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Hereditary sensory and autonomic neuropathies (HSAN) encompass a group of peripheral nervous system disorders characterized by remarkable heterogeneity from a clinical and genetic point of view. Mutations in SPTLC1 gene are responsible for HSAN type IA, which usually starts from the second to fourth decade with axonal neuropathy, sensory loss, painless distal ulcerations, and mild autonomic features, while motor involvement usually occur later as disease progresses. Beyond the classic presentation of HSAN type IA, an exceedingly rare distinct phenotype related to SPTLC1 mutations at residue serine 331 (S331) has recently been reported, characterized by earlier onset, prominent muscular atrophy, growth retardation, oculo-skeletal abnormalities, and possible respiratory complications. In this report, we describe clinical, instrumental, and genetic aspects of a 13-year-old Sri Lankan male carrying the rare de novo p.S331Y heterozygous mutation in SPTLC1 gene found by whole exome sequencing. Patient's phenotype partly overlaps with the first case previously reported, however with some additional features not described before. This work represent the second report about this rare mutation and our findings strongly reinforce the hypothesis of a clearly distinct "S331 syndrome", thus expanding the spectrum of SPTLC1-related disorders.

Dominant Optic Atrophy and Deafness (DOAD) may be associated with one or more of the following disorders such as myopathy, progressive external ophthalmoplegia, peripheral neuropathy, and cerebellar atrophy ("DOA-plus"). Intra- and interfamilial variability of the "DOA-plus" phenotype is frequently observed in the majority of the patients carrying the same mutation in the OPA1 gene. We are describing two familial cases of "DOA-plus" carrying the same c.1334G>A (p.Arg445His) mutation in OPA1 and disclosing different clinical, pathological and biochemical features. The two patients showed different expression levels of the mitochondrial OMI/HTRA2 molecule, which acts as a mitochondrial stress sensor and has been described to interplay with OPA1 in in vitro studies. Our data offer the cue to inquire the role of OMI/HTRA2 as a modifier gene in determining the "DOAplus" phenotype variability.

Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-?-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive, and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the 13 LOPD offspring. These latter resulted to have all a single GAA mutation but low GAA levels. Immunostaining with the autophagy markers LC3 and p62 confirmed the autophagic nature of lymphocytes vacuoles. ROC curve assessment of PAS-positive lymphocytes disclosed 100% of sensitivity and 94% of specificity in recognizing both compound heterozygous and heterozygous GAA carriers. The other myopathies with more than 4 PAS-positive lymphocytes appeared to be all related to impaired autophagy, which seems to be responsible of PAS-positive vacuolated lymphocytes formation. Quantification of PAS-positive lymphocytes in blood films is useful to identify autophagic vacuolar myopathies and should be routinely used as first level test for Pompe disease.

Aging is a primary risk factor for both neurodegenerative disorders (NDs) and tumors such as adult-onset brain tumors. Since NDs and tumors are severe, disabling, progressive and often incurable conditions, they represent a pressing problem in terms of human suffering and economic costs to the healthcare systems. The current challenge for physicians and researchers is to develop new therapeutic strategies in both areas to improve the patients' quality of life. In addition to genetics and environmental stressors, the increase in cellular oxidative stress as one of the potential common etiologies has been reported for both disorders. Recently, the scientific community has focused on the beneficial effects of dietary antioxidant classes, known as nutraceuticals, such as carotenoids, vitamins, and polyphenols. Among these compounds, polyphenols are considered to be one of the most bioactive agents in neurodegeneration and tumor prevention. Despite the beneficial activity of polyphenols, their poor bioavailability and inefficient delivery systems are the main factors limiting their use in medicine and functional food. The development of polymeric nanoparticle-based delivery systems able to encapsulate and preserve polyphenolic compounds may represent a promising tool to enhance their stability, solubility, and cell membrane permeation. In the present review we provide an overview of the main polyphenolic compounds used for ND and brain tumor prevention and treatment that explores their mechanisms of action, recent clinical findings and principal factors limiting their application in medicine.

