Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia.

Myelination is a complex, developmentally regulated process whereby myelin proteins and lipids are coordinately expressed by myelinating glial cells. Homozygosity mapping in nine patients with childhood onset spasticity, dystonia, cognitive dysfunction, and periventricular white matter disease revealed inactivating mutations in the FA2H gene. FA2H encodes the enzyme fatty acid 2-hydroxylase that catalyzes the 2-hydroxylation of myelin galactolipids, galactosylceramide, and its sulfated form, sulfatide. To our knowledge, this is the first identified deficiency of a lipid component of myelin and the clinical phenotype underscores the importance of the 2-hydroxylation of galactolipids for myelin maturation. In patients with autosomal-recessive unclassified leukodystrophy or complex spastic paraparesis, sequence analysis of the FA2H gene is warranted.

Longitudinal assessment of genetic and epigenetic markers in oligodendrogliomas.

PURPOSE: Because little is known about the evolution of genetic and epigenetic changes that occur during tumor progression in oligodendrogliomas, we evaluated these changes in paired early and progressive oligodendrogliomas. EXPERIMENTAL DESIGN: 1p36, 19q13, 10q22-26, and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed in 46 paired early and progressive oligodendrogliomas from 23 patients. RESULTS: In early tumors, 60.8% were of low grade compared with only 17% low-grade tumors at recurrence. Of 17 early tumors described as pure oligodendrogliomas, 76.5% remained in this lineage, regardless of their grade, whereas others changed to astrocytic tumors. Oligoastrocytic tumors had a significantly higher tendency to transform to astrocytic tumors. All pure oligodendrogliomas with 1p/19q codeletions remained phenotypically unchanged, unlike mixed tumors with codeletions, of which 83% changed their cell lineage. Of tumors with early 1p deletion, 80% remained oligodendroglial at progression, whereas 75% of tumors with an intact 1p changed to astrocytic phenotype. 10q loss was uncommon in both early and progressive tumors. The proportional gain in methylation at progression was 31% for tumors with early 1p deletion, unlike tumors with an intact 1p, which had an 87.5% gain of methylation at progression. CONCLUSIONS: Pure oligodendrogliomas with 1p/19q deletion tend to retain their cell phenotype and genetic profile unlike tumors with no deletions or mixed histology. MGMT promoter methylation is more pronounced at tumor progression, particularly in tumors with an intact 1p. These observations suggest that MGMT promoter methylation is a late event in progressive oligodendrogliomas, and therefore, their chemosensitivity is not necessarily related to MGMT methylation status.

A novel autosomal recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p12.

We describe a new autosomal recessive myopathy of early onset and very slow progression distinguished by the prominent external ophthalmoplegia in 16 subjects of eight families from a large and highly inbred Arab community. Characteristic clinical features include mild facial and skeletal muscle weakness and atrophy more pronounced proximally in the upper limbs, facial dysmorphism and scoliosis associated with conjugate, non-restrictive ocular motility impairment greatest in the upgaze and without ptosis or aberrant eye movements. Orbital MRI in the patients demonstrated atrophy with fatty replacement of the oculorotatory muscles. The major pathological alteration on skeletal muscle biopsy was a marked type 1 fibre predominance with core-like formations. A genome wide search for regions of homozygosity in the affected members from two informative families identified linkage with chromosome 17p13.1-p12 markers. Maximum two-point logarithm of odds scores were obtained at loci D17S1803 and AFMA070WD1 (Zmax = 3.74 at = 0). Two independent recombination events at D17S1812 and D17S947 further defined a critical region of 12 cM. Several genes map to this interval, including a cluster of sarcomeric myosin heavy chain genes. One of these genes, MYH2, is involved in inclusion body myopathy 3, but no exonic mutations were found by direct sequencing. The molecular basis for this new myopathy remains to be identified.

Cerebral amyloid angiopathy--a disease or age-related condition.

Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomeninged and cerebral blood vessels. Its most common form, sporadic CAA that results from deposition of beta-amyloid peptide, which is the subject of this short review, is present in virtually all cases of Alzheimer disease and is also common among non-demented subjects where its prevalence increases with age. Stroke due to massive cerebral lobar hemorrhage is the main clinical presentation of CAA, but transient neurologic symptoms due to microhemorrhages may also occur. CAA is also a risk factor for cerebral infarction and there is increasing evidence that CAA contributes to cognitive impairment in the elderly, usually in association with white matter abnormalities on imaging. Although the definitive diagnosis of CAA is neuropathologic, reliable diagnosis can be reached clinically, based on the occurrence of strictly lobar hemorrhages, particularly in the cortico-subcortical area when using gradient-echo or T2*-weighted magnetic resonance imaging. Experimental studies have shown that the origin of the vascular amyloid is neuronal, and that age-related degenerative changes in the vessel walls prevent its clearance from the brain along perivascular spaces and promote Abeta aggregation and CAA formation. The entrapped Abeta aggregates are toxic to various vascular wall components, including smooth muscle cells, pericytes and endothelial cells, leading to their eventual destruction and predisposition of the vessel wall to rupture and hemorrhage. However, more research is necessary to decipher the mechanism of CAA formation and its relation to cognitive decline in the elderly.

