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Background: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia., Objective: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies., Methods: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases., Results: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment., Conclusion: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns., Purpose and Background: With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome., Methods and Results: This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome., Conclusions: Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS., (© 2024. The Author(s).)

Aging and its related disorders are important issues nowadays and the first cause of this physio-pathological condition is the overproduction of ROS. Ascorbic acid is an antioxidant mediator and its anti-aging proprieties are well known. Our previous data demonstrated that Voghera sweet pepper (VP), a distinctive type of pepper cultivated in Italy, is particularly rich in ascorbic acid. Based on these data, the anti-aging effect mediated by extracts of the edible part of VP was evaluated on an in vitro model of both young and old Normal Human Diploid Fibroblasts (NHDF). Using phase contrast microscopy, we observed that VP may help cells in the maintenance of physiological morphology during aging. Cytofluorimetric analyses revealed that VP extracts led to an increase in DNA synthesis and percentage of living cells, linked to a consequent increase in mitotic events. This hypothesis is supported by the enhancement of PCNA expression levels observed in old, treated fibroblasts, corroborating the idea that this extract could recover a young phenotype in adult fibroblasts, confirmed by the study of p16 and p53 expression levels and TEM analyses. Based on these results, we may suppose that VP can lead to the partial recovery of "young-like" phenotypes in old fibroblasts.

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity., (© 2024. The Author(s).)

Objective: The aim of this study was to estimate the Friedreich's ataxia (FRDA) prevalence in a highly populated region of Italy (previous studies in small geographic areas gave a largely variable prevalence) and to define the patients' molecular and clinical characteristics., Methods: For the point-prevalence study, we considered patients belonging to families with a molecular diagnosis of FRDA and resident in Latium on 1 January 2019. The crude prevalence of FRDA, specific for age and sex, was calculated and standardized for age using the Italian population. Moreover, we investigated possible correlations among patients' genetic profile, symptoms, and age of onset., Results: We identified 63 FRDA patients; the crude prevalence for total, males, and females were 1.07 (95% CI: 0.81-1.37), 0.81 (95% CI: 0.54-1.22), and 1.32 (95% CI: 0.97-1.79), per 100,000 inhabitants. We divided FRDA patients by three age-at-onset groups (early-EOFA 73%; late-LOFA 11.1%; very late-VLOFA 15.9%) and found significant differences in the scale for the assessment and rating of ataxia (SARA; p = 0.001), a biased distribution of the shorter allele (p = 0.001), an excess of scoliosis and cardiomyopathy (p = 0.001) in EOFA. To determine the contribution of patients' molecular and clinical characteristics to the annual rate of progression, we performed a multivariate regression analysis that gave an R2 value of 45.3%., Conclusions: We estimated the crude and standardized prevalence of FRDA in Latium. A clinical classification (EOFA, LOFA, VLOFA) gave significant correlations. This epidemiological estimate allows monitoring disease prevalence over time in cohort studies and/or for developing disease registry., (© 2022 S. Karger AG, Basel.)

Hereditary transthyretin amyloidosis (ATTRv, v for variant) prevalence in Italy, a non-endemic region, has been established by ATTRv amyloidosis Italian Registry. However, values of prevalence were extremely heterogeneous, considering different regions. To properly establish the prevalence of the disease in the Lazio region, a survey was sent to university regional hospitals and to main regional hospitals, in order to collect all affected patients regularly followed. We identified 100 ATTRv patients and, considering a Lazio population of 5.8/million, we estimated a ATTRv prevalence of 17.2/million. The ATTRv amyloidosis Italian Registry reported a prevalence of 8.0/million in Lazio, while our survey showed a value of double this. Our survey documented a high-prevalence for a non-endemic country. The increased awareness of the disease among general practitioners and medical specialists is a fundamental step to reduce the diagnostic delay and start an effective treatment of this disease.

The etiology of sporadic Parkinson's disease is (PD) still not understood but it is believed that a complex interplay between environmental and genetic factors could trigger the pathology. Pro-inflammatory TNF-α is released by activated microglia and is up-regulated in the brain and cerebrospinal fluid of PD patients; TNF-α modulates neuroinflammation and can activate the molecular mechanisms that lead to neurotoxicity and neuronal death. We analyzed two functional SNPs within the TNF-α gene promoter (rs361525 and rs1800629) in 354 Italian PD patients and 443 healthy controls (HC). In our cohort of patients, no significant associations could be observed between rs361525 and rs1800629 SNPs and either PD onset risk or PD-associated clinical parameters including age at onset of fluctuations, UPDRS-ME (Unified Parkinson Disease Rating Scale-Motor Examination), Schwab & England, Hohen & Yahr stage scale, and MMSE (Mini-Mental State Examination) score. Conflicting results on the role played by TNF-α rs1800629 SNP on PD onset risk are present in the literature. We could not find any association between TNF-α rs361525 and rs1800629 and PD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases.

