A new classification of glenoid bone loss to help plan the implantation of a glenoid component before revision arthroplasty of the shoulder.

AIMS: Glenoid bone loss can be a challenging problem when revising a shoulder arthroplasty. Precise pre-operative planning based on plain radiographs or CT scans is essential. We have investigated a new radiological classification system to describe the degree of medialisation of the bony glenoid and that will indicate the amount of bone potentially available for supporting a glenoid component. It depends on the relationship between the most medial part of the articular surface of the glenoid with the base of the coracoid process and the spinoglenoid notch: it classifies the degree of bone loss into three types. It also attempts to predict the type of glenoid reconstruction that may be possible (impaction bone grafting, structural grafting or simple non-augmented arthroplasty) and gives guidance about whether a pre-operative CT scan is indicated. PATIENTS AND METHODS: Inter-method reliability between plain radiographs and CT scans was assessed retrospectively by three independent observers using data from 39 randomly selected patients. Inter-observer reliability and test-retest reliability was tested on the same cohort using Cohen's kappa statistics. Correlation of the type of glenoid with the Constant score and its pain component was analysed using the Kruskal-Wallis method on data from 128 patients. Anatomical studies of the scapula were reviewed to explain the findings. RESULTS: Excellent inter-method reliability, inter-observer and test-retest reliability were seen. The system did not correlate with the Constant score, but correlated well with its pain component. TAKE HOME MESSAGE: Our system of classification is a helpful guide to the degree of glenoid bone loss when embarking on revision shoulder arthroplasty.

The biological response to a failed extra-articular polyester ligament used for AC Joint reconstruction at the shoulder girdle: a retrieval analysis of five cases.

The LockDown device (previously called Surgilig) is a braided polyester mesh which is mostly used to reconstruct the dislocated acromioclavicular joint. More than 11,000 have been implanted worldwide. Little is known about the tissue reaction to the device nor to its wear products when implanted in an extra-articular site in humans. This is of importance as an adverse immunological reaction could result in osteolysis or damage to the local tissues, thereby affecting the longevity of the implant. We analysed the histology of five LockDown implants retrieved from five patients over the last seven years by one of the senior authors. Routine analysis was carried out in all five cases and immunohistochemistry in one. The LockDown device acts as a scaffold for connective tissue which forms an investing fibrous pseudoligament. The immunological response at the histological level seems favourable with a limited histiocytic and giant cell response to micron-sized wear particles. The connective tissue envelope around the implant is less organised than a native ligament.

Multiple Symmetrical Lipomatosis--a mitochondrial disorder of brown fat.

Multiple Symmetrical Lipomatosis (MSL) is an unusual disorder characterized by the development of axial lipomas in adulthood. The pathoetiology of lipoma tissue in MSL remains unresolved. Seven patients with MSL were followed for a mean period of 12 years (8-20 years). All patients had cervical lipomas ranging from subtle lesions to disfiguring masses; six patients had peripheral neuropathy and five had proximal myopathy. Myoclonus, cerebellar ataxia and additional lipomas were variably present. All patients showed clinical progression. Muscle histopathology was consistent with mitochondrial disease. Five patients were positive for mtDNA point mutation m.8344A>G, three of whom underwent lipoma resection--all samples were positive for uncoupling protein-1 mRNA (unique to brown fat). Lipoma from one case stained positive for adipocyte fatty-acid protein-2 (unique to brown fat and immature adipocytes). This long-term study hallmarks the phenotypic heterogeneity of MSL's associated clinical features. The clinical, genetic and molecular findings substantiate the hypothesis that lipomas in MSL are due to a mitochondrial disorder of brown fat.

Sustained response to deep brain stimulation in LRRK2 parkinsonism with the Y1699C mutation.

