Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP

The authors describe a case of clinically diagnosed young onset progressive supranuclear palsy (PSP) with symptom onset at 40 years of age and no family history of neurodegenerative disease. There was no history of falls during the first year of symptoms. Genetic analysis identified this patient as having a tau exon 10 +16 mutation (MAPT, IVS10, C-U, +16). Neuropathologic examination confirmed the genetic diagnosis of frontotemporal dementia. An age at onset younger than 50 years combined with the absence of early falls may indicate the possibility of a tau mutation in clinically diagnosed PSP.     

Progression in familial and nonfamilial MS

OBJECTIVE: To investigate whether the timing of secondary or primary progression is different between patients with familial and nonfamilial multiple sclerosis (MS). METHODS: Information on the family history of 313 patients with MS was taken from our prospective hospital-based database. We used Kaplan-Meier analyses and Cox regression models to evaluate differences between familial and nonfamilial MS in several endpoint measures. We investigated the risk of developing secondary progression in all patients with a relapsing-remitting disease onset, the length of the relapsing-remitting phase and age at onset of progression in patients with secondary progressive MS and the age at disease onset in patients with primary progressive MS (PPMS). RESULTS: Among the primary progressive patients, those with familial MS had a significantly younger age at disease onset than patients with nonfamilial MS (mean 33.04 years versus mean 37.73 years in nonfamilial MS, P = 0.02). There were no significant differences between familial and nonfamilial MS patients in any other investigated measure. CONCLUSIONS: Familial MS appears related to the time of disease onset in PPMS. Patients with familial PPMS may be an important patient group for future genetic research in MS.     

Predictors of progression in patients with Friedreich ataxia

Friedreich ataxia is an inherited, progressive, neurodegenerative disorder that is clinically heterogeneous. It is caused by a trinucleotide (GAA) repeat expansion resulting in frataxin loss and oxidative stress. We assessed clinical features including the development of cardiomyopathy and scoliosis and disease progression including loss of ambulation and interference with activities of daily living relative to the length of the GAA repeat, age of onset, and age of diagnosis in a retrospective cohort study of 61 genetically confirmed patients. The use of antioxidants such as vitamins, dietary supplements, and idebenone was also examined. Linear regression and Cox proportional hazard models assessed predictors to disease milestones. The shorter GAA allele accounted for part of the variability in the age of diagnosis (46%) and less in the age of onset (27%). Multivariate analysis demonstrated that age at diagnosis, which may incorporate other genetic and environmental factors, is more important than GAA length in predicting cardiomyopathy, scoliosis, and disease progression. © 2008 Movement Disorder Society     

Early-onset progressive encephalophathy with migrant,continuous myoclonus

Three unusual cases of focal continuous myoclonus with onset during the first months of life, lasting from dozens of minutes to hours, are reported. During disease evolution, prolonged bilateral myoclonic seizures and generalized tonic-clonic seizures occur. Subsequently, a progressive encephalopathy with hypotonia and ataxia appears. A net worsening of the neurological condition is observed after the age of 4–5 years. Cortical atrophy is shown by CCT and MRI. Neurometabolic screening is not contributory. Repeated polygraphic recordings show continuous and segmental myoclonic jerks, localized in different muscles, at frequencies ranging between 0.5–1 c/s and 6–8 c/s. Moreover action myoclonus is recorded. During the first period of disease the EEG does not show any paroxysmal activity. As to the classification, this syndrome corresponds to an early onset progressive encephalopathy of unknown origin, similar in some aspects to Alper's disease. Another problem is the interpretation of the myoclonic phenomena. Some important aspects suggest a cortical origin of the diverse myoclonic phenomena observed in these cases.     

Signs of rapidly progressive dementia in a case of intravascular lymphomatosis

Intravascular lymphomatosis (IVL), a rare type of non–Hodgkin’s lymphoma, is an uncommon cause of progressive dementia, usually followed by death within a few months of onset of clinical disease. Often this aggressive tumor is only diagnosed at autopsy, because of misleading clinical features mimicking a broad spectrum of syndromes and the absence of circulating lympoma cells in the blood, bone marrow or cerebrospinal fluid in many cases. Here we present IVL in a 78–year–old woman with findings leading to the clinical diagnosis of vascular dementia with sudden beginning and positive 14–3–3 protein in the CSF, commonly reported in Creutzfeldt–Jakob disease (CJD).     

Huntington’s Disease Genetics

Summary:Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children of HD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a “trinucleotide repeat” disorder, which is caused by an increase in the number of CAG repeats in the HD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36–39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.     

