CT and MR imaging of neuroaxonal leukodystrophy presenting as early-onset frontal dementia.

CT and MR imaging showed diffuse changes of the frontal white matter and genu of the corpus callosum with minimal atrophy and no contrast enhancement in a 41-year-old woman with progressive dementia. Brain biopsy disclosed axonal spheroids and gliosis in the white matter without macrophage or inflammatory infiltration or vessel abnormalities consistent with neuroaxonal leukodystrophy. This disease can be suspected on CT and MR imaging findings but requires neuropathologic examination to be diagnosed.

Stereotactic brain biopsy in human immunodeficiency virus-infected patients.

OBJECTIVE: To evaluate prospectively the diagnostic efficacy and safety of stereotactic brain biopsy and its impact on treatment, outcome, and survival in human immunodeficiency virus-infected patients with focal brain lesions. METHODS: Computed tomography-guided stereotactic brain biopsy was performed in 26 patients, of whom 17 failed to respond to a 2- to 3-week anti- Toxoplasma regimen. Exclusion criteria for biopsy were overt acquired immunodeficiency syndrome for 2 years or longer, Karnofsky score less than 50, and severe coagulopathies. RESULTS: A definitive diagnosis was obtained in 24 patients (92%), of whom 12 (46%) had primary brain lymphoma, six (23%) had progressive multifocal leukoencephalopathy, and four (15%) had Toxoplasma encephalitis. Two thirds of contrast-enhancing lesions on computed tomography were lymphoma and three fourths of contrast-negative lesions were leukoencephalopathy. Three patients had biopsy-related cerebral hemorrhages (morbidity, 11.5%). Median follow-up and survival for the entire group were 24 weeks (range, 6 to 135 weeks). Twenty patients (77%) received specific therapy and 13 (50%) responded to treatment. Of 11 patients with lymphoma undergoing irradiation treatment (whole-brain radiotherapy in seven and gamma-knife treatment in four), nine (82%) had clinical and radiologic response, with a median survival of 34 weeks (range, 13 to 57 weeks). CONCLUSIONS: Stereotactic brain biopsy has high diagnostic efficacy and clinical benefit in carefully selected human immunodeficiency virus-infected patients. The procedure should be performed essentially in patients with contrast-enhancing lesions on computed tomography who have a high frequency of treatable cerebral diseases.

A novel mutation af Cln3 associated with delayed-classic juvenile ceroid lipofuscinois and autophagic vacuolar myopathy.

Juvenile neuronal-ceroid-lipofuscinosis (JNCL) is a lysosomal storage disease caused by mutations in CLN3. The most frequent mutation is a 1.02-kb deletion that, when homozygous, causes the classical clinical presentation. Patients harboring mutations different than the major deletion show a marked clinical heterogeneity, including protracted disease course with possible involvement of extraneuronal tissues. Cardiac involvement is relatively rare in JNCL and it is usually due to myocardial storage of ceroid-lipofuscinin. Only recently, histopathological findings of autophagic vacuolar myopathy (AVM) were detected in JNCL patients with severe cardiomyopathy. We describe a 35-year-old male showing a delayed-classic JNCL with visual loss in childhood and neurological manifestations only appearing in adult life. He had an unusual CLN3 genotype with an unreported deletion (p.Ala349_Leu350del) and the known p.His315Glnfs*67 mutation. Autophagic vacuolar myopathy was shown by muscle biopsy. At clinical follow-up, moderately increased CPK levels were detected whereas periodic cardiac assessments have been normal to date. Adult neurologists should be aware of protracted JNCL as cause of progressive neurological decline in adults. The occurrence of autophagic vacuolar myopathy necessitates periodic cardiac surveillance, which is not usually an issue in classic JNCL due to early neurological death.

Melanoma cells homing to the brain: an in vitro model.

We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 µm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvß3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion.

Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.

The tau gene has been found to be the locus of dementia with rigidity linked to chromosome 17. Exonic and intronic mutations have been described in a number of families. Here we describe a P301S mutation in exon 10 of the tau gene in a new family. Two members of this family were affected. One individual presented with frontotemporal dementia, whereas his son has corticobasal degeneration, demonstrating that the same primary gene defect in tau can lead to 2 distinct clinical phenotypes. Both individuals developed rapidly progressive disease in the third decade. Neuropathologically, the father presented with an extensive filamentous pathology made of hyperphosphorylated tau protein. Biochemically, recombinant tau protein with the P301S mutation showed a greatly reduced ability to promote microtubule assembly.

Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation.

Mutations in the gene coding for the Schwann cell transcription factor early growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain development, have been observed in few cases of inherited neuropathy. The authors describe a unique combination of cranial nerve deficits in one member of a Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding further supports the role of EGR2 in cranial nerve development.

Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.

BACKGROUND: The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms. OBJECTIVE: To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A. METHODS: We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0). RESULTS: Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula. CONCLUSION: We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.

Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22.

We describe a patient with congenital hypomyelination neuropathy. The pathological and morphometrical findings in the sural nerve biopsy were consistent with a defect of myelin formation and maintenance. Direct sequence analysis of the genomic regions coding the peripheral myelin proteins P0 and PMP22 disclosed a heterozygous missense point mutation that leads to a Ser72Leu substitution in the second transmembrane of PMP22. Codon 72 mutations of PMP22 are associated with different phenotypes encompassing the Dejerine-Sottas syndrome and including congenital hypomyelination neuropathy.

Subunit A of factor XIII regulates subunit B plasma concentration.

