Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Laparoendoscopic single site (LESS) radical prostatectomy: a review of the initial experience.

Surgical treatment for prostate cancer has changed dramatically in recent years due to the incorporation of minimally invasive techniques in the surgical armamentarium. Open surgical approaches to the prostate have largely given way to laparoscopic and robotic techniques. In order to further reduce incisional morbidity and improve cosmesis, there has been a recent interest in laparoendoscopic single site (LESS) approaches to the prostate. Despite a rising interest, there is little available data on these procedures. We performed a systematic review of the literature using MEDLINE, OVID, and Web of Science to identify all publications including LESS radical prostatectomy to date. Manual bibliographic review of cross-referenced items was also performed. We attempt to identify and summarize existing data on these procedures both with and without robotic assistance. Additionally, we review the emerging devices, instruments, cameras, and ports that have made these procedures possible. Next, we offer insight into how this rapidly moving field may transition in the future. Finally, we provide our commentary on this surgical approach, its impact on urology, and how it may help us evolve in the future.

Prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy.

The clinical significance of atypical glands suspicious for malignancy (atypia) on prostate biopsy is unclear. We studied a cohort of 139 patients with atypia who underwent repeat prostate biopsy. We analyzed clinical and pathological variables that may be associated with cancer on repeat biopsy. Cancer was diagnosed in 41 (29%) of patients with atypia: 26 of 41 (66%) were Gleason 6, 20% were Gleason 7 and 7% were Gleason 8 (Gleason < 6 not reported). There were no significant associations of age, race, family history, PSA, PSA density (PSAd), number of previous biopsies or time to repeat biopsy with cancer diagnosis. In multivariate regression, histological inflammation was associated with an 85% decreased probability of cancer on repeat biopsy (odds ratio; OR 0.15; 95% confidence interval; CI 0.04-0.57; P=0.04). Radical prostatectomy was performed in 14 of 41 (34%) patients with cancer; 6 (43%) were Gleason sum ≥7, 3 (21%) were pT3a and 1 (7%) had lymph node metastases. In conclusion, inflammation was independently associated with a significantly decreased risk of cancer on repeat biopsy. However, some patients with initial atypia have higher-risk prostate cancer. Additional studies are needed to elucidate these associations.

Robot-assisted laparoscopic radical prostatectomy in men with human immunodeficiency virus.

The aim of this study is to evaluate the outcomes of robot-assisted laparoscopic prostatectomy (RALP) in prostate cancer (PCa) patients with human immunodeficiency virus (HIV). This is a prospective cohort study of HIV patients undergoing RALP, comparing the demographics, tumor characteristics, complications, and short-term oncological outcomes of HIV-positive men to HIV-negative men using univariate (χ(2), Mann-Whitney test) and multivariable (logistic regression) analyses. From 2007 to 2010, 298 men underwent RALP, 8 of whom were known to be HIV positive. Preoperatively, all eight were taking highly active antiretroviral therapy (HAART) and had undetectable viral loads (<50); mean CD4 count was 634 cells per mm(3). HIV-positive men were younger (54 versus 62 years, P=0.010) and less likely to be white (P=0.007). There were no significant differences between groups with respect to clinical staging, pathological and oncological outcomes or most complication rates. However, the prevalence of perioperative transfusions (P=0.031) and ileus (P=0.021) were higher in HIV-positive patients. HIV remained significantly associated with risk of transfusion after adjustment for age, race, Gleason sum and clinical T stage (P=0.002). After a median of 2.6 (range 0.03-19.2) months of follow-up, PSA remained undetectable in all eight HIV patients. These data suggest that RALP is safe for, and demonstrates short-term oncological efficacy in, HIV-positive patients with PCa.

Prostate cancer prevention: concepts and clinical recommendations.