Although effective deep brain stimulation of the subthalamic nucleus (STN-DBS) is reported in G2019S leucine-rich repeat kinase 2 (LRRK2) parkinsonism, response to surgery in other LRRK2 mutations has not been previously reported. We present an affected individual from the Lincolnshire pedigree (Y1699C), on whom bilateral STN-DBS was performed to control severe motor fluctuations and dyskinesias. He showed a marked improvement in Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores in the "on" and "off" states, sustained for more than three years. Bilateral STN-DBS in LRRK2-parkinsonism with the Y1699C mutation can be as effective as in sporadic PD.

A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis.

We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.

Two cases of Cryptococcus meningitis presenting as leukoencephalopathy prior to amphotericin therapy.

We report two patients with cryptococcal meningitis and combined immunodeficiency with unusual magnetic resonance imaging findings of gadolinium-enhancing white matter lesions, quite different from cryptococcomas and seen prior to anti-fungal treatment. The lesions resembled demyelinating plaques and resolved. In one patient, biopsy of the lesion revealed cryptococci, non-specific inflammatory changes and occasional small perivascular lymphocyte collections, but not demyelination. Leukoencephalopathy, previously rarely observed in Cryptococcal meningitis, was thought to be the sequelae of amphotericin toxicity. Our cases demonstrate cryptococcal meningitis may present with leukoencephalopathy, possibly as an immune response to the organism.

Genetics of movement disorders: an abbreviated overview.

Linkage of the Huntington's disease gene to chromosome 4 in 1983 marked the birth of modern genetics in movement disorders. The discovery that an expanded trinucleotide DNA repeat was central to the mechanism of this disease has been repeated over and over in a growing list of inherited ataxias. In 1997, a different mutation and genetic mechanism was discovered in a severe type of generalized primary torsion dystonia - Oppenheim's dystonia. Before this, only the genetic cause for rare metabolic dystonias was known, notably dopa-responsive (Segawa's) dystonia. In the same year, from the identification of mutation in the alpha-synuclein gene in rare pedigrees with autosomal dominant parkinsonism, arose the concept that Parkinson's disease may be part of a broader group of 'synucleinopathies', in which there is a fundamental defect in protein processing. In the following year, mutations in autosomal recessive juvenile onset parkinsonism were found in a gene called 'parkin'. Parkin mutations are a more common cause of parkinsonism than the rare alpha-synuclein mutations, particularly in young-onset disease. However, a most important understanding, occurring in the last year, has been the relationship between the parkin gene product, alpha-synuclein and abnormal protein degradation in the cell. A unified theory of neuronal death in Parkinson's disease is emerging, pointing to potential new therapies in the future.

A novel clinical phenotype of myopathy, sensorimotor neuropathy, infertility, and hypogonadism with multiple mitochondrial DNA deletions.

We describe a patient with myopathy, sensorimotor neuropathy, hypogonadism, and infertility with abnormal sperm mobility and morphology. Analysis of the deltoid muscle DNA revealed a G to A change at nt 1102 in the twinkle gene and multiple mitochondrial DNA deletions. Histochemistry revealed "ragged-red" fibers and many cytochrome-c oxidase negative fibers (32%) that lacked the mitochondrial encoded respiratory chain subunits I and II and the nuclear encoded subunit VIc. Respiratory chain enzyme analysis showed severe deficiency of complex I, III, and IV. This patient has no documented family history of progressive external ophthalmoplegia, which suggests either a sporadic or autosomal-recessive syndrome. This case is a novel phenotype for twinkle gene mutations and multiple mitochondrial DNA deletion syndromes, as these syndromes generally follow an autosomal-dominant inheritance pattern.

A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy.

