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1.
Eur J Neurol ; 27(3): 498-505, 2020 03.
Article in English | MEDLINE | ID: mdl-31571321

ABSTRACT

BACKGROUND AND PURPOSE: Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. METHODS: Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. RESULTS: Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. CONCLUSIONS: Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.


Subject(s)
Spinocerebellar Ataxias/physiopathology , Adult , Age of Onset , Aged , Brain/diagnostic imaging , Cognition Disorders/etiology , Cohort Studies , Female , Humans , Italy , Magnetic Resonance Imaging , Male , Middle Aged , Mood Disorders/etiology , Mutation/genetics , Phenotype , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/genetics , Trinucleotide Repeat Expansion , Ubiquitin-Protein Ligases/genetics
2.
Eur J Neurol ; 26(1): 80-86, 2019 01.
Article in English | MEDLINE | ID: mdl-30098094

ABSTRACT

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.


Subject(s)
ATPases Associated with Diverse Cellular Activities/genetics , Cerebellar Ataxia/epidemiology , Cerebellar Ataxia/genetics , Metalloendopeptidases/genetics , Age of Onset , Aged , Aged, 80 and over , Cohort Studies , Female , Genetic Association Studies , Heterozygote , Homozygote , Humans , Italy/epidemiology , Male , Middle Aged , Mutation , Polymerase Chain Reaction , Prevalence
3.
Acta Neurol Scand ; 133(6): 410-4, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26370385

ABSTRACT

BACKGROUND: Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS. METHODS: One hundred and seventeen MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening. RESULTS: Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state. CONCLUSIONS: The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response.


Subject(s)
Cytochrome P450 Family 7/genetics , Multiple Sclerosis/genetics , Spastic Paraplegia, Hereditary/genetics , Steroid Hydroxylases/genetics , Adolescent , Adult , Brain/pathology , Child , Female , Heterozygote , Humans , Male , Middle Aged , Multiple Sclerosis/complications , Multiple Sclerosis/diagnosis , Mutation , Spastic Paraplegia, Hereditary/complications , Spastic Paraplegia, Hereditary/diagnosis
4.
Eur J Neurol ; 22(2): 253-60, 2015 Feb.
Article in English | MEDLINE | ID: mdl-24848193

ABSTRACT

BACKGROUND AND PURPOSE: Apathy may be either a symptom of major depression or a behavioral disturbance occurring in concomitance with depression or alone in Parkinson's disease (PD). The aim of the present study was to determine the progression of cognitive impairment in drug-naïve untreated PD patients with or without clinically significant apathy. METHODS: Sixty-two PD patients with a disease duration <2 years and without history of present or past therapy with pro-dopaminergic agents were included and underwent the Apathy Evaluation Scale (S-AES), a clinical interview based on diagnostic criteria for apathy and a comprehensive neuropsychological battery to assess memory, frontal functions and visuospatial functions. Two years after the first assessment, all patients were re-evaluated on the S-AES, a clinical interview and neuropsychological tests. RESULTS: According to the cut-off value of the S-AES and diagnostic criteria for apathy, eight patients experienced apathy at both baseline and follow-up (A+A+), nine patients had apathy only at follow-up (A-A+), 37 patients never experienced apathy (A-A-) and eight patients showed apathy at the baseline only (A+A-). Cognitive performance significantly declined in all four groups. At both baseline and follow-up A+A+ performed worse than A-A- on visuospatial and frontal tests; A-A+ had lower scores than A-A- on the interference task of the Stroop test (IT-ST). Regression analysis showed that poor performance on the IT-ST at baseline was the only independent predictor of onset of apathy at follow-up. CONCLUSIONS: The results indicated a relationship between apathy and dysexecutive syndrome in early PD. Reduced scores on the IT-ST may predict development of apathy in PD patients.


Subject(s)
Apathy/physiology , Cognition Disorders/etiology , Executive Function/physiology , Parkinson Disease/complications , Aged , Cognition Disorders/physiopathology , Disease Progression , Female , Follow-Up Studies , Humans , Male , Middle Aged , Parkinson Disease/physiopathology
5.
Eur J Neurol ; 21(5): 802-7, 2014 May.
Article in English | MEDLINE | ID: mdl-23551560

ABSTRACT

BACKGROUND AND PURPOSE: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD. METHODS: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2 years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. RESULTS: At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. CONCLUSIONS: Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up.


