Nunzio Cutuli

No association between apolipoprotein E polymorphisms and recurrent pregnancy loss.

Our study does not support the reported association between APOE and recurrent pregnancy loss (RPL) than the clinical management of these patients should not be influenced by the presence or not of APO E polymorphisms.

FRAXE intermediate alleles are associated with Parkinson’s disease

There is evidence that male subjects with a clinical picture of action tremor, Parkinsonism, and cerebellar ataxia may have Fragile X premutations (FRAXA). We analyzed FRAXA and FRAXE triplet repeats in 203 male subjects with Parkinsons disease (PD) and 370 healthy controls. No full mutations or premutations at the FRAXA and FRAXE loci were found in the subjects with PD or in the controls. FRAXA allele distribution was similar in patients and controls. FRAXE intermediate alleles (31-60 repeats CCG) were found in 13 of 203 (6.4%) subjects with PD and in only one of the 370 (0.27%) healthy controls (P < 0.001), thus indicating that these relatively large alleles may be associated with PD.

Unexplained infertility and inherited thrombophilia

Approximately 15%–30% of couples (1) will be diagnosed with unexplained infertility after their diagnostic workup, as suggested in guidelines (2), fails to reveal any abnormality. The treatment for unexplained infertility is therefore, by definition, empiric because it does not address a specific defect or functional impairment (1). The principal treatments for unexplained infertility include expectant observation with timed intercourse and lifestyle changes, clomiphene citrate (CC) and IUI, controlled ovarian hyperstimulation (COH) with IUI, and IVF. In addition, the likelihood of pregnancy without treatment among couples with unexplained infertility is less than that of fertile couples but greater than zero. It is possible that unexplained infertility represents the lower extreme of the normal distribution of fertility with no defect present. Recently a possible association between unexplained infertility and genetic thrombophilia gene mutations have been reported (3), with a significant statistically association with MTHFR C677T polymorphisms. We have examined 32 couples with unexplained infertility compared with a control group of 130 couples with recurrent pregnancy loss referred to our Centre for genetic counseling. The infertile couples had been trying to achieve a successful pregnancy for more than 1 year without success and known causes of infertility were excluded (semen anomalies, karyotype abnormalities, uterine malformations, tubal occlusion, hormonal dysfunctions, and celiac disease). In the recurrent pregnancy loss group all pregnancy losses were registered in the first trimester of pregnancy, anatomical anomalies of the uterus, chromosomal, immunologic risk factors (including antiphospholipid antibodies, antinuclear antibodies, antithyroid antibodies, and lupus anticoagulant), and celiac disease were excluded. Genetic evaluation included factor V (G1691ALeiden and H1299R); factor II prothrombin (G20210A), and methylenetetrahydrofolate reductase (MTHFR) with C677T and A1298C mutations that represent the most common, clinically significant, inherited thrombophilias. The other gene mutations included in the thrombophilic diagnostic tests were performed but were excluded for this analysis. Our results showed a statistically significant association between the two groups for factor VH1299R mutation heterozygosity (P1⁄4.001) and for MTHFR C677T homozygosity (P1⁄4.02). No significant associations were found for factor V-Leiden, MTHFR-A1298C homozygosity, compound heterozigosity for C677T and A1298C, and heterozigosity for C677T or A1298C. Inherited thrombophilia is believed to

Gene dosage influences the age at onset of SCA2 in a family from southern Italy.

