Serum copper, zinc and selenium levels in Tunisian patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. The etiology of this disease is still not fully clear, but free radicals have been proposed to cause neuronal injury. Metals play a key role in the intracellular oxidative balance. However their implication in the degeneration process remains unknown. AIM: To assess Cu, Zn and Se concentrations in serum of a group of PD patients in order to determinate, in comparison with age-matched controls, whether alteration in their levels could be involved in PD. METHODS: A serum level of 3 trace elements (Cu, Zn and Se) was investigated in 48 patients with PD and 36 matched controls using plasma atomic absorption spectrometry. We compared these parameters in PD patients with controls, and we also compared the variations within the PD group according to age, illness duration, stage of the disease and levodopa intake. RESULTS: Patients with PD had significantly lower Cu levels compared to controls. The mean Zn and Se levels in PD patients did not differ significantly from those of controls. Levodopa therapy, age, stage, and illness duration did not significantly influence the measured parameters. CONCLUSION: These results suggest that a disturbance of the plasmatic rate of Cu could be a marker of PD or at least, a risk factor for the development of this disease. Although zinc participates to the reduction of oxidative stress and the antioxidant role of the selenium, their implication in the onset of PD is not clearly established. Perspectives for the future could include antioxidant therapy. For this reason, other prospective studies should be conducted on this subject to elucidate the implication of trace elements in PD.

[Conclusions and recommendations of a WHO expert consultation meeting on iron supplementation for infants and young children in malaria endemic areas]. / Conclusions et recommandations à l'issue de la consultation de l'OMS sur la lutte contre la carence martiale chez le nourrisson et le jeune enfant dans les pays d'endémie palustre.

This article presents the results of an expert consultation meeting aimed at evaluating the safety and public health implications of administering supplemental iron to infants and young children in malaria-endemic areas. Participants at this meeting that took place in Lyon, France on June 12-14, 2006 reached consensus on several important issues related to iron supplementation for infants and young children in malaria-endemic areas. The conclusions in this report apply specifically to regions where malaria is endemic.

Peripheral blood markers of oxidative stress in Parkinson's disease.

Oxidative stress and generation of reactive oxygen species are believed to be implicated in Parkinson's disease (PD). Erythrocyte activity of superoxide dismutase (SOD) and catalase, the blood glutathione system, and plasma levels of thiobarbituric-acid-reactive substances (TBARS) were measured in 80 PD patients. These biochemical parameters were also measured in 29 age-matched controls. Patients with PD had significantly higher red blood corpuscle (RBC) activity of SOD. The mean RBC activity of catalase in PD patients did not differ significantly from those of controls. RBC catalase activity was significantly lower in advanced cases of PD compared to early cases. Oxidized glutathione was significantly higher in RBCs of PD patients, although there were no changes in total glutathione and reduced glutathione compared to controls. TBARS content was increased in patients with PD. Levodopa therapy, age and duration of illness did not significantly influence the measured parameters. Our study supports the previous hypothesis that oxidative stress is implicated in the pathogenesis of PD. Perspectives for treatment of PD in the future could include antioxidant therapy.

Melatonin and jet lag: confirmatory result using a simplified protocol.

This study replicates the alleviation of jet-lag with melatonin in a simplified protocol for eastward flight. At 22-n hr (n is the time-lag between the North American departure point and France), subjects took either melatonin (8 mg, n = 15), or placebo (n = 15) on the day of the return flight and for 3 consecutive days. On day 8, self-ratings significantly discriminated between melatonin and placebo for global treatment efficacy, morning fatigue, and evening sleepiness.

A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression.