Prevention is an important strategy for limiting prostate cancer morbidity and mortality. Two major types of prevention are primary (reduction of incident cases) and tertiary (inhibition of disease progression and recurrence). Pharmacological and dietary interventions have potential functions in both the primary and tertiary prevention of prostate cancer. Five-α reductase inhibitors (5-ARIs) reduce the incidence of prostate cancer in both general and higher-risk populations and are currently under study for tertiary prevention in active surveillance and biochemical recurrence patients. Selenium, vitamin E, and vitamin C do not prevent incident prostate cancer in the general population; however, other promising diet-based interventions are currently under study for tertiary prevention. We recommend consideration of 5-ARIs for prostate cancer prevention in (1) asymptomatic men with a PSA ≤ 3.0 ng ml(-1) who are undergoing or anticipate undergoing PSA screening for early detection of prostate cancer and (2) asymptomatic men with PSA ≥ 2.5 and ≤ 10 ng ml(-1) and an earlier prostate biopsy negative for cancer. Men should be informed of the potential risks of 5-ARI therapy. Currently, there is neither clinical evidence to support the use of 5-ARIs for tertiary prevention in active surveillance or biochemical recurrence populations, nor micronutrients for prostate cancer prevention of any type.

Lymph node dissection during robot-assisted radical prostatectomy: where do we stand?

Since the initial report of robot-assisted laparoscopic prostatectomy (RALP) in 2001, the technique has gained rapid acceptance and utilization. When compared with more traditional forms of surgical intervention, there is still much debate with respect to cost, and impact on potency and continence. Less often is the focus on oncologic outcomes. Pelvic lymph node dissection (PLND) at the time of prostatectomy is an important part of the surgical intervention for prostate cancer and is currently underreported during robotic procedures. Herein, we review the current controversies on the value and extent of PLND and the status of emerging data regarding robot-assisted PLND.

HIV and prostate cancer: a systematic review of the literature.

Malignancy occurs with increased frequency in the HIV-positive population. The true incidence of prostate cancer in this population is unknown. In the few cases that have been presented in the literature, prostate cancer in HIV-positive men appears to behave much like it does in HIV-negative men. Prostate cancer is the most common malignancy in men and the second leading cause of cancer death. Approximately 800,000 men in the United States are HIV positive, and innovative therapies have dramatically improved survival. HIV disproportionately impacts ethnic groups with increased risk of prostate cancer and has been associated with increases in the incidence of certain malignancies. Despite the high prevalence of both diseases, there is relatively little literature about prostate cancer in HIV-positive patients. There is no consensus on how to screen or treat this patient population. We review the literature with regards to incidence, screening, treatment, and outcomes of this poorly characterized population. We briefly discuss the impact of highly active antiretroviral therapy and testosterone supplementation in the development of prostate cancer. A systematic review of the literature was conducted using MEDLINE key words 'HIV,' 'prostate,' 'prostate cancer' and 'AIDS.' Manual bibliographic review of cross-referenced items was also performed. A total of 176 unique abstracts and publications were reviewed; many authors provided data on the incidence of HIV and various malignancies including prostate cancer. Twelve unique publications providing detailed information on 60 patients with HIV and prostate cancer were identified. Prostate cancer is a common malignancy in HIV-positive men. With improved therapies for HIV and increasing survival, the importance for screening and treating prostate cancer is increasing. Acute outcomes of treatment do not demonstrate increased acute morbidity; however long-term outcomes have not been reported.

Occurrence of Rett syndrome in boys.

The neurologic disorder Rett syndrome was originally described exclusively in girls. We present two boys with clinical features of Rett syndrome. Other than head circumference deceleration, no longer considered mandatory, patient 1 meets all of the criteria. Using fluorescent in situ hybridization analysis, 97.6% of cells were found to be karyotypically normal (46,XY). No mutation was detected on screening of the coding region of the MECP2 gene. The second patient also has classic features of Rett syndrome. However, cytogenetic analysis of peripheral blood revealed a karyotype 47,XXY[23]/46,XY[7] confirming mosaicism for Klinefelter's syndrome. A T158M missense mutation in the methylcytosine-binding domain of the MECP2 gene was identified. A diagnostic bias against the clinical identification of Rett syndrome in boys may exist. This presentation of the male phenotype could be more common than it would appear, although boys with MECP2 mutations might also manifest in other ways. Rett syndrome remains a clinical diagnosis that should not be dismissed in boys, and thorough evaluation including karyotype and mutation testing is warranted.

