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Biomedical subjects

J J Martin

Publications and source records attributed to J J Martin.

At least 109 records · Page 6Linked to original sources
PubMed1997

Adult neuronal ceroid-lipofuscinosis--personal observations.

A workshop on the diagnostic criteria of adult neuronal ceroid-lipofuscinosis (ANCL) or Kufs' disease represented an unique opportunity to make a critical review of the ANCL material from the files of the Born-Bunge Foundation. Our review included the clinical data when available, the light microscopic sections and the electron micrographs. When the postmortem material had not been immediately fixed in glutaraldehyde, we sampled formalin-fixed material, post-fixed it and used classical electron microscopic techniques to better define the ultrastructure of the stored products. Only one family fulfilled the criteria for ANCL Neurons and vascular smooth muscle cells contained membrane-bound inclusions with curvilinear, rectilinear and fingerprint profiles.

Adult↗
PubMed1996

Retarded and aberrant splicings caused by single exon mutation in a phosphoglycerate kinase variant.

The molecular abnormality of a phosphoglycerate kinase variant which was associated with severe tissue enzyme deficiency and episodes of muscle contractions and myoglobinuria was examined. Analysis of the patient's DNA showed the existence of a nucleotide transversion A/T - C/G in exon 7. No other nucleotide change was detected in the coding region of the variant gene. The mutation should produce a single amino acid substitution Glu - Ala at protein position 251 counting from the NH2-terminal acetyl serine residue. The protein abnormality caused by the amino acid substitution cannot explain the enzyme deficiency. Northern blot hybridization indicated that the PGK mRNA content of the patient's lymphoblastoid cells was only about 10% of that of normal. Nucleotide sequence analysis revealed the existence of two PGK mRNA components in the patient's cells. The major component corresponds to the normal PGK mRNA except for A - C change at nucleotide position 755 counting from adenine of the chain initiation codon. The minor component contains 5' region (52 bases) of intron 7 between exon 7 and exon 8. An inframe chain termination codon exists in the minor mRNA component, and the COOH-terminal half is expected to be deleted in the translation product. These results indicate that the low PGK activity in the patient's tissues is mainly due to retarded and aberrant pre-mRNA splicings caused by the change of the consensus 5' splice sequence AGgt to a nonconsensus sequence CGgt at the junction between exon 7 and intron 7 of the variant gene.

Adolescent↗
PubMed1996

Discovery of the hemifumarate and (alpha-L-alanyloxy)methyl ether as prodrugs of an antirheumatic oxindole: prodrugs for the enolic OH group.

Ether, ester, and carbonate derivatives of the antirheumatic oxindole 1 were prepared and screened as potential prodrugs of 1. This effort led to the discovery of the (alpha-L-alanyloxy)-methyl ether and hemifumarate derivatives of 1 which deliver the drug efficiently into the circulation of test animals, are stable in the solid state, and possess good stability in solution at low pH as required to ensure gastric stability. Success in achieving acceptable bioavailabilities of 1 across species (rats, dogs, and monkeys) followed the inclusion of ionizable functionality within the promoiety to compensate for masking the polar enolic OH group of the free drug. However, the introduction of ionizable functionality was often associated with decreased stability, as demonstrated by the hemisuccinate, hemiadipate, hemisuberate, and alpha-amino ester derivatives of 1 which could not be isolated. A clear exception was the hemifumarate derivative of 1 which was not only isolable but actually more stable at neutral pH than the nonionizable ester analogues. The solution and solid state stability of the hemifumarate, together with its activity as a prodrug of 1, suggests that hemifumarate be considered as an alternative to hemisuccinate as a prodrug derivative for alcohols, particularly in situations where solution state stability is an issue.

Animals↗
PubMed1996

Beta-amyloid precursor protein and early-onset Alzheimer's disease.

One of the major pathological hallmarks of Alzheimer's disease is the deposition in the brain parenchyma and cerebral blood vessel walls of amyloid beta-protein, a 4kDa proteolytic product of the longer beta-amyloid precursor protein (APP). Six different single base mutations in the APP gene have been reported causing early-onset Alzheimer's disease (age at onset < or = 65 years) or related amyloidosis in a small number of families. Cell transfection experiments using wild-type and mutant APP cDNA indicated that APP mutations result in the production of more or longer, aggregation prone, A beta peptides.

Alzheimer Disease↗
PubMed1996

Molecular genetic analysis of the 17p11.2 region in patients with hereditary neuropathy with liability to pressure palsies (HNPP).

