Biomedical subjects

Joost Haan

Publications and source records attributed to Joost Haan.

8 recordsLinked to original sources

PubMed2003

Evaluation of diagnostic NOTCH3 immunostaining in CADASIL.

CADASIL is caused by mutations in the NOTCH3 gene. Although increasingly recognized as a disease entity, the diagnostic confirmation can be lengthy or inconclusive. Recently, NOTCH3 immunostaining of skin biopsy specimens has been introduced as a new diagnostic test. The aim of this study was to independently assess the diagnostic value of NOTCH3 immunostaining, and determine whether the degree of immunostaining correlates with other disease parameters. We determined NOTCH3 mutation carrier status in 62 symptomatic and asymptomatic individuals from 15 CADASIL families. Skin biopsy specimens of these individuals, as well as of a disease control group, were immunostained with NOTCH3 antibody and blindly analyzed by two independent observers to determine sensitivity and specificity. A semiquantitative NOTCH3 immunostaining score was correlated with clinical, genetic and MRI parameters. The sensitivity was 90.2% and 85.4%, respectively, for the two observers, the specificity 95.2% and 100%; both lower than previously reported. Certain NOTCH3 mutations may underlie false-negative results. False-positive results were found in a non-mutated control, and also in one disease control. There was no difference in immunostaining between symptomatic and asymptomatic NOTCH3 mutated individuals. Furthermore, the NOTCH3 immunostaining score did not correlate with clinical or MRI parameters. NOTCH3 immunostaining is a supportive, but not definitive, CADASIL diagnostic test, and should be interpreted in the context of clinical and radiological data. Confirmation by DNA analysis is requisite for positive results, and when there exists high clinical suspicion, also for negative results.

Adult↗

PubMed2003

Incipient CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited. OBJECTIVE: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years. DESIGN: Clinical characterization and blinded survey comparing MCs with non-MCs. SETTING: Referral center. PARTICIPANTS: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria. METHODS: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale. RESULTS: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps. CONCLUSIONS: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.

Adult↗

PubMed2003

Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na(+),K(+)-ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.

Adolescent↗

PubMed2003

Migraine genetics.

The genetics of migraine is a fascinating and moving research area. Familial hemiplegic migraine, a rare subtype of migraine with a Mendelian pattern of inheritance, is caused by mutations in the chromosome 19 CACNA1A gene in approximately 75% of the families. The finding of mutations in an ionchannel subunit defines migraine as a channelopathy (eg, epilepsy). The genetics of the more frequent variants, migraine with and without aura, is more complex. Several loci have been studied in families and case-control studies, but need to be confirmed.

Adult↗

PubMed2003

Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical microvascular changes are found throughout the arterial tree, but the documented disease expression is confined to the central nervous system. In an ongoing CADASIL study, we noted a number of patients with early acute myocardial infarction (before the age of 50 years), as well as patients with electrocardiogram (ECG) abnormalities. We analyzed these data to determine whether myocardial ischemia is associated with NOTCH3 mutations. ECGs were recorded in mutated (n = 41) and nonmutated (n = 22) individuals from 15 genetically confirmed CADASIL families, and blindly classified according to the Minnesota code. Cardiologic history was assessed and cardiovascular disease risk factors were determined. Evidence for myocardial infarction was defined as a positive history for acute myocardial infarction and/or a Minnesota Code 1 (Q-waves) on ECG. We examined CADASIL myocardial tissue ultrastructurally and immunohistochemically for evidence of microangiopathy. We found that almost 25% (10/41) of mutation carriers had evidence of myocardial infarction, versus none of the 22 nonmutation carriers (p = 0.011). Five had a medical history of acute myocardial infarction, and 5 had current pathologic Q-waves on ECG. Acute myocardial infarction occurred at a mean age of 39.6 +/- 5.22 years, and predated major neurologic symptoms of CADASIL in all cases. Pathologic examination of myocardial tissue revealed typical CADASIL arteriopathic changes of the coronary microvasculature. To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart.

Acute Disease↗

PubMed2003

Cerebral hemodynamics and white matter hyperintensities in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 +/- 10 years) and 22 nonmutated family members (mean age 39 +/- 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities.

Adult↗

PubMed2002

Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.

BACKGROUND: Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura that in half of the families is caused by mutations in the CACNA1A gene on chromosome 19p13. In sporadic hemiplegic migraine (SHM), that is, hemiplegic migraine without affected family members, the contribution of the CACNA1A gene is unknown. OBJECTIVE: To investigate the involvement of the CACNA1A calcium channel subunit gene in SHM. METHODS: We screened 27 patients with SHM for mutations in the CACNA1A gene by a combination of single-strand conformational polymorphism analysis and sequence analysis. RESULTS: One patient with SHM also had ataxia, nystagmus, and cerebellar atrophy on computed tomography and carried a T666M mutation. Another patient with SHM who had no cerebellar signs carried an R583Q mutation. No mutations or interictal neurological abnormalities were found in the remaining 25 patients with SHM. CONCLUSIONS: Most patients with SHM do not have a CACNA1A mutation. The results of this study, combined with the findings reported in the literature, show that the presence of cerebellar symptoms in addition to the hemiplegic attacks increases the chance of finding a CACNA1A mutation. In addition, to our knowledge, we have found a first patient with SHM without cerebellar signs with a mutation.

Adolescent↗

PubMed2002

Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

PURPOSE: To assess the prevalence and distribution of subcortical lacunar lesions (SLLs) in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to determine whether SLLs are an abnormal finding by studying their prevalence in healthy subjects, and to assess whether SLLs occur in other conditions associated with small vessel disease and white matter areas of high signal intensity (WMH). MATERIALS AND METHODS: The presence of SLLs, their location, and their relation to other abnormalities were assessed on magnetic resonance (MR) images (T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery) obtained in 34 CADASIL patients and 20 healthy family members. Three additional control groups of healthy volunteers, elderly patients with vascular risk factors, and patients with another hereditary small vessel disease were also screened for the presence and location of SLLs. Sensitivity and specificity of the presence of SLLs for the diagnosis of CADASIL were assessed. RESULTS: SLLs were found in 20 (59%) of CADASIL patients. Incidence of SLLs increased with age (20%, <30 years; 50%, 30-50 years; 80%, >50 years). SLLs invariably occurred in the anterior temporal lobes and in areas where diffuse WMH expanded into arcuate fibers. From the anterior temporal lobe, the lesions could extend dorsally into the temporal lobes and rostrally into the frontal lobes. Lesions were not found in the parietal and occipital lobes. None of the control subjects had SLLs. Specificity and sensitivity of SLLs for CADASIL were 100% and 59%, respectively. CONCLUSION: SLLs are an abnormal finding at MR imaging that frequently occur in CADASIL patients.

Adult↗