The prevalence of multiple sclerosis in the north–west Italian province of Genoa

The objective of this study was to assess the prevalence of multiple sclerosis (MS), calculated as point prevalence on 31 December 1997, in the province of Genoa, North–western Italy. Methods The province of Genoa is located in North–western Italy, an area of 1835 km². On the point prevalence day the population consisted of 913,218 inhabitants. MS cases were identified by analysing archives of the hospitals with neurological or rehabilitation wards, neurologists serving the community, files of local chapters of the Italian MS society, all requests for oligoclonal bands analysis on CSF in the studied area. Patients included in the study were MS cases diagnosed before 31 December 1997 according to the Poser criteria resident in the province under study. Results A total of 857 subjects were alive and residing in the province of Genoa on the prevalence day. The overall crude prevalence rate was 94 per 100,000 (95% CI 88–100); 291 were males (34%) with a crude prevalence of 67 per 100,000 (95 % CI 60–76) and 566 were females (66%) with a prevalence of 118 per 100,000 (95% CI 108–128). The female/male ratio was 1.9. When age and sex were adjusted to the Italian standard population of 1991 prevalence was 85 per 100,000. Five hundred and thirty two out of the 857 patients agreed to be interviewed. The interviewed sample was representative of the prevalence sample: sex and gender distributions were identical in the two samples. The overall mean age was 48 (± 13) years (48 ± 12 years in males; 48 ± 14 years in females). Mean disease duration was 15 (± 10) years for males and 16 (± 11) years for females. Two hundred and ninety one (55 %) subjects had a relapsing remitting (RR) clinical course, 150 (28%) were secondary progressive (SP) and 91 (17%) were primary progressive (PP). Mean EDSS score was 5 (± 2; median 5). The mean age at time of onset was 33 (±10) years for males and 32 (± 11) years for females. The disease onset was monosymptomatic in 76% (n = 407) patients and polysymptomatic in 24% (n = 125). The mean length of time between clinical onset and diagnosis was 5 (± 6) years. Conclusion We confirmed that the province of Genoa is a very high risk area for MS. We found a high rate of patients with a PP course; also the proportion of patients with high disability scores is greater compared to previous studies.     

Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients

BACKGROUND: Juvenile Huntington disease (JHD) is a rare clinical entity characterized by an age at onset younger than 20 years. Patients usually have an expansion of more than 60 CAG repeats in the Huntington disease (HD) gene, and the disease is usually inherited from the father. In general, precise age at onset is difficult to assess in HD because of insidious onset and anosognosia. Onset of motor difficulty signs is usually used to define age at onset. OBJECTIVES: To evaluate diagnosis delay in patients with JHD and to analyze the clinical and genetic features of JHD. DESIGN: Retrospective clinical and genetic review. SETTING: Referral center for HD at Salpêtrière Hospital, Paris, France. PATIENTS: Twenty-nine patients with HD with onset before or at age 20 years who carried an abnormal CAG repeat expansion in the HD gene. RESULTS: The mean +/- SD delay before diagnosis was 9 +/- 6 years (range, 0-21 years). The most remarkable signs at onset were severe psychiatric and cognitive disturbances (19 of 29 [65.5%]); rigidity was absent. Unusual signs at onset included myoclonic head tremor in 3 patients, severe isolated drug or alcohol addiction in 2, psychotic disorder in 1, and difficulty writing in 1. One patient had progressive cerebellar signs associated with cerebellar atrophy on cerebral magnetic resonance imaging before signs suggestive of HD appeared. During the course of the disease, psychiatric disturbances were severe, with at least 1 suicide attempt in 7 of 29 patients. Transmission was maternal in 25% of patients. Forty-six percent of patients with JHD had fewer than 60 CAG repeats; 6 of these patients inherited the disease from their father. Anticipation (mean +/- SD, 18 +/- 9 vs 25 +/- 11 years; P = .27) and age at onset (mean +/- SD, 17.14 +/- 2.2 vs 13.29 +/- 5.5 years; P = .09) was similar in patients with maternal compared with paternal transmission, respectively. CONCLUSIONS: Patients with JHD started showing disease symptoms through nonspecific features, mostly psychiatric and cognitive difficulties. This led to misdiagnosis or diagnosis delay, especially in cases without a familial history of HD. Maternal transmissions and expansions of fewer than 60 CAG repeats were unexpectedly frequent in this series and should not be considered exceptional.     