Protein engineering by expressed protein ligation.

By allowing the controlled assembly of synthetic peptides and recombinant polypeptides, expressed protein ligation permits unnatural amino acids, biochemical probes, and biophysical probes to be specifically incorporated into semisynthetic proteins. A powerful feature of the method is its modularity; once the reactive recombinant pieces are in hand and the optimal ligation conditions have been developed, it is possible to quickly generate an array of semisynthetic analogs by simply attaching different synthetic peptide cassettes--in most cases the synthetic peptides will be small and easy to make. From a practical perspective, the rate-determining step in the process is usually not the ligation step (it is based on a simple and efficient chemical reaction), but rather the generation of the reactive polypeptide building blocks. In particular, optimizing the yields of recombinant polypeptide building blocks can require some initial effort. However, it should be noted that the initial investment in time required to optimize the production of the recombinant fragment is offset by the ease and speed with which one can produce the material thereafter. In the example described in this chapter, the yield of soluble intein fusion protein was slightly better using the GyrA intein than for the VMA intein, although in both cases significant amounts of fusion protein were present in the cell pellet. Studies are currently underway to identify optimal refolding conditions for GyrA fusion proteins solubilized from inclusion bodies.

Mechanical strain memory in airway smooth muscle.

We investigated the effect of a single rapid stretch on poststretch force and myosin phosphorylation in bovine tracheal smooth muscle. When unstimulated muscle strips were stretched from suboptimal length to optimal length (L(o)), poststretch steady-state force was not significantly different from that of unstretched control at L(o). However, when carbachol-activated muscle strips were stretched from suboptimal length to L(o), poststretch force and myosin phosphorylation were lower than control and significantly correlated with initial length. When poststretch muscle strips were allowed to relax for 1 h and then activated by K(+) depolarization, the developed force remained significantly correlated with initial length. When the same strain was applied in 23 increments to minimize peak stress, poststretch force and myosin phosphorylation increased significantly, approaching the levels expected at L(o). Furthermore, poststretch force development increased after each cycle of contraction and relaxation, approaching the control level after four cycles. These results suggest that activated airway smooth muscle cells can retain relatively precise memory of past strain when they are stretched rapidly with high stress.

Successful use of intravenous immunoglobulins in Landau-Kleffner syndrome.

A detailed history of a boy with Landau-Kleffner syndrome is presented, demonstrating a close relationship between language functioning and paroxysmal electroencephalogram activity. During a 3-year 6-month follow-up period, three abrupt deteriorations of all language functions occurred: the child became totally noninteractive with his environment within 1 week's time. Two of these deteriorations were reversed with steroid treatment, with an identical recovery phase. Intravenous immunoglobulins had a very dramatic and comparable effect in the third relapse; both language functions and electroencephalogram abnormalities were influenced significantly by the intravenous immunoglobulin treatment.

Empty sella, growth hormone deficiency and pseudotumour cerebri: effect of initiation, withdrawal and resumption of growth hormone therapy.

UNLABELLED: An 11-year-old boy with normal visus and eye fundus, but with empty sella, growth hormone (GH) deficiency and central diabetes insipidus was found to have intracranial hypertension with papilloedema after 6 months of catch-up growth under recombinant human GH (rhGH) replacement therapy. Withdrawal of rhGH therapy was associated with normalisation of intracranial pressure within 1 week. Three months later, resumption of rhGH therapy at a lower dose was again followed by pronounced growth acceleration, but now without papilloedema. CONCLUSION: Children with empty sella and GH deficiency may be prone to rhGH-induced pseudotumour cerebri which appears to be rapidly reversible and dose-dependent.