To the Editor: Spinocerebellar ataxia type 2 (SCA2) is the most common form of autosomal dominant cerebellar ataxia in southern Italy (1). The expansion of a CAG trinucleotide repeat in exon 1 of the SCA2 gene, located on chromosome 12q23-24.1, is responsible for the disease. Normal alleles have 14 to 31 CAG repeats interrupted by one to three CAA trinucleotides, whereas expanded alleles have 33 to over 200 pure repeats, as reported in neonatal cases (2). Clinically, SCA2 is characterized by gait and limb ataxia, dysarthria, slow saccadic eye movements, supranuclear ophthalmoplegia and peripheral neuropathy. Recently, several patients have been described with expansion in the SCA2 gene and an L-dopa responsive parkinsonism (3). In the present study, we reported an Italian SCA2 family in which two brothers and their nephew (the son of another now deceased brother) were affected by progressive ataxia [Fig. 1(a)]. Both parents of these brothers originated from the same isolated village in mid-eastern Sicily (southern Italy); however, no consanguinity was reported between the two parents’ families. Both parents died before the beginning of this study, and the surviving children reported that their father developed gait instability and progressive difficulty in walking when he was 60 and died in an accident at the age of 62. They also recalled that their mother suffered from vertigo; she had fallen many times when she was 80 years of age and died at 82 years for unknown reasons. After having obtained a signed informed consent from three affected family members, genomic DNA was extracted from peripheral blood leukocytes using the standard procedure. The SCA2 gene region containing the CAG repeats was amplified by polymerase chain reaction (PCR). The PCR conditions had been previously published (4). SCA2 genotyping was performed by capillary electrophoresis on ABI 3130XL Avant Apparatus using the GENESCAN software version 3.1 (Applera, Foster City, CA). Each allele was obtained using denaturating high-performance liquid chromatography, and the length of the CAG repeated region was confirmed by direct sequencing on an ABI 3130XL Genetic Analyzer (Applera). In the proband (II-11), SCA2 gene molecular analysis revealed two expanded alleles with 35 and 36 uninterrupted CAG repeats; the proband’s brother (II-6) and the nephew (III-1) were heterozygous for expanded alleles containing 35 and 42 CAG repeats, respectively [Fig. 1(b)]. Considering the clinical features of the affected family members, the proband (35/36 repeats) showed an earlier onset age and a more severe clinical phenotype than his brother (22/35 repeats); the proband developed gait instability at the age of 35 years, dysarthria when he was 40 years and was unable to walk independently at the age of 50 years. At the time of the study (1996), when the proband was 58 years old, he showed dysphagia, severe ataxia in the upper extremities, bilateral Babinski sign and urinary incontinence. Ocular movements were normal. No parkinsonism was noticed in the proband. The severity of disease rating on the inherited ataxia progression scale (IAPS) was 4 (5). T2weighted magnetic resonance imaging (MRI) of the brain, also performed in 1996, showed marked cerebellar atrophy. On contrary, the proband’s brother developed mild ataxia at the age of 65 years; he presented dysarthria, dysphagia and lower motor impairment when he was 67 years old. The IAPS was 2. T2-weighted MRI of the brain performed when this man was 74 years old (1996) revealed a mild cerebellar atrophy. Finally, the age of disease onset and the progression rate and severity of SCA2 symptoms in the nephew (22/42 repeats) were similar to those observed in the proband; the nephew developed gait instability at the age of 30 years and dysarthria at the age of 40 years. The IAPS was 4. The proband’s affected relatives had normal ocular movements and did not show peripheral neuropathy.

Clinical management of Rendu-Osler-Weber syndrome and genetic thrombophilia.

Rendu-Osler-Weber syndrome or hereditary haemorragic telangectasia (HHT) is an autosomal dominant disorder. The four clinical diagnostic criteria include epistaxes, telangiectasia, visceral lesions, and family history. HHT diagnosis can be made if three criteria are present and cannot be established in patients with only two criteria, but should be recorded as possible or suspected in order to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although, children of affected individuals should be considered at risk in view of age-related penetrance in this disorder [1]. Genetic heterogeneity was indicated by the results of linkage studies, moreover, mutations in endoglin (ENG) and activin receptor-like kinase 1 (ALK1) genes were reported [2]. The coexistence of HHT and thrombophilia, two genetic disorders that theoretically may have the opposite actions on hemostasis has been rarely reported [3,4]. Such states pose a difficult management problem when occurring together in one patient. We have observed a 45-year-old man, who was referred to our centre for genetic counselling. He was affected by HHT characterized by spontaneous, recurrent epistaxis (onset childhood), nasal mucosa, finger pad telangiectases and, three transient ischemic attack (TIA) with hemiparesis which subsided completely within few weeks. A similar clinical situation was reported for the patient’s father who died of a stroke at 58 years. Testing for acquired thrombophilia showed normal values. Genetic test for inherited thrombophilia showed that the patient was heterozygous for Factor V-Leiden mutation, homozygous for C677T mutation of methylenetetrahydrofolate reductase (MTHFR) gene and, homozygous for 4Gallele polymorphism of plasminogen activator inhibitor (PAI-1) gene. Cyclic aspirin treatment after TIA was reported complicated by nasal haemorrhages treated with tranexamic acid. Biochemical test for homocysteinemia revealed hyperhomocysteinemia that was treated with

High Prevalence of Hepatitis G Virus in Multitransfused Sicilian Patients with Beta‐Thalassaemia

We studied the prevalence of hepatitis G virus (HGV) RNA in 100 ß-thalassaemia major patients (46 males, 54 females), aged between 7.5 and 33 years, using a reverse transcription polymerase chain reaction (RT-PCR) technique in serum and in peripheral blood mononuclear cells (PBMCs) [1]. Hepatitis C virus (HCV) antibodies and HCV RNA were found in 56 out of 100 patients (56%). HGV RNA was detected in 28 of 100 patients (28%). The presence of HGV RNA associated with HCV antibodies was detected in 15 of 28 (53.5%) patients. In our experience, there is no correlation between HGV and chronic hepatitis ( ̄2 = 0.002, p = 0.961), and all patients affected with chronic hepati-