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Biomedical subjects

R H King

Publications and source records attributed to R H King.

At least 19 recordsLinked to original sources
PubMed2001

Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A, a hereditary demyelinating neuropathy, is usually caused by overexpression of peripheral myelin protein 22 (PMP22) due to a genomic duplication. We have generated a transgenic mouse model in which mouse pmp22 overexpression can be regulated. In this mouse model, overexpression of pmp22 occurs specifically in Schwann cells of the peripheral nerve and is switched off when the mice are fed tetracycline. Overexpression of pmp22 throughout life (in the absence of tetracycline) causes demyelination. In contrast, myelination is nearly normal when pmp22 overexpression is switched off throughout life by feeding the mice tetracycline. When overexpression of pmp22 is switched off in adult mice, correction begins within 1 week and myelination is well advanced by 3 months (although the myelin sheaths are still thinner than normal), indicating that the Schwann cells are poised to start myelination. Upregulation of the gene in adult mice (which had previously had normal pmp22 expression) is followed by active demyelination within 1 week, which had plateaued by 8 weeks. This indicates that Schwann cells with mature myelin are sensitive to increased amounts of pmp22 such that they rapidly demyelinate. Thus, demyelination can largely be corrected within a few months, but the correction will be sensitive to subsequent upregulation of pmp22.

Animals↗
PubMed2001

Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies.

A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy-Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q.

Adolescent↗
PubMed2001

Inherited early onset severe axonal polyneuropathy with respiratory failure and autonomic involvement.

We report dizygotic twins who first presented at the age of 6 months with severe diaphragmatic weakness and marked abnormalities of autonomic function. A female sibling had earlier died from a disorder with similar clinical features. Both twins had a severe axonal polyneuropathy with generalized hypotonic limb weakness together with diaphragmatic paralysis resulting in respiratory failure. Associated features were tachycardia, increased sweating, elevated body temperature, and hypertension, suggesting autonomic dysfunction. Nerve conduction studies indicated an axonopathy affecting both motor and sensory nerve fibres. Sural nerve biopsy in one twin performed at the age of 7 months showed a reduced population of myelinated nerve fibres, particularly those of larger diameter, with no indication of hypomyelination, demyelination or axonal atrophy. Examples of axonal forms of hereditary motor and sensory neuropathy (HMSN) with onset in infancy are very rare and autonomic involvement associated with this condition has not so far been described.

Age of Onset↗
PubMed2001

Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin.

Focally folded myelin has been recognized as a distinctive feature in some individuals with severe inherited demyelinating neuropathy, with an onset in childhood. Such cases have been shown to be genetically heterogeneous. Alterations in the myotubularin-related protein 2 (MTMR2) gene on chromosome 11q22 have recently been shown to give rise to this phenotype. Mutations have been identified in the 3' region of the MTMR2 gene in four unrelated families, in two of whom the disorder had been mapped to chromosome 11q22 by genetic linkage analysis. We have sequenced the entire coding region and flanking intronic regions of the MTMR2 gene in eight families with early onset autosomal recessive neuropathies. Two novel mutations were identified in exon 4 at the 5' end of the MTMR2 gene in an English and an Indian family. The clinical phenotype and sural nerve pathology in these two families differs in severity, with the proband in the English family having an earlier onset and more severe neuropathy with prominent cranial nerve involvement. This is probably due to mutation type and possible involvement of small nucleotide polymorphisms in phenotype modulation. Detailed sural nerve pathology is presented in both cases. Mutations in the MTMR2 gene are thus an important cause of autosomal recessive demyelinating neuropathy. Identifying further mutations and defining their phenotype will help to clarify the genetic classification of this group of disorders.

5' Untranslated Regions↗
PubMed2001

A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.

A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high-affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic.

Biopsy↗
PubMed2001

The role of glycation in the pathogenesis of diabetic polyneuropathy.

The most common neuropathy associated with diabetes mellitus is a distal sensory polyneuropathy. The relative importance of the direct effects of prolonged glycaemia on nervous tissue compared with indirect damage resulting from changes in blood vessels is not known. Although the importance of glycaemia is confirmed by a study showing that the incidence of neuropathy is greatly reduced by strict glycaemic control, many of the details of the deleterious effects of glycaemia on the peripheral nervous system (PNS) are not understood. These may be the result of direct damage to any of the cells in the PNS or the disruption of neuronal metabolism, axonal transport mechanisms, or repair capabilities; in addition, they may result from the effects of glycation on PNS connective tissue or a combination of some or all of the above mentioned mechanisms. The relative importance of these various mechanisms by which diabetes damages the PNS is a matter of conjecture. Therapeutic approaches targeting a specific mechanism such as those utilising aldose reductase inhibitors, or advanced glycation endproduct inhibitors have met with limited success. Clearly, it is difficult to design a treatment for diabetic neuropathy while its pathogenesis is still poorly understood.