A retrospective study was performed on 27 patients with hepatitis C (HCV)-related mixed cryoglobulinemia (purpura, arthralgia, hepatitis, glomerulonephritis, peripheral neuropathy) to assess peripheral nerve involvement during follow-up of up to 8 years. All patients had the same degree of organ/system involvement initially and were clinically evaluated at least annually. All 27 patients received steroids; 15 also received recombinant interferon-alpha 2b (rIFN-alpha 2b). At first examination, neurological signs and electrodiagnostic findings consistent with peripheral neuropathy were found in 20 (74%) and in 24 (88.8%) patients, respectively. Neurological evaluation and electrodiagnostic data at 3 and 8 years revealed worsening of neuropathy, whereas the other manifestations of mixed cryoglobulinemia (MC) were stable. At the last examination, clinical and electrodiagnostic signs of neuropathy were found in 25 patients (92.5%), occurring in 1 of 3 patients with normal initial findings, and worsened in 8. A more severe neuropathy was observed in 3 (25%) of the patients treated with prednisone alone and in 6 (40%) of the patients additionally treated with rIFN-alpha 2b. Our data confirm that in patients with HCV-related MC, peripheral nerve involvement is frequent, is progressive, and does not seem to benefit by addition of rIFN-alpha 2b to steroid treatment.

To assess the presence of viral ribonucleic acid (RNA) in nerve tissues of 15 patients with hepatitis C virus (HCV) infection and peripheral neuropathy with (11) or without (4) mixed cryoglobulinemia, nested reverse transcription-polymerase chain reaction (RT-PCR) was performed. Amplification of HCV-RNA was successful in 7 patients with and 3 without mixed cryoglobulinemia. This study demonstrates that the nested RT-PCR technique is a sensitive method to detect viral RNA in nerve tissue, and offers further evidence that in patients with HCV infection peripheral neuropathy can occur in the absence of mixed cryoglobulinemia.

Objective To determine the utility of breast ultrasono- graphy in the diagnostic work-up of precocious puberty and to create a prognostic index for early differentiation between non/slowly progressive or transient forms of precocious puberty and rapidly progressive central precocious puberty. Methods We recruited consecutively 60 girls with precocious pubertal development. In all the girls we evaluated Tanner stage, basal and gonadotropin-releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, estradiol (E2) levels, and bone age, and performed pelvis and breast ultrasound examinations. Logistic regression models were fitted to identify possible diagnostic factors for rapidly progressive central precocious puberty and non/slowly progressive or transient forms. Results Ultrasound breast volume ≥ 0.85 cm3 was associated with rapidly progressive central precocious puberty (P = 0.01). Uterine volume ≥ 5 cm3, LH peak ≥ 7 IU/L, presence of an endometrial echo, E2 levels ≥ 50 pmol/L and bone age > 2 SD above expected were significantly associated with rapidly progressive central precocious puberty. A multivariate model including uterine volume, E2 level, bone age, presence of an endometrial echo and ultrasound breast volume revealed a strong ability to classify rapidly progressive forms. From this multivariate analysis a prognostic index for rapidly progressive central precocious puberty was defined. Conclusions Ultrasound imaging allows better definition of the breast and the maturation stage than does use of Tanner's stages. Ultrasound breast volume ≥ 0.85 cm3 is an independent predicting factor of rapidly progressive central precocious puberty. A prognostic index that was created from a multivariate model including uterine volume, E2 level, presence of an endometrial echo, bone age and ultrasonographically determined breast volume, may help in the early differentiation between rapidly progressive central precocious puberty and non/slowly progressive or transient forms. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Aim: The effectiveness of early intervention in schizophrenia is still under discussion. The guidelines described in the present paper were aimed at contributing to the current debate by providing Italian practitioners, families, patients and health managers with evidence-based information on early intervention. They also examined the diagnostic tools that are currently available for assessing different stages of psychotic disorders. Methods: A multidisciplinary panel of experts (the Guidelines Development Group) used a set of key-questions to develop an explicit search strategy to conduct a systematic review of the literature published from January 2000 to June 2006. Trained personnel then selected papers from those yielded by the literature search. The Guidelines Development Group's final recommendations were scaled according to the Italian National Guidelines System grading system. Results: The evidence available up to the time of the literature search does not allow for recommendation of early intervention targeting prodromal or at-risk patients to prevent progression from the prodromal phase to acute, full-blown psychosis, nor to improve prognosis. Conversely, identification and timely treatment of first-episode psychotic patients through specific early intervention programmes are highly recommended. Conclusions: The Italian Guidelines on early intervention in schizophrenia are based on a comprehensive assessment of an updated, large-scale body of literature. They draw specific, evidence-based conclusions to assist clinicians and stakeholders in the planning and implementation of appropriate intervention programmes. Further research is needed to ascertain the effectiveness of early intervention in delaying or preventing the conversion to psychosis and improving prognosis in prodromal or at-risk patients. Further investigation is also required for first-episode and critical period patients.