The temporal organization of plasma melatonin and cortisol secretion was examined in healthy rested controls and in depressed patients: 11 patients suffering from a primary affective disorder (10 female, 1 male) and 8 male controls were studied over a 24-hr period; blood was collected at 2-hr intervals during the day at 1-hr intervals at night. Plasma melatonin and cortisol levels were determined by radioimmunoassay. In addition, melatonin was determined in plasma sampled at 3 AM in older male controls (n = 8) and in females (n = 10) at ovulation. The controls showed low or undetectable (less than 5 pg/ml) diurnal plasma melatonin levels and a very marked nocturnal rhythm (acrophase: 2.27 AM, mesor: 34.4 pg/ml, amplitude: 58.7 pg/ml). For the three control groups, no significant difference was observed in the nocturnal melatonin peak at 3 AM. The depressed patients also showed a significant melatonin rhythm but with lower amplitude (14.5 pg/ml) and mesor (19.1 pg/ml). The latter rhythm was not significantly phase-advanced with respect to the controls (acrophase at 1.18 and 2.34 AM, respectively). In 9 of the 11 patients, nocturnal melatonin secretion was less marked and frequently associated with hypercortisolemia. An additional episodic melatonin secretion was observed in the late afternoon in only two patients. In depressed patients, there was an increase in the mean cortisol secretion level (mesor at 13.6 micrograms/100 ml against 9.1 micrograms/100 ml in the controls), but the amplitude and the acrophase were not significantly modified. These data are discussed in terms of both the hypothalamus-pituitary-adrenal-epiphysis and aminergic abnormalities.

Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson's disease.

OBJECTIVE: To determine the changes in basal ganglia iron content associated with various stages of idiopathic Parkinson's disease. DESIGN: Prospective magnetic resonance imaging study using a 2-T magnet. SETTING: Ambulatory care referral center. PATIENTS AND PARTICIPANTS: Forty-five patients suffering from levodopa-responsive Parkinson's disease and 45 age-matched controls. MAIN OUTCOME MEASURES: The T2 relaxation time calculated in various regions of the basal ganglia, the duration of Parkinson's disease, and the age of subjects. RESULTS: Patients with Parkinson's disease exhibited significantly decreased T2 relaxation time in the pars compacta of the substantia nigra compared with controls (P < .01), regardless of disease duration. Patients with a duration of illness above 10 years (n = 12) exhibited significantly increased T2 relaxation time in the anterior and posterior putamen (P < .005 and P < .01, respectively) and in the pallidum (P < .05) compared with age-matched controls. Putamental T2 relaxation time positively correlated with disease duration (P < .05). CONCLUSION: These results suggest that more complex brain iron changes than those previously reported are associated with idiopathic Parkinson's disease, including increased nigral iron content and decreased putamenal and pallidal iron concentration in patients with a duration of illness above 10 years.

Giant lambl excrescences. An unusual source of cerebral embolism.

BACKGROUND: A possible association of giant Lambl excrescences (LEs) with stroke has been suggested. However, the treatment of giant LEs is controversial because minimal data are available. OBJECTIVE: To clarify the management of giant LEs through a clinicopathologic study. CASE SERIES: Three young patients (2 women and 1 man) who experienced ischemic stroke were studied. Results of general examinations were normal, as were chest x-ray films, electrocardiograms, ultrasonograms of the neck, and cerebral angiograms. Extensive serological and blood testing failed to show any coagulopathies or systemic disorders that favored a stroke in these patients. Transesophageal echocardiography showed a mitral valve lesion (width, > 1 mm). Two patients (cases 1 and 3) were discharged on a regimen of anticoagulant therapy and sequential transesophageal echocardiographic monitoring was planned, whereas 1 patient (case 2) was promptly scheduled for surgery. A second stroke occurred in patients 1 and 3 at 3 and 6 months, respectively, thus leading to surgery in these 2 patients. Findings from histopathologic studies were consistent with the diagnosis of giant LEs. The patients' outcomes were uneventful after surgery, and none had a recurrence of a stroke. CONCLUSIONS: A relationship between giant LEs and stroke may be suggested. In patients who have transesophageal echocardiographic findings that are consistent with this diagnosis and recurrent stroke despite antithrombotic therapy and without an alternative explanation for the ischemic symptoms, surgery should be considered in view of these findings.