Animals↗
PubMed2000

N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom.

Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused research on the mechanisms of early development, cell differentiation, and cell-cell interactions in the peripheral nervous system. Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT, and understanding their molecular basis may provide a new perspective on these mechanisms. Here we report the identification of the gene responsible for hereditary motor and sensory neuropathy-Lom (HMSNL). HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon-glia interactions play a major role in its pathogenesis. The gene was previously mapped to 8q24.3, where conserved disease haplotypes suggested genetic homogeneity and a single founder mutation. We have reduced the HMSNL interval to 200 kb and have characterized it by means of large-scale genomic sequencing. Sequence analysis of two genes located in the critical region identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1). NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. We have studied expression in peripheral nerve and have detected particularly high levels in the Schwann cell. Taken together, these findings point to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann-cell signaling necessary for axonal survival.

Amino Acid Motifs↗
PubMed2000

The extracellular matrix of peripheral nerve in diabetic polyneuropathy.

The pattern of collagenisation in peripheral nerve in diabetic polyneuropathy was examined in nerve biopsy specimens from patients with diabetic polyneuropathy in comparison with organ donor control nerves and disease controls (other neuropathies). There was increased endoneurial collagenisation both in the diabetic polyneuropathy cases and the disease controls, this predominantly involving types I and III. Type II collagen was not detected in organ donor control nerves or in the diabetic and the disease control nerves. There was a relative increase in type VI collagen in the endoneurium in the diabetic nerves immediately surrounding groups of Schwann cells. This was not a feature in the other neuropathies. The quantity of types IV, V and VI collagen was increased around the endoneurial microvessels in the diabetic patients and, to a lesser extent, in those with hereditary motor and sensory neuropathy (HMSN). Increased deposition of types IV and V collagen was observed in the perineurium in the diabetic nerves, the latter being most evident in the innermost lamellae where the amount of laminin was possibly also increased. The diameter of the general endoneurial collagen fibrils was greater in the diabetic nerves, although this was not more than in a disease control (HMSN). The collagen fibrils that were present within the basal laminal tubes that had surrounded degenerated myelinated fibres in the diabetic nerves, and those within the onion bulbs of the HMSN cases, were of the normal endoneurial calibre. The expression of laminin by Büngner bands in diabetic neuropathy did not differ from that in disease control nerves, nor were any differences detected for fibronectin. Whether the changes observed are important for the impaired regenerative capacity in diabetic neuropathy requires further investigation.

Adult↗
PubMed2000

Hereditary motor and sensory neuropathy--Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries.

Hereditary motor and sensory neuropathy type Lom, initially identified in Roma (Gypsy) families from Bulgaria, has been mapped to 8q24. Further refined mapping of the region has been undertaken on DNA from patients diagnosed across Europe. The refined map consists of 25 microsatellite markers over approximately 3 cM. In this collaborative study we have identified a number of historical recombinations resulting from the spread of the hereditary motor and sensory neuropathy type Lom gene through Europe with the migration and isolation of Gypsy groups. Recombination mapping and the minimal region of homozygosity reduced the original 3 cM hereditary motor and sensory neuropathy type Lom region to a critical interval of about 200 kb.

Adolescent↗
PubMed2000

Hereditary motor and sensory neuropathy-Lom (HMSNL) in a Spanish family: clinical, electrophysiological, pathological and genetic studies.

The clinical, electrophysiological, pathological and genetic findings are described in the first Spanish family diagnosed with hereditary motor and sensory neuropathy type Lom (HMSNL) initially identified by Kalaydjeva et al. in 1996. The three affected patients belong to a non-consanguineous family with Gypsy background that were followed up over 10 years. Serial clinical and neurophysiological examinations and genetic analysis were undertaken in every patient. Sural nerve biopsy was performed in the oldest patient. The clinical features are similar to those previously described in HMSNL and all of them showed abnormal brain auditory evoked potentials. The oldest brother developed sensorineural deafness at the age of 20. Conduction velocities were unobtainable in all patients and nerves tested except for the median nerve in the youngest child in whom conduction was severely slowed. Neuropathological examination revealed a severely depleted nerve with very few surviving myelinated fibers which possessed thin myelin sheaths. Schwann cell processes were arranged in circular configurations without typical onion bulb configuration. Genetic analysis showed that the maternal chromosome inherited by all three affected siblings displayed a very unusual haplotype. Our patients show the characteristic clinical, electrophysiological and pathological findings described in HMSNL and represent the first reported Spanish family affected from the disease. The genetic findings in this family have contributed to refine the HMSNL critical linkage region.

Adolescent↗
PubMed2000

Hypertrophic perineurial dysplasia in multifocal and generalized peripheral neuropathies.