Objectives Treatment with growth hormone (GH), alone or in combination with oxandrolone, is used in patients affected by Turner syndrome to improve growth velocity and adult height. Since GH interacts with gonadotropins in the stimulation of the human ovary, the aim of our study was to evaluate the possible effects of GH administration on uterine and ovarian characteristics. Methods We performed pelvic ultrasound assessment in 29 patients with Turner syndrome aged 7.5–16.6 years (19 with 45,X karyotype; 10 with variant karyotypes) before and during treatment with GH alone. Uterine volume and ovarian size and morphology were compared to those of 23 age-matched girls with Turner syndrome not treated with GH. Both patients and controls were divided into prepubertal and pubertal groups. Cross-sectional and longitudinal studies (before and every 6 months during GH treatment for 2 years) were performed. Results We observed a significantly higher uterine anteroposterior diameter and volume in younger (≤ 11 years) GH-treated Turner syndrome girls than in those who were untreated. Also visualization and heterogeneous echopattern of the ovaries were significantly more frequent in treated than in untreated Turner syndrome patients, particularly before the age of 11 years. The longitudinal study showed a significant increase in uterine volume, more related to treatment than to age. Spontaneous breast development and menarche were found more frequently in GH-treated Turner syndrome girls. Conclusion Growth hormone therapy can have a co-gonadotropin role in patients with Turner syndrome. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.

As several studies have reported that 35% of patients with polycystic ovary syndrome are obese and that this syndrome seems to originate during the early phase of sexual maturation, we undertook a study of such subjects. We studied ultrasound and hormonal findings in 49 obese girls aged from 7.9 to 19.10 years, with a mean excess weight of 44%; 23 premenarcheal girls and 26 postmenarcheal girls with mean gynecological age of 2.5 years. As controls, we studied 18 girls in the pubertal phase and 17 healthy girls with regular menses, matched for age and gynecological age. Pelvic ultrasonography was carried out in all girls and estrone, estradiol, progesterone, prolactin, follicle stimulating hormone, luteinizing hormone, sex hormone binding globulin (SHBG), testosterone, free testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), androstenedione and 17-hydroxyprogesterone (17-OHP) were measured by radioimmunoassay in 11 of the 18 postmenarcheal girls. Five girls (10.2%) with excess weight of > 40% presented with mild or severe hirsutism based on Ferriman and Gallway scores; six (12.2%) presented with acne and 14 (28.5%) presented with acanthosis nigricans. Hormonal evaluation showed elevated levels of estrone (p < 0.005) and testosterone (p < 0.01) but lower than normal levels of SHBG (p < 0.05) and estradiol (p

Objective: To evaluate immunohistochemical and ultrastructural changes in sural nerve biopsies from patients with peripheral neuropathy and hepatitis C virus (HCV) infection. Methods: Frozen and plastic-embedded nerve specimens were obtained from 19 HCV-positive patients with (16) or without (3) mixed cryoglobulinemia (MC). Immunoperoxidase and immunofluorescence studies were performed on cryostat cross-sections using antibodies recognising cellular subsets and humoral factors involved in the inflammation (CD68, CD11a-b-c, CD20, CD3, CD4, CD45, C1q, C3d, TCC, IgG, IgA, IgM). Semi and ultrathin sections were studied by standard protocols. Results: Nerve biopsy showed an axonal degeneration with micro- angiopathy (perineurial > endoneurial). IgM and IgG were observed as a thin sub-perineurial band and in the wall of endo and perineurial vessels in MC patients only. Immunoglobulin deposition colocalised in some nerves with complement factors. Macrophages and T memory/activated lymphocytes were seen perivascularly and in endoneurium while rare B-cells were detected in perineurium. In the MC-negative patients, the peripheral neuropathy was characterised by a prominent myelin degeneration. The pattern of distribution of immunoreactivity for humoral and cellular factors was similar but not identical to that of MC patients. Conclusions: Axonal degeneration characterises the HCV-related MC neuropathy and is likely secondary to ischaemia. The vascular damage is prevailing in perineurium and appears to be mediated by both T-cells and immune complex. Myelin alterations mainly occur in MC-negative patients. These last findings suggest a primary pathogenetic role for HCV in the induction of the nerve damage.