Age of onset of phobic disorders: A reevaluation

The age of onset of agoraphobia with spontaneous panic attacks (DSM III) was studied in 100 consecutive patients. A uniform unimodal age of onset distribution was found. Mean age of onset was 24 years. Sixty-five percent of cases began in the 15–29 age group. Ninety-six percent first started before age 40 years. The finding in two other studies of a bimodal age of onset distribution may result from artifacts inherent in their small sample sizes.The age of onset of simple single phobias without spontaneous panic attacks or other psychopathology was studied in 62 consecutive monophobic patients. The age of onset in this variety of phobic disorder was evenly distributed over all age groups.No evidence was found for a facilitatory period in the development of phobias for the first decade as compared to the second or third life—although age may determine which environmental stimuli become phobic stimuli at different ages.There was a statistically significant difference between the age of onset distribution and the sex ratio in both groups of phobic disorder.The findings are consistent with the authors classification of phobic disorders, into endogenous and exogenous varieties based on the presence or absence of concurrent spontaneous panic attacks with the phobias. It is also consistent with the model that biological factors are preeminent in the genesis of endogenous phobias, while conditioning by environmental stress is preeminent in exogenous phobias.     

Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK

OBJECTIVE—To investigate the clinical anddemographic characteristics of primary progressive multiple sclerosis(PPMS) in Northern Ireland and to establish a database of such patientsfor genetic and immunological studies and future therapeutic trials.
METHODS—Diagnosis and categorisation wereperformed by two neurologists, potential cases being identified fromthe following sources: neurology outpatient clinics; neurologyinpatients; a review of hospital discharges; and an ongoingepidemiological study of multiple sclerosis in Northern Ireland. Onlythose with a progressive course from onset and a clear history of noprior relapses were accepted. Potential cases were invited forinterview and assessment, the minimal record of disability (MRD) being established.
RESULTS—One hundred and eleven cases of PPMS havebeen identified, 63 women and 48 men (ratio 1.3:1), with a mean age atonset of 39.5 (SD 11.0) (range 17-66)years, and mean disease durationof 13.6 (SD 9.3)years. The mean interval between onset and diagnosis was 4.7 (SD 4.2) years. Nineteen patients (17.1%) did not satisfy therequirements for any category in the Poser criteria. Motor disturbancewas the commonest mode of onset (67.6%) with visual loss occurringonly rarely at onset (3.6%). Kurtzke EDSS scores were concentrated atthe upper end of the scale with a median of 6.0 and levels ofunemployment and financial dependence were high.
CONCLUSIONS—PPMS in Northern Ireland has agenerally later age at onset, lower female preponderance, andpredominantly motor onset compared with other subgroups of multiplesclerosis. The delay to diagnosis reflects the often insidious onsetand the nature of the clinical course makes application of the Posercriteria difficult. Levels of neurological impairment, disability, andhandicap as measured by the MRD are high.

     

Early visual seizures and progressive myoclonus epilepsy in neuronopathic Gaucher disease due to a rare compound heterozygosity (N188S/S107L)

PURPOSE: Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, is characterized by genotypic and phenotypic heterogeneity. We recently characterized the glucocerebrosidase alleles of a patient with an unusual clinical presentation of type 3 Gaucher disease. METHODS: Initial clinical manifestations appeared at age 11 years as visual seizures. RESULTS: Subsequent progressive myoclonus and generalized seizures were consistent with an adolescent-onset form of progressive myoclonus epilepsy. However, a specific diagnosis was established only at age 16, because of the absence of hematologic abnormalities and a fairly moderate hepatomegaly. Bone marrow aspirate was slightly positive for Gaucher cells. Demonstration of reduced glucocerebrosidase in the fibroblasts confirmed the diagnosis. The child died at age 19 years. Postmortem sequencing of the glucocerebrosidase gene from cultured fibroblasts demonstrated a rare compound heterozygote for N188S/S107L. CONCLUSIONS: This unusual presentation of Gaucher disease indicates that if clinical and neurophysiological findings in adolescents with initial visual seizures and myoclonus suggest a progressive disorder, enzymatic assay is mandatory, even in the absence of the classic neurologic and systemic signs of the disease. Early differential diagnosis from other forms of progressive myoclonus epilepsy with similar clinical presentation may help provide appropriate genetic counseling.     

