Recovery of chronic motor neuropathy due to acute intermittent porphyria after givosiran treatment in a young boy: a case report.

BACKGROUND: We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks' recurrence. CASE REPORT: A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory-motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years. CONCLUSIONS: A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy.

Expanding the spectrum of SOX1-antibodies in neuropathy: the coexistence of anti-SOX1 and Guillain-Barré syndrome-a case report.

BACKGROUND AND AIMS: Antibodies against SOX1 (or anti-glial nuclear antibody, AGNA) are partially characterized onconeural antibodies, firstly described in association with small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome is the most frequent paraneoplastic syndrome (PNS) found in patients with anti-SOX1-antibody positivity. Other associations are chronic axonal polyneuropathy, paraneoplastic limbic encephalitis, and paraneoplastic cerebellar degeneration. METHODS: We describe a case of Guillain-Barré syndrome (GBS) with classical demyelinating phenotype associated with a positivity for anti-SOX1-antibodies. RESULTS: A therapy with intravenous immunoglobulin led to progressive clinical improvement. After 12 months, clinical and neurophysiological pictures showed complete recovery. A thorough paraneoplastic screening was negative for underlying tumors. CONCLUSIONS: This is the first case of GBS associated with anti-SOX1-antibodies described in literature. Although the concept of paraneoplastic GBS is controversial, different cases have been reported and GBS is considered a non-classical paraneoplastic syndrome. Our case expands the anti-SOX1-antibody clinical spectrum with relevant implications for the clinical practice.

New onset status epilepticus in influenza associated encephalopathy: The presenting manifestation of genetic generalized epilepsy.

We hereby present a case of a young woman with no history of seizures or epilepsy who experienced a de novo generalized Non Convulsive Status Epilepticus (NCSE) followed by encephalopathy lasting for several days during influenza B infection. Influenza can have a broad spectrum of presentation ranging from an uncomplicated illness to many serious conditions as is the case of influenza associated encephalitis/encephalopathy (IAE). In this context however, it is possible to observe seizures and/or status epilepticus as the presenting manifestation of a genetic generalized epilepsy.

Identifying congenital hearing impairment: preliminary results from a comparative study using objective and subjective audiometric protocols.

To compare objective and subjective protocols assessing hearing loss in young children and evaluate frequency-specific hearing impairment through a comparison between auditory steady state responses (ASSR), auditory brainstem responses (ABR), transient otoacoustic emissions and conditioned orientation reflex responses (COR). Thirty-five hearing-impaired children (20 male and 15 female), aged between 14 months and 4 years, participated in the study. Hearing threshold levels and peripheral auditory function were assessed by measurements of ABR, ASSR, otoacoustic emissions and COR. The analysis of the COR and ASSR variables showed significant correlations in the majority of tested frequencies. The data highlight a characteristic of the COR procedure, which is an underestimation of the hearing threshold in comparison to the ASSR estimate. The data show that the COR threshold assessment follows the pattern of the other two established electrophysiological methods (ABR, ASSR). The correlation analyses did not permit evaluation of the precision of these estimates. Considering that the ASSR variables show a better relationship with ABR (higher correlation values) than COR, it might be advantageous to utilize the ASSR to gain frequency-specific information.

[Occupational accidents, work performance and obstructive sleep apnea syndrome (OSAS)]. / Infortuni e performances sul lavoro in lavoratori affetti da sindrome delle apnee ostruttive nel sonno (OSAS).

