A qualitative study of pediatric nurses' perception of factors affecting negotiation of care in a pediatric stem cell transplant unit.

BACKGROUND: The adoption of a 'family-centered-care' philosophy is essential for the care process and its negotiation. A better understanding of nurses' perception of factors that affect the process of negotiation could allow us to better address future interventions and to improve FCC. The purpose of our study was to investigate pediatric nurses' perception of factors that affect the process of negotiation of care with Stem Cell Transplantation pediatric patients and their parents. METHODS: A qualitative research design with in-depth interviews was chosen. Sixteen interviews (16 nurses) were audio recorded and transcribed verbatim. Two researchers conducted independently a thematic analysis of the verbatim transcripts of the interviews. RESULTS: Four themes emerged from the data as factors that affect the process of negotiation: (a) communication, (b) personal factors (c) specificity, and (d) organization. CONCLUSIONS: These themes represent interesting points for future improvement interventions. Negotiation in the Stem Cell Transplant setting would deserve further research, with special focus on children' and parents' perception of factors affecting this important aspect. Furthermore, in the future, negotiation guidelines could be validated and implemented effectively and an already validated tool could be used to document the negotiation process in the Stem Cell Transplant setting.

Mitochondrial diseases: advances and issues.

Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders.

Becker muscular dystrophy due to an intronic splicing mutation inducing a dual dystrophin transcript.

We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript. However, protein of normal molecular weight but in reduced amounts was observed on Western Blot analysis. Reverse transcription analysis on muscle RNA showed production, via alternative splicing, of a transcript missing exon 11 as well as a low abundant full-length transcript which is enough to avoid the severe Duchenne phenotype. Our study showed that a reduced amount of full length dystrophin leads to a mild form of Becker muscular dystrophy. These results confirm earlier findings that low amounts of dystrophin can be associated with a milder phenotype, which is promising for therapies aiming at dystrophin restoration.

A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype.

SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the "mixed" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain "in toto," even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations.

Prevalence of asymptomatic vertebral fractures in late-onset Pompe disease.

CONTEXT: Bone fragility and low bone mass have been reported in small case series of patients with Pompe disease with severely reduced muscle strength or immobilization. OBJECTIVE: Our objective was to determine the prevalence of morphometric vertebral fractures and to evaluate bone mass in adults with late-onset Pompe disease. DESIGN: We conducted a multicenter cross-sectional observational study from August 2012 to December 2013. STUDY SETTING: All subjects were outpatients referred to University Referral Centers. PATIENTS: PATIENTS included 22 late-onset Pompe disease patients with progressive proximal myopathy and minimal respiratory involvement without other diseases affecting bone mass. MAIN OUTCOME MEASURE: The prevalence of morphometric vertebral fractures was systematically assessed by semiquantitative analysis of lateral spine x-rays (T4-L5). RESULTS: A high prevalence of morphometric vertebral fractures was found. At least 1 vertebral fracture was present in 17 of 22 patients (77%). All vertebral fractures were asymptomatic. Bone mineral density was normal in 36.5% of the patients, whereas 36.5% were osteopenic and 27% were osteoporotic in at least 1 site. Fracture prevalence was independent of muscular and respiratory functional parameters and of genotype. CONCLUSIONS: Our data show for the first time that asymptomatic and atraumatic vertebral fractures occur frequently in late-onset Pompe disease patients without a significant impairment of bone mass. Screening for asymptomatic vertebral fractures should be routinely performed in Pompe disease irrespective of the disease severity. Fracture risk should be confirmed in longitudinal studies.

Strategies for treating mitochondrial disorders: an update.

Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.

Very late-onset friedreich ataxia with laryngeal dystonia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.

Radiotherapy in low-grade glioma adult patients: a retrospective survival and neurocognitive toxicity analysis.

PURPOSE: The treatment of low-grade glioma is still debated. Surgery is the first-line approach, and the correct timing of radiation therapy has not yet been defined since "early" radiation therapy improves relapse-free survival but not overall survival. Since a longer progression-free survival is desirable, the main issue related to radiotherapy is the incidence of late neurocognitive toxicity. MATERIALS AND METHODS: Ninety-five patients with low-grade glioma were consecutively treated with early (within 3 months) or late (at disease progression) post-surgical radiation therapy. Clinical and therapeutic factors were entered into the analysis overall (OS) and progression-free (PFS) survival, and the distribution in two accrual periods identified based on the evolution of imaging procedures and radiotherapy techniques were compared. For 6/18 long survivors (LS) without evidence of disease, neurocognitive evaluation was obtained and the dose to the hippocampus region was retrospectively calculated. RESULTS: Univariate analysis of OS showed a statistically significant advantage for grade 1 and oligodendroglioma histology, better performance status [Karnofsky index (KI)], age <40 years, radical surgery, no steroid treatment; PFS was significantly related with younger age, better KI and "early" radiotherapy. Multivariate analysis of OS confirmed the significance of all variables except surgery; for PFS, only "early" radiotherapy and better KI retained significance. Memory impairment was evident in 4/6 of the LS tested; quality of life was good and executive functions were normal. CONCLUSION: Radiotherapy remains an essential component in the treatment of low-grade glioma. Prospective studies are needed to evaluate the relative contributions of the disease itself and of surgery, radiation and chemotherapy to long-term neurocognitive damage.