Clinical and angiographic follow-up of childhood-onset moyamoya disease

To clarify the differences between childhood-onset moyamoya disease and that with onset in adulthood, we studied the clinical course and angiographic findings of adult patients (over 20 years of age) with moyamoya disease of childhood onset (up to 15 years of age). The clinical course in 25 patients could be assessed. The follow-up period was 5–27 years. Neurological deficits were noted in 11/23 and mental disorders in 9/21. In all except one, the illness had started before the age of 7 years. Neither neurological nor mental condition changed during or after adolescence (15–20 years of age). Two patients died of intracranial hemorrhage. The disease progressed in angiographic stage until adolescence, but had stabilized or almost stabilized by the age of 20 years. This study indicates that moyamoya disease with onset in childhood carries high morbidity and mortality. The disease advances in angiographic stage between childhood and adolescence, but stabilizes or almost stabilizes between adolescence and adulthood.     

Mental outcome following encephaloduroarteriosynangiosis in children with moyamoya disease with the onset earlier than 5 years of age

The mental prognosis of children with moyamoya disease, in whom the onset was when they were younger than 5 years of age, has been reported to be very poor. We studied the mental outcome of these patients after encephaloduroarteriosynangiosis (EDAS) in relation to the age at the onset of the disease and the age at operation. For patients in whom the onset of moyamoya disease occurs when they are younger than 2 years of age, the prognosis is very poor with regard to mental abilities even if they have an operation within a year after the onset. Slight hope remains if the operation is within 3 months of the onset. For patients in whom the disease begins when they are 2–5 years of age, EDAS performed before the age of 9 years may result in a good outcome with regard to mental ability, as well as resolution of the paroxysmal symptoms and crebral revascularization.     

Phenotypic heterogeneity in two unrelated Danon patients associated with the same LAMP-2 gene mutation

Danon disease, an X-linked cardioskeletal myopathy caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2), is clinically characterized by cardiomyopathy, myopathy, and variable mental retardation. The pathological hallmark of the disease is the absence of LAMP-2 immunohistochemical staining in muscle. The LAMP-2 gene mutations reported thus far are generally private mutations. We describe two cases of Danon disease with different clinical presentation, in whom we identified the same exon skipping mutation c.928G>A in the LAMP-2 gene. The first patient was affected by an early onset myopathy and hypertrophic cardiomyopathy (HCM) that partially improved with drug treatment. A first muscle biopsy at age 4 months showed markedly increased glycogen, and acid maltase deficiency was ruled out biochemically. A second muscle biopsy, performed at age 3(1/2) years, showed very mild abnormalities. The second child at age 15 years had mild, diffuse muscle weakness and wasting, moderate mental deficiency, and HCM. Two serial biopsies performed at age 8 and 15 years showed similar findings of multiple esterase-positive vacuoles in type I myofibers. In both patients the immunohistochemical study demonstrated the absence of LAMP-2 in skeletal muscle.     

Clinical course of progressive multiple sclerosis in Brazilian patients

OBJECTIVE: To describe the clinical course and outcome of multiple sclerosis with progressive onset in Brazilian patients. A total of 238 medical records were reviewed, 26 cases (10.9%) fulfilled Thompson criteria (2000), and 5.80% classified as primary progressive and 5.04% relapsing progressive according to Lublin and Reingold. STUDY POPULATION: 19 Caucasians and 7 non-Caucasians; male:female ratio 1.2:1, mean age at onset was 34 +/- 7.9 years. RESULTS: Non-Caucasian patients had earlier onset of disease. The most common manifestations at onset were pyramidal and cerebellar (89% and 34.6%). After 11.3 +/- 6.35 years of disease more than 50% of the patients had involvement of most of their functional systems. No statistically significant differences were observed between the subgroups. CONCLUSION: The clinical course and outcome of progressive multiple sclerosis in Brazil, a tropical country with low prevalence, were very similar to those in the multiple sclerosis high prevalence areas.     

Early age of onset in fatal familial insomnia

Abstract. Fatal familial insomnia (FFI) is a prion disease exhibiting the PRNP D178N/129M genotype. Features of this autosomal dominant illness are progressive insomnia, dysautonomia, myoclonus, cognitive decline and motor signs associated with thalamic nerve cell loss and gliosis. In contrast to the new variant of Creutzfeldt-Jakob disease (vCJD) the onset of FFI is in middle to late adulthood. We report two male patients who belong to a large German FFI kindred. They were examined clinically, and postmortem neuropathological examination was carried out in collaboration with the German reference centre for prion disease. Additionally, the prion protein gene (PRNP) was analysed. To identify further patients with disease onset under 30 years of age a comprehensive literature review was carried out. Two male patients presented with typical symptoms of FFI at the age of 23 and 24 years. In their kindred, the age of onset has never before been under 44 years of age. Our literature review identified five additional early onset cases who died at age 21 to 25 years. In all 22 reviewed FFI families the median manifestation age was 49.5 years. Although phenotypic variability of FFI is common, age of onset under 30 years has been considered to be a hallmark of vCJD with a mean manifestation at 27 years of age. Our findings underline that in addition to vCJD, FFI must be considered in cases of young-onset prion disease. This has considerable impact on clinical management and genetic counselling.* These two authors contributed equally     