Hereditary neuropathy with liability to pressure palsies (HNPP) is in most cases associated with an interstitial deletion of the same 1.5-Mb region at 17p11.2 that is duplicated in Charcot-Marie-Tooth type 1A (CMT1A) patients. Unequal crossing-over following misalignment at flanking repeat sequences (CMT1A-REP), either leads to tandem duplication in CMT1A patients or deletion in HNPP patients. With the use of polymorphic DNA markers located within the CMT1A/HNPP duplication/deletion region we detected the HNPP deletion in 16 unrelated HNPP patients, 11 of Belgian and 5 of French origin. In all cases, the 1.5-Mb size of the HNPP deletion was confirmed by EcoRI dosage analysis using a CMT1A-REP probe. In the 16 HNPP patients, the same 370/320-kb EagI deletion-junction fragments were detected with pulsed field gel electrophoresis (PFGE), while in CMT1A patients, a 150-kb EagI duplication-junction fragment was seen. Thus, PFGE analysis of EagI-digested DNA with a CMT1A-REP probe allows direct detection of the HNPP deletion or the CMT1A duplication for DNA diagnostic purposes.

Blotting, Southern↗
PubMed1996

Malignant hyperthermia susceptibility in a patient with concomitant motor neuron disease.

Laboratory confirmation of a clinical suspicion of malignant hyperthermia (MH) susceptibility by the standard in vitro contracture test remains inconclusive in patients reacting only to caffeine or halothane (called 'Equivocal') or in patients with concomitant neuromuscular disease. The detection of point mutations in the ryanodine receptor gene potentially provides additional information in these cases. The diagnostic value of the Gly341 Arg mutation in a patient reacting in vitro only to caffeine was reported previously by Quane et al. (1994). The present report describes a patient with motor neuron disease carrying the Gly341 Arg mutation, expanding the diagnostic value of this mutation to the group of patients with neuromuscular diseases.

Adolescent↗
PubMed1996

Tuberculous meningitis in immunocompetent adults: two cases with a clinico-radiological discussion.

In developed countries with a low incidence of tuberculosis, infection with Mycobacterium tuberculosis is easily overlooked as the cause of meningitis in an immunocompetent adult. Two cases are presented, with emphasis on the main reasons for delay of diagnosis. Neuroradiology revealed a progressive hypertrophic basal meningitis. The clinical and radiological outcome was good after tuberculostatic and corticosteroid treatment.

Adult↗
PubMed1996

Distal hereditary motor neuropathy type II (distal HMN II): mapping of a locus to chromosome 12q24.

The distal hereditary motor neuropathy (distal HMN) or the spinal form of Charcot-Marie-Tooth (CMT) disease is an exclusively motor disorder of the peripheral nervous system. The disorder clinically resembles the hereditary motor and sensory neuropathies (HMSN) type I and type II or CMT type 1 and type 2. Distal HMN might also be related to the spinal muscular atrophies (SMA) since, in both disorders, the lower motor neurons are affected. Electrophysiological and neuropathological examinations of peripheral nerves show the absence of sensory involvement. We performed a genome search in an extended Belgian family with autosomal dominant distal HMN type II. Significant linkage was obtained with markers located at chromosome 12q24, and the gene for distal HMN II was assigned to the 13 cM interval between D12S86 and D12S340.

Adolescent↗
PubMed1996

Pure familial spastic paraplegia: clinical and genetic analysis of nine Belgian pedigrees.

We ascertained 9 multigeneration Belgian families with pure dominant spastic paraplegia (SPG) for clinical and genetic studies. Linkage was examined using simple tandem repeat (STR) markers located near the 5 loci for familial SPG on chromosomes Xq28 (SPG1), Xq21.3-q22 (SPG2), 2p21-p24 (SPG4), 14q12-q23 (SPG3) and 15q11.1 (SPG6). Positive linkage results were obtained only for markers at the SPG4 locus mapping the SPG4 gene between D2S400 and D2S367, a region of 4 cM. In order to facilitate the positional cloning of the SPG4 gene, we constructed a contiguous YAC map covering the SPG4 candidate region. Our physical mapping data indicate that the SPG4 gene resides within maximal 5 Mb.

Belgium↗
PubMed1996

Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13.

A locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2A) was assigned by linkage analysis to chromosome 1p35-p36. We examined 11 unrelated CMT2 families for linkage to CMT2A using short tandem repeat (STR) polymorphisms. Only one family showed suggestive evidence for linkage to 1p35-p36. Further, because of an overlap in electrophysiologic data between CMT2 and CMTX female patients, we screened 6 of 11 CMT2 families compatible with dominant X-linkage for mutations in the connexin 32 (Cx32) gene at Xq13. There was a Cx32 mutation in one family, whereas another family showed suggestive evidence for Xq13 linkage upon analysis with STR polymorphisms. Our results suggest that the CMT2A locus is a minor locus for CMT2, additional linkage studies are needed to localize other CMT2 loci, and Cx32 mutations may be the underlying genetic defect in some CMT2 families.