Impact of Resecting Radiation Necrosis and Pseudoprogression on Survival of Patients with Glioblastoma.

INTRODUCTION: Radiation necrosis (RN) and pseudoprogression are known as postradiation treatment effects and may simulate tumor progression. The disease course of glioblastoma patients who had developed RN and the impact of resecting RN on survival have not been evaluated. This study examines the clinical course of patients considered candidates for repeat surgery for a recurring brain mass proven to be RN and compared these with patients who had true tumor recurrence at surgery. METHODS: Of 159 patients with glioblastoma who were reoperated on because of a presumed recurrent tumor requiring repeat surgery, 18 had RN as the major component of the resected mass. The characteristics and outcome of these 18 patients were retrospectively analyzed and compared with patients in whom active and bulky tumor was found during surgery. RESULTS: Radiation necrosis occurred significantly earlier than true tumor recurrence. Patients with RN harbored larger lesions and were significantly more symptomatic before the second surgery. Most patients with RN who underwent GTR of the lesion in the second operation experienced faster resolution of the surrounding edema compared with patients who underwent STR or biopsy only. There was no significant difference in survival between the 2 groups. CONCLUSIONS: These data provide an opportunity to examine the clinical course of a selected group of patients with histologically verified RN. Although RN is associated with more severe neurologic symptoms that improve after surgery, its occurrence or surgical removal carries no survival advantage compared with patients who undergo a repeat operation for true tumor recurrence.

Early clinical heterogeneity in choreoacanthocytosis.

BACKGROUND: Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene. OBJECTIVE: To describe the early clinical features and possible genotype-phenotype correlation in CHAC. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS AND MAIN OUTCOME METHODS: Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A. RESULTS: Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear. CONCLUSIONS: These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.

Cerebral amyloidoma diagnosed intraoperatively with squash preparations: a case report.

BACKGROUND: Amyloidoma (tumoral amyloidosis) is the rarest form of central nervous system (CNS) amyloidosis. CASE: A 51-year-old woman presented with recurrent right-sided otitis media and hearing loss. Computed tomography and magnetic resonance imaging revealed a mass in the right temporal lobe. Cytologic findings at the time of stereotactic biopsy for suspected glioma were compatible with amyloidoma. Subsequent histologic and electron microscopic findings confirmed the diagnosis of amyloidoma. Auxiliary testing ruled out systemic amyloidosis and plasma cell dyscrasia. CONCLUSION: To our knowledge, this is the first report on the cytologic findings in a case of CNS amyloidoma.

Childhood macrophagic myofasciitis-consanguinity and clinicopathological features.

Macrophagic myofasciitis has been almost exclusively detected in adults only. We describe six children of Arab Moslem origin with this disorder. Three presented with hypotonia, developmental delay and seizures and were evaluated for a mitochondrial disorder. The other three children had hypotonia and predominantly motor delay. Five of the six families were consanguineous. A massive collection of macrophages was present in the fascia and adjacent epimysium in all biopsies. The macrophages were periodic-acid-Schiff positive and immunoreactive for CD68. One biopsy which was evaluated by electron microscopy and energy-dispersive X-ray microanalysis showed crystalline structures containing aluminum in macrophages. Two children with motor delay and hypotonia were treated with oral prednisone for 3 months with no clinical improvement. Genetic predisposition probably accounts for the variability in the prevalence of macrophagic myofasciitis in different populations. At least in childhood, there seems to be no connection between macrophagic myofasciitis as a pathological entity and the clinical symptoms and signs.

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family.

BACKGROUND: Frontotemporal dementia with parkinsonism linked to chromosome 17q21-22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes. OBJECTIVES: To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation. METHODS: Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband. RESULTS: The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1-2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3-5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene. CONCLUSIONS: The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations.

Clinical characteristics and muscle pathology in myopathic mitochondrial DNA depletion.

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity.

Early peripheral nervous system manifestations of infantile Krabbe disease.

Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It can be easily diagnosed when it presents with the classic clinical picture characterized by central nervous system manifestations of spasticity, irritability, motor regression and seizures associated with a positive family history. We studied eight children diagnosed with Krabbe disease. In two of these children (25%), peripheral neuropathy was the single initial symptom and the only neurologic finding noted for a period of months. In these patients, diagnosis of Krabbe's disease was delayed and established only 9-11 months after the initial symptoms. In two other children with "classical picture" Krabbe disease, areflexia was noted on admission. The occurrence of peripheral neuropathy as an initial symptom in early infantile Krabbe disease may be underestimated. Krabbe disease should be considered in the differential diagnosis of early infantile peripheral neuropathy. Early diagnosis of affected children might be important for genetic counseling for families at risk.

Generalized convulsive status epilepticus in Creutzfeldt-Jakob disease.