Although many patients with obstructive sleep apnea syndrome (OSAS) form part of the work force, the impact of OSAS on occupational accidents and on work performance is unclear. To address this issue, we investigated 100 referents workers without OSAS (50 blue-collar and 50 white-collar) and 331 workers affected by OSAS (144 blue-collar and 187 white-collar). Workers affected by OSAS had been involved in occupational accidents more often than referents (27.2% vs. 20%). The mean number of accidents/year was slightly higher in blue-collar workers with OSAS and significantly higher (p=0.013) in white-collar workers with OSAS than referents. Furthermore, workers with OSAS referred more impairments in work performance as difficulties in memory (p=0.000), vigilance (p=0.000), concentration (p=0.000), performing monotonous tasks (p=0.000), responsiveness (p=0.000), learning new tasks (0.006) and manual ability (p=0.023), with the mean number of impairments being higher (p=0.000) in workers with a more severe OSAS (referents = 0.32; mild OSAS = 1.11; severe OSAS = 1.70). These results suggest OSAS increases the risk of occupational accidents and impaired work performance. Given the impact of OSAS on fitness for duty assessment, occupational physicians should be aware of it and could play a strategic role in its diagnosis, in monitoring treatment, and in providing appropriate information.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment.

BACKGROUND: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4. METHODS: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Z(low) and Z(high), representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene-environment and gene-gene interactions. RESULTS: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data. CONCLUSION: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

Familial aggregation of tinnitus: a European multicentre study.

INTRODUCTION AND AIM: Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects. METHODS: In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member. RESULTS: All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15. CONCLUSION: The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.

Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12.

Hearing impairment (HI) is the most frequent sensory defect with wide genetic heterogeneity. Approximately 80% of genetic hearing loss is non-syndromic and 15-25% of exhibit autosomal dominant inheritance. We analysed an Italian three generation family in which non-syndromic hearing impairment is transmitted as an autosomal dominant trait. Onset of HI in all affected subjects occurred in the second decade of life, with subsequent gradual progression from moderate to profound loss. HI was bilateral and symmetrical, involving all frequencies. After exclusion of the known DFNA loci with markers from the Hereditary Hearing Loss Homepage (URL: http://dnalab-www.uia.ac.be/dnalab/hhh), a genome wide scan was carried out using 358 highly informative microsatellite markers. Significant linkage (Zmax=4.21, theta=0) was obtained with chromosome 2p12 markers. The results were confirmed by multipoint analysis (Zmax=4.51), using the location score method. Haplotype analysis defined a 9.6 cM disease gene interval on chromosome 2 without overlap with the other identified loci. Fine mapping and identification of candidate genes are in progress.

Spiral CT evaluation of pulmonary emphysema using a low-dose technique.