Small nerve fiber pathology in critical illness.

BACKGROUND: Degeneration of intraepidermal nerve fibers (IENF) is a hallmark of small fiber neuropathy of different etiology, whose clinical picture is dominated by neuropathic pain. It is unknown if critical illness can affect IENF. METHODS: We enrolled 14 adult neurocritical care patients with prolonged intensive care unit (ICU) stay and artificial ventilation (≥ 3 days), and no previous history or risk factors for neuromuscular disease. All patients underwent neurological examination including evaluation of consciousness, sensory functions, muscle strength, nerve conduction study and needle electromyography, autonomic dysfunction using the finger wrinkling test, and skin biopsy for quantification of IENF and sweat gland innervation density during ICU stay and at follow-up visit. Development of infection, sepsis and multiple organ failure was recorded throughout the ICU stay. RESULTS: Of the 14 patients recruited, 13 (93%) had infections, sepsis or multiple organ failure. All had severe and non-length dependent loss of IENF. Sweat gland innervation was reduced in all except one patient. Of the 7 patients available for follow-up visit, three complained of diffuse sensory loss and burning pain, and another three showed clinical dysautonomia. CONCLUSIONS: Small fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in neurocritical care survivors. Its impact on long term disability warrants further studies involving also non-neurologic critical care patients.

MR neurography in diagnosing nondiabetic lumbosacral radiculoplexus neuropathy.

Here we describe the imaging findings in a 73-year-old woman who had pain in the right inguinal region, followed by progressive weakness of muscles innervated by the right femoral and obturator nerves, diagnosed as nondiabetic lumbosacral radiculoplexus neuropathy. Magnetic resonance neurography showed thickening and increase in signal intensity of the right femoral and obturator nerves.

Retreatment of recurrent adult medulloblastoma with radiotherapy: a case report and review of the literature.

INTRODUCTION: Medulloblastoma, the most frequent brain tumor in childhood, also occurs with a wide range of characteristics in adult patients. Late relapse is common in adult medulloblastoma, and the overall survival of relapsed patients usually ranges from 12 to 15 months. Treatment at recurrence is still debated and after reoperation includes stereotactic or normofractionated radiotherapy, and high-dose chemotherapy with autologous bone marrow transplantation. CASE PRESENTATION: We report on the case of a 31-year-old Caucasian woman who underwent re-irradiation for a recurrence of medulloblastoma at nine years after first irradiation (56Gy), focusing on the radiobiological background and a review of previous studies involving re-irradiation of recurrent medulloblastoma. After surgical excision of the relapsed tumor and medical multi-agent treatment, the site of recurrence was treated using three-dimensional conformal radiotherapy to a total dose of 52.8Gy (1.2Gy/fraction/twice daily). A total biological equivalent dose of 224.6Gy (α:ß = 2 Gy) was delivered to the posterior fossa (first and second treatments). No radionecrosis or local recurrence was evident at 18 months after re-irradiation. CONCLUSION: Re-irradiation can be considered a possible and safe treatment in selected cases of recurrent medulloblastoma in adults. The reported radiobiological considerations could be useful in other cases involving re-irradiation of brain tumors.

Glutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme.