Subject(s)
Cognition Disorders/diagnosis , Cognition Disorders/etiology , Insulin-Like Growth Factor I/metabolism , Parkinson Disease/blood , Parkinson Disease/complications , Acoustic Stimulation , Analysis of Variance , Female , Humans , Longitudinal Studies , Male , Neuropsychological Tests , Regression Analysis , Verbal Learning/physiology
6.
Science ; 271(5254): 1423-7, 1996 Mar 08.
Article in English | MEDLINE | ID: mdl-8596916

ABSTRACT

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.


Subject(s)
Chromosomes, Human, Pair 9/genetics , Friedreich Ataxia/genetics , Introns , Iron-Binding Proteins , Proteins/genetics , Trinucleotide Repeats , Alleles , Amino Acid Sequence , Base Sequence , DNA Primers , Female , Genes, Recessive , Heterozygote , Humans , Male , Molecular Sequence Data , Pedigree , Point Mutation , Polymerase Chain Reaction , Proteins/chemistry , Sequence Alignment , Frataxin
7.
J Med Genet ; 45(9): 596-602, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18524835

ABSTRACT

AIMS AND BACKGROUND: Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism. RESULTS: Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity. CONCLUSION: To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.


Subject(s)
DNA, Mitochondrial/chemistry , Electron Transport Complex I/genetics , Mutation, Missense , Parkinsonian Disorders/genetics , Protein Kinases/genetics , Adult , Cells, Cultured , DNA Mutational Analysis , DNA, Mitochondrial/analysis , Electron Transport Complex I/metabolism , Female , Fibroblasts/enzymology , Fibroblasts/metabolism , Genotype , Humans , Oxidative Phosphorylation , Parkinsonian Disorders/enzymology , Parkinsonian Disorders/metabolism , Phenotype , Superoxides/metabolism
8.
J Neurol Neurosurg Psychiatry ; 79(1): 82-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17634216

ABSTRACT

OBJECTIVE: Neuropathological descriptions of the brain in Friedreich's ataxia (FRDA) were obtained before availability of the current molecular genetic tests for this disease. Voxel-based morphometry (VBM) enables an unbiased whole-brain quantitative analysis of differences in gray matter (GM) and white matter (WM) volume. METHODS: Using VBM, we assessed the brain structural damage in 22 patients with genetically confirmed FRDA and 25 healthy controls. The results were correlated with the disease duration and the severity of the patients' clinical deficits--evaluated using the International Cerebellar Ataxia Rating Scale and Inherited Ataxia Clinical Rating Scale. RESULTS: In patients with FRDA, VBM showed a symmetrical volume loss in dorsal medulla, infero-medial portions of the cerebellar hemispheres, the rostral vermis and in the dentate region. No volume loss in cerebral hemispheres was observed. The atrophy of the cerebellum and medulla correlated with the severity of the clinical deficit and disease duration. CONCLUSIONS: In patients with FRDA, significant GM and WM loss was observed only in the cerebellum and dorsal medulla. These structural changes correlate with the severity of the clinical deficit and disease duration.


Subject(s)
Brain/anatomy & histology , Brain/physiopathology , Friedreich Ataxia/diagnosis , Friedreich Ataxia/physiopathology , Adolescent , Adult , Aged , Alleles , Atrophy/pathology , Atrophy/physiopathology , Cerebellum/pathology , Cerebellum/physiopathology , Dentate Gyrus/pathology , Dentate Gyrus/physiopathology , Disability Evaluation , Disease Progression , Female , Friedreich Ataxia/genetics , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Surveys and Questionnaires , Time Factors
9.
J Neurol Sci ; 275(1-2): 60-3, 2008 Dec 15.
Article in English | MEDLINE | ID: mdl-18755482

ABSTRACT

Autonomic nervous system dysfunction is part of the spinocerebellar ataxia (SCA) clinical picture, but few data are available on this topic. The present study is aimed to report a detailed investigation of autonomic nervous system in patients with molecular diagnosis of SCA type 2, one of the most frequent forms and the commonest in Italy. Nine patients with a mild to moderate form of SCA2 underwent a questionnaire about dysautonomic symptoms and a complete cardiovascular neurophysiologic evaluation of both sympathetic and parasympathetic system, comprising head-up tilt, standing, isometric hand grip, cold pressure, mental arithmetic, Valsalva manoeuvre, deep breathing, and hyperventilation tests. An echocardiographic study and Holter-ECG recording were also performed. All patients complained dysautonomic problems regarding urinary tract, cardiovascular system, or gastrointestinal dysfunction. The neurophysiologic study showed both sympathetic and parasympathetic involvement, with highly variable degree and pattern of dysautonomia. The present study results show that the autonomic dysfunction is common in SCA2 representing a significant component of the complex picture of the disease. We found a wide spectrum of cardiovascular autonomic abnormalities, without a typical pattern of dysfunction and without correlation with clinical variables.