Treatment of Huntington disease with gamma-acetylenic GABA an irreversible inhibitor of GABA-transaminase: increased CSF GABA and homocarnosine without clinical amelioration.

gamma-Acetylenic GABA (GAG, RMI 71.645), a potent irreversible inhibitor of gamma-aminobutyric acid transaminase, was given orally in various dosage schedules to 14 patients with Huntington disease. The biochemical effects of the drug on cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) and the GABA-containing dipeptide, homocarnosine, were measured in 10 of 14 patients. Treatment with GAG increased CSF concentrations of GABA and homocarnosine as compared to pretreatment values, suggesting that the drug increased brain GABA concentration. Despite this neurochemical effect, the clinical state was not improved. Except for single seizure episodes in five patients, GAG therapy was well tolerated. These results do not exclude the possibility that agents that augment CNS GABAergic function may prove useful in therapy of Huntington disease.

Prevalence and clinical characteristics of migraine in France.

OBJECTIVE: To determine the prevalence and clinical features of migraine and related headache types in France. METHODS: The authors recruited a population of subjects with headache representative of the national population using a stratified sampling method. They screened 10,585 subjects aged 15 and older who were representative of the general population. They identified 1,486 of these as having headaches, and these subjects were subsequently interviewed for information on clinical features, natural history, and functional impact of headache. The authors categorized subjects based on the International Headache Society (IHS) classification and assessed disability using the MIDAS questionnaire. RESULTS: The authors found a standardized prevalence for migraine (IHS categories 1.1 and 1.2) of 7.9% (11.2% for women and 4.0% for men) and 9.1% for migrainous disorder (IHS category 1.7). Migraine attacks were associated with a considerable degree of handicap in activities of daily living, with a MIDAS grade distribution of 74.7% (grade 1), 13.3% (grade 2), 7.7% (grade 3), and 4.3% (grade 4). The prevalence of migraine with MIDAS grade 3 or 4 was 1.6%. CONCLUSIONS: The prevalence of migraine (IHS categories 1.1 and 1.2) in France is 7.9%, and that of total migraine is 17.0%; this does not seem to have evolved over the past 10 years.

Motor imagery of a lateralized sequential task is asymmetrically slowed in hemi-Parkinson's patients.

We examined seven right-handed, asymmetrical (right side affected) Parkinson's disease patients and seven age-matched controls in a manual finger sequencing test using left and right hands in vision, no vision, and motor imagery conditions. All patients displayed motor asymmetry, favoring the left hand. They also displayed motor imagery asymmetry, mentally simulating movement more slowly with their right affected hand than with their left hand. Additionally, impairment in mental hand rotation correlated significantly with the imagery asymmetry. These data support two related hypotheses: (a) Motor sequence imagery and execution share common neural structures. (b) The frontostriatal system is among these shared structures.

Melatonin: from the hormone to the drug?

Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained by the light/dark cycle. Light is able to both suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone is determined by repeated measurement of plasma of saliva MLT or urine sulfatoxymelatonin, the main hepatic metabolite. Melatonin can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows central and sympathetic nervous pathways, an abnormality at any level unspecifically modifies the melatonin secretion, especially in patients with sympathalgia or dysautonomia. Melatonin plays the role of an endogenous zeitgeber on sleep-wake cycle or core temperature. Exogenous melatonin is able to influence the endogenous secretion of the hormone according to a phase response curve. There are therapeutic implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind or elderly people, shift-work). Improvement of pharmaceutical forms studied in controlled trials under the responsibility of the medical community or development of melatonin analogs could lead to decisive progress in this field.

Subthalamic nucleus stimulation in Parkinson's disease: clinical evaluation of 18 patients.

