[X-Linked Adrenoleukodystrophy or the Management of Rare Diseases in the General Practice]. / Die X-chromosomale Adrenoleukodystrophie oder vom Umgang mit seltenen Erkrankungen in der hausärztlichen Praxis.

X-Linked Adrenoleukodystrophy or the Management of Rare Diseases in the General Practice Abstract. We report on a 48-year-old patient with X-linked adrenoleukodystrophy with slowly progressive leg-accentuated spastic paraparesis, vegetative dysfunction with bladder and sexual dysfunction, and primary adrenal insufficiency. The diagnosis of adrenomyeloneuropathy, the adult form of adrenoleukodystrophy, and Addison's disease was made at the age of 20 by evidence of an increased concentration of long-chain fatty acids in the plasma. The therapy is symptom-oriented.

Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development.

A comprehensive review of published literature was conducted to elucidate the genetics, neuropathology, imaging findings, prevalence, clinical course, diagnosis/clinical evaluation, potential biomarkers, and current and proposed treatments for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare, debilitating, and life-threatening neurodegenerative disorder for which disease-modifying therapies are not currently available. Details on potential efficacy endpoints for future interventional clinical trials in patients with ALSP and data related to the burden of the disease on patients and caregivers were also reviewed. The information in this position paper lays a foundation to establish an effective clinical rationale and address the clinical gaps for creation of a robust strategy to develop therapeutic agents for ALSP, as well as design future clinical trials, that have clinically meaningful and convergent endpoints.

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.

Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.

Long-Term Effects of Repeated Cycles of Intrathecal Triamcinolone Acetonide on Spasticity in MS Patients.

MAIN PROBLEM: Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters. METHODS: A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25-foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle. RESULTS: Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long-lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months. CONCLUSION: Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re-administration of TCA and that an interval of 3 months between the treatments might be too long.

CSF and Blood Levels of GFAP in Alexander Disease

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.

Prognostic value of soluble ST2 in an unselected cohort of patients admitted to an intensive care unit - The Linz Intensive Care Unit (LICU) study.

BACKGROUND: Soluble ST2 (sST2) has emerged as a prognostic biomarker in patients with heart disease. We tested the hypothesis that sST2 is an independent predictor of mortality in patients admitted to an intensive care unit (ICU). METHODS: We performed measurements of sST2 plasma concentrations in 530 consecutive patients admitted to a medical ICU of a tertiary care hospital during a study period of one year. The patients recruited during the first six months were used for the derivation cohort (n=274) and the patients recruited during the second six months were used for the validation cohort (n=256). The endpoint was defined as 90-day all-cause mortality. RESULTS: In the derivation cohort, sST2 was higher among decedents (n=56; median, 146 U/mL) than survivors (n=218; median 42 U/mL, p<0.001). In multivariate Cox proportional-hazard regression analysis (offering age, sex, BMI, APACHE II score, SAPS II, CRP, IL-6, PCT, creatinine, total cholesterol, albumin, hs-cTnT, BNP and sST2 as independent variables), sST2 was a significant predictor of mortality (risk ratio 1.48, 95% CI 1.15-1.90; p=0.002 per 1 SD increase in log transformed values). In this statistical model, only sST2 and SAPS II contributed independently to mortality prediction. We further observed an additive effect of an sST2 plasma concentration of >84 U/mL and an increased SAPS II for mortality prediction. The findings from the derivation cohort were confirmed in the independent validation cohort. In those patients with a length of stay of >48 h at the ICU (n=225), sST2 obtained two days after baseline measurement had a better capability than baseline sST2 to predict mortality. CONCLUSIONS: In an unselected cohort of patients admitted to the ICU, sST2 was an independent predictor of 90-day all-cause mortality and added prognostic information to the SAPS II.

Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC. METHODS: Neurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented. RESULTS: Spastic paraplegia in patients with spatacsin mutations (n = 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, >30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intraaxonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11. INTERPRETATION: We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.

The modified distal horizontal metatarsal osteotomy for correction of bunionette deformity.

BACKGROUND: Bunionette is a common deformity for which a number of operative procedures have been described. The objective of this study was to evaluate the results of a modified distal horizontal metatarsal osteotomy in the correction of symptomatic bunionette. METHODS: Metatarsal osteotomies were done in 21 feet in 14 patients (11 females, three males) with an average age of 44 (range 20 to 67) years at the time of operation. The average followup was 32 (range 12 to 52) months. RESULTS: The average Lesser Toe Metatarsophalangeal-Interphalangeal Score of the American Orthopaedic Foot and Ankle Society increased from 42 points (range 24 to 50) preoperatively to 87 points (range 60 to 100) at the last followup. The fifth metatarsophalangeal angle averaged 18 degrees (5 to 38 degrees) preoperatively and 5 degrees (-5 to 26 degrees) at final followup. The 4-5 intermetatarsal angle averaged 14 degrees (10 to 20 degrees) preoperatively and 9 degrees (5 to 12 degrees) at final followup. Hardware was removed from two feet and scheduled for a third foot because of symptomatic skin irritation. CONCLUSIONS: The modified distal horizontal metatarsal osteotomy is a stable and reliable method for correction of bunionette. Unsatisfactory results in our patients were related to prominent hardware.

Intraosseous lipoma: retrospective analysis of 29 patients.

We reviewed 29 patients with intraosseous lipoma treated between 1985 and 2002. Mean patient age was 48 (20-75) years. According to Milgram's classification, ten cases were classified as stage I, 14 as stage II, and three as stage III. All patients were initially treated by curettage. In 11 cases an additional phenolization was performed. The average follow-up was 32 (6-208) months. At the last follow-up, none had any clinical or radiological signs of recurrence. The adequate treatment of a symptomatic intraosseous lipoma is curettage and bone grafting. In the current study, phenolization showed no added benefit. An asymptomatic intraosseous lipoma without impending pathological fracture can be treated conservatively.