Background and Purpose: The hereditary spastic paraplegias (HSP) are characterized by progressive spasticity of the lower limbs, mostly inherited as an autosomal dominant trait. Analyses of large HSP pedigrees could help to better characterize the phenotype due to a single causative mutation. Patients in a seven-generation kindred carrying a large deletion in SPAST/SPG4 are described., Methods: Individuals originating from Sardinia were clinically and genetically studied., Results: Sixty-seven subjects carried a heterozygous deletion encompassing exons 2-17 of SPAST. Fifty patients (53.2 ± 15.4 years) presented a pure form of spastic paraparesis characterized by mild impairment and slow progression. Most patients showed spasticity, increased tendon reflexes in the lower limbs and Babinski sign, whilst weakness was rarely detected and urinary disturbances occasionally reported. Amongst the 17 asymptomatic carriers of the mutation, minimal neurological signs were detected in 11 cases., Conclusions: A focus on spasticity, increased tendon reflexes and Babinski sign, more than on weakness, could help clinicians to promote early diagnosis in asymptomatic carriers of SPAST deletions., (© 2013 The Author(s) European Journal of Neurology © 2013 EAN.)

The few epidemiological studies conducted to date on the heterogeneous group of hereditary spastic paraplegias (HSPs) indicate a prevalence of 1.27-12.1 per 100,000. This study aims to explore the epidemiological, clinical, and genetic variability of HSPs among Sardinians, a population of peculiar ethnicity.A population-based prevalence study was performed in north-western Sardinia between January 2000 and December 2010. Multiple sources were used for case ascertainment. Familial and sporadic cases were diagnosed according to generally accepted criteria, and clinical diagnoses were validated by expert neurological examination. Clinical data and pedigree information were recorded and blood samples drawn for genetic testing.Sixty-seven HSP patients were included in the study: 59 belonged to 11 families with autosomal dominant transmission (AD-HSP), three cases were from two unrelated autosomal recessive families, and the remaining five cases were apparently sporadic. On 31 December 2010, the total crude prevalence was 19.9 per 100,000 (95 % CI 18.4-21.4), while the crude prevalence of AD-HSP was 17.5 (24.4 M, 15.7 F; M:F ratio 1.55). The mean age at examination was 48.4 years, and the mean age at onset of HSP was 36.6 years. A molecular diagnosis was obtained in 82.1 % of the cases (52 cases with mutations in SPAST/SPG4, two in SPG7, and one in SPG11).The prevalence of HSP among Sardinians is high compared with other Western European populations. The multiple search strategy used in this study and the specific socio-demographic characteristics of Sardinians may account for this finding.

Wilson's disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003., Patients and Methods: After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m(2), and cyclophosphamide 1.5 g/m(2) alternating with cisplatin 90 mg/m(2) plus VP16 450 mg/m(2) for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m(2), and cyclophosphamide 3 g/m(2)) for 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression., Results: We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT., Conclusions: Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

N1 non-small-cell lung cancer has heterogeneous prognosis in relation to node descriptors. There is no agreement on the ideal type of resection. A new classification of N1 descriptors was proposed in the 7(th) edition of the TNM staging system. A retrospective study was conducted on 384 patients with T1-T3N1 non-small-cell lung cancer who underwent complete pulmonary resection. The prognostic role of N1 descriptors according to the current and new staging systems and type of resection was investigated. The 5-year survival rate was 46%. Involvement of hilar node stations, multiple stations, and multiple nodes were poor prognostic factors (5-year survival, 33%, 21%, and 30%, respectively), as well as involvement of the hilar zone and multiple zones (5-year survival, 27% and 23%, respectively). Pneumonectomy showed significantly better survival rates compared to lobectomy or bilobectomy (5-year survival, 60% vs. 29%). Multivariate analysis showed that the number of N1 zones and type of resection were independent prognostic factors. Patients with hilar nodal, multiple-level, or multiple-zone involvement had poor prognosis. Standard lobectomy remains the procedure of choice, but in cases of fixed nodes in the hilar zone, sleeve resection or even pneumonectomy should be considered.