Two cases are described, one with a multifocal cranial and limb neuropathy of adult onset associated with optic neuropathy, and the other with a diffuse demyelinating neuropathy characterized by congenital cataract, mental retardation and progressive lower limb paresis with an onset in childhood. Extensive investigation in both failed to establish the causation. No family history of similar disorder was obtained in either case. Nerve biopsy in both showed similar perineurial abnormalities, the endoneurium being compartmentalized by hypertrophic perineurial cells that exhibited dysplastic features. The appearances resemble those described in a previously reported case of multifocal neuropathy and probably represent an unusual but non-specific response to a peripheral neuropathy.

Adolescent↗
PubMed2000

Neurological manifestations in chronic mountain sickness: the burning feet-burning hands syndrome.

OBJECTIVE: To characterise the clinical features and nerve biopsy findings in patients with chronic mountain sickness (CMS) living in the Peruvian Andes, with particular attention to the occurrence of the "burning feet-burning hands" syndrome. METHODS: Symptoms and signs were documented clinically in 10 patients with CMS and compared with those in five healthy subjects all living at 4338 metres altitude. Sural nerve biopsies were obtained from three patients with CMS. The nerve fibre population and endoneurial microvessels were analyzed morphometrically. RESULTS: All patients with CMS experienced burning and tingling paraesthesiae in the distal parts of their limbs. Similar but milder symptoms confined to the feet occurred in four of five controls. Three patients with CMS had a mild sensory neuropathy on examination, controls were clinically normal. Nerve biopsies showed a mild demyelinating neuropathy in all three with a reduction in the unmyelinated axon population in one. The endoneurial blood vessels showed a reduced thickness in the basal laminal zone compared with control values but were otherwise normal. CONCLUSIONS: Apart from well recognised symptoms and signs of CMS, the study has shown that such patients may also exhibit a mild sensory neuropathy. Its relation to the burning feet-burning hands syndrome, which was not confined to the patients but was also found in controls at altitude, is uncertain. The time course and pattern of the centrifugal resolution of the burning paraesthesiae complex on low altitude sojourn of high altitude natives raises the possibility that a mechanism involving altered axonal transport may be involved. The reduced thickness of the basal laminal zone of microvessels implies that adaptive structural changes to hypobaric hypoxia may also occur in peripheral nerve and are similar to those reported in other tissues of high altitude natives.

Aged↗
PubMed2000

Interrelationships between dietary lysine, sex, and porcine somatotropin administration on growth performance and protein deposition in pigs between 80 and 120 kg live weight.

Sixty male and 60 female crossbred pigs were allocated to an experiment to investigate the effects of porcine somatotropin (pST) administration (0 or 6 mg/d) and dietary lysine content on growth performance, tissue deposition, and carcass characteristics over the live weight range of 80 to 120 kg. Pigs receiving pST were given diets containing 6.9, 7.8, 8.8, 9.7, 10.6, or 11.5 g lysine/kg, whereas control pigs received diets containing 4.8, 5.8, 6.9, 7.8, 8.8 or 9.7 g lysine/kg. These dietary levels ranged from 0.40 to 0.70 g available lysine/MJ of DE for pST-treated pigs and from 0.28 to 0.58 g available lysine/MJ of DE for control pigs. Pigs were individually housed in pens, and there were five replicates of each treatment. All diets contained 14.5 MJ of DE/kg and were offered for ad libitum consumption to pigs between 80 and 120 kg live weight. Growth rate increased exponentially and food conversion ratio (FCR) decreased exponentially with increasing levels of lysine. In addition, there was a significant sex x pST interaction such that pST reduced the sex difference in FCR. Growth rate was faster in boars than in gilts and was increased by pST at the higher levels of dietary lysine. Similarly, FCR was lower for boars than for gilts and was decreased by pST at the higher dietary lysine levels. The optimum growth rate and FCR were defined as the lysine level at which growth rate and FCR were 95% and 105%, respectively, of the lysine plateau. The optimum growth rate and FCR were achieved at similar dietary lysine contents and were approximately 0.35 and 0.52 g available lysine/MJ of DE for control and pST-treated pigs, respectively. Protein deposition in the carcass increased exponentially with increasing dietary lysine level, was higher in boars than in gilts, and was increased by pST at the higher dietary lysine contents. Sex had no effect on dietary lysine required to maximize protein deposition. The dietary lysine contents required to ensure 95% of plateau protein deposition of 104 and 153 g/d were 0.39 and 0.55 g available lysine/MJ of DE for control and pST-treated pigs, respectively. The increase in lysine requirement with pST seems to be commensurate with the increase in protein deposition.

Animal Feed↗
PubMed2000

The influence of suckling interval on milk production of sows.

