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B A Kakulas

Publications and source records attributed to B A Kakulas.

At least 37 records · Page 2Linked to original sources
PubMed1998

Age-related congophilic inclusions in the brains of apolipoprotein E-deficient mice.

The hippocampal region of apolipoprotein E-deficient mice of varying ages was examined for any morphological changes by light and electron microscopy. Unusual periodic acid-Schiff-positive granules were seen in the hippocampal area of these animals as early as the fourth week of life and their numbers increased gradually with age. These granules were never found in control C57BL/6J (B6) mice before six months-of-age and their numbers were invariable low. They were strongly congophilic when stained with a modified Congo Red technique and reacted with a monoclonal antibody specific to amino acids 17-24 and 35-43 of the beta-amyloid peptide. The immunostaining of these granules with the beta-amyloid peptide was lost after specific adsorption with the appropriate synthetic peptide. These granules were identified ultrastructurally as non-membrane-bound fibrillogranular material in the cytoplasm of protoplasmic astrocytes. The data indicate that an amyloid-like protein accumulates in the protoplasmic astrocytes of the hippocampus of apolipoprotein E-deficient mice, especially in the brains of old animals.

Aging↗
PubMed1998

Arthrogryposis multiplex congenita in Western Australia.

OBJECTIVE: Determination of the prevalence of arthrogryposis multiplex congenita in Western Australia as well as the causes of the condition. Overseas reports varied considerably and no such survey had been conducted in Western Australia. METHODOLOGY: Case names were obtained from various registers and records as well as from private practitioners covering the 14 years birth cohort between 1980 and 1993. The records, and where possible the patients, were seen by one of the authors. Diagnosis was further established through relevant investigation where possible. RESULTS: Thirty cases were identified, giving a birth prevalence of approximately 1 in 12000. In nine cases there were significant abnormalities of the central nervous system, in seven cases anterior horn cell and/or peripheral nervous involvement was the cause and in three there was primary muscle disease. The remaining 11 had various syndromes for which no definite neuropathological lesions could be demonstrated, but most of these had syndromes such as distal arthrogryposis or amyoplasia. Mortality was 37%. Talipes occurred in 23 of 30 cases. Early intervention and, in more severe cases, radical surgical intervention was the management adopted in most cases. CONCLUSION: The birth prevalence of arthrogryposis in Western Australia is somewhat less than that reported in Canada and Finland but somewhat greater than the Edinburgh figures, which appear to be the extremes quoted in the literature. Prognosis is worse in cases with serious central nervous system involvement and/or chest involvement, and better in cases of localised arthrogryposis (e.g. distal), as well as in the specific syndrome of amyoplasia as described by Hall.

Arthrogryposis↗
PubMed1998

Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation.

A two generation family of Greek origin with mild myotonia, predominantly proximal muscle weakness, and cataracts compatible with the syndrome of proximal myotonic myopathy, is reported. In addition, brain MRI showed a diffuse leukoencephalopathy in the propositus. Molecular genetic studies showed the R894X mutation in exon 23 of the muscle chloride channel gene in the propositus but in only one of her two clinically affected offspring, indicating that it is not the mutation causing disease in this family.

Abnormalities, Multiple↗
PubMed1997

Problems and potential for gene therapy in Duchenne muscular dystrophy.

