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J J Martin

Publications and source records attributed to J J Martin.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.

Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.

Adolescent↗
PubMed2001

Infantile demyelinating neuropathy associated with a de novo point mutation on Ser72 in PMP22 and basal lamina onion bulbs in skin biopsy.

Codon 72 has been designated as a hot spot for distinct missense mutations in the peripheral myelin protein 22 (PMP22) gene. Ser72Leu substitution was associated with Dejerine-Sottas syndrome (DSS) in four patients and with congenital hypomyelination neuropathy (CHN) in one patient. Our objective was to report one other DSS patient with Ser72Leu substitution in PMP22 and to concurrently illustrate how less invasive procedures such as skin biopsy could provide a rapid and reliable alternative to conventional sural nerve biopsy for the characterization of histophenotypic features. A skin biopsy was carried out in a 2 4/12-year-old girl with muscle atrophy, hypotonia and weakness, as well as generalized areflexia and absent sensory and motor nerve responses. Standard electron microscope techniques were used. PMP22 was screened by automated direct nucleotide sequencing analysis. Morphological examination revealed basal lamina onion bulbs surrounding a de- or hypomyelinated axon in all nerve bundles. Mutation analysis demonstrated a missense point mutation in codon 72 of the PMP22 gene leading to a Ser72Leu substitution. Further genotype-phenotype correlations will have to determine whether morphologically distinct phenotypes can be correlated with specific mutations. For this purpose, cutaneous nerve bundles could serve as an alternative tool to help identify and classify subtypes in this heterogeneous syndrome.

Amino Acid Substitution↗
PubMed2001

CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia.

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.

Adult↗
PubMed2001

Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.

Adult↗
PubMed2001

Light adaptation: night vision goggle effect on cockpit instrument reading time.

BACKGROUND: Light adaptation to the intensified image provided by a night vision device may handicap pilots who have set cockpit instrument luminance too low. METHODS: Under conditions simulating night flying, subjects adapted to an NVG image at 3 or 10 footlamberts (fL), then used a joystick to indicate the position of the horizon in an ADI illuminated by NVIS-compatible light at luminances 2 to 3.5 log units lower than the NVG image. RESULTS: Response times increased no more than a few tenths of a second when the decrease in luminance was only 2 log units. Greater decreases produced correspondingly longer delays in response, reaching as much as 5.5 s for subjects in their twenties and 8-15 s for older subjects. CONCLUSIONS: While a decrease of more than 2 log units is not likely to occur under most operational conditions, it is certainly possible, and pilots should be aware that significant risk can be incurred by setting cockpit instruments to luminance levels below 0.03 fL.

Adaptation, Ocular↗
PubMed2001

The many faces of human prion diseases in Belgium and the world.

Prion diseases are rare neurodegenerative disorders that always lead to death and that can be transmissible under certain conditions. Although sporadic Creutzfeldt-Jakob's disease (CJD) is the best known human variant of these transmissible spongiform encephalopathies with an incidence of about 1 in 106 inhabitants, several other types of human prion disease have been described (e.g. Familial CJD, Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia,...). In 1996, a variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy (BSE). Therefore, vigilance concerning prion diseases was increased throughout the whole of Europe. In Belgium, a comprehensive, nation-wide study has been conducted both retrospectively (1960-1997) and prospectively (1998-...) to identify prion disease patients. In 1998, a surveillance system has also been created to monitor the incidence of CJD and other prion diseases. Using data from both studies and the surveillance program, the occurrence and phenotype of all types of prion diseases in Belgium was investigated. The sporadic type of CJD was identified in 116 patients, while 4 suffered from a hereditary form. In our series, we could find no evidence for variant or iatrogenic CJD, neither for the more rare types of prion diseases.

Belgium↗
PubMed2000

A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. Tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control DNA samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated.

Alleles↗
PubMed2000

Retrospective study of Creutzfeldt-Jakob disease in Belgium: neuropathological findings.

Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that affects about 1 in 10(6) inhabitants in most countries. Recently, a new variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy. Therefore, vigilance concerning the disease's incidence has been increased. We conducted a comprehensive, nation-wide and retrospective study. In 79 Belgian autopsies, we found the characteristic triad of spongiosis, neuronal loss and reactive gliosis. The occipital cortex was most affected, while the cerebellum was mostly spared. Immunohistochemistry was performed using hydrated autoclave pretreatment and several monoclonal antibodies directed against the prion protein. We identified prion-immunoreactive patterns and locations reflecting the important heterogeneity, independently of the antibody that was used. Granular prion immunoreactivity was observed in astrocytes. We studied the regional intensity of the prion immunostaining and determined that the frontal cortex with 95% positive immunoreactivity was best suited for a biopsy. We studied the disease duration in sporadic CJD patients who showed neuropathological lesions of other neurodegenerative disorders (such as Alzheimer's disease). The study shapes the framework in which a prospective neuropathological registry will be able to function.

Amyloid beta-Peptides↗
PubMed2000

Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion.

We describe a patient who was clinically diagnosed with familial early-onset Alzheimer disease (AD) carrying both the E318G substitution in presenilin 1 (PSEN1) and an insertion of 7 octapeptide coding repeats in the prion protein gene (PRNP). Neuropathological examination revealed elongated cerebellar prion protein deposits in the absence of AD pathology. Further analysis of other family members showed that the Creutzfeldt-Jakob disease phenotype in this family was caused solely by the PRNP insertion. This observation is consistent with our previous finding that PSEN1 E318G is not causally related to AD.

