Objective: The purpose of this study was to investigate the prevalence of peripheral neuropathy in patients with bthalassaemia. Methods: Thirty six patients with a mean age of 29.2¡8.2 years and 17 healthy controls with a mean age of 27.6¡9.1 were included in this study. Measurements included the neuropathy symptoms score (NSS), the neuropathy disability score (NDS) as well as nerve conduction studies of two motor (ulnar and peroneal) and two sensory (ulnar and sural) nerves of the right limbs. Results: A mainly sensory axonal polyneuropathy was present in 19 out of 36 patients (52.7%). Eight out of these 19 patients also had abnormal NDS values. The neuropathy correlated significantly with the age of the patients and the hematocrit. However, it did not correlate with the presence of antibodies against HCV, the ferritin levels, or with a history of transfusions, desferrioxamine treatment, or splenectomy. Conclusions: This study showed a high prevalence of a predominantly sensory neuropathy in patients with bthalassaemia. The electrophysiological data suggest that the underlying pathology is an axonopathy. Chronic hypoxia of the nerves resulting from severe anaemia may contribute to the pathogenesis of this neuropathy.T halassaemia comprises a heterogeneous group of hereditary disorders characterised by a decrease in the production of one or more globin chains. Multiple complications can result from chronic anaemia on one hand to transfusion related haemosiderosis on the other. The peripheral nervous system, however, is rarely affected. Myopathic syndromes 1-3 and peripheral neuropathy have been reported. [4][5][6] Desferrioxamine (DFO), used as chelation therapy to reduce transfusion induced iron overload, can cause ophthalmological disorders and high frequency sensorineural hearing loss. [7][8][9] Sensorimotor neurotoxicity, associated with high dose DFO treatment has also been reported. 10In this study we evaluated patients with b-thalassaemia clinically and electrophysiologically, and investigated whether factors such as age, clinical severity of thalassaemia (homozygous b or intermedia), antibodies against hepatitis C virus (HCV), ferritin levels, haematocrit (Ht), and history of transfusions, splenectomy, or DFO treatment are associated with abnormal findings. PATIENTS AND METHODSWe examined a consecutive series of 36 patients with thalassaemia (19 women, 17 men; mean age 29.2¡8.2 years, range 16-58) followed up at two tertiary referral centres.Patients with diabetes or other known possible causes of neuropathy were excluded from the study. Thirty two had homozygous b-thalassaemia and four b-thalassaemia intermedia. All patients had normal vitamin B 12 , folic acid, and serum protein electrophoresis and immunofixation. No patient had clinical evidence of visual or auditory dysfunction. The control group consisted of 17 healthy individuals (12 women, 5 men; mean age 27.6¡9.1 years, range 16-55).In all patients the electrophysiological studies were performed by the same investigator. Standard procedures were ...

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We report a new type of non-deletional hereditary persistence of fetal hemoglobin that is due to a C-->T transition at position -158, relative to the Cap site of the human Agamma-globin gene. This mutation was identified in three unrelated adult cases presenting slightly elevated levels of fetal hemoglobin (Hb F), i.e. 2.9-5.1%, and normal hematological indices. Our sequencing results, from both polymerase chain reaction-amplified and subcloned DNA fragments, indicate that the A gamma -158C-->T mutation occurred by two independent gene conversion events in the three cases studied. In addition, hematological and molecular data, including restriction fragment length polymorphism haplotyping in the beta-globin gene cluster, extended haplotype analysis inside the gamma-globin gene region and routine analysis of three tandem repeat loci (D1S80, 3'HVR/apoB and F8vWf), led us to conclude that the A gamma -158C-->T mutation in one of the three cases occurred recently in the parental germ line (P=99.47%), representing the first example of a de novo gene conversion event identified in humans.

This study illustrates the relationship between a group of nucleotide variations within the 5' regulatory region of the Agamma-globin gene [Agamma-588 A-->G, Agamma-499 T-->A and the 4-bp deletion (Agamma-225 to -222 AGCA)] and the spectrum of delta- and beta-thalassemia mutations in the Hellenic population. These sequence variations, screened by means of denaturing gradient gel electrophoresis, form four separate frameworks (Agamma-haplotypes), each one of which was found to be linked in cis with certain delta- and beta-thalassemia mutations found in the Hellenic population. In addition, two novel base substitutions inside the 5' regulatory region of the Agamma-globin gene (Agamma-521 C-->A and Ay-500 C-->T) were identified during this study, which together with Agamma-haplotypes seem to be silent polymorphisms during adult life, as indicated by transient expression assays. Our data show that Agamma-haplotypes represent genetic markers for the spectrum of thalassemic mutations, found in the Hellenic population and can constitute an important genetic repository upon which mutations leading to thalassemia and hemoglobinopathies occurred.

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA2 levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.