Childhood neuroborreliosis: clinicoradiological correlation.

We report the cranial CT and MRI findings in three children with Lyme disease (neuroborreliosis). The neuroimaging findings in children have been rarely reported. We found cranial MRI far superior to cranial CT. Ring-enhancing lesions have been described in acute disseminating encephalomyelitis and multiple sclerosis but not in neuroborreliosis. Although other infectious and inflammatory diseases cannot be excluded, Lyme disease should be included in the differential diagnosis and put forward as being the most likely diagnosis in the appropriate clinical setting. Gadopentetate dimeglumine is helpful in assessing the response to antibiotic treatment.

Fibrodysplasia ossificans progressiva: still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who "turned to wood", its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable "clues from the fly" reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.

Optic atrophy as the presenting sign in Hallervorden-Spatz syndrome.

A girl of eight years of age is described with the Hallervorden-Spatz syndrome. Optic atrophy with progressive visual loss was the only presenting symptom for three years. Behavioural and motor disturbances emerged after that time. Optic atrophy can be the first and for some time only symptom of the Hallervorden-Spatz syndrome.

The clinical significance of type 1 fiber predominance.

In the course of investigating children with hypotonia, muscle biopsy of the vastus lateralis frequently demonstrates greater than 55% predominance of the aerobic type 1 fibers of "type 1 fiber predominance" (T1FP). The clinical significance of T1FP is not well known. T1FP can be associated with a variety of neurological disorders but a significant proportion has no apparent cause. We followed up 23 children with T1FP to establish whether a neurological disorder subsequently became apparent or whether a distinct clinical entity of T1FP could be identified. Sixty percent of the children were found to have a specific neurological disorder, while 40% did not and may represent a distinct clinical entity. The majority of children with the clinical entity of T1FP improved although some were left with mild motor disability. Such information is important for counseling when patients with T1FP are first assessed.

Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE.

We retrospectively studied the long-term (2-year) outcome of 50 consecutive patients admitted to our inpatient headache program because of chronic daily headache (CDH) associated with the overuse of analgesics, ergotamine, or both. They had been detoxified, given repetitive intravenous dihydroergotamine (IV DHE) and prophylactic medications as part of the program, and had become headache-free on this regimen. At the time of admission, 37 of the 50 patients had transformed migraine (TM), 12 had new daily persistent headache (NDPH), and 1 had chronic tension-type headache; 29 of the patients with TM, 7 of those with NDPH, and the single patient with chronic tension-type headache had coexistent migraine. Substances abused, alone or in combination, included: caffeine in 39 patients (av. 441 mg/d), acetaminophen in 32 (av. 2187 mg/d), aspirin in 24 (av. 1807 mg/d), ibuprofen in 9 (av. 1156 mg/d), narcotics in 7 (av. 10.1 mg morphine equivalents/d) and ergotamine in 11 (av. 2.3 mg/d). Twenty patients were using preventive medication at the time of admission. Follow-up evaluations were performed at 3, 6, 12, and 24 months after discharge. Forty-three patients were analyzed at 3 months. Of these, 44% had an excellent or good result and 28% a fair result; 3 were overusing analgesics. At 24 months, 39 patients were analyzed: 59% had a good or excellent result and 28% a fair result; 5 were overusing analgesics, 4 of whom were doing poorly.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropsychological impairment in female alcoholics.

Cognitive performance of women alcoholics was assessed to determine whether level and pattern of impairment would be similar to that found in male alcoholics. Subjects were 25 female alcoholics enrolled in residential treatment and 25 female nonalcoholics equated on age, education and vocabulary. Both groups were screened for medical and drug problems before neuropsychological testing.