Faculty Bibliography

The cognitive mechanisms for the analysis of flavour information remain poorly understood. Patients with semantic dementia (SD) could potentially provide a window on these mechanisms; however, while abnormal eating behaviour and altered food preferences are common in SD, flavour processing has been little studied in this disorder. Here we undertook a detailed investigation of flavour processing in three patients at different stages of SD. One patient with a clinical syndrome of logopenic aphasia (LPA) was studied as a disease control, and six healthy control subjects also participated. Olfaction was assessed using the University of Pennsylvania Smell Identification Test and processing of flavours was assessed using a novel battery to assess flavour perception, flavour identification, and congruence and affective valence of flavour combinations. Patients with SD performed equivalently to healthy controls on the perceptual subtest, while their ability to identify flavours or to determine congruence of flavour combinations was impaired. Classification of flavours according to affective valence was comparable to healthy controls. In contrast, the patient with LPA exhibited a perceptual deficit with relatively preserved identification of flavours, but impaired ability to determine flavour congruence, which did not benefit from affective valence. Olfactory and flavour identification performance was correlated in both patients and controls. We propose that SD produces a true deficit of flavour knowledge (an associative agnosia), while other peri-Sylvian pathologies may lead to deficient flavour perception. Our findings are consistent with emerging evidence from healthy subjects for a cortical hierarchy for processing flavour information, instantiated in a brain network that includes the insula, anterior temporal lobes and orbitofrontal cortex. The findings suggest a potential mechanism for the development of food fads and other abnormal eating behaviours.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. RESULTS:Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 +/- 54 ml/min/1.73 m(2)) was greater than for perinatal patients (62 +/- 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 +/- 32) in comparison with medullary involvement only (131 +/- 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. CONCLUSIONS:In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.

PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.