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinson's disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9+/-6 years; mean disease duration: 13.5+/-4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9+/-0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140+/-16 Hz and pulse width 68+/-13 micros. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9+/-13.4 vs at 6 months: 20.2+/-10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9+/-9.2 and 23+/-12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3+/-3 and 2.5+/-3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9+/-6.5 preop versus 12.7+/-7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose -- mg/D -- was 1045 +/- 435 before surgery and 360 +/- 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.

Slowly progressive anarthria with late anterior opercular syndrome: a variant form of frontal cortical atrophy syndromes.

We describe eight patients with slowly progressive speech production deficit combining speech apraxia, dysarthria, dysprosody and orofacial apraxia, and initially no other deficit in other language and non-language neuropsychological domains. Long-term follow-up (6-10 years) in 4 cases showed an evolution to muteness, bilateral suprabulbar paresis with automatic-voluntary dissociation and frontal lobe cognitive slowing without generalised intellectual deterioration. Most disabled patients presented with an anterior opercular syndrome (Foix-Chavany-Marie syndrome), and pyramidal or extrapyramidal signs. CT and MRI findings disclosed asymmetric (left > right) progressive cortical atrophy of the frontal lobes predominating in the posterior inferior frontal region, notably the operculum. SPECT and PET revealed a decreased cerebral blood flow and metabolism, prominent in the left posterior-inferior frontal gyrus and premotor cortex, extending bilaterally in the most advanced cases. Pathological study of two cases showed non-specific neuronal loss, gliosis, and spongiosis of superficial cortical layers, mainly confined to the frontal lobes, with no significant abnormalities in the basal ganglia, thalamus, cerebellum, brain stem (except severe neuronal loss in the substantia nigra in one case), and spinal cord. We propose to call this peculiar syndrome Slowly Progressive Anarthria (SPA), based on its specific clinical presentation, and its metabolic and pathological correlates. SPA represents another clinical expression of focal cortical degeneration syndromes, that may overlap with other similar syndromes, specially primary progressive aphasia and the various frontal lobe dementias.

Brain responses to detection of right or left somatic targets are symmetrical in unilateral Parkinson's disease: a case against the concept of "parkinsonian neglect'.

Signs of attentional dysfunction mimicking spatial neglect have been described both in humans with lateralised Parkinson's Disease (PD) and in animals with MPTP-related hemiparkinsonism. Such deficits have been attributed to dopamine loss in basal ganglia and cortical targets. However, in previous studies the existence of neglect was assumed from behavioural tests which needed a motor output, thus entailing interpretation ambiguities due to effects of directional hypokinesia. We recorded brain event-related potentials (ERPs) evoked by the presentation of target somatic stimuli to the affected and non-affected sides in 44 patients with unilateral or asymmetrical PD. The N2 and P3 ERP components were specifically analysed, since (a) they are triggered selectively by task-relevant, attended sensory stimuli; (b) their latency reflects stimulus evaluation time, independently from the execution of a motor response, and (c) they have proved to be abnormal in hemineglect syndromes due to focal brain lesions. Irrespective of the side (left or right) of motor symptom predominance there were no significant ERP differences to stimulation of the affected and non-affected limbs, nor was there any correlation between ERP latencies and the degree of dopamine-related motor impairment. The P3 latency was abnormally delayed in 23% of the patients, but there was no trend for abnormalities to concentrate on the affected side. This study does not confirm the existence of a significant attentional impairment toward the affected limb in lateralised PD, and suggests that previous clinical evidence of "neglect' behaviour in PD might be linked to directional hypokinesia, thus reflecting intentional, rather than attentional lateralised deficits.

Apomorphine in patients with Parkinson's disease.

