Prenatal genetic counseling referrals for advanced maternal age: still room for improvement.

OBJECTIVE: The objective of this study is to evaluate genetic risks already present before pregnancy in a cohort of pregnant women referred for prenatal genetic counseling exclusively for advanced maternal age (AMA). METHOD: We retrospectively reviewed the records of 1353 women referred over 1 year (2010) for pre-test genetic counseling with the only indication of AMA at three Italian Clinical Genetic Services. RESULTS: Of the 1353 women fulfilling the inclusion criteria of the study, 87 (6.4%) had cumulatively 94 genetic risk factors not previously identified (one risk factor in 80 patients and two risk factors in seven). Twenty-six risk factors (27.7%) concerned heterogeneous or multifactorial conditions and 68 (72.3%) Mendelian or chromosomal disorders and consanguinity.In nine out of these 87 women, the estimated risk for the offspring of a genetic disease or a significant structural anomaly was >5%. Additional testing according to the identified risks was performed in 36 of these 87 women/families. CONCLUSIONS: The proportion of cases with additional risk factors is smaller than reported in previous studies, but it remains substantial and confirms the need for strategies to increase awareness of the public and health professionals responsible for the care of women in childbearing age.

A novel family with Lamin B1 duplication associated with adult-onset leucoencephalopathy.

BACKGROUND AND AIMS: Duplication of the lamin B1 gene (LMNB1) has recently been described in a rare form of autosomal dominant adult-onset leucoencephalopathy. The aim of the study was to evaluate the presence of LMNB1 gene defects in a series of eight patients with diffuse adult-onset hereditary leucoencephalopathy. METHODS: Clinical features of tested patients included a variable combination of pyramidal, cerebellar, cognitive and autonomic dysfunction. Neuroradiological data (MRI) showed symmetrical and diffuse white-matter lesions in six cases, and multifocal confluent lesions in two. LMNB1 full gene deletion/duplication and point mutations were searched using a TaqMan real-time PCR assay and direct sequencing of all coding exons. RESULTS: One patient carried a 140-190 kb duplication involving the entire LMNB1 gene, the AX748201 transcript and the 3' end of the MARCH3 gene. Clinical and neuroimaging data of this proband and an affected relative overlapped with the features already described in patients with LMNB1 duplication. Lamin B1 expression was found increased in lymphoblasts. No LMNB1 gene defect was identified in the remaining seven probands. CONCLUSIONS: LMNB1 gene duplication appears characteristic of a subset of adult-onset autosomal dominant leucoencephalopathies, sharing autonomic dysfunction at onset, diffuse T2-hyperintensity of supra- and infratentorial white matter, sparing of U-fibres and optic radiations. The variable phenotypes in the remaining cases lacking LMNB1 defects (five with autosomal dominant transmission) suggest that adult-onset leucoencephalopathies are genetically heterogeneous.

Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) are characterized by progressive lower extremity spasticity due to an axonal degeneration of motor and sensory neurons. We report a four-generation pedigree segregating an autosomal dominant phenotype for HSP and showing a linkage to the SPG10 locus, coding for Kinesin family member 5A. Subsequent to a denaturing high performance liquid chromatography (dHPLC) mutation screening we found a new missense mutation 838C>T (R280C) at an invariant arginine residue in a region involved in the microtubule binding activity.

Mole maker phenotype: possible narrowing of the candidate region.

Recent data has suggested that familial recurrent hydatidiform mole is a rare autosomal recessive trait in women experiencing this gestational disease (MIM 231090). Here we provide molecular data on an additional family confirming that recurrent familial hydatidiform moles are diploid, biparental and arise from independent conceptions. A narrowing of the gene interval on chromosome 19q13.3-13.4 is suggested by haplotype analysis in two sisters.

Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families.

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.

Saethre-Chotzen syndrome: review of the literature and report of a case.

Saethre-Chotzen syndrome is an autosomal acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p (TWIST). A case of a 13-year-old girl with Saethre-Chotzen syndrome (ACS III) is described. The features of the syndrome include: turriplagiocephaly with a cranial circumference of 52 cm, facial asymmetry, low hairline, proptosis, antimongoloid slanting of palpebral fissures, nasal deviation with high bridge, angled ears, scoliosis and torticollis, clinodactyly of the fourth and fifth toes, large halluxes, and neurosensorial hypoacusia. For correction of the deformity, a cranioorbital remodeling was performed. The craniofacial approach with remodeling of the frontal bar and reduction of the turricephaly resulted in a satisfactory morphological and functional outcome, with complete three-dimensional reshaping and remodeling of the frontonasoorbital area.

Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families.

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 +/- 3.3 in 85 expanded alleles, with a range of 34-52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range -3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

Determinants of cognitive disorders in Autosomal Dominant Cerebellar Ataxia type 1.