Subject(s)
Autonomic Nervous System Diseases/etiology , Blood Pressure/physiology , Heart Rate/physiology , Spinocerebellar Ataxias/complications , Adult , Echocardiography/methods , Electroencephalography , Female , Hand Strength/physiology , Humans , Hyperventilation/etiology , Magnetic Field Therapy/methods , Male , Middle Aged , Posture , Severity of Illness Index , Spinocerebellar Ataxias/pathology , Surveys and Questionnaires , Valsalva Maneuver/physiology , Young Adult
10.
Nutr Metab Cardiovasc Dis ; 17(1): 6-12, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17169539

ABSTRACT

AIMS: To evaluate the association of serum concentrations of glycated apolipoprotein B (ApoBg) with the incidence of myocardial infarction (MI) in subjects with and without diabetes. METHODS: The design is a nested case-control study. The cohort included 5632 subjects over 50 years of age attending the clinical laboratories of a small geographic area in southern Italy. After five years, 4563 subjects were traced and 103 had developed MI. We sampled from the cohort two controls for each incident case of MI, frequency matched for sex and diabetes. ApoBg was measured using a monoclonal antibody. Logistic regression was used for statistical analysis of the data. RESULTS: ApoBg at baseline was higher in subjects who developed myocardial infarction than in controls in both non-diabetic and diabetic subjects (t test, P=0.009 and P=0.05 respectively). MI odds ratio in the third tertile of ApoBg was 2.01 (95% CI 0.93-4.33) in non-diabetic and 2.88 (0.85-9.68) in diabetic subjects (chi-square test for trend; non-diabetics P=0.03, diabetics P=0.06). Serum triglycerides, cholesterol, HDL and LDL cholesterol, glucose and insulin were not associated with MI (P>0.10). CONCLUSION: ApoBg at baseline is directly associated with the development of MI in the following five years in both diabetic and non-diabetic individuals.


Subject(s)
Lipoproteins, LDL/blood , Myocardial Infarction/etiology , Aged , Atherosclerosis/blood , Atherosclerosis/etiology , Case-Control Studies , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cohort Studies , Electrocardiography , Female , Glycation End Products, Advanced , Humans , Logistic Models , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/mortality , Odds Ratio
11.
J Med Genet ; 43(7): 557-62, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16443856

ABSTRACT

BACKGROUND: Parkinson's disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson's disease in sibships from North America. OBJECTIVE: To make a thorough assessment of the SPR gene region in sporadic Parkinson's disease. METHODS: A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson's disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non-parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models. RESULTS: Significant LOD scores between 2 and 3 were obtained at the two SPR-flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p-value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter-correlated SNPs were significantly associated with Parkinson's disease affection status (p-value 0.004). CONCLUSIONS: DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson's disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson's disease.


Subject(s)
Alcohol Oxidoreductases/genetics , Parkinson Disease/genetics , Parkinsonian Disorders/genetics , Age of Onset , Chromosome Mapping , Genetic Markers , Germany/epidemiology , Humans , Lod Score , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Reference Values , Siblings
12.
Eur J Neurol ; 13(9): 1014-21, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16930370

ABSTRACT

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFNbeta-1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFNbeta-1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 +/- 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with < or = 2 relapses in the previous 2 years and with baseline EDSS scores of < or = 2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFNbeta-1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Adult , Disability Evaluation , Disease Progression , Drug Administration Schedule , Female , Humans , Interferon beta-1a , Longitudinal Studies , Male , Middle Aged , Neurologic Examination , Retrospective Studies , Statistics, Nonparametric , Time Factors , Treatment Outcome
13.
Can J Neurol Sci ; 33(2): 237-9, 2006 May.
Article in English | MEDLINE | ID: mdl-16736738

ABSTRACT

BACKGROUND: The cervico-oculo-acoustic syndrome comprises Klippel-Feil anomaly, sensorineural deafness and Duane's retraction syndrome. Polygenic, autosomal dominant, and X-linked inheritance have been hypothesized. The disorder has rarely been reported in males. CASE REPORT: A 42-year-old male, born of consanguineous parents, presented with Duane's syndrome, mixed hearing loss, C2-C3 fusion, neck stiffness, and right facial palsy. A variety of cardiac, neurological and urogenital anomalies occurred in his relatives. The electro-oculographic studies showed impaired abduction and adduction of the right eye and impaired abduction of the left eye. Vergence, vertical eye movements and peripheral vestibular responses were normal. Somatosensory evoked potentials showed absence of the N13 peak and brainstem auditory evoked potentials bilateral delay of the I-III interpeak latencies. CONCLUSIONS: Consanguinity of the patient's parents, not previously reported, suggests autosomal recessive inheritance, but autosomal dominant inheritance is indicated by the family history. The pattern of the oculomotor deficit is consistent with bilateral dysplasia of the abducens nuclei with preserved internuclear neurons in the right abducens nucleus. Neurophysiological investigations revealed lower brainstem and cervical cord involvement.