The objective of this study was to determine whether a mitochondrial DNA mutation and defective oxidative phosphorylation are present in a pedigree with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy. We sequenced the mitochondrial-encoded ribosomal RNA, cytochrome c oxidase, and transfer RNA genes by cycle sequencing. A polymerase chain reaction-based restriction enzyme assay with mismatched primers was employed to show heteroplasmy of a novel 12SrRNA mutation in the proband and to screen control subjects. Spectrophotometric mitochondrial respiratory chain assays were performed in transformed lymphoblasts from the proband and 12 normal controls. A novel, heteroplasmic, maternally inherited 12SrRNA point mutation (T1095C) was found in the pedigree. Respiratory chain enzyme analysis in cultured lymphocytes from the proband revealed a significant reduction in cytochrome c oxidase activity. Secondary structure predicts that this mutation disrupts a highly conserved loop in the small subunit ribosomal RNA, which is important in the initiation of mitochondrial protein synthesis. The mutation was not found in 270 controls of diverse ethnic origins. We conclude that this mutation is pathogenic and causes an oxidative phosphorylation defect by interfering with mitochondrial protein synthesis.

Dystonia: recent advances.

Dystonia may be primary or symptomatic. Most, if not all, primary torsion dystonias are genetic diseases and manifest as 'pure dystonia', without consistent biochemical or neuropathological changes. Symptomatic dystonias may be (a) secondary to drugs or other environmental factors, (b) part of a 'dystonia plus' syndrome or (c) part of several heredodegenerative diseases. In the last few years, there have been rapid advances in the genetic classification of primary torsion dystonia. The gene for one form (DYT1dystonia), particularly common in Ashkenazi Jews, has been isolated. In this review, I present a basic clinical overview of dystonia and focus on the recent advances in molecular genetics of primary torsion dystonia (PTD). Treatment of dystonia is a large subject, worthy of a review in itself, and is not covered here. Several of the paroxysmal movement disorders may manifest with dystonia, but these are usually considered separately, as I have done in this review. Copyright 1999 Harcourt Publishers Ltd.

Post-traumatic shoulder 'dystonia': persistent abnormal postures of the shoulder after minor trauma.

The authors describe two patients with fixed shoulder elevation and prominent regional muscle hypertrophy that developed within days after local minor injury. The condition lacked several typical features of dystonia, such as the presence of torsional movements, task specificity, or relief by antagonistic gestures. These patient reports add to the growing literature indicating that persistent post-traumatic abnormal postures and muscle hypertrophy in different body parts may be a distinct response of the nervous system to injury.

The fate of human sperm-derived mtDNA in somatic cells.

Inheritance of animal mtDNA is almost exclusively maternal, most likely because sperm-derived mitochondria are actively eliminated from the ovum, either at or soon after fertilization. How such elimination occurs is currently unknown. We asked whether similar behavior could be detected in somatic cells, by following the fate of mitochondria and mtDNAs after entry of human sperm into transformed cells containing mitochondria but lacking endogenous mtDNAs (rho0 cells). We found that a high proportion (10%-20%) of cells contained functioning sperm mitochondria soon after sperm entry. However, under selective conditions permitting only the survival of cells harboring functional mtDNAs, only approximately 1/10(5) cells containing sperm mitochondria survived and proliferated. These data imply that mitochondria in sperm can enter somatic cells relatively easily, but they also suggest that mechanisms exist to eliminate sperm-derived mtDNA from somatic cells, mechanisms perhaps similar to those presumed to operate in the fertilized oocyte.

Rapid-onset dystonia-parkinsonism in a second family.

Rapid-onset dystonia-parkinsonism (RDP), first described in a large Midwestern family, is now reported in a second, apparently unrelated, family in which four individuals have this same syndrome. All four developed sudden onset of dysarthria, dysphagia, severe dystonic spasms, bradykinesia, and postural instability over less than 1 hour to a few days. Three of the four had stable limb dystonia for several years preceding the onset of combined dystonia-parkinsonism. Treatment with levodopa/carbidopa provided little benefit. We propose diagnostic criteria for RDP and further define the spectrum of this unusual disease.

A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis.

