Timothy Lynch

The Natural History of CADASIL A Pooled Analysis of Previously Published Cases

BACKGROUND AND PURPOSE Although numerous families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported, our understanding of the disease remains incomplete. Thus, we performed this study to investigate the phenotypic range and natural history of CADASIL. METHODS We performed a pooled analysis of previously published cases. RESULTS We identified 105 symptomatic patients in 33 families. Vascular risk factors were uncommon, with hypertension reported in only 8 patients. The mean age of symptom onset was 36. 7+/-12.9 years. Stroke or transient ischemic attack was an initial symptom in 45 patients, with a mean age of onset of 41.2+/-9.2 years. Migraine was also a common initial symptom, reported by 42 patients at a younger mean age of 28.3+/-11.7 years. Other initial symptoms included depression in 9 patients, cognitive impairment in 6 patients, and seizures in 3 patients. Regarding clinical course, 71 patients experienced a stroke or transient ischemic attack, and 52 of those patients had 1 or more recurrent ischemic events. Dementia was reported in 44 patients. Only 3 additional patients experienced migraine at a later time, while 13 additional patients developed depression. Six patients had seizures. Twenty-two of the 105 patients had died, with a mean age of death of 54.8+/-10.6 years. Nineteen of those 22 patients had experienced a stroke or transient ischemic attack and 19 patients were demented. CONCLUSIONS CADASIL typically becomes evident in early or middle adulthood with migraine or an ischemic event, later manifests itself through recurrent subcortical ischemic strokes leading to a stepwise decline and dementia, and results in reduced survival.

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22

Objective The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. Background Several dementing disorders have clinical and pathologic similarities with AD, Picks disease, and the “nonspecific” dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. Methods The authors performed a clinical assessment gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. Results HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Picks disease. Salient clinical features are global dementia with disproportionate dysphasia and “frontotemporal” symptoms. A linkage between HDDD and 17q 21–22 was shown, with a maximum lod score of 3.68 at zero recombination. Conclusions Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Frequency of tau mutations in three series of non‐Alzheimer's degenerative dementia

Splice‐site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non‐Alzheimers (non‐AD) degenerative dementia. The groups included (1) a community‐based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice‐site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community‐based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series. Ann Neurol 1999;46:243–248

Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians

We describe several families of African origin with SCA3/Machado‐Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L‐dopa–responsive Parkinsons disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis‐acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans‐acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.

CADASIL in a North American family Clinical, pathologic, and radiologic findings

Objective: To expand the reported phenotypic range of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Background: Despite numerous patient reports, our knowledge of the phenotypic range of CADASIL remains incomplete. Method: We performed clinical, pathologic, and radiologic examinations on members of a family with CADASIL. Results: The proband is a 61-year-old man with a history of migraine and depression who has experienced multiple subcortical infarctions resulting in a stepwise decline. Neuropsychological testing documented a dementia syndrome with frontal lobe features and neurologic examination noted a left hemiparesis and a right-sided palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff positive granular changes in the media and white matter gliosis, with unremarkable cortex. Genetic testing confirmed a Notch 3 mutation. The probands first cousin has a history of depression, one seizure possibly resulting from an acute stroke, and a learning disorder. Neuropsychological testing demonstrated deficits in executive function and neurologic examination noted persistent extraneous adventitial movements, poor coordination, and primitive reflexes. Skin biopsy with electron microscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be pathognomonic of CADASIL. The probands older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extending into the temporal lobes, and lacunar infarctions in these four nonhypertensive patients. Other family members have experienced migraine, recurrent stroke, dementia, and depression. Conclusions: CADASIL is a genetic basis for vascular dementia that may be manifest earlier in life than previously reported.

Rapidly progressive autosomal dominant Parkinsonism and dementia with Pallido-Ponto-Nigral Gegeneration (PPND) and Disinhibition-Dementia-Parkinsonism-Amyotrophy Complex (DDPAC) are clinically distinct conditions that are both linked to 17q21-22

Genetic analysis provides specific etiologic information about disease that cannot be deduced by clinical and pathologic investigations alone. Two large families have been characterized with multi-system degeneration: rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) and disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC). Linkage analysis identified a locus, wld, on-17q21-22 that is responsible for DDPAC. Analysis of a PPND family shows that PPND is also due to a gene on 17q21-22. Comparison of genealogic, clinical, diagnostic, and pathologic data shows that DDPAC and PPND are distinct disorders suggesting two different mutations in wld. Literature review identifies many kindreds with multi-system degeneration that may be allelic.

Type 1 protease resistant prion protein and valine homozygosity at codon 129 of PRNP identify a subtype of sporadic Creutzfeldt-Jakob disease

A man was studied with sporadic Creutzfeldt-Jakob disease (sCJD) who had serial cortical syndromes evolving over 15 months without significant ataxia, prominent myoclonus, or periodic complexes on EEG examinations. This clinical phenotype correlated with a predominantly cortical and striatal distribution of lesions and accumulation of protease resistant prion protein with relative sparing of the brainstem or cerebellum. No amyloid plaques were seen and prion protein (PrP) immunohistochemistry only demonstrated very faint granular deposits in the cerebral cortex. Molecular analysis showed homozygosity for valine at codon 129 in the prion protein gene (PRNP) and protease resistant prion protein type 1 deposition. The comparison of molecular and clinicopathological features of the present case with those previously reported in sCJD, indicates that valine homozygosity at codon 129 and type 1 protease resistant prion protein are associated with a distinct phenotypic variant of sCJD. The data also support the view that thePRNP codon 129 polymorphism and the physicochemical properties of the protease resistant prion protein are major determinants of phenotypic variability in sCJD.

Generalized chorea in an infant with semilobar holoprosencephaly

We report chorea in an infant with holoprosencephaly. Congenital structural brain disease has not been a reported cause of chorea. Cranial magnetic resonance imaging revealed small, fused frontal lobes with hypoplastic caudates. Our patient responded to symptomatic treatment with dopamine-depleting agents. It is likely that the mechanism for the chorea was a dysfunction of the striatum. The differential diagnosis of childhood chorea should include holoprosencephaly.