Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families. Expression of mutant TRPV4 constructs in cells from the HeLa line revealed diminished surface localization of mutant proteins. In addition, TRPV4-regulated Ca(2+) influx was substantially reduced even after stimulation with 4alphaPDD, a TRPV4 channel-specific agonist, and with hypo-osmotic solution. In summary, we describe a new hereditary channelopathy caused by mutations in TRPV4 and present evidence that the resulting substitutions in the N-terminal ankyrin domain affect channel maturation, leading to reduced surface expression of functional TRPV4 channels.

OBJECTIVES: Although Spiritual Transformation (ST) occurs in a sizable proportion of people with HIV (about 39%), there is little research on the potential benefits of ST with respect to psychological well-being, health, and survival in this population. Our study attempts to fill this gap. METHOD: Using a mixed method approach, we related interviews of 147 people with HIV (identifying the presence/absence of ST) to questionnaires measuring demographics, medical history, treatment adherence, physical symptoms, and psychological well-being (i.e., stress, coping, life attitude, and spirituality), and assessments of CD4-counts and viral load and survival 3 to 5 years later. RESULTS: At comparable times since HIV-diagnosis and antiretroviral medications prescribed, the presence of ST was significantly associated with better treatment success (undetectable viral loads, higher CD4 counts), better medication adherence, fewer symptoms, less distress, more positive coping, different life attitudes (i.e., existential transcendence, meaning/purpose in life, optimism, death acceptance), more spiritual practices, and increased spirituality. ST was also associated with substance-use recovery and with being African American. Survival up to 5 years was 5.35 times more likely among participants with ST (p(f)=.044). According to a Cox-regression adjusted for baseline CD4-counts, age, race-ethnicity, gender, education, years since HIV-diagnosis, and a history of substance-use problems, ST still reduced the risk of death (HR = 0.07, 95% CI = 0.01-0.53, p =.010). CONCLUSIONS: ST has associated benefits for psychological well-being, health, and survival.

OBJECTIVES: Spiritual Transformation (ST) is accompanied by dramatic changes in spiritual beliefs along with major changes in behaviors, self-view, and attitudes. This study examined types of ST, as well as its antecedents and consequences in people with HIV. METHOD: Qualitative content analysis was used to analyze interviews about ST in people's lives in two samples: people with chronic HIV-disease (chronic disease sample, n = 74) and people with HIV who identified themselves as spiritual (spiritual sample, n = 73). RESULTS: ST occurred in 39% of the chronic disease and 75% of the spiritual sample. These STs were generally positive (95%) and enduring (M = 8.71 +/- 7.43 years). ST was most frequently associated with spiritual experience (in particular near-death experience), substance-use recovery, and HIV/AIDS-diagnosis. Main antecedents were substance-use disorder, education/upbringing, and desire to change. Further themes were depression/helplessness, confrontation with illness/death, social support, and lifestyle. The top six consequences include spiritual intensification, more spiritual practices, positive feelings toward self, recovery from substance-use, finding new meaning and purpose in life, and increased self-knowledge. In the spiritual sample, there was a common pattern of hitting rock bottom with drugs, having a spiritual experience (in particular a near-death experience), and joining a drug program. CONCLUSIONS: Positive ST occurs in a sizable proportion of people with HIV. Importantly, ST often results in an enduring substance-use recovery, and an improved quality of life as indicated by enhanced gratitude, appreciation, joy, sense of peace, and reduced fear of death.

PURPOSE. Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome associated, interaction partners of whirlin and thereby obtain more insights into the function of whirlin. METHODS. The database of ciliary proteins was searched for proteins that are present in both retina and inner ear and contain a PDZ-binding motif. Interactions with whirlin were evaluated by yeast two-hybrid analyses, and validated by glutathione S-transferase pull-down assays, co-immunoprecipitations and co-localization in the retina with immunofluorescence and immunoelectron microscopy. RESULTS. The L-type calcium channel subunit Cav1.3 (alpha1D) specifically interacts with whirlin. In adult photoreceptors, Cav1.3 (alpha1D) and whirlin co-localize in the region of the connecting cilium and at the synapse. During murine embryonic development, the expression patterns of the Whrn and Cacna1d genes show significant overlap and include expression in the eye, the inner ear and the central nervous system. CONCLUSIONS. Our findings indicate that Cav1.3 (alpha1D) is connected to the Usher protein network. We hypothesize that in the retina whirlin scaffolds Cav1.3 (alpha1D), and therefore contributes to the organization of calcium channels in the photoreceptor cells, where both proteins may be involved in membrane fusions.

Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both respiratory complex II and the TCA cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin-adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma (PGL), a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.

OBJECTIVES: We analyzed the phenotype in a 5-generation DFNA20/26 family with a novel missense mutation in the ACTG1 gene (c.151G>A) and compared the findings to previous reports on DFNA20/26 families. METHODS: Audiometric data were collected from the family members of a Dutch kindred with the novel ACTG1 mutation. Cross-sectional and/or longitudinal analyses were performed on pure tone and speech audiometry data of the mutation carriers. Age-related typical audiograms were constructed. Vestibular examination was performed in all mutation carriers. RESULTS: Overall, high-frequency hearing impairment, most prominent at ages over 30 years, was observed with a progression rate of 1.1 to 2.1 dB/y, increasing with frequency. It ultimately resulted in residual hearing. Speech recognition scores remained good at given pure tone average (1, 2, and 4 kHz) levels, but were slightly poorer than those at similar levels in a group of patients with presbycusis. Vestibular examination did not reveal any consistent, statistically significant abnormalities. CONCLUSIONS: The audiometric phenotype of the Dutch DFNA20/26 family with a novel mutation in ACTG1 was largely consistent with previous reports on DFNA20/26. Considerable variations were found in audiogram configurations within the family. This is the first known DFNA20/26 family that has experienced tinnitus.

OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. RESULTS: Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5>A and c.496 + 5>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5>A resulted in less ATM protein and kinase activity than the missense mutations. CONCLUSIONS: Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented with dementia, spastic paraparesis, and frontal executive function impairments, mimicking familial Creutzfeldt Jakob disease and frontotemporal dementia. CSF studies, revealing increased total tau and phosphorylated-tau levels with decreased amyloid-beta<formula>_{42}</formula>, distinguished familial AD from Creutzfeldt Jakob disease and frontotemporal dementia. A causative p.L424R PSEN1 mutation was subsequently identified.

The objective of this non-controlled interventional clinical study was to evaluate the efficacy of imiquimod in the treatment of fields with multiple, multiform AK. 180 office-based dermatological practices in Germany participated. Patients with clinically typical, visible AK lesions on the head were treated with 5% imiquimod cream 3 times per week for 4 weeks followed by a 4 week treatment pause. If lesions were still present, a second treatment course of treatment (COT) was given. Complete clearance rate, i.e. no clinically visible AK lesions in the treatment area, was the main outcome measure. 829 patients were enrolled. The complete clearance rate was 40.5% after the first COT and 68.9% overall. Altogether, 85.4% of the 7,427 baseline lesions were cleared. Patients with hyperkeratotic/hypertrophic lesions showed comparable responses. Local skin reactions were the most commonly reported adverse effects, causing discontinuation in only 4 patients. Severity of the local skin reactions was a strong predictor of the outcome. Patients with multiple multiform AK on the head can be successfully and safely treated with topical imiquimod in daily practice. Assurance of patient understanding that treatment success is closely correlated to proper drug administration is important.