Subunit a of Factor XIII is found absent in homozygotes and reduced in heterozygotes. Since a concomitant reduction of subunit b occurs in these cases, an interaction between the loci controlling the synthesis of the two subunits was suggested. However in the present study we have shown that the administration of subunit a in two totally devoid homozygotes produced an increase of subunit b, reaching the maximum concentration five days after infusion. This strongly suggests that subunit b plasma level is regulated on the subunit a plasma amount.

Neuropathology of Gerstmann-Sträussler-Scheinker disease.

Gerstmann-Sträussler-Scheinker disease is a familial neurodegeneration characterized clinically by adult-onset ataxia, postural abnormalities, and cognitive decline, and pathologically by amyloid deposits mostly localized in the cerebral and cerebellar cortices and the basal ganglia. The disease is due to mutations in the prion protein gene. Processing of the mutant proteins originates the amyloidogenic fragments that accumulate in the tissue. PrP-immunoreactive amyloid deposits are the morphological hallmark of the disease. Hypertrophic astrocytes, activated microglia, and nerve cell loss are consistently associated with PrP-amyloid deposits, while spongiosis, diffuse PrP immunoreactivity, neurofibrillary tangles, Lewy bodies, and long fiber tracts degeneration are occasionally associated. The clinical and pathological variability observed in GSS families is related to both mutations and the M/V polymorphism at codon 129 of the mutated gene.

HIV-associated PML presenting as epilepsia partialis continua.

Two patients with human immunodeficiency virus (HIV) type 1 infection presented new-onset epilepsia partialis continua (EPC) as an early manifestation of progressive multifocal leukoencephalopathy (PML). EPC occurred with no other seizures and was associated with negative radiographic and electrophysiological findings for several weeks. PML represents an increasingly recognized cause of new-onset seizures in both seropositive and seronegative patients, with no report of EPC as a presenting complaint.

Adult polyglucosan body disease in a patient originally diagnosed with Fabry's disease.

Adult polyglucosan body disease is a rare autosomal recessive disease, caused by glycogen branching enzyme gene mutations, characterised by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Fabry's disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations; neurological manifestations include cerebrovascular accidents, small-fibre neuropathy and autonomic dysfunction. Here, we report the case of a 44-year-old Sicilian male with stroke-like episodes, hypohidrosis and mild proteinuria, which led to the diagnosis of Fabry's disease after a hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene was detected. Subsequently, he developed progressive walking difficulties and dementia, which were considered atypical for Fabry's disease. Therefore, we performed additional investigations that eventually led to the diagnosis of adult polyglucosan body disease caused by two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene. Recently, the pathogenic role of the p.Ala143Thr mutation in causing Fabry's disease has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.

Four novel cases of periaxin-related neuropathy and review of the literature.

OBJECTIVE: To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. METHODS: Case reports and literature review. RESULTS: Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. CONCLUSIONS: These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.

Revelation of a novel CLN5 mutation in early juvenile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCLs) are relatively common storage diseases of childhood and early adolescence. Ultrastructural shape of storage cytosomes, type of disease gene, and age of onset serve to classify the different NCLs, some of which appear to cluster in Scandinavian countries. The CLN5 form usually presents as a classical epileptiform encephalopathy of late infancy but a more aggressive cognitive impairment has been described in a single family. We report two sibs harbouring a novel mutation (p.Tyr258Asp) in the CLN5 gene and displaying behaviour disturbances and mental deterioration, rather than epilepsy, as the dominant disease manifestation at onset.

Failure to measure plasma activated factor XIII during disseminated intravascular coagulation.

The search for activated products of coagulation factors in blood is of considerable clinical interest because its detection would indicate activation of the clotting system. Factor XIII circulates as inactive zymogen and becomes enzymatically active after thrombin or factor Xa activation. Employing an amine-incorporating system, activated factor XIII was measured in normal and pathological plasma from leukemic patients with overt laboratory signs of disseminated intravascular coagulation (DIC). Only traces of the activated factor were detected in both normal and DIC plasma. The method, sensitive and specific, as shown by the results of measurements on the plasma of 8 patients with congenital deficiency and on normal serum, did not prove to be useful for detecting pathological in vivo thrombin generation.

IDPN impairs post-traumatic regeneration of rat sciatic nerve.

The role played by cytoskeletal proteins in nerve regeneration was investigated in a model in which the axonal transport of neurofilaments (NF) is almost selectively impaired. The administration of beta, beta'-iminodipropionitrile (IDPN), a synthetic lathyrogenic compound, induces an axonopathy characterized by proximal axonal enlargements, due to NF accumulation, and by diffuse atrophic changes associated with spatial segregation of NF from microtubules (MT). We investigated post-axotomy regeneration of rat sciatic nerve following IDPN administration. Changes induced by IDPN, as examined in the proximal and distal nerve stump at 15 and 30 days after lesion, consisted of a statistically significant reduction of the mean axonal diameter (P < 0.0001) as compared to control rats. In addition, the number of regenerating myelinated fibres was smaller in dosed rats (P < 0.001) 15 days after crush, whereas at the later stage the number of axons approached that of control animals. Electrophysiological investigation revealed a delay in target reinnervation in dosed rats. Regenerating IDPN axons, both 15 and 30 days after crush contained fewer NF (P < 0.001), while the number of MT was slightly increased as compared to controls. Taken together, our results suggest that severe alteration of NF transport, coupled with mild alteration of other components of cytoskeletal proteins, impairs the longitudinal and radial growth of regenerating myelinated axons and confirm that the number of NF is the major determinant of the cross-sectional area of each segment of the axon.