PURPOSE: To evaluate the diagnostic accuracy and clinical acceptability of low-dose spiral CT for determining pulmonary volumes and emphysema extension in patients with pulmonary emphysema, in comparison with studies based on spiral CT at conventional dose. MATERIALS AND METHODS: We prospectively evaluated eighteen patients, current or former smokers, with a clinical diagnosis of chronic obstructive pulmonary disease. All the patients underwent: HRCT with three scans at predetermined levels; quantitative spiral CT, with two inspiratory scans, one conventional scan at 240 mA, and the second one a low-dose scan at 80 mA. We used the following parameters: 120 kV, rotation time 0.8", scan time less than 20" (single inspiratory breath-hold), layer thickness 7.5 mm, pitch 6 (high speed), interpolation algorithm at 180 degrees. A 3D reconstruction was performed, with segmentation of the lungs and automatic quantification of pulmonary volumes. We compared the volumes of absolute and percent emphysema and the ratings of the dose delivered to the patient (CTDIw and DLP) obtained with the two spiral CT scans with each other and with the respiratory function tests. RESULTS: The average total lung capacity (TLC) obtained by conventional-dose spiral CT (CTs1) was 6889.4 cc (SD +/-1813.2), and the capacity with low-dose spiral CT (CTs2) was 6929.4 cc (SD +/-1811.6). The percentage of emphysema was 39.7% (range: 2.2-63.5%; SD: +/-19.9) for the CTs1 and 41.1% (range: 2.1-66.4%; SD: +/-20). The CTDIw corresponding to CTs1 was 12.2 mGy (range: 11.9-16.4; SD: +/-1), the one corresponding to CTs2, 3.6 mGy (range: 3.6-4.9; SD: +/-0.3). The DLP corresponding to CTs1 was 391.7 mGy x cm (range: 333.3-518.9; SD: +/-46.7), the one corresponding to CTs2 was 117.8 mGy x cm (range: 100.3-156; SD: +/-14). As for the respiratory function tests, the total lung capacity (TLC) obtained by body plethysmography was 7061 cc (SD: +/-2029.7); the percent TLC was 115.9 (range: 66-165; SD: +/-27.6), the forced expiratory volume at one second (FEV1%, percentage of predicted value) was 46.7% (range: 17-123; SD: +/-27.3), residual volume (RV%) as a percentage of predicted value was 186.3 (range: 84-359; SD: +/-80.7), the Tiffeneau index (TI) was 46% (range: 25-71; SD: +/-15.7). We observed a very significant correlation between radiological and functional TLC for both CT methods. The percentage scores for emphysema obtained with the two methods correlated significantly with the functional indexes. The pixel index of CTs1 correlated with TLC% (r=0.87; p<0.0001), FEV1% (r=-0.53; p<0.02), RV% (r=0.76; p=0.004), TI (r=-0.79; p=0.0001). The pixel index of CTs2 correlated with TLC% (r=0.87; p<0.0001), FEV1% (r=-0.56; p=0.01), RV% (r=0.78; p=0.003), TI (r=-0.8; p=0.0001). The adoption of the method with low tube current entailed a highly significant reduction in the estimated dose delivered to patients (CTDIw and DLP) with r=0.9 and p < 0.0001. DISCUSSION AND CONCLUSIONS: Quantitative low-dose spiral CT is a very good method to quantify pulmonary volumes and calculate the extension of the anatomic emphysema. The reduction of mA from 240 to 80 lowers the estimated dose by 30%, without compromising the accuracy of the results. Our study achieved a highly significant correlation between the results obtained with the two spiral CT techniques and between these results and the respiratory function tests. In clinical practice, the easiest way to reduce the dose in spiral CT of the lung is to reduce the tube current. The low-dose method allows a significant reduction in radiation exposure. Further studies are required to establish to what extent the dose can be reduced without increasing in quantum noise and thereby compromising the quality of the study.

Exploring the clinical and epidemiological complexity of GJB2-linked deafness.

GJB2 mutation analysis was performed in 179 unrelated subjects with sporadic or familial hearing loss (HL). Among 57 families, 18 showed a vertical transmission of HL, the disease being present in two or three generations. Besides 155 nonsyndromic cases, 24 patients presenting with extra-auditory clinical signs were included in the molecular study. GJB2 mutation analysis was also performed in 19 subjects with an anamnestic history of perinatal risks factors for acquired HL. The 35delG mutation accounted for 22.1% of analyzed chromosomes in sporadic cases and 39.4% in familial cases; 35delG prevalence reached 41% in autosomal recessive and 44.4% in pseudodominant pedigrees. Two novel GJB2 mutations were identified in compound heterozygosity with 35delG allele (D159V, 284ins/dup[CACGT]). Two 35delG homozygous subjects were identified among HL cases classified as environmental in origin. Four patients 35delG heterozygous (35delG/V95M, 35delG/L90P, 35delG/167delT, and 35delG/?) and two homozygous presented with extra-auditory clinical signs involving different organs (skin, vascular system, hemopoietic lineages, and thyroid). In a high proportion of 35delG heterozygous HL patients (52%), no second GJB2 mutation was detected. The reported data highlight the complexity of the genetic epidemiology of GJB2-linked deafness, further enlarging the spectrum of situations in which GJB2 mutation analysis should be performed. The presence of extra-auditory signs in a significant portion of GJB2-mutated patients suggests the possibility that GJB2 loss of function could contribute to clinical phenotypes presenting in association with deafness. This hypothesis deserves further investigation. The failure to identify a presumed partnering GJB2 mutation in a high proportion of deaf patients remains a challenging problem to be clarified.