A T-to-C transition at nucleotide (nt) 9176 in the mitochondrial adenosine triphosphatase 6 (ATPase 6) gene was detected in 2 brothers with a neurological disorder resembling Leigh syndrome. The mutation was also present in the 2 other siblings and in the mother, who were asymptomatic. In the more severely affected boy (the proband), the mutation was homoplasmic in muscle, leucocytes, and fibroblasts. In leucocytes from his affected brother, 98% of mtDNA was mutant. Heteroplasmy of varying degrees was seen in leucocytes from the mother and the 2 unaffected siblings. The mutation changes a highly conserved leucine residue near the carboxyl terminus of the mitochondrial ATPase 6 subunit to proline. It could not be detected in 168 control subjects. Studies of ATP synthesis and hydrolysis in fibroblasts from the proband were normal.

Magnetic resonance imaging in brachial plexopathy of cancer.

We retrospectively reviewed the clinical records of all patients with cancer and brachial plexopathy who had an MRI of the brachial plexus between 1984 and 1993 (71 patients). The MRIs were reevaluated in a blinded fashion. The presence of a mass adjacent to the brachial plexus on MRI was highly predictive of tumor infiltration as determined by clinicopathologic criteria and was the most useful feature in distinguishing radiation plexopathy from tumor infiltration. Increased T2 signal in or near the brachial plexus was commonly seen in both groups and was not useful in this distinction. MRI was very sensitive for brachial plexus abnormalities in this condition, and limited comparison with CT suggested that MRI is superior to CT as an imaging modality. CT performed sufficiently well, however, to suggest that a prospective comparison study of the cost effectiveness and clinical utility of the two imaging modalities in this clinical setting is warranted.

Influence of local tissue temperature on vibration detection threshold.

We used the Computer Assisted Sensory Examination (CASE IV) and a new, rapid 4, 2, and 1 stepping algorithm to determine the influence of local temperature on vibratory detection threshold (VDT) in the great toe of 11 healthy adult subjects. We found that over a broad range of temperatures, VDT did not vary much. A large cooling offset resulted in a small increase in VDT, but warming did not change VDT significantly.

Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction.

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cytopathies indicated a wide range between different mitochondrial genes in the degree of nucleotide variation from the standard Cambridge sequence. Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t). Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entire mtDNA coding region was 0.21% for cytopathies (n = 16) as opposed to 0.18% for a control group (n = 4). Within the cytopathy group, the greatest pairwise divergence was observed in ND3 and ND6 subunits of complex I (0.46 and 0.70% respectively) and the magnitude of specific gene divergences differed considerably from those observed for the corresponding genes in the control population. The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small control group. Regardless as to which of these suggestions is correct, the possibility exists that increased nucleotide variation in certain mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor individual mutagenic potential.

Emetine myopathy in a patient with an eating disorder.

OBJECTIVE: To alert physicians to the dangers of a readily available, non-prescription drug by describing the clinical and pathological features of myopathy due to chronic poisoning with ipecac syrup in a patient with an eating disorder. CLINICAL FEATURES: A 27-year-old woman presented in 1991 with a right foot drop, followed a few months later by progressive severe neck and limb weakness associated with dysphagia, faecal incontinence and diffuse body ache. It emerged that she had been consuming increasing quantities of ipecac syrup (up to 200 mL per week) for three months to induce vomiting and weight loss. The serum creatine kinase activity was slightly elevated and electromyographic examination results were in keeping with a necrotising proximal myopathic process. Muscle biopsy showed vacuolar degeneration with myofibrilolysis and fine cytoplasmic body formation, consistent with a diagnosis of emetine myopathy. INTERVENTION AND OUTCOME: The patient was advised to stop taking ipecac and observed for the next few months. The symptoms resolved gradually and strength returned to normal in four months. CONCLUSION: Chronic emetine toxicity, with its potentially catastrophic consequences, should be remembered in the evaluation of neuromuscular symptoms in young women, in whom eating disorders are common and often unrecognised.