The authors have gone through the complaints concerning all the cases of shoulder accidents at work filed by the Genoa office of the Italian Workers' National compensation Agency (INAIL) during the two years' period 2006-2007, reviewing in particular those somehow affecting rotator components. The aim of this paper is to assess the real role played by the occupational trauma in the rotator cuff tear. The data gathered so far have shown, on the one hand, a high prevalence of pre-existing inflammatory and degenerative diseases and, on the other, a rather modest influence of the trauma which, for this reason, has usually borne, as an immediate medico-legal consequence, the rejection of a cause-effect relationship between the accident and the rotator cuff lesion, without taking into any account whether the worker was likely to be affected by an occupational disease (ex table Ministerial Decree n. 81 April 9th 2008- item 78). In such cases a systematic and in-depth investigation of the occupational case history is suggested, in order to highlight the possible pre-existence of a former biomechanical overload of the upper limbs, so as to allow the physician to detect a pathology often misdiagnosed.

Background and Purpose: A possible association between Parkinson's disease (PD) and the polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies that nevertheless yielded-contrasting result. The purpose of this study was to analyze such possible association in a cohort of Italian PD patients., Methods: The BDNF polymorphisms were analyzed in 294 Italian patients with PD; results were compared to those obtained in 233 age- and sex-matched healthy controls (HC) enrolled from two tertiary centres in Italy. Polymorphisms were determined by Restriction Fragment Length Polymorphism (RFLP) analysis; correlations between BDNF G196A polymorphism, and cognitive function were established by sub analyzing the results upon dividing PD patients based on their Mini Mental State Examination (MMSE) score., Results: Univariate analysis showed a highly significant correlation between the BDNF(AA) genotype and a MMSE score < or =24. Hence, the distribution of this genotype in PD individuals with a MMSE score < or =24 was significantly increased compared to PD patients with an MMSE score >24 and HC (P < 0.001 in both cases). Multivariate analyses showed that BDNF (AA) genotype was associated to a sixfold risk of cognitive impairment., Conclusions: The BDNF(AA) homozygote genotype is over-represented in PD patients compared with normal individuals; this genotype was significantly correlated to cognitive impairment, age and disease severity. These results, although preliminary, could be important in establishing novel diagnostic and therapeutic approaches to PD.

Spastic paraplegia with thinning of the corpus callosum (ARHSP-TCC) is a relatively frequent form of complicated hereditary spastic paraplegia in which mental retardation and muscle stiffness at onset are followed by slowly progressive paraparesis and cognitive deterioration. Although genetically heterogeneous, ARHSP-TCC is frequently associated with mutations in the SPG11 gene, on chromosome 15q. However, it is becoming evident that ARHSP-TCC can also be the clinical presentation of mutations in ZFYVE26 (SPG15), as shown by the recent identification of eight families with a variable phenotype. Here, we present an additional Italian ARHSP-TCC patient harboring two new, probably loss-of-function mutations in ZFYVE26. This finding, together with the report of a mutation in another Italian family, provides confirmation that ZFYVE26 is the second gene responsible for ARHSP-TCC in the Italian population.

We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.

Background: A complicated form of recessive hereditary spastic paraplegias (HSPs) with thin corpus callosum (TCC) was first described in Japan, and most of the Japanese families showed linkage to chromosome 15q13-15. A recessive HSP locus (SPG11) has also been mapped to chromosome 15q13-15 in Italian and North American families with and without TCC, and it overlaps the region identified in the Japanese families., Objective: To study clinically and genetically 12 Italian families with HSP and TCC., Methods: The authors investigated 18 affected and 30 healthy individuals from 12 unrelated Italian families with recessive HSP-TCC. Clinical, neurophysiologic, and neuroradiologic studies were undertaken. All patients were negative for SPG7 mutations. Genetic linkage analyses were carried out with polymorphic DNA markers on 15q13-15., Results: Five families were consistent with linkage, thus defining a 19.8-cM region between markers D15S1007 and D15S978, encompassing the SPG11 interval. In one consanguineous family, linkage could be firmly excluded, confirming genetic heterogeneity. Two families appeared not linked to the region, but this could not be firmly proved because of the small family size. The remaining four families were uninformative for linkage purposes., Conclusion: HSP-TCC is common in Italy. The phenotype is fairly homogeneous and is associated with impaired cognition. There are at least two loci for HSP-TCC, one of which is on chromosome 15q13-15.