Pericardial effusion with cardiac tamponade as a cardiac manifestation of duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common hereditary neuromuscular disease in children. It is an X‐linked hereditary dystrophinopathy due to the absence of dystrophin. Its onset is often in early childhood and presents with proximal distribution of weakness and a progressive course. Cardiac involvement in DMD is common, and its onset is usually after the age of 10 years. The most common cardiac manifestations are a dilated cardiomyopathy and cardiac arrhythmia. However, pericardial effusion with cardiac tamponade is a very rare cardiac complication of DMD. We report a boy with DMD who initially presented with progressive dyspnea and an enlarged cardiac silhouette on chest radiography who subsequently developed a large pericardial effusion with cardiac tamponade. Early recognition of pericardial effusion with cardiac tamponade is important for institution appropriate therapy. Muscle Nerve, 2009     

Occult dysraphism in adulthood: clinical course and management

We present a series of 23 patients with dysraphic malformations and adult onset of symptoms (4 meningoceles, 19 spinal hamartomas). Mean age at presentation was 39±21 years (range 23–67 years). Patients were followed up for a mean period of 19 months (range 0.5–68 months). Only patients with progressive neurological disease were operated on (3 meningoceles and 16 spinal hamartomas). The remaining patients were treated conservatively and continue to be observed clinically. Two of three patients operated for meningoceles improved without recurrence of symptoms. Patients with spinal hamartomas could be divided into two groups according to their main symptom: paraparesis (group A, n = 8) or pain (group B, n = 11). Malformations in group B were typically associated with a tethered cord and tended to be more complex than in group A. The majority of patients in group A showed better long-term results than patients in group B, due to their considerably lower rate of recurrence.     

Clinical and genetic aspects of juvenile absence epilepsy

Fifteen patients aged 11–25 years (mean 15.37, SD 3.89) suffering from juvenile absence epilepsy are presented. Only 3 (20%) had absences (AS) as the only seizure type, 12 (80%) had associated generalized tonic-clinic seizures (GTCS) and in the remaining 3 with absences and GTCS there was also sporadic myoclonus. We found a higher frequency of AS in our patients by clinical history and video-EEG than has been previously reported. In our patients the mean age of onset in years was 11.4, SD 1.24 for AS, 13.12, SD 2.31 for GTCS and 12.5, SD 2.18 for myoclonus. The correct diagnosis was not made on referrals for any of the patients. It took an average of 3–5.5 years from the onset of the AS (range: 6–120 months) and 2 years from the occurrence of GTCS (average: 1–72 months) to make the correct diagnosis and institute proper treatment, which was valproic acid (VPA). The GTCS were controlled in all patients whereas AS continued in 6 (40%), but to a significantly lesser degree. The frequency and the duration of the GTCS before the start of VPA treatment seemed to have an adverse effect on AS control. We documented no circadian rhythm in either AS or the GTCS, except in 2 patients who had AS and GTCS mainly when they awoke in the morning. The sample size was too small to perform a proper genetic study, though a positive history of epilepsies of mixed types was obtained in 35.7% of the parents and the siblings of the probands.     

Clinical features of familial moyamoya disease

Objects This study aims to clarify the genetic background of moyamoya disease by comparing clinical features between familial and sporadic cases to reveal the responsible genes for familial moyamoya disease.Methods This study included 155 Japanese patients with moyamoya disease, which included 24 familial cases (10 family pedigrees) and 131 sporadic cases. Clinical features were compared between the familial and sporadic cases.Results and conclusion A female preponderance was significantly more prominent in the familial than in the sporadic group (P=0.0421). Mean age at onset was significantly lower in familial than in sporadic cases (P=0.004). In eight parent–offspring pairs, mean age at onset was significantly lower in the second than in the first generation (P<0.0001). These results suggest that familial moyamoya disease is associated with genetic anticipation and female predominance and that a genetic analysis study focused on expanded triplet repeats may clarify the pathogenesis of the disease.