Hopes ran high that a cure for Duchenne muscular dystrophy (DMD) would quickly follow the discovery of dystrophin by Lou Kunkel and his group in the 1980's. Myoblast transplantation, the favoured method of gene 'complementation', unfortunately did not progress beyond the experimental stage. A more sober approach to gene therapy followed using a variety of transfection or direct methods to introduce the normal gene. In view of these advances it is timely for the potential of gene therapy for DMD to be considered in the light of the disease process. It may be assumed that if dystrophin is replaced muscle fibre necrosis will cease. For this purpose expression of the gene should be continuous and expressed throughout the body well before there are irreversible changes. It would seem that gene therapy would not be particularly helpful if this occurs when the muscle lesions are near the end stage. If our objective is to retain ambulation dystrophin must be replaced well before the end stage. It should be kept in mind that even when the disorder first becomes clinically apparent at the age of about 5 years, muscle lesions are very advanced in the limb girdle groups. Therefore, the best that may be hoped to achieve by gene therapy at the age of 5 years would be to arrest the process at that stage of involvement with the patient having permanent but static weakness. Cardiac lesions are probably minimal at this time. To improve life expectancy, the respiratory muscles would need to be preserved. The enormous size of the gene is another difficulty so that some thought has been given to the introduction of a 'minigene' converting the clinical phenotype from DMD to the more benign Becker phenotype with improved life expectancy.

Dystrophin↗
PubMed1997

Use of the dog model for Duchenne muscular dystrophy in gene therapy trials.

Golden retriever muscular dystrophy (GRMD) is an excellent model for the study of the efficacy of gene therapy in dystrophin deficient myopathies for there are many similarities between affected dogs and Duchenne muscular dystrophy (DMD) in boys. GRMD is not caused by deletion mutation but results from a point mutation in the consensus splice acceptor in intron 6 of the canine dystrophin gene. As a result exon 7 is skipped during processing of the GRMD dystrophin messenger RNA. We have developed a rapid test which makes direct use of exon 7 specific genomic PCR products. We have undertaken preliminary experiments on gene therapy using the mini-gene and the full length gene alone and in combination with lipofectin and/or the bacterial beta-galactosidase reporter gene Lac Z. Following direct injection of the Lac Z plasmid, either alone or with lipofectin, about 50% of the sites showed expression when biopsied some 14 days later. The beta-galactosidase activity was present in muscle and granulation tissue but was never abundant. Pups injected intraperitoneally with Lac Z were found to have positive material in their mesenteric lymph nodes, liver and spleen. Those injected with Lac Z and lipofectin also had positive material in the diaphragm, intercostal muscles and abdominal muscles, but again only a small amount of positive material was present at any of the sites. In animals directly injected into the muscle with the dystrophin mini-gene, half had positive staining for dystrophin in biopsies taken 14 days later. Of the 6 sites in the muscles of animals given the mini-gene and lipofectin only one had fibres positive for dystrophin when examined 14 days later. Six pups were injected directly with full-length gene construct and when biopsies were taken 10 days later two of the animals had strongly stained peripheries to a small number of fibres.

Adenoviridae↗
PubMed1997

Neuropathology of human spinal cord injury sustained in sports-related activities.

The neuropathology of 20 cases of traumatic human spinal injury is described. Cases were classified as having "complete" or "incomplete" spinal cord injuries based upon the neuropathological findings. Special attention was directed to those cases with neuropathological evidence of continuity of long tract axons across the lesion but that were obtained from individuals with clinically complete sensory and motor loss. Clinical and neuropathological data were obtained from the Western Australian Spinal Cord Injury Database and were selected from those cases involving sports-related injuries. From the total of 20 cases of spinal injury, 6 exhibited neuropathologically and clinically complete cord injuries, 4 were neuropathologically incomplete yet clinically complete, and 4 were neuropathologically and clinically incomplete (one being motor complete yet sensory incomplete). The clinical/neuropathological correlation was indeterminate in 6 cases because of death at or shortly after the accident. The neuropathological findings varied with the severity of trauma and the length of survival. In those cases examined less than 3 months postinjury, there was typically swelling of the cord from vasogenic edema with petechial hemorrhage and myelomalacia. Central hemorrhagic necrosis was common as was hyperemia with free red cells present among disrupted tissue. Activated astrocytes and polymorphs or macrophages were observed and early stages of glial cell scar formation were evident. Wallerian degeneration was evident in motor tracts caudal to the level of insult and in sensory tracts rostral to the lesion. Cases examined 3-6 months postinjury often revealed multilocular cysts with gliotic walls often extending several millimeters above and below the primary locus of injury. In the "chronic" cases (i.e., those surviving more than 6 months), there was evidence of varying degrees of preserved long tract parenchyma, nerve root regeneration, and Schwann cell remyelination of long tract axons. The degree of sparing of long motor and sensory tract parenchyma generally correlated well with the clinical observations of residual function. In four cases, however, there was a residuum of motor or sensory tract axons that appeared to have been spared injury, but the clinical data reported chronically complete sensory and motor loss. The presence of clinically complete yet neuropathologically incomplete injury was more often associated with crush or flexion injuries than with extension or compression trauma. The preserved parenchyma in these types of lesion may provide the anatomical substrate for restorative intervention.