The objective of this study was to determine whether sow milk yield per gland could be increased by reducing the interval between suckles (suckling interval). Eighteen sows were allocated at their first farrowing to three treatments comprising litter sizes of 6 or 12 piglets or a cross-suckling treatment that was imposed to increase suckling frequency. The cross-suckled treatment comprised two groups of six piglets each. Each suckling group was allowed to suckle the sow during 30-min intervals each day between d 6 and d 28 of lactation. The suckling interval was shorter (P < .05) for cross-suckled sows than for sows suckling single litters of 6 or 12 piglets during early lactation (d 10 to 14) and late lactation (d 24 to 28). Average piglet growth rate between birth and 28 d of age was greatest (P < .05) for piglets in the single litters of six and lowest for piglets in the cross-suckled treatments. Single litters of 12 piglets had the highest (P < .05) litter growth rates, followed by the cross-suckled litters and then the single litters of six piglets. The concentration of lactose and fat in milk from sows remained relatively stable, although milk from the cross-suckled sows contained more protein in early lactation (P < .05). Milk yield of sows was not significantly increased (P > .05) by the cross-suckle treatment, although during early lactation, milk yield tended to be greater from sows in the cross-suckle treatment than from sows suckling single litters of six (8,920 g/d vs 7,819 g/d, P < .1). The concentration of DNA and total RNA and the RNA:DNA ratio in mammary glands was unaffected by treatment (P > .05). Sows with single litters of 12 piglets had the greatest total DNA in their udders (P < .05). However, individual gland weights were heavier (P < .05) in cross-suckled sows than in sows with single litters of 6 or 12 piglets. Increased suckling frequency seemed to play a role in increased mammary gland weight and milk production during lactation.

Animals↗
PubMed1999

Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome.

Observations have been made on the peripheral nerve changes in four patients, ranging in age from 4 to 32 years, with the congenital cataracts facial dysmorphism neuropathy syndrome. Myelinated fibre density was within normal limits. The salient abnormality was diffuse hypomyelination which, in the older patients, was associated with demyelination and then axonal degeneration. These findings could be correlated with the relative preservation of sensory action potential amplitude despite markedly reduced nerve conduction velocity. Unmyelinated axon density was preserved. The morphological observations suggest the operation of a developmental process affecting myelination with a later superimposed degenerative disorder.

Adult↗
PubMed1999

Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy.

A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory neuropathy (HMSN II). The clinical features differ from those reported in previously described cases of autosomal recessive HMSN II. This disorder may therefore represent a new variant.

Adult↗
PubMed1999

Moderate doses of porcine somatotropin do not increase plasma insulin-like growth factor-I (IGF-I) or IGF binding protein-3.

The growth rate of the young pig is generally much less than its potential and may be constrained by endocrine status as well as by nutrient intake. The aim of this study was to determine whether porcine somatotropin (pST) could increase growth in the nursing pig. Fourteen sows nursing litters of 6 (n = 7) or 12 (n = 7) piglets were utilized to establish a high and low plane of nutrition for sucking pigs. On Day 4 of lactation, the median two male pigs from each litter were randomly allocated to one of two doses of pST (0 or 60 micrograms/kg/d) until weaning on Day 31. Pigs were bled on Days 4, 13, 22, and 31 of lactation and the plasma was analyzed for insulin-like growth factor (IGF)-I, IGF-II, and IGF binding protein-3 (IGFBP-3). Pigs were weaned into conventional accommodation and further weighed on Days 63, 91, and 119. Pigs from litters of 6 grew more quickly and weighed 2.2 kg (P = 0.01) and 3.5 kg (P = 0.04) more than pigs from litters of 12 at 31 and 63 d of age, respectively. There was no effect of pST on preweaning growth of sucking pigs (261 vs. 258 g/d, P = 0.68), although growth rate increased in the final 3 d before weaning at 31 d (241 vs. 294 g/d, P = 0.01). IGFBP-3 was greater (1.09 vs. 0.78 micrograms/ml, P < 0.001), whereas IGF-I tended to be greater (206 vs. 176 ng/ml, P = 0.14), in pigs from the small litters. There was no effect of pST on plasma IGF-I (182 vs. 195 ng/ml, P = 0.454) or IGFBP-3 (0.93 vs. 0.94 microgram/ml, P = 0.85) concentrations. Plasma IGF-I and IGFBP-3 were highly correlated with the growth rate of nursing pigs (R = 0.638 and 0.756, respectively). There were no effects of pST (340 vs. 328 ng/ml, P = 0.48) or litter size (336 vs. 333 ng/ml, P = 0.88) on IGF-II. In conclusion, pST had no little or no effect on growth performance or plasma IGF-I, IGF-II, or IGFBP-3 in sucking pigs on either a high or low plane of nutrition.

Animals↗