Boon, A.J.W.

Phenotypes and genetic architecture of focal primary torsion dystonia (Article)

2012-10-01T00:00:00Z

Background: The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. Objective: To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. Patients and methods: A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. Results and conclusions: Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writer's cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations (Article)

2011-11-01T00:00:00Z

Early-onset Parkinson's disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirmMLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy (Article)

2011-07-01T00:00:00Z

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Autosomal dominant restless legs syndrome maps to chromosome 20p13 (RLS-5) in a Dutch kindred (Article)

2010-08-15T00:00:00Z

Six chromosomal loci have been mapped for restless legs syndrome (RLS) through family-based linkage analysis (RLS-1 to RLS-6), but confirmation has met with limited success, and causative mutations have not yet been identified. We ascertained a large multigenerational Dutch family with RLS of early onset (average 18 years-old). The clinical study included a follow-up of 2 years. To map the underlying genetic defect, we performed a genome-wide scan for linkage using high-density SNP microarrays. A single, strong linkage peak was detected on chromosome 20p13, under an autosomal-dominant model, in the region of the RLS-5 locus (maximum multipoint LOD score 3.02). Haplotype analysis refined the RLS-5 critical region from 5.2 to 4.5 megabases. In conclusion, we provide the first confirmation of the RLS-5 locus, and we reduce its critical region. The identification of the underlying mutation might reveal an important susceptibility gene for this common movement disorder.

Survival in progressive supranuclear palsy and frontotemporal dementia (Article)

2010-04-01T00:00:00Z

Objective To compare survival and to identify prognostic predictors for progressive supranuclear palsy and frontotemporal dementia. Background Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are related disorders. Homozygosity for H1 haplotype is associated with PSP, whereas several MAPT mutations have been identified in FTLD-s. Survival duration probably reflects underlying pathophysiology or disease. Methods Patients with PSP and FTD were recruited by nationwide referral. Survival of 354 FTD patients was compared with that of 197 PSP patients. Cox regression analysis was performed to identify prognostic predictors. FTLD-s was defined as Pick disease and FTDP-17 with MAPT mutations. Semiquantitative evaluation of s-positive pathology was performed on all pathologically proven cases. Results The median survival of PSP patients (8.0 years; 95% CI 7.3 to 8.7) was significantly shorter than that of FTD patients (9.9 years; 95% CI 9.2 to 10.6). Corrected for demographic differences, PSP patients were still significantly more at risk of dying than FTD patients. In PSP, male gender, older onset-age and higher PSP Rating Scale score were identified as independent predictors for shorter survival, whereas in FTD a positive family history and an older onset-age were associated with a poor prognosis. The difference in hazard rate was even more pronounced when comparing pathologically proven cases of PSP with FTLD-s. Conclusion Survival of PSP patients is shorter than that of FTD patients, and probably reflects a more aggressive disease process in PSP. Independent predictors of shorter survival in PSP were male gender, older onsetage and higher PSP rating scale score, whereas in FTD a positive family history and higher onset-age were predictors for worse prognosis.

Familial aggregation of parkinsonism in progressive supranuclear palsy (Article)

2009-07-01T00:00:00Z

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier? (Article)

2009-04-27T00:00:00Z

We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.

New device to control combined lingual and palatal myoclonus (Article)

2007-03-15T00:00:00Z

Lingual myoclonus is a poorly understood disorder that may occur in isolation or combined with palatal myoclonus. In this report, we present the case history of a 21-year-old patient with a therapy-resistant essential lingual and palatal myoclonus where a simple dental device was able to control symptoms. The use of this device will be highlighted and compared to previously described methods. Cases of previously recorded lingual and palatal myoclonus will be reviewed and compared to the case of our patient.

Blue rubber bleb nevus syndrome (Article)

2007-03-01T00:00:00Z

The Dutch Normal-Pressure Hydrocephalus Study (Doctoral Thesis)

1999-03-31T00:00:00Z

In 1965 Hakim and Adams described 6 patients with a mild impairment of the memory, slowness and paucity of thought and action, unsteadiness of gait and unwitling urinary incontinence.' These symptoms had evolved over a period of weeks or a few months. The pneumoencephalogram of these patients showed a quadriventricular hydrocephalus with no air in the cerebral sUbarachnoid spaces. A normal cerebrospinal fluid (CSF) pressure was measured by lumbar puncture. They all dramatically improved on CSF shunting. Hakim and Adams named this syndrome of symptomatic occult hydrocephalus with normal CSF pressure normal-pressure hydrocephalus (NPH). Afterwards many patients were described with the clinical triad of a gait disturbance, mental deterioration and urinary incontinence in combination with a communicating hydrocephalus on computed tomography and a normal CSF pressure. In studies on dementia NPH was found in 0% to 5.4% of the study population. NPH should be distinguished from acute hydrocephalus, in which CSF pressure is increased and headache, nausea, vomiting, and visual symptoms are present, and from chronic high-pressure hydrocephalus in which symptoms and signs of increased pressure are less pronounced. Symptomatic cases of NPH mainly follow sUbarachnoid hemorrhage, trauma, meningitis or intracranial surgery. Many cases, especially over the age of 60, have no known cause and are therefore idiopathic.