Accidental Falls↗
PubMed1997

Beta-amyloid protein-containing inclusions in skeletal muscle of apolipoprotein-E-deficient mice.

The tibialis anterior muscle and soleus muscle of apolipoprotein-E-deficient mice were examined by light and electron microscopy. By light microscopy, sarcoplasmic inclusions were seen in tibialis anterior muscle and 40% of type 2 myofibers were affected in all animals over 8 months of age. These inclusions reacted for nonspecific esterase, cytochrome oxidase, and myoadenylate deaminase and were also periodic acid Schiff positive and stained basophilic with hematoxylin. Moreover, they reacted immunocytochemically with an antibody specific to fragment 17 to 24 of the published sequence of Alzheimer's cerebrovascular amyloid peptide. Immunoreactivity was lost when the antibody was adsorbed with the appropriate synthetic peptide. Ultrastructurally, the inclusions consisted of tubular arrays and were similar to those observed in human muscle in several pathological conditions. In type 1 myofibers of both tibialis anterior and soleus muscle, however, mitochondrial abnormalities including an increase in their number and size were detected, but tubular aggregates were not seen. These large mitochondria possessed an electron-dense inner chamber with an increased number of tightly packed cristae. The results obtained suggest that in these mice there is a disturbed lipid metabolism in skeletal muscle fibers that manifests itself with an accumulation of phospholipid in the form of sarcoplasmic reticulum tubules in the type 2 fibers and enlarged mitochondria with tightly packed cristae in the type 1 fibers. In addition, beta-amyloid protein was closely associated with the accumulated tubules and vesicles of sarcoplasmic reticulum and may represent dysregulation of amyloid precursor protein metabolism.

Amyloid beta-Protein Precursor↗
PubMed1996

Alzheimer's disease and apolipoprotein E genotype in Western Australia: an autopsy-verified series.

OBJECTIVE: To determine the relationship between the apolipoprotein E epsilon 4 allele and autopsy-verified Alzheimer's disease (AD) in an Australian population. DESIGN: Retrospective case-control study. SETTING: Royal Perth Hospital, Perth, Western Australia (a tertiary referral hospital). SUBJECTS: 50 subjects with "definite" AD (according to the histological and clinical criteria of the Consortium to Establish a Registry for Alzheimer's Disease [CERAD]) and 30 control subjects who had died from a non-neurological disease were randomly selected from the hospital's neuropathology register. OUTCOME MEASURES: Histological grading of brain sections stained with the modified Bielschowsky stain according to the criteria of CERAD; number (burden) of neuritic plaques; apolipoprotein E genotype (APOE). RESULTS: Frequency of the epsilon 4 allele was significantly higher in the AD group (37%) than in the control group (2%) (chi 2 = 25.8; P < 0.00001). In the AD group, 50% of subjects were heterozygous for the epsilon 4 allele and 12% were homozygous, while in the control group one subject was heterozygous for the allele and none were homozygous. No association was seen between the epsilon 4 allele and neuritic plaque burden in the hippocampus, entorhinal cortex, middle frontal gyrus or inferior parietal lobule in subjects with AD. CONCLUSIONS: Our findings confirm an association between the epsilon 4 allele and autopsy-verified AD. The epsilon 4 allele may be an important risk factor for susceptibility to AD in the general Australian population.