BACKGROUND: Glutamine synthetase (GS) is an astrocytic enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Its up-regulation has been related to higher tumor proliferation and poor prognosis in extra-cerebral tumors. We have previously reported a GS deficiency in patients with glioblastoma multiforme (GBM) who also developed epilepsy, which is a favorable prognostic factor in glioma. Here, we investigated the prognostic value of GS expression in patients with GBM with or without epilepsy and its correlation with survival. METHODS: We conducted a clinical and histopathological study on 83 (52 males) consecutive patients with newly diagnosed GBM. Immunohistochemical expression of GS was scored semi-quantitatively on the basis of cell number, staining intensity, and distribution of immunoreactive cells. Several clinical and neuropathological variables were analyzed in relation to survival and GS expression. RESULTS: Median age at diagnosis was 62 years. At the last evaluation, with a median follow-up of 11.5 months (range, 1.5-58 months), 5 patients (6%) were still alive and 78 (94%) were dead. GS expression patterns in neoplastic cells were inversely correlated to the presence of epilepsy (P < .0001 for intensity and P < .009 for homogeneity of GS distribution, respectively). Univariate analysis showed that RPA score, epilepsy, O6-methylguanine-DNA methyltransferase (MGM)T status, application of Stupp protocol, and GS intensity pattern had a significant impact on survival. Absent/low intensity of GS expression was significantly associated with a longer survival in both uni- (19 vs 8 months; P < .0005) and multivariate (P = .003) analyses. CONCLUSIONS: Absent/low-intensity GS expression pattern represents a valuable biomarker of both epilepsy and overall survival in GBM.

Non-muscle involvement in late-onset glycogenosis II.

Glycogenosis II (GSD II) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase deficiency, subsequent accumulation of glycogen in tissues, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The late-onset form is characterized by wide variability in residual enzyme activity, age of onset, rate of disease progression and phenotypical spectrum. Although the pathological process mainly affects the skeletal muscle, several other tissues may be involved in the course of the disease; therefore GSD II should be regarded as a multisystem disorder in which glycogen accumulation is present in skeletal and smooth muscle, heart, brain, liver, spleen, salivary glands, kidney and blood vessels. In this review, we briefly summarize the main non-muscle targets of the pathological process in late-onset GSD II. Further studies aimed at evaluating the extra-muscle involvement in this group of patients will help to better define clinical features and prognostic factors and to delineate the natural history of the disease.

Clinical spectrum and evolution of monoclonal gammopathy-associated neuropathy: an observational study.

BACKGROUND: Paraproteinemic neuropathy (PPN) is often under-diagnosed because of its clinical and electrophysiological variability. Progression of neuropathy is considered an alarm bell for possible malignant conversion of underlying monoclonal gammopathy (MG). OBJECTIVE: To report clinical presentation, course, and evolution in a group of patients with PPN in order to identify findings useful for achieving the diagnosis, suspecting progression, and recognizing the underlying hematological conditions. PATIENTS AND METHODS: Thirty-nine patients with PPN underwent clinical examination, electrodiagnostic studies, cerebrospinal fluid analysis, and laboratory tests. These parameters were compared between the different peak groups. RESULTS: IgM MG was found in 51.4%, IgG MG in 33.3%, and IgA MG in 10.3% of our cohort. PPN appeared as mainly sensory, demyelinating, mildly progressive neuropathy, regardless of the type of peak or light chain. However, axonal findings were present in many IgG patients and in part of the IgM patients and a small number of the IgG patients may have presented with motor symptoms at the onset. The IgM patients had a significant tendency toward clinical worsening and IgG subjects had a more elevated rate of malignancy. IgA-related neuropathies were rare, heterogenous, and with a high tendency to evolution and malignancy. CONCLUSIONS: Most of PPN often present a relatively monomorphic clinical picture but they can be clinically heterogenous and must be suspected even if sensory impairment and demyelination are not the dominant features. Tendency to malignancy seems globally elevated and needs intensive follow-up. Diagnostic approach to patients presenting with peripheral neuropathy should always include the typing of monoclonal immunoglobulins in serum and urine. In contrast, patients presenting with MG should be submitted to nerve conduction study/electroneurography and neurological evaluation.

Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment.

Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency with unknown genetic defect.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessively inherited disorder of fatty acid metabolism due to ETFA, ETFB or ETFDH mutations. Riboflavin treatment ameliorates symptoms and metabolic profile in ETFDH-related MADD patients. We report on a 20-year-old boy with an 8-year history of progressive difficulty in walking, running and climbing stairs. Muscle biopsy showed a lipid myopathy and the acylcarnitine profile analysis was suggestive of MADD. Nevertheless, no evidence of molecular defects in the ETFA, ETFB and ETFDH exons or intron-exon boundaries was found. Treatment with riboflavin for 1 year resulted in a clear improvement in motor functions. Our report shows that some cases of MADD are not linked to ETFA, ETFB and ETFDH exon or intron-exon boundary changes. They could be due to quite rare promoter or deep intronic mutations or, most likely, to some unknown genetic defect. We therefore suggest to extend in these cases molecular studies to cDNA analysis and indicate the need of extensive pedigree studies to identify other possible disease-related loci. Most important, treatment of these cases with riboflavin can also be effective. Therefore, early diagnosis is essential to achieve the best treatment response.

The role of mitochondria in neurodegenerative diseases.

Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field.