Subject(s)
Duane Retraction Syndrome/diagnosis , Duane Retraction Syndrome/physiopathology , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/physiopathology , Klippel-Feil Syndrome/diagnosis , Klippel-Feil Syndrome/physiopathology , Abducens Nerve/abnormalities , Abducens Nerve/pathology , Abducens Nerve/physiopathology , Adult , Brain Stem/abnormalities , Brain Stem/pathology , Brain Stem/physiopathology , Chromosome Disorders/genetics , Consanguinity , Duane Retraction Syndrome/genetics , Evoked Potentials, Auditory , Evoked Potentials, Somatosensory , Genes, Dominant/genetics , Genes, Recessive/genetics , Genetic Predisposition to Disease/genetics , Hearing Loss, Sensorineural/genetics , Humans , Inheritance Patterns/genetics , Klippel-Feil Syndrome/genetics , Male , Neck Muscles/innervation , Neck Muscles/physiopathology , Ocular Motility Disorders/diagnosis , Ocular Motility Disorders/genetics , Ocular Motility Disorders/physiopathology , Pedigree , Spinal Cord/abnormalities , Spinal Cord/pathology , Spinal Cord/physiopathology , Syndrome
14.
Parkinsonism Relat Disord ; 23: 102-5, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26725142

ABSTRACT

INTRODUCTION: PARK20 is a rare autosomal recessive parkinsonism related to the SYNJ1 gene and characterized by early-onset of disease and atypical signs such as supranuclear vertical gaze palsy, dementia, dystonia, and generalized tonic-clonic seizures. OBJECTIVE: Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene. METHODS: The Non-Motor Symptoms, the SCOPA-AUT, the Mayo Sleep Questionnaires and polysomnography were used to investigate non-motor signs (NMS), autonomic dysfunction and REM Behavioural Disorder (RBD). Cognitive functions were examined by an extensive battery of neuropsychological tests. In addition, motor and sensory nerve conduction studies and evoked laser potentials were performed. Cardiac sympathetic innervation was assessed in the two patients by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, computing early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates (WR). RESULTS: Among the non-motor symptoms and autonomic signs, case 1 had cold intolerance, drooling and dysphagia, while case 2 had pain and urinary dysfunction. Both cases showed mood and behavioural disorders. RBD were not found, whereas the neuropsychological assessment revealed a progressive cognitive impairment. Neurophysiological studies revealed no abnormalities. Indexes of cardiac sympathetic innervation in the two patients did not differ from those of control subjects. CONCLUSIONS: Our findings expand the phenotypic profile of SYNJ1-related parkinsonism. Preserved cardiac sympathetic function and absence of RBD suggest that PARK20 should be explained by a pathogenic mechanism different from Lewy Body pathology, or that the latter is not as widespread as idiopathic Parkinson's disease.


Subject(s)
Heart/innervation , Parkinson Disease/complications , Parkinson Disease/genetics , Phosphoric Monoester Hydrolases/genetics , Sympathetic Nervous System/physiopathology , Adult , Heart/diagnostic imaging , Humans , Male , Mutation , Myocardial Perfusion Imaging , Parkinson Disease/physiopathology , Phenotype , Siblings
16.
J Med Genet ; 41(12): 900-7, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15591275

ABSTRACT

OBJECTIVE: To undertake a full genome-wide screen for Parkinson's disease susceptibility loci. METHODS: A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at approximately 10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test. RESULTS: There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11-q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11-q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (approximately 17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance. CONCLUSIONS: These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11-q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.


Subject(s)
Genetic Linkage , Parkinson Disease/genetics , Adult , Aged , Aged, 80 and over , Chromosome Mapping , Cohort Studies , Europe , Genetic Predisposition to Disease , Genetic Testing , Genome, Human , Genotype , Humans , Lod Score , Microsatellite Repeats/genetics , Middle Aged , United States
17.
J Neurol ; 262(12): 2755-63, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26530509

ABSTRACT

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.