We present a review of the recent literature and personal experience with apomorphine in patients with Parkinson's disease. Apomorphine is a potent D1 and D2 dopaminergic agonist. It has a rapid and short duration effect after subcutaneous administration at doses ranging from 15 to 180 micrograms/kg. Plasma maximal concentration is reached in 8-16 minutes, with a plasma half life of 34-70 minutes. Bioavailability is close to 100%. Repeated injections in patients show post-stimulative hyposensitivity. Apomorphine test appears very useful for the differential diagnosis between idiopathic Parkinson's disease and other Parkinson plus syndromes, and as a predictive test for dopaminergic responsiveness. Appropriate doses are able to alleviate akinesia, rigidity and tremor. Recent therapeutic trials have demonstrated the high interest of intermittent multiple subcutaneous apomorphine injections to cut the "off" motor phases in fluctuating parkinsonian patients under chronic levodopa treatment. In some cases, continuous apomorphine subcutaneous infusion with a portable pump may be required, particularly when levodopa treatment is temporarily interrupted, as after abdominal surgery. During long-term treatment, the apomorphine dose able to relieve akinesia remains stable. Peripheral side effects such as nausea and hypotension may be prevented by the co-administration of domperidone, a peripheral dopaminergic antagonist. Cutaneous fibrous nodules and psychiatric symptoms may occur, but usually at high dosages with continuous infusion. Local allergic effects have limited the use of other routes of administration, such as intranasal, sublingual, and rectal routes. Apomorphine is also used as a pharmacological tool for clinical research with the aim of a better understanding of the pathophysiology of Parkinson's disease.

The natural history of Machado-Joseph disease. An analysis of 138 personally examined cases.

We have examined 138 cases of a disorder previously described in people of Portuguese origin and which has received many names. By computer analysis of 46 different items of a standardized neurological examination carried out in each patient, we have been able to delineate the main components of the clinical presentation, to conclude that the marked variability in clinical expressions does not negate the homogeneity of the disorder, and to describe the natural history of this entity which should be called, for historical reasons, "Machado-Joseph Disease". This hereditary disease has an autosomal dominant pattern of inheritance, presenting as a progressive ataxia with external ophthalmoplegia, and should be classified within the group of "Ataxic multisystem degenerations". When the disease starts before the age of 20, it may present with marked spasticity, of a non progressive nature but often so severe that it can be accompanied by "Gegenhalten" countermovements and dystonic postures but little frank dystonia. There are few true extrapyramidal symptoms except akinesia. When the disease starts after the age of 50, the clinical spectrum is mostly that of an amyotrophic polyneuropathy with fasciculations accompanying the ataxia. For all the other cases the clinical picture is a continuum between these two extremes, the main determinant of the clinical phenotype being the age of onset and a secondary factor, the place of origin of the given kindred. The ataxic and amyotrophic components are clearly progressive with time in contrast to the spasticity component. Although the majority of known cases are of Portuguese origin, this is not obligatory. The next research endeavour should be a search for the chromosomal site of the gene, using molecular biology technology such as those for recombinant DNA.

[Melatonin in humans: a biochemical marker of the circadian clock and an endogenous synchronizer]. / La melatonine: un marqueur biochimique de l'horloge circadienne et un synchroniseur endogene chez l'homme.

Melatonin (MLT) is a methoxyindole secreted principally by the pineal gland. It is synthesized at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and activated by the light/dark cycle. Light is able to both suppress or activate melatonin production on the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurements of plasma or saliva MLT or urine sulfatoxy-MLT, the main hepatic metabolite. Melatonin can be considered as the output (the hand) of the endogenous clock. Since the regulating system follows a central and sympathetic nervous pathway, an abnormality at any level could unspecifically modify the MLT secretion, especially in patients with sympathalgia or dysautonomia. Melatonin plays the role of an endogenous zeitgeber on core temperature or sleep-wake cycle. Exogenous MLT is able to influence the endogenous secretion of the hormone according to a phase response curve. There are practical implications for this property in situations when biological rhythms are disturbed (jet-lag syndrome, delayed sleep phase syndrome, insomnia in blind people, shift-work, insomnia in elderly people). Improvement of pharmaceutical forms (controlled release preparations) or development of MLT analogs could lead to decisive progress.