Multidetector CT-urography in the study of urological complications in renal transplant.

PURPOSE: To evaluate the value of CT-urography in the diagnosis and follow-up of the urological complications of renal transplantation. MATERIALS AND METHODS: We performed 19 CT-urography examinations (3 of which were follow-up) on 15 patients by using a spiral multislice CT scanner and multiplanar reconstructions. The examinations were carried out directly after administration of 100 ml of iodinated contrast medium by slow iv infusion, with acquisitions starting 5 minutes after the end of the infusion. Surgery was regarded as the gold standard for the diagnosis of urological complications in the operated patients, whereas in patients who had undergone medical therapy or stent placement the gold standard was 1 month ultrasound and clinical follow-up with evaluation of diuresis and renal function. RESULTS: Between January 1999 and December 2001 a total of 210 kidney transplantations were performed at our hospital. There were 34 urological complications in 28 patients with a 16.1% prevalence, consistent with the major international studies. The complications detected were 14 urine leaks and 19 ureteral obstructions secondary to stones, oedema, blood clots and stricture. We observed one case of reflux in the allograft ureter. Fourteen out of 16 CT-urography examinations yielded important clues for the diagnosis of urological complications in kidney allografts, completely replacing standard urography. In particular, CT-urography correctly detected 5 urinary fistulas by demonstrating iodinated contrast material leaks along the ureteral tract, and 8 cases of obstructive uropathy due to different causes (1 submucosal tunnel edema, 1 blood clot, 1 stone and 5 cases of ureteral stricture). One case of urinary fistula and one of obstructive uropathy were not detected. DISCUSSION AND CONCLUSIONS: CT-urography proved to be an important diagnostic tool in the evaluation of urological complications of kidney allografts, showing a diagnostic accuracy over 90%; it is useful for confirming the type and site of urological lesions, and therefore to provide guidance for a targeted surgical approach. Compared with excretory urography, which is no longer used in this diagnostic field, CT-urography is more complete and precise as it provides information not only about the urinary tract, but also about the kidney parenchyma and pararenal fluid collections. The only disadvantage, which limits its use to selected cases, is the risk associated with the use of iodinated contrast agents in patients with impaired renal function.

Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26.

Hearing impairment is the most common inherited human sensory defect. Nonsyndromic Hearing Impairment (NSHI) is the most genetically heterogeneous trait known. Over 70 loci have been mapped and a total of 19 genes have been identified. We report here a novel locus (DFNA 30) for autosomal dominant NSHI that we mapped to chromosome 15q25-26 in an Italian four-generation family. The haplotype analysis has identified a critical interval of 18 cM between markers D15S151 and D15S130. This region does not overlap with DFNB16 locus but partially coincides with the otosclerosis (OTS) locus. Localisation of the locus DFNA30 is a first step towards the identification of the gene.

Hearing in the elderly: a population study.

An epidemiological study comparing speech audiometry with self-assessed hearing disability and an analysis of other factors influencing the quality of life was conducted. In the Veneto region (Italy), a representative sample of 2700 independently living individuals of 65 years of age and older was selected for the study. All participants were administered a comprehensive questionnaire and a brief examination at their home, including a general physical examination, speech audiometry, Sanders' Speech Disability test, part I and III, Mini Mental State Examination, CES-D scale for depression, visual acuity, self-reported diseases and physical function. Auditory function was worst in the older individuals: auditory performance was within acceptable limits up to the 75-79 age group, while it rapidly deteriorates in the older groups. This trend is consistent with self-reported auditory disability (Sanders' test). A detailed analysis of the type of errors made in the speech audiometry was conducted for each subject. Speech audiometry is a good indicator of real hearing difficulties faced by the elderly, and it might be preferred to pure-tone audiometry, since hearing deficits with age are not always limited to an increased detection threshold, but include other aspects of hearing such as distortion of sounds, comprehension of speech and noise discrimination.

Achievements of the European Working Group on Genetics of Hearing Impairment.