We assessed neuropsychological performances of 22 patients affected by Autosomal Dominant Cerebellar Ataxia type 1. All subjects completed a comprehensive battery of standardized tests requiring a verbal response, without time constraints. In order to verify the hypothesis that disease severity is the major factor in determining the cognitive status in this syndrome, patients were divided into three groups according to the severity of the clinical picture, as evaluated by the Inherited Ataxias Progression Scale (IAPS). Statistical analysis of the three groups' raw scores showed a significant decrement in patients with more severe clinical pictures on verbal short-term memory tasks. A similar trend, but not significant, was seen for general intelligence tests and verbal learning tasks. The decrement of verbal short-term memory could be related to motor speech problems. On the other hand, the decline of cognitive abilities over the course of the Autosomal Dominant Cerebellar Ataxia type 1 was not homogeneous enough to ensure statistically reliable trends. Therefore, this cross-sectional study suggests that the progression of the disease is a necessary factor in determining cognitive decline, but it is not sufficient. Other disease-related factors (age at onset, genotypic variety) could play a critical role: among these, the size of the expanded CAG repeats is significantly related to a decline of verbal intelligence and short-term memory in SCA2 patients.

Increased incidence of preeclampsia in pregnancies complicated by fetal malformation.

There seems to be a correlation between preeclampsia and congenital abnormalities, but whether it is positive or negative is a matter of controversy. Since it has been demonstrated that reduced perfusion of the trophoblast, which is an early feature of preeclampsia, can also represent a cause of fetal malformation, a positive correlation between the two conditions should be found. In the search for such a correlation we retrospectively examined 8,894 cases collected until 1994 by the IMER group (Indagine Malformazioni Emilia-Romagna). In the presence of malformation a higher incidence of preeclampsia was found (4.60 versus 3.47) with an odds ratio of 1.34 (95% CI = 1.08-1.67). Furthermore multivariate analysis showed that malformations of the male genital apparatus and those named 'multiple congenital abnormalities' can be considered as risk factors for preeclampsia. Since it is known that the development of male genitalia occurs under the influence of androgens, it can be hypothesized that hypoxia could act by favoring low end organ responsiveness. In our opinion the positive correlation with fetal malformations should be interpreted as clinical evidence of the early onset of the physiopathologic mechanism of preeclampsia.

Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers.

The length of the CAG repeat responsible for Huntington disease has been analysed by two PCR methods in blood and sperm DNA of 13 expansion carriers, two carriers of intermediate alleles, and four normal subjects. The two methods consistently confirmed size heterogeneity, more pronounced in sperm and confined to the CAG stretch. Based on densitometric scanning of films, four indexes addressed to different features of the PCR pattern were used to quantitate mosaicism. These revealed strong correlations with CAG size and intergenerational instability. However, mosaicism did not show a greater similarity in sibs who shared the same HD chromosome, nor was correlated with instability in the proband's pedigree. Our data do not support the hypothesis that cis-acting factors play a major role in the instability and leave the CAG size per se as the major determinant of sperm cell CAG instability.

Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes.

We studied 83 patients from 36 Italian families with autosomal dominant cerebellar ataxia type I. Mean onset age +/- SD was 34.2 +/- 12.8 years with a mean anticipation of 12.8 +/- 15.1 in 52 parent-offspring pairs. Onset age anticipation occurred predominantly through paternal transmission. Mean age at death was at 56.5 +/- 15.5 years. The most common associated features were supranuclear ophthalmoplegia, corticospinal signs, peripheral neuropathy and cognitive impairment. Cerebellar atrophy was constant at MRI and usually associated with shrinkage of the pons and degeneration of the pontine transverse fibres. Direct mutation analysis in 29 families showed two families with SCA1 and none with Machado-Joseph/SCA3 mutation. We performed linkage analysis in the ten largest families. Two of them showed linkage to SCA2 locus and none to SCA4 and SCA5 loci. SCA2 patients showed higher occurrence of peripheral neuropathy and slow saccades, rarer corticospinal signs and a milder course of the disease in comparison with SCA1 patients.

Raised level of amniotic endothelin in pregnancies with fetal aneuploidy.

Amniotic fluid endothelin-1 (ET-1) levels were measured in 38 euploid and in 15 aneuploid pregnancies in the 17th gestational week. Varying distribution of the peptide levels was found in the two groups, with higher values in the pathological cases. Should this finding be confirmed in maternal blood, ET-1 could represent a further analyte to be used in prenatal screening for aneuploidy.

Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus.

Twenty two patients from 17 families with Friedreich's disease phenotype but with onset ranging from the ages of 21 to 36 are described. Comparison with "typical" Friedreich's disease with onset before 20 years of age showed only a lower occurrence of skeletal deformities. The peripheral and central neurophysiological findings, sural nerve biopsy, and the neuroradiological picture did not allow the differentiation between "late onset" and "typical" Friedreich's disease. Duration of disease from onset to becoming confined to a wheelchair was five years longer in late onset patients. Sixteen patients and 25 healthy members from eight families were typed with the chromosome 9 markers MLS1, MS, and GS4 tightly linked to the FRDA locus. All families showed positive lod scores with a combined value of 5.17 at a recombination fraction of theta = 0.00. It is concluded that "late onset" Friedreich's disease is milder than the "typical" form and that it maps to the same locus on chromosome 9.