Subject(s)
Fibroblasts/metabolism , Mitochondrial Diseases/metabolism , Muscle Spasticity/metabolism , Oxidative Stress/physiology , Skin/metabolism , Spinocerebellar Ataxias/congenital , Adult , Female , Heat-Shock Proteins/genetics , Humans , Male , Middle Aged , Mitochondrial Diseases/etiology , Muscle Spasticity/complications , Muscle Spasticity/genetics , Skin/cytology , Spinocerebellar Ataxias/complications , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/metabolism
18.
Neurosci Biobehav Rev ; 7(3): 385-90, 1983.
Article in English | MEDLINE | ID: mdl-6322065

ABSTRACT

The effects of intraventricular administration of neurotensin (0.9, 3.75 and 15.0 micrograms) on hyperactivity and stereotypy induced by either amphetamine (1 mg/kg), nomifensine (20 mg/kg), apomorphine (0.5 mg/kg) or N-n-propylnorapomorphine (0.5 mg/kg) were examined. Results indicate that for each drug treatment, the effects of neurotensin were identical: hyperactivity was significantly reduced while stereotypy remained unaffected. Results also revealed that neurotensin significantly increased the hypothermia induced by apomorphine and N-n-propylnorapomorphine. Possible mechanisms which could underly neurotensin's selective inhibitory action on hyperactivity produced by both pre and post synaptic dopaminergic stimulation are discussed.


Subject(s)
Dopamine/physiology , Hyperkinesis/chemically induced , Neurotensin/pharmacology , Stereotyped Behavior/drug effects , Synaptic Transmission/drug effects , Amphetamine/administration & dosage , Animals , Apomorphine/administration & dosage , Apomorphine/analogs & derivatives , Humans , Male , Nomifensine/administration & dosage , Rats , Rats, Inbred Strains
19.
Eur J Hum Genet ; 1(2): 133-43, 1993.
Article in English | MEDLINE | ID: mdl-7914465

ABSTRACT

We investigated linkage disequilibrium between Friedreich's ataxia (FRDA) and four tightly linked multi-allele markers in 140 families from France and Italy. These markers include three microsatellites (D9S111, D9S15 and D9S110) and one RFLP (D9S5). Their chromosomal order, D9S111-D9S15-D9S110-D9S5, had previously been established by physical mapping. Linkage disequilibrium was evaluated between each marker and FRDA and between markers. Extended haplotypes were obtained and their frequencies on FRDA and normal chromosomes were evaluated. We obtained evidence of strong allelic association of FRDA with D9S5 only. Analysis of linkage disequilibrium between markers revealed a significant decrease between D9S110 and D9S5, suggesting the presence of a recombination hot spot in the interval between these markers. Probably for this reason, no major FRDA-associated extended haplotype could be identified. Our data suggest the presence of a few common disease-causing mutations in the examined population, and indicate a putative localization for the FRDA gene. Transcribed sequences have been found in this candidate region.


Subject(s)
Friedreich Ataxia/genetics , Linkage Disequilibrium , Alleles , Base Sequence , DNA, Satellite/genetics , Friedreich Ataxia/ethnology , Haplotypes , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , White People/genetics
20.
Eur J Hum Genet ; 8(10): 777-82, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11039578

ABSTRACT

Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disorder characterised by progressive spasticity of the lower limbs. Beside 'pure' forms of HSP, 'complicated' forms are reported, where spasticity occurs associated with additional symptoms. We recently described an Italian family with a complicated dominant form of HSP (SPG9) and we mapped the gene responsible to 10q23.3-q24.2, in a 12cM interval between markers D10S564 and D10S603. The phenotypic manifestations in our family are reminiscent of those already described in a smaller British pedigree. We typed individuals from this British family using markers located in the SPG9 critical interval and haplotype reconstruction showed the disorder co-segregating with SPG9. To characterise the SPG9 region better, we constructed a contig of 22 YACs, assigned it to 18 polymorphic markers and positioned 54 ESTs. Furthermore, we searched for ESTs containing a trinucleotide repeat sequence, since anticipation of symptoms was reported in both families. Finally, analysis of a muscle biopsy specimen from one patient was normal, suggesting that, contrary to SPG7, mitochondrial disturbance could not be a primary feature of SPG9.


Subject(s)
Chromosomes, Human, Pair 10/genetics , Physical Chromosome Mapping/methods , Spastic Paraplegia, Hereditary/genetics , Trinucleotide Repeats/genetics , Biopsy , Chromosome Mapping , Contig Mapping , Expressed Sequence Tags , Female , Genotype , Humans , Male , Microsatellite Repeats , Muscles/surgery , Pedigree , Sequence Analysis, DNA , Spastic Paraplegia, Hereditary/complications
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