Three years ago an European Working Group for the study of genetics of hearing impairment was founded with the aim to standardise terminology and protocols in order to collect families with genetic hearing impairments for a European-based epidemiological, clinical and genetic analysis. Hereditary hearing impairments include a large variety of genetic causes. The occurrence of the different forms is rare, but the overall genetic aetiology is thought to account for up to 50% of newborns' hearing impairment as well as several late onset, progressive cases. In the later years, several locations associated with non-syndromal hearing impairments and different mutations for the syndromic diseases have been identified. Five subgroups have been formed: Definitions and protocols, Epidemiology, Vestibular involvement, Otological and cranial malformations, Molecular biology. Meetings were organised for discussion and establishment of common ground work. Application of the agreed documents was performed to verify protocols. Final agreements were circulated by Infoletter (1-5). Informatic working tools on the Internet have been designed. Standardised definitions, audiological and vestibular protocols have been defined. Pilot studies using experimental protocols to identify informative carriers or to help clinical differentiation between non-syndromic forms have also been performed. Two web sites related to the work have been created. A description of phenotypes of locations identified has been defined. Joining forces to standardise definitions and protocols and collaboration between clinicians and geneticists has contributed considerably to progress in this field.

Clinical applicability of transient evoked otoacoustic emissions: identification and classification of hearing loss.

The study aimed at the development of a clinically applicable methodology that could: (1) discriminate transient evoked otoacoustic emission (TEOAE) recordings from normal hearing or hearing impaired individuals; (2) classify the nature of the hearing loss as conductive or as cochlear, and (3) define clear-cut TEOAE clinical criteria. A classification algorithm based on a multivariate discriminant analysis of fast Fourier transform data from recordings evoked by click stimuli of 50 +/- 2, 62 +/- 2, 68 +/- 2 and 80 +/- 2 dB SPL was used to discriminate 302 normal subjects from 383 subjects suffering from mild to moderate hearing losses. The best discriminant model (QDF80) produced a sensitivity of 93.8% and a specificity of 79.4%. When extra correlation criteria were serially applied to the classification outcome, the specificity was increased to 85.3%, but the sensitivity was marginally decreased to 91.7%. The classification of the correctly identified hearing-impaired cases yielded 93.8% identification of conductive and 75.1% identification of cochlear cases. A sensitivity analysis of the misclassified hearing-impaired cases suggested that the TEOAE spectra are well correlated with the 2-kHz but poorly correlated with the 4-kHz octave frequency.

Audiometric patterns of genetic non-syndromal sensorineural hearing loss.

Sixty-five families with non-syndromal sensorineural hearing loss (NS-SNHL) of genetic aetiology were subtyped according to Gorlin et al. Individual audiogram shapes were also classified in order to detect inter- and intra-familial variations. In 48 families with an Autosomal Dominant (AD) inherited form, 26 exhibited the features of (high-frequency) progressive NS-SNHL, 12 those of mid-frequency NS-SNHL, 5 were affected by congenital low-frequency NS-SNHL; 1 kindred showed a progressive low-frequency pattern and another 1 a unilateral NS-SNHL; only 3 kindreds were affected by severe congenital NS-SNHL. Autosomal Recessive (AR) inherited forms were composed of 9 kindreds with severe congenital NS-SNHL, and 7 with moderate congenital NS-SNHL. One X-linked form was identified. AD- and AR-inherited NS-SNHL differed significantly both in severity of hearing impairment and in audiogram shapes. With few exceptions, in each family classified according to Gorlin, most of the affected subjects shared the same audiogram profile. Intrinsic progression of the disease versus ageing was studied in the larger subtype of individuals with the high-frequency loss. Gorlin's classification still remains the best system to classify NS-SNHL, and can provide a broad base to separate a very heterogeneous group of disorders. Results obtained in gene mapping in single large human families or in homologous gene search could be tested in our families. For some of them, namely those with high frequency progressive and low-frequency NS-SNHL, testing should already be feasible.