Adult↗
PubMed2000

Charcot joint in idiopathic sensorimotor neuropathy.

Charcot joint or neuropathic arthropathy is described in certain neurological conditions. We report the case of a man who presented with a swollen ankle 10 days after a long walk, which rapidly progressed to a Charcot joint. A neurological examination revealed areflexia and insensitivity to temperature and pain. Electromyographic analysis showed a mixed sensorimotor polyneuropathy. Besides axonal loss and demyelinisation on sural nerve biopsy, prominent loss of unmyelinated fibres was demonstrated. Despite extensive investigations, no definite cause for this neuropathy could be found.

Arthropathy, Neurogenic↗
PubMed2000

Recurring aseptic meningitis after travel to the tropics: a case of Mollaret's meningitis? Case report with review of the literature.

Recurrent aseptic meningitis in a 35-year-old caucasian woman is described. She had many attacks over a period of 9 years. The first attack occurred after travel in the tropics. In spite of extensive examinations no cause could be found for the recurrent attacks. Both the clinical presentation and characteristics of the cerebrospinal fluid are compatible with the diagnosis of Mollaret's meningitis. There is no known cure for this condition, although colchicine and indomethacin have been mentioned to relieve symptoms. In our patient, a treatment with indomethacin during the last attack resulted in a clear and rapid improvement of symptoms. Since this episode only mild relapses have occurred, all of which responded well to the same treatment. This case highlights the long time span in which attacks of Mollaret's meningitis can occur, and the spectacular benefit of indomethacin.

Adult↗
PubMed2000

Clinical and neuropathological parameters affecting the diagnostic yield of nerve biopsy.

The value of nerve biopsy in the investigation of peripheral neuropathies is an important and controversial issue, partially obscured by the large variations in the diagnostic yield routinely reported for this procedure. The aim of this study was to evaluate the clinical and neuropathological parameters affecting the yield of nerve biopsy. We compared the experience of two independent neuropathology laboratories with different patient recruitment and neuropathological methods over 11 years (01/1987-12/1997). Clinicopathological correlations were studied retrospectively in 355 patients. Using the same criteria of evaluation, contributive biopsies accounted for 35.5% in one laboratory, and 47.3% in the other. Clinical parameters affecting the yield of nerve biopsy were: (a) the presumptive diagnosis at time of referral for biopsy; (b) the distribution of symptoms; and (c) the interval between disease onset and biopsy. Greater yield was associated with clinically suspected vasculitis, inflammatory demyelinating neuropathy or hereditary sensorimotor neuropathies. Contributive findings were more often reported with multifocal or asymmetrical presentations, and onset-to-biopsy interval of less than 6 months. The contribution of nerve biopsy varied according to neuropathological techniques: (a) serial sections on frozen. paraffin-embedded and resin-embedded material improved sensitivity for interstitial pathology: (b) combined muscle biopsy increased sensitivity in the detection of vasculitis; and (c) teasing of nerve fibers added critical information to other classical techniques in only 4/102 cases.

Adolescent↗
PubMed2000

Homocysteine.

Homocysteine does not occur in the diet but it is an essential intermediate in normal mammalian metabolism of methionine. Each compound, methionine or homocysteine, is the precursor of the other. Similarly, the synthesis of one is the mechanism for the detoxification of the other. The ubiquitous methionine cycle is the metabolic basis for this relationship. In some tissues the transsulfuration pathway diverts homocysteine from the cycle and provides a means for the synthesis of cysteine and its derivatives. Methionine, (or homocysteine) metabolism is regulated by the disposition of homocysteine between these competing sequences. Both pathways require vitamin-derived cofactors, pyridoxine for transsulfuration and both folate and cobalamin in the methionine cycle. The clinical consequences of disruption of these pathways was apparent first in rare inborn errors of metabolism that cause homocystinuria, but recent studies focus on "hyperhomocysteinemia"--a lesser metabolic impairment that may result from genetic variations, acquired pathology, toxicity and nutritional inadequacy. Hyperhomocysteinemia is an independent risk factor for thrombovascular diseases however it is not clear whether the minimally increased concentration of the amino acid is the causative agent or merely a marker for the pathology. Until we resolve that question we cannot predict the potential efficacy of therapies based on folate administration with or without additional cobalamin and pyridoxine.

Animals↗
PubMed2000

Type I sialidosis: a clinical, biochemical and neuroradiological study.

We report biochemical, morphological and neuroradiological findings in a 40-year-old woman affected with type I sialidosis. The clinical symptoms, consisting of a cerebellar syndrome, were first noted at the age of 17 years. The macular cherry-red spot was first observed after 23 years of disease. A CT scan performed at 21 years of age showed enlargement of the fourth ventricle. Nuclear magnetic resonance imaging of the brain performed at the age of 40 showed severe atrophy of the cerebellum and pontine region; atrophy of cerebral hemispheres and of the corpus callosum was also observed. We emphasize the prolonged course of illness in this patient, observed over a long period of time. Of particular interest is the neuroradiological study showing our findings both at the beginning of the disease and after 20 years.

Adult↗
PubMed2000

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations.

We describe 3 new families affected by Alzheimer's disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large "cotton wool" plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin-1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Abeta42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid-beta concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimer's disease and have implications for the pathogenesis of the disease in general.

Alzheimer Disease↗