Novel and recurrent spastin mutations in a large series of SPG4 Italian families.

BACKGROUND: Hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders, genetically classified according to the identified disease gene or locus. Clinically, HSP are distinguished in pure and complicated forms. Mutations in the spastin gene (SPAST) are responsible for SPG4 and account approximately for 50% of the dominantly inherited paraplegias with a pure HSP phenotype. METHODS: Molecular screening of the SPAST gene allowed the identification of 31 Italian mutation carriers, from 19 unrelated families. Genetic testing was performed by direct sequencing and multiplex ligation-dependent probe amplification. Subjects carrying SPAST mutations were retrospectively evaluated for clinical phenotype and disability score assessment. RESULTS: We found 12 recurrent mutations, and 7 novel SPAST mutations. Twenty-eight patients exhibited a pure spastic paraplegia phenotype, while 3 subjects were asymptomatic mutation carriers. Four patients were sporadic cases. Age at onset ranged from 10 to 61 years. Disability score increased with age at examination and disease duration. Patients with onset >38 years presented a faster disease progression, and a higher disability functional index, than the patients with earlier onset (p<0.04). CONCLUSIONS: Our study enlarges the number of pathogenic SPAST mutations, and confirms the association with a pure spastic paraplegia phenotype. Age at onset was highly variable and correlates with the rate of disease progression. Future longitudinal clinical studies are needed to confirm these observations.

A novel palladium-catalyzed synthesis of phenanthrenes from ortho-substituted aryl iodides and diphenyl- or alkylphenylacetylenes.

[reaction--see text] 1,5-Selectively disubstituted 9,10-diphenyl- or alkylphenylphenanthrenes are obtained by reaction of ortho-substituted aryl iodides and diphenyl- or alkylphenylacetylenes in the presence of palladium and norbornene as catalysts. The reaction outcome is controlled by the steric effect exerted by the ortho substituent in the aryl iodide.

Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families.

Charcot-Marie-Tooth neuropathy type 1 (CMT1), the most common hereditary neurological disorder in humans, is characterized by clinical and genetic heterogeneity. It is caused mainly by a 1.5 Mb duplication in 17p11.2, but also by mutations in the myelin genes PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), Cx32 (connexin 32; also called GJB1), and EGR2 (early growth response 2). In this study, we have screened 172 index cases of Italian families in which there was at least one subject with a CMT1 diagnosis for the duplication on 17p11.2 and mutations in these genes. Among 170 informative unrelated patients, the overall duplication frequency was 57.6%. A difference could be observed between the duplication frequency in familial cases (71.6%) and that observed in non-familial cases (36.8%). Among the non-duplicated patients, 12 were mutated in Cx32, four in MPZ, two in PMP22, and none in the EGR2. In the non-duplicated cases, the overall point mutation frequency for these genes was 25.0%. We describe the mutations identified, and consider possible genotype-phenotype correlation.

Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation.

Mutations in the gene coding for the Schwann cell transcription factor early growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain development, have been observed in few cases of inherited neuropathy. The authors describe a unique combination of cranial nerve deficits in one member of a Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding further supports the role of EGR2 in cranial nerve development.

Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial fatty acid beta-oxidation manifesting with episodes of metabolic decompensation or isolated recurrent myoglobinuria. In this report the clinical, biochemical, and molecular studies in a series of five patients (four Italian and one Spanish) with this disorder are discussed. Biochemical studies included the determination of fibroblast substrate oxidation rates and enzyme activity and Western blot analysis of VLCAD protein. Molecular analysis was performed by sequencing the VLCAD gene from the genomic DNA. Clinical features were within the spectrum previously reported. Four patients presented in infancy or childhood with episodes of severe metabolic decompensation and dicarboxylic aciduria. Two exhibited cardiomyopathy. The fifth patient presented with isolated recurrent rhabdomyolysis, with no cardiomyopathy or dicarboxylic aciduria. In all patients a significant loss of VLCAD activity associated with a marked reduction of VLCAD protein levels occurred. Molecular analysis disclosed one novel missense mutation (Cys437Tyr) and four previously reported mutations, including two missense substitutions (Phe418Leu and Arg419Trp), a single amino acid deletion (Lys258del), and one splice site mutation (IVS8-C(-2)), which was present in all four Italian patients. All patients exhibited compound heterozygosity. The phenotypic variability and the high genotypic heterogeneity of this hereditary metabolic disorder is reported.

Reciprocating gait orthoses: a multicenter study of their use by spinal cord injured patients.