Objective: Evaluation of hepatitis C virus (HCV) by reverse transcription-polymerase chain reaction (RT-PCR) in peripheral nerve tissues from HCV infected patients with peripheral neuropathy. METHODS: RT-PCR was performed on homogenates of nerve biopsies from 17 consecutive HCV-positive patients with peripheral neuropathy, with or without mixed cryoglobulinemia, hospitalised from 1996 to 2000. Sural nerve specimens were frozen in iso-pentane pre-cooled in liquid nitrogen and stored at −80°C until use. RNA was extracted from ten 7-μm thick cryostatic sections or from a nerve trunk specimen of about 3 mm length, collected from each biopsy. Three different protocols of RNA extraction were tested (1–3). Complementary DNAs (cDNAs) were obtained without or with RNasin (Promega, Madison, WI) addition in the reaction mixture to inhibit residual RNase activity. Two sets of commercially available PCR primers for the outer and the nested reaction were used. PCR products were analysed by agarose gel electrophoresis and ethidium bromide staining. Serum samples and liver specimens from proven HCV positive patients served as positive controls, whereas sera from healthy subjects were negative controls. RESULTS: Sufficient amount of RNA could be obtained either by cryostatic sections or by in toto nerve specimens. Extraction by Trizol (Gibco-BRL) allowed the best concentration and purity of RNA as assessed by biophotometry. The presence of RNasin didn't improve the cDNA synthesis. The resulting amplification product of the nested PCR was 187 bp long. We have always observed this product in our positive controls and never in the negative. Six samples from patients either with or without cryoglobulinemia resulted positive; 7 were negative. Four samples gave variable results. CONCLUSIONS: While 40% of the nerves in our series were undoubtedly HCV positive, the cause(s) of negative and variable results in the remaining samples is likely more complex than variations in the detection protocols and deserve further investigations. REFERENCES: 1) Chomczynski P, Sacchi N (1987). Anal Biochem 162:156. 2) Marquardt O et al. (1996). Med Microbiol Lett 5:55. 3) Chomczynski P (1993). Bio/Techniques 15:532.

Objective: To evaluate the prevalence and features of peripheral neuropathy in HCV-related mixed cryoglobulinemia (MC). Methods: 133 consecutive patients (23 males and 110 females, age range 23–73 years) with MC (double immunodiffusion) were studied. Immuno-fixation electrophoresis was performed in 127 cases: in 117 a type II, and in 10 type III MC was found. In all the patients circulating anti-HCV antibodies and in 79/87 HCV-RNA were detected. ENG was performed in 52 patients and sural nerve biopsy in 16. Results: Neurological examination revealed a peripheral neuropathy in 107 patients (80.4%): 50 had a distal symmetric sensory-motor polyneuropathy, 55 multiple mononeuropathies, 2 a mononeuropathy. During the course of the illness, mononeuropathies tend to overlap giving a polyneuropathy. ENG showed neuropathic features in 48/52 patients (92.3%), 8 of them without clinical symptoms of peripheral neuropathy. Axonal damage, mainly sensitive, more expressed in the lower limbs, was the commonest electroneurographic finding. Sural nerve biopsy showed axonal degeneration with perineurial and endoneurial microangiopathy, rare cellular infiltrates, erytrocyte diapedesis. Conclusions: Peripheral neuropathy is a common, early, and often severe complication in HCV-related MC. The pattern of nerve changes suggests a vascular mediated damage. Hypoxia and immunological factors may be concurrent pathogenetic mechanisms.