We report clinical and molecular findings in 14 patients with cleidocranial dysplasia (CCD), a well defined skeletal disorder with characteristic clinical findings and autosomal dominant inheritance. We identified ten heterozygous base changes in the RUNX2 gene, including six novel mutations [c.522insA, c.389G>A (W130X), c.662T>G (V221G), IVS2+T>A, c.1111&#95;1129del19, and c.873&#95;874delCA]. We did not establish a clear correlation between clinical features and genotype, the phenotypes of all patients analyzed falling within the range of variation described in CCD without an effect related to the length of the predicted protein. In two cases, however, a limb-girdle myopathy affecting the shoulder muscles was also identified. Our data add new variants to the repertoire of RUNX2 mutations in CCD., (Copyright 2003 Wiley-Liss, Inc.)

The authors report on a novel frameshift mutation (c.1688insA) in the SPG3A gene resulting in premature translation termination of the gene product atlastin. These data add a new variant to the second disease gene in autosomal dominant hereditary spastic paraplegia (ADHSP) and lend definitive support to its causative role. By combining direct testing of SPAST and SPG3A, at least 50% of ADHSP families can now receive appropriate genetic diagnosis.

An epidemiological survey of Charcot-Marie-Tooth disease (CMT) was conducted in Molise, a central-southern region of Italy, from March 1998 to June 2000. Fifty-eight cases of CMT in 13 unrelated families were identified within the selected area. The prevalence of all subtypes of CMT was 17.5/100,000. All families underwent a bio-molecular analysis to disclose the duplication at gene locus 17p11.2 in order to ascertain the diagnosis of CMT type 1A. Our data revealed that 64% of all the observed patients had CMT1A, thus confirming the high prevalence of duplication of the 17p11.2 locus., (Copyright 2002 S. Karger AG, Basel)

We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70. Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-func-tion with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological significance in pure AD-HSP and suggesting implications for the presumed function of spastin.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 5-10% of the patients have a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 20% of FALS cases. We found SOD1-gene mutations in five of 34 unrelated FALS, and in two of 44 SALS patients. Three FALS patients carried the previously described A4V (two cases) and L84F mutations (one case), while two FALS patients carried new missense mutations: a G12R substitution in exon 1, and a F45C substitution in exon 2, respectively. The newly identified mutations were both associated with a slowly progressive disease course. Two SALS patients carried the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an A95T amino acid substitution, that is apparently a non-pathogenic SOD1 variant. Our study increases the number of ALS-associated SOD1 gene mutations.

The authors studied a family with pure autosomal dominant spastic paraplegia (ADHSP) that showed a marked intrafamilial variability in both age at onset and clinical severity, ranging from severe congenital presentation to mild involvement after age 55. They found a novel mutation in the SPG4 gene, which segregates with the disease in six patients. The mutation affects the consensus donor splice site of SPG4 intron 16, resulting in a premature termination codon at amino acid 578. The data confirm the pathologic significance of SPG4 mutations in pure ADHSP and add to the list of known SPG4 allelic variants.

Objective: To determine whether patients with migraine without aura with maternal "inheritance" are affected by a monosymptomatic form of the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) or carry the most common mitochondrial DNA (mtDNA) mutation associated with MELAS, namely the A3243G transition in the transfer RNA (tRNA)Leu(UUR) gene., Background: The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical, and neuroradiological grounds. Migraine attacks with vomiting and cerebral infarctions, most often in the posterior cerebral regions, which are reminiscent of complicated migraine, are typical features of MELAS. The observation that migrainous patients have affected mothers more often than affected fathers suggests a possible role for maternally transmitted genetic factors., Methods: We studied 25 patients with migraine with aura whose mothers were also affected. A sensitive polymerase chain reaction restriction fragment length polymorphism analysis was used to detect mutated genomes., Conclusions: We failed to detect the MELAS mutation, but migraine may still be associated with point mutations of mtDNA other than A3243G or with as-yet-unidentified nuclear DNA factors related to mitochondrial function.

We report an Italian family with maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiological evidence of brainstem dysfunction. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 5814 in the tRNA gene for cysteine (A5814G), previously reported in a 5-year-old girl of Portuguese origin. The mutation was very abundant (> 95%) in both muscle and blood from the proposita and was present in lower proportions (average 85 +/- 6%) in blood from three less severely affected maternal relatives. This observation confirms pathogenicity for the A5814G mutation.