[Amyotrophic lateral sclerosis: a role for enteroviruses?]. / La sclérose latérale amyotrophique : implication des entérovirus ?

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Although it is a clinically well defined disease, its etiology remains unknown. Among, various hypotheses, the putative role of enteroviruses has been recently suggested by the detection of enteroviral sequences in neurons of spinal cord samples from ALS patients. However, there is a lack of consensus on the role of EV in ALS. In the present paper, we summerized the pathogenic role of these viruses, analyzed the discrepancy between different studies and speculated on the possible role of enteroviruses in ALS.

[Motor negligence in a case of right thalamic hematoma (author's transl)]. / Négligence motrice par hématome thalamique droit.

In a patient with left motor negligence CT scan showed a right thalamic hematoma of small size, involving the posterior thalamic region. The clinical picture was pure, including neither marked distal or proximal motor deficiency, nor auditory or visual or somesthetic disorders except sensory extinction. Cortical somesthetic evoked potentials were normal. Motor negligence presented 3 basic elements: 1) lack of spontaneous movements of the left side of the body, particularly of the upper limb; 2) absence of nociceptive reactivity; 3) immediate total reversibility of the disorder following verbal commands. Emphasis is placed on this latter sign which indicates the thalamic origin of the disturbance. Of the various explanations proposed for the disorder the most likely one would appear to be a disorder of a relatively specific activation system of motor activities, a system arising from the posterior thalamic nuclei: 1) pulvinar and laterodorsal nuclei projecting over area 23 (posterior cingulum); 2) intralaminar formations, particularly the lateral superior central nucleus, projecting over area 24 (anterior cingulum). The disturbance in this system, at its thalamic origin, might explain the differences between this motor negligence behaviour and lack of spontaneous motility syndromes resulting from frontal cortical lesions. It might also be that the right lateralisation of the lesion plays a relatively minor role.

[Incidence and clinical profile of familial forms of Parkinson's disease. A study of 428 index-cases from a department of neurology]. / Fréquence et profil clinique des formes familiales de maladie de Parkinson. Enquête portant sur 428 cas-index recrutés dans un service de neurologie.

Although the cause of Parkinson's disease remains to be determined, several lines of evidence favor the role of a genetic factor. We therefore studied a series of 428 index-cases of Parkinson's disease that were referred to our Department of Neurology between 1986 and 1993, with the aim to identify secondary family cases. Index-cases were divided into 2 groups. In groups A (279 cases), a retrospective analysis of patients records was performed. In group B (149 cases), a prospective study was carried out by 1992, which allowed a more complete investigation of family history. In group A, 31/279 index-cases (11.1 p. 100) had secondary familial cases of Parkinson's disease. This percentage increased up to 22.8 p. 100 among index-cases in group B (34/149 cases). In most instances, only one secondary case was detected, and very few proponents had 2, or 3 other family cases. No large family with numerous Parkinson's disease cases was disclosed. Age at onset of disease was similar in group A between sporadic and familial index-cases, whereas in group B age at onset was earlier index-cases with positive family history as compared to those without (53.9 +/- 10.4 years versus 59.7 +/- 12.1 years respectively). This may be due to the different sizes of groups A and B, whereas clinical profile analysis did not differentiate index-cases with positive family history from those without family history (sporadic cases). An anticipation of age at onset of illness of 13.9 +/- 12.2 years was found in 9 of the 15 index-cases from group B with first degree parental vertical inheritance, where clinical data were available for the second family case. These findings about age at onset may be at least partly explained by a more accurate estimation of age at onset in index-cases than that in secondary family cases. Further analysis on the possible mode of transmission of the disease among familial cases was consistent with the implication of a genetic factor in the ethiopathogenesis of the disease, with a mendelian autosomal dominant inheritence with reduced penetrance.