OBJECTIVE: Use of reciprocating orthosis (RGO, ARGO, HGO) by 74 patients with complete traumatic spinal cord injury was studied. Lesion levels ranged from T1 to T12. STUDY DESIGN: Patients were enrolled in seven Italian rehabilitation centers an average of 37 weeks after acute trauma. The training period averaged 39 days. Discontinued use of the device was recorded at follow-up. Before discharge, functional walking, gait velocity, donning and doffing time, and the ability to climb stairs were recorded. The same items were evaluated at 6-month follow-up. RESULTS: At follow-up, 24 patients had abandoned the orthosis, 19 used the device for therapeutic exercise, 31 used it for functional gait, and 9 also used it outside the home. Functional walking was correlated with age, level of lesion, ability to climb stairs, duration of training, and lapse of use of the orthosis. The results showed a correlation between use of the orthosis and the ability to climb stairs, as well as a high Garrett score. CONCLUSION: This orthosis is not considered as an alternative to the wheelchair, despite its greater speed, simplicity of use, and greater autonomy provided to the user.

[Psychiatric disorders in elderly patients with physical problems. Critical review of the recent literature]. / Disturbi psichici nel paziente anziano ricoverato per problemi fisici. Rassegna critica della recente letteratura.

The authors review some studies of the recent psychiatric literature on the elderly medically ill. The large variability in setting, screening instruments, and diagnostic criteria makes comparison of results somehow difficult and probably accounts for the differences in prevalence rates. We also outline methodological issues relating to the standardization of screening instruments and to special features ("pseudodementia", "masked" depression) of psychiatric disorders in old age.

The perception of life events in two different cultural settings.

The perceived stressfulness of 63 life events was compared in a North Italian and a South Italian sample, using a 0-20 equal-interval scale. Each sample comprised 48 psychiatric patients and 34 relatives. Three-way analyses of variance for each event showed that South Italians consistently rated events as more upsetting, while patient or relative status and item order of the life event list did not affect the ratings. Multiple regression analysis showed that sociodemographic variables were not related to overall mean scaling scores with the exception of marital status which revealed a significant interaction with the city of residence. Southern Italians scaled recent events as more upsetting than events which had not occurred. This was not the case for the North Italian sample.

Validation of a screening questionnaire for alcoholism (MAST) in an Italian sample.

One hundred fifty subjects (75 index cases and 75 controls) completed the Italian version of the Michigan Alcoholism Screening Test (MAST). Using Relative Operating Characteristic (ROC) analysis, the 5/6 cut-off point was found to be the best as for discriminating between "cases" and "non-cases" in terms of balance between sensitivity (96%) and specificity (89%). The positive predictive value, the negative predictive value, and the overall misclassification rate were 90%, 95%, and 7% respectively. Using item by item assessment of discriminating capacity, we developed a brief ten item Italian version (2/3 cut-off point). This discriminated between alcoholics and non-alcoholics as well as the longer version, and is thus superior in situations where a brief evaluation is necessary.

Transcultural differences in the perception of life events.

The perception of life events of Italian and English subjects was compared. Psychiatric patients and relatives rated 58 life events according to the degree to which the event was regarded as upsetting. The similarity between the two groups was noted, although Italian subjects tended to rate events as less upsetting than the English. The findings excluded that the rating differences between the two groups reflected differences in reaction to life and confirmed the existence of scaling similarity over national groups.

Inter-rater reliability of the Italian version of the Paykel Scale of stressful life events.

The inter-rater reliability of the Italian version of the Scale for evaluating stressful life events, developed by Paykel, was studied in 15 psychiatric patients and in 15 normal subjects. Agreement between the two raters was satisfactory for total number of events, impact and independence of event areas and categories. These preliminary findings suggest that the Scale is a reliable instrument for the assessment of life events in Italian samples.

Urinary PABA recovery after oral N-benzoyl-L-tyrosyl-PABA administration combined with various exocrine pancreatic stimulants.

Eleven healthy volunteers (C) and nine patients affected by chronic relapsing pancreatitis (CP) were administered N-Benzoyl-L-Tyrosyl-PABA orally, at a dose of 150 mg combined, on different days, with: 1) water alone (schedule a); 2) Lundh meal (schedule b); 3) Secretin-Caerulein by i.v. infusion (0.5 CU/kg/hr and 75 ng/kg/hr respectively) (schedule c); 4) Caerulein by i.m. injection (300 ng/kg) (schedule d). The mean urinary PABA recovery in CP was lower than in C with all the schedules, but this was statistically significant only with schedules a and c (P less than 0.02 and P less than 0.05 respectively). With respect to b, c, and d, the mean urinary PABA recovery seemed to increase both in C and in CP as compared with schedule a, but only in the CP group with schedule b was the increase statistically significant (P less than 0.05). The present data show that the exocrine pancreatic stimulants do not improve the reliability of the PABA test.