Amino Acid Sequence↗
PubMed1996

Parinaud's syndrome in a patient with multifocal glioma.

We describe the clinical and neuroradiological findings in a 63-year-old man with Parinaud's syndrome. Magnetic resonance (MR) imaging showed a mass lesion within the quadrigeminal plate. Additional MR findings included a right frontoparietal subcortical lesion as well as periventricular white matter edema due to acute deterioration of hydrocephalus. On MR, the diagnosis of multifocal glioma was proposed. Neuropathological examination after resection of the supratentorial lesion revealed an oligodendroglioma, grade II.

Brain Neoplasms↗
PubMed1996

Sporadic early adult-onset distal myopathy with rimmed vacuoles: immunohistochemistry and electron microscopy.

We report the histoenzymology, immunohistochemistry and electron microscopy of the tibialis anterior muscle of a 50-year-old male patient affected by a sporadic distal myopathy with onset during adolescence. There was no family history of muscle disorder and no clinical signs of cardiomyopathy. Extremely large variations in muscle fibre diameter (the size of some fibres exceeding 200-250 microns), rimmed vacuoles, necrotic fibres invaded by macrophages, atrophic fibres and perimysial fibrosis were observed. Using a wide range of antibodies raised against membrane- and cytoskeletal muscle proteins, granular desmin immunoreactivity was observed in muscle fibre lesions. There were no inflammatory parameters. Of special interest was the occurrence of autophagic vacuoles without 18-20 nm thick sarcoplasmic filaments and the presence of small aggregates of intermediate desmin-like filaments among a great diversity of ultrastructural findings. The morphological differential diagnosis is discussed. Our results stress the importance of combined immunohistochemistry and electron microscopy in the delineation of distal myopathies. DNA defects, however, still have to be identified which would improve the present classifications of distal myopathies.

Cytoskeletal Proteins↗
PubMed1996

Hereditary disorders of the nervous system from anatomo-clinical studies to molecular biology.

Hereditary disorders of the nervous system have been defined in the past by their main clinical and neuropathological features. The genetic approach has evolved from the traditional collection of pedigrees to molecular biology techniques which nowadays identify the responsible genes, recognize their defects and describe the gene products. We illustrate these changes by a few examples from the group of spinocerebellar atrophies, hereditary motor and sensory neuropathies and Alzheimer's disease. Modern neurology has found in molecular biology an extremely powerful tool to study the hereditary disorders of the nervous system.

Alzheimer Disease↗
PubMed1996

Localization of merosin in the normal human brain: implications for congenital muscular dystrophy with merosin deficiency.

A particular form of congenital muscular dystrophy with merosin deficiency has recently been described. Magnetic resonance imaging has shown that affected children show brain abnormalities. We investigate the localization of merosin in the normal human brain by immunohistochemistry. Other organs, such as the kidney, lung and liver, were also included in this study. We show that in the normal central nervous system merosin is localized in the basement membrane of blood vessels. No expression of merosin was found at the level of the liver and lungs, whereas the glomerular mesangial matrix of the kidney was intensely positive. These results suggest that merosin deficiency in the basement membrane of blood vessels in the central nervous system could play an important role in the physiopathology of brain abnormalities found in children affected by the congenital muscular dystrophy associated with merosin deficiency. Furthermore, the potential absence of merosin in the glomerular mesangial matrix of the kidney suggests a multi-system involvement.

Adult↗
PubMed1996

Thyrotoxic periodic paralysis, an unusual cause of hypokalemic periodic paralysis.

Over a two-year period two patients were admitted to the hospital with episodes of paralysis and hypokalemia. In the first patient, familial hypokalemic periodic paralysis was initially suspected. Only several months later was Graves' disease diagnosed and this diagnosis linked to thyrotoxic periodic paralysis. The second patient came to notice after treatment with thyreostatic drugs was stopped prematurely and paralysis together with hypokalemia developed. Thyrotoxic periodic paralysis, being rare outside Asia, closely mimics the clinical presentation of familial hypokalemic periodic paralysis. Mainly men in the third decade with a negative family history are affected. Graves' disease is the most common cause of hyperthyroidism. This disorder is not always clinically apparent since signs of hyperthyroidism may be easily missed. Therefore thyroid function tests are part of the diagnostic workup of hypokalemic periodic paralysis. Correction of thyroid function is essential to treatment. The pathophysiology is still controversial.

Antithyroid Agents↗