Aged↗
PubMed1996

The differential diagnosis of the human dystrophinopathies and related disorders.

In addition to the now well recognized dystrophinopathies, recent investigation of the dystrophin-associated proteins has revealed a new group of disorders referred to as the 'sarcoglycanopathies'. These autosomal recessive muscle diseases are results of mutations of alpha-, beta-, or gamma-sarcoglycans and may be severe (Duchenne muscular dystrophy-like) or mild (limb girdle muscular dystrophy) depending upon whether there is a 'null' mutation with no gene product formed or a 'missense' mutation in which reduced amounts of the protein product are made. The relationship between the severe Duchenne muscular dystrophy-like phenotype and the milder limb girdle muscular dystrophy phenotype is therefore similar to that of Duchenne muscular dystrophy to Becker muscular dystrophy, where there is absence of dystrophin in Duchenne muscular dystrophy and reduced amounts in Becker muscular dystrophy. Not all of the limb girdle muscular dystrophies have been identified in molecular terms and, as yet, no disorder has been associated with mutations of the syntrophin or the dystroglycan genes. Nevertheless, progress in this field has been so rapid and of such practical importance that the clinical neurologist should become aware of these developments.

Diagnosis, Differential↗
PubMed1995

Minicores and congential fibre type disproportion observed in a family.

OBJECTIVE: To report a family in which congenital fibre type disproportion (CFTD) and minicore disease have been observed in members of the same family, and raise the question of the relationship between CFTD and minicores. METHODOLOGY: A follow-up clinical and biopsy study of a girl who presented to hospital because of marked hypotonia and non-progressive weakness. She had muscle biopsies at the age of 18 months and again at 4 1/2 years. Her asymptomatic parents were also biopsied. The muscle specimens were processed for histopathological and morphometric studies. RESULTS: The histopathological findings of the muscle of the daughter were consistent with CFTD. The muscle biopsy of her father was normal whereas her mother's revealed minicore formation. CONCLUSIONS: The findings of CFTD and minicore disease in members of the same family suggest that CFTD and minicore formation may both be the result of a common pathological mechanism rather than each being a distinct clinicopathological entity.

Biopsy↗
PubMed1995

Autosomal dominant distal myopathy: linkage to chromosome 14.

We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64--the family structure precludes a two-point LOD score > or = 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity.

Adolescent↗
PubMed1994

Identification of a point mutation and germinal mosaicism in a Duchenne muscular dystrophy family.

Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked disorders arising from mutations in the (2.4 Mb) dystrophin gene at Xp21. We have applied the reverse transcriptase-polymerase chain reaction (RT-PCR) to identify a larger than normal dystrophin mRNA from a male with Duchenne muscular dystrophy and his younger affected brother. The increased size of the dystrophin mRNA was due to a splice-site mutation at the exon 26:intron 26 junction where a T to G substitution prevented normal RNA processing. A cryptic splice-site, downstream of the mutation, was activated during processing, resulting in the inclusion of 117 bases of intron 26. This insertion introduced an in-frame stop codon into the mature dystrophin mRNA. An allele-specific test was developed to identify the mutation and was applied to this family. Interestingly, the mother of the two affected boys did not carry the mutation, as determined by allele-specific amplification and direct DNA sequence analysis, indicating gonadal mosaicism. Her eldest daughter, designated as a carrier based upon conventional testing and haplotype analysis, also did not carry the family mutation. Initial haplotyping of the family appeared to be straightforward with gonadal mosaicism becoming evident only after allele-specific analysis. The application of linked markers to identify the disease allele for conventional genetic counselling would have been erroneous in this family and highlights the diagnostic power of precise identification of the disease-causing mutation.

Alleles↗