleles with up to 40 repeats were linked to the DXS548/FRAXAC1 haplotype 7-3, the most commonly reported in normal populations. Four out of five intermediate alleles were in linkage with the two haplotypes most frequently associated to the FMR1 full mutation, 2-1 and 6-4. These four alleles showed long uninterrupted CGG repeats at the 3' end. The 9+9+22, 9+9+23 and 9+9+28 alleles were linked to the haplotype 2-1, and the 9+37 allele, to the haplotype 6-4. The pattern of AGG interspersion of these alleles and the associated haplotypes were in accordance with the two main pathways toward mutation previously proposed.

Descrevemos uma duplicação do cromossomo 20 (20pter-> 20q12), resultante de uma translocação t(14;20)(q11;q13)mat, em uma menina com retardo do desenvolvimento neuropsicomotor e anomalias congênitas múltiplas. Trata-se da mais extensa duplicação do cromossomo 20 presente em indivíduo nascido vivo até agora publicada.

Partial duplication of chromosome 20 (20pter->20q12) resulting from a maternally inherited translocation t(14;20)(q11;q13) is described in a female child with neuropsychomotor retardation and multiple congenital anomalies. To our knowledge this is the largest duplication of chromosome 20 that includes segments of both the short and the long arms thus far described in a live-born child.

Entrevistamos 193 mulheres de famílias com afetados pela síndrome do cromossomo X frágil, quanto a sua história ginecológica e reprodutiva. Entre as 101 portadoras da pré-mutação, 14 tiveram menopausa precoce, mas nenhuma das 37 portadoras da mutação completa ou das 55 não portadoras apresentaram esta anomalia. Observamos uma tendência para a concentração da menopausa precoce em certas famílias, o que poderia significar uma peculiariedade de certas pré-mutações. Entretanto, o fato de as mulheres pré-mutadas tenderem a entrar em menopausa mais cedo do que as não portadoras sugere que a menopausa precoce seja o extremo do espectro de efeitos ovarianos da pré-mutação.

The gynecological and reproductive histories of 193 women from fragile X families were surveyed. Among the 101 carriers of the premutation, 14 experienced premature menopause, contrarily to their 37 fully mutated and 55 noncarrier female relatives. Although premature menopause showed a tendency to cluster in certain fragile X families, as a group, the premutated women experienced menopause earlier than noncarriers. This suggests that premature menopause may be the extreme effect of a spectrum of ovarian anomalies associated with the fragile X premutation.

Realizamos análises citogenéticas e moleculares em 55 famílias com a mutação da síndrome do cromossomo X frágil, loco FMR-1 (318 indivíduos e 15 amostras de vilosidade coriônica). Foram estudados 129 indivíduos do sexo masculino, 75 com retardo mental e 54 normais. Entre os 54 normais, 11 eram portadores da pré-mutação e nenhum apresentou o sítio frágil. Foram detectados 73 portadores da mutação completa e 18% eram mosaicos, ou seja, apresentavam também a pré-mutação. Todos expressaram o sítio frágil em pelo menos um dos sistemas de indução utilizados. O tamanho da expansão de trinucleotídeos CGG (<FONT FACE="Symbol">D</FONT>) e a freqüência de manifestação do sítio frágil apresentaram correlação positiva. Entre as 153 mulheres normais, 85 eram portadoras da pré-mutação e 15 da mutação completa. A freqüência de expressão do fra(X) foi zero ou extremamente baixa entre as pré-mutadas e essa freqüência não diferiu da expressão das não portadoras da mutação. Portanto, a análise citogenética é ineficaz na detecção de indivíduos pré-mutados, homens ou mulheres. Entre as 51 mulheres com a mutação completa, 70% manifestaram algum grau de comprometimento mental. Encontramos também correlação entre o <FONT FACE="Symbol">D</FONT> e a freqüência de expressão do fra(X) nessas mulheres. Contudo, a detecção citogenética das mulheres com mutação completa foi menos eficiente do que no caso dos homens, pois 14% de falsos negativos foram observados. A análise de segregação confirmou que o risco de prole afeta- da aumenta com o <FONT FACE="Symbol">D</FONT>, e o risco médio de prole afetada para todas as heterozigotas foi de 30%. Não houve indicação de desvio de segregação nas famílias estudadas, pois o número de indivíduos que herdaram a mutação não diferiu do número daqueles que herdaram os alelos normais. Não foi detectada nenhuma mutação nova nas 55 genealogias investigadas

We report on the cytogenetic and DNA analysis of 55 families with the fragile X (FMR-1 locus) mutation (318 individuals and 15 chorionic villi samples). A total of 129 males were investigated, 54 mentally normal and 75 presenting mental retardation. Among the 54 normal males, 11 had the premutation, and none expressed the fragile site. The full mutation was detected in 73 retarded males, and 14 (18%) presented a premutation along with the full mutation (mosaics). All of them manifested the fragile site. The frequencies of fragile site expression correlated positively with the sizes of the expansion of the CGG repeats (<FONT FACE="Symbol">D</FONT>). Among 153 normal females, 85 were found to be heterozygous for the premutation and 15 had the full mutation. In the premutated females the fragile site was not observed or it occurred at frequencies that did not differ from those observed in 53 noncarriers. Cytogenetic analysis was thus ineffective for the diagnosis of premutated males or females. Among the 51 heterozygotes for the full mutation, 36 (70%) had some degree of mental impairment. As in males, a positive correlation was detected between the frequencies of fragile site manifestation and the size of the expansion. However, the cytogenetic test was less effective for the detection of fully mutated females, than in the case of males, since 14% false negative results were found among females. Segregation analysis confirmed that the risk of mental retardation in the offspring of heterozygotes increases with the length of <FONT FACE="Symbol">D</FONT>. The average observed frequency of mental retardation in the offspring of all heterozygotes was 30%. There was no indication of meiotic drive occurring in female carriers, since the number of individuals who inherited the mutation did not differ from the number of those inheriting the normal allele. No new mutations were detected in the 55 genealogies studied here.