We report a patient who was referred to our department because of generalized status epilepticus. His condition deteriorated rapidly and he died 1 month after admission. Autopsy confirmed the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). CJD should be added to the list of rare but possible causes of generalized status epilepticus.

Severe infantile carnitine palmitoyltransferase II deficiency in 19-week fetal sibs.

Antenatal presentation of carnitine palmitoyltransferase type II deficiency due to mutations in the CPT2 gene has been rarely reported. We report an Ashkenazi Jewish family with 3 terminated pregnancies for multicystic kidneys and/or hydrocephalus. Fetal autopsy after termination of the couple's 4th pregnancy (sib 2) showed renal parenchyma replaced by cysts that appeared to increase in diameter toward the medulla. Fetopsy after termination of the 7th pregnancy (sib 3) revealed micrognathia; hypospadias; cystic renal dysplasia; hepatosteatosis; and lipid accumulation in the renal tubular epithelium, myocardium, and skeletal muscle. Microvascular proliferative changes and focal polymicrogyria were seen in the brain. A beta-oxidative enzyme deficiency was suspected. CPT2 gene analysis showed a homozygous complex haplotype for the F448L mutation associated with a c.del1238_1239AG (p.Q413fs) truncating mutation in exon 4. Carnitine palmitoyltransferase type II deficiency should be included in the differential diagnosis in fetuses of Ashkenazi origin with multicystic kidneys and unusual cerebral findings.

Dural arachnoid granulations and "giant" arachnoid granulations.

Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99 years (mean 69 years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92 years (mean 69 years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65 years) and that they can reach remarkable size (up to 2.5 cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderly.

Primary T-cell CNS lymphoma presenting with leptomeningeal spread and neurolymphomatosis.

Primary CNS lymphoma (PCNSL), a rare form of non-Hodgkin lymphoma that is confined to the brain, is usually of B-cell origin. Primary leptomeningeal lymphoma, regardless of T or B-cell origin, is an unusual site of presentation. Out of 100 consecutive PCNSL patients that we have followed up in our center during the last 10 years, five had T-cell lymphoma (5%). All presented with leptomeningeal involvement as the sole manifestation and four of them presented with neuronal lymphomatosis. Presenting symptoms included signs of elevated intracranial pressure with 6th nerve palsy; headache and bilateral 3rd nerve palsy; mononeuritis multiplex and unilateral hearing loss; bilateral 7th nerve paralysis and bilateral uveitis. Because neither the CSF nor the MRI were indicative, meningeal or nerve biopsies were required for conclusive diagnosis. Four patients died 10-19 months from disease onset and one patient is alive 36 months following the diagnosis. We conclude that T-cell PCNSL can present as an isolated leptomeningeal involvement which may be associated with neurolymphomatosis affecting cranial and peripheral nerves. These manifestations mimic other neurological conditions such as pseudotumor cerebri or vasculitis. Diagnosis is difficult and, as a result, frequently delayed. This calls for early consideration of meningeal or nerve biopsy whenever CSF findings are inconclusive.

Extended phenotype in the transthyretin Tyr77 familial amyloid polyneuropathy.

The transthyretin Tyr77 variant of familial amyloid polyneuropathy (FAP) has been identified in a few North American and European patients, but the full spectrum of its clinical manifestations is still not known. We report a 3-generation family of Jewish-Yemenite origin with Tyr77 FAP presenting with atypical features. The affected individuals had sensorimotor and autonomic neuropathy and cardiomyopathy accompanied by prominent dysphagia, hearing loss and asymptomatic carpal tunnel syndrome. Brain MRI in the proband showed multifocal white matter lesions. These features extend the reported Tyr77 phenotype and support the modifying effect of additional factors on the disease expression.

Pathogenesis of acute viral disease induced in fish by carp interstitial nephritis and gill necrosis virus.

A lethal disease of koi and common carp (species Cyprinus carpio) has afflicted many fish farms worldwide since 1998, causing severe financial losses. Morbidity and mortality are restricted to common carp and koi and appear in spring and autumn, when water temperatures are 18 to 28 degrees C. We have isolated the virus causing the disease from sick fish, propagated it in koi fin cell culture, and shown that virus from a single clone causes lethal disease in carp and koi upon infection. Intraperitoneal virus injection or bathing the fish in virus-containing water kills 85 to 100% of the fish within 7 to 21 days. This virus is similar to the previously reported koi herpesvirus; however, it has characteristics inconsistent with the herpesvirus family, and thus we have called it carp interstitial nephritis and gill necrosis virus. We examined the pathobiology of this disease in carp by using immunohistochemistry and PCR. We found large amounts of the virus in the kidneys of sick fish and smaller amounts in liver and brain. A rapid increase in the viral load in the kidneys was detected by using both immunofluorescence and semiquantitative PCR. Histological analyses of fish at various times after infection revealed signs of interstitial nephritis as early as 2 days postinfection, which increased in severity up to 10 days postinfection. There was severe gill disease evidenced by loss of villi with accompanying inflammation in the gill rakers. Minimal focal inflammation was noted in livers and brains. This report describes the etiology and pathology of a recently described viral agent in fish.