Successful parathyroidectomy improves cognition in patients with primary hyperparathyroidism: A prospective study in a tertiary medical center and comprehensive review of the literature.

Context: The recent American and European guidelines on management of patients with primary hyperparathyroidism (PHPT) did not endorse neurocognitive evaluation as part of standard work-up and did not consider it as a surgery criterion.The neurocognitive deleterious effects of hyperparathyroidism and impact of parathyroidectomy on PHPT patients is yet to be elucidated. Objective: To evaluate specific neurocognitive functions in PHPT patients prior to parathyroidectomy and describe the changes during follow-up with serial evaluations. Design: A prospective case-control study including parathyroidectomy candidates evaluated at a tertiary teaching university hospital. Thorough neurocognitive evaluation was conducted before and 1- & 6-months following parathyroidectomy: Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (ROCF), Trail Making Test A, Trail Making Test B, Addenbrooke's Cognitive Examination-III (ACE), Frontal Assessment Battery (FAB), Beck Depression Inventory (BDI). Results: 18 consecutive patients underwent successful parathyroidectomy. Various neurocognitive functions improved significantly after successful parathyroidectomy: long term auditory memory (RAVLT, p=0.008), short- and long-term visual memory (ROCF, p=0.006 and p=0.002 respectively), visual attention and complex concentration skills (trail making A, p<0.001) and executive abilities (trail making B, p=0.005). No change was identified in frontal-lobe abilities. Depression symptoms were absent or minimal prior to surgery and no significant change was observed after surgery. Conclusions: PHPT is associated with significant various neurocognitive dysfunctions when mindfully evaluated before surgery. Successful parathyroidectomy results in several neurocognitive aspect improvements. The data suggest that neurocognitive deterioration may be considered an added parathyroidectomy criterion when surgical decision is not straightforward.

Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.

Severe methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia.

IMPORTANCE: Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy. OBSERVATIONS: Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients. CONCLUSIONS AND RELEVANCE: Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation.

A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced ß-glucocerebrosidase activity.

Action myoclonus renal failure (AMRF) syndrome is a rare form of progressive myoclonus epilepsy with renal dysfunction related to mutations in the SCARB2 gene. This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of ß-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease. We report a family with myoclonic epilepsy, ataxia and skeletal muscle atrophy but without cognitive impairment or overt renal disease. A novel SCARB2 mutation was indicated by a striking discrepancy between lymphocyte and fibroblast GC activity in the proband evaluated for possible Gaucher disease. Our findings expand the genetic and phenotypic diversity of AMRF and suggest that low GC activity may present an important biochemical clue to the diagnosis of AMRF.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.

BACKGROUND: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. METHODS: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. RESULTS: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. CONCLUSION: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.

Investigating the neural correlates of psychopathy: a critical review.

In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with psychopathy. The results of such studies could have significant implications for the clinical and legal management of psychopaths, as well as for neurobiological models of human social behavior. In this article, we provide a critical review of structural and functional neuroimaging studies of psychopathy. In particular, we emphasize the considerable variability in results across studies, and focus our discussion on three methodological issues that could contribute to the observed heterogeneity in study data: (1) the use of between-group analyses (psychopaths vs non-psychopaths) as well as correlational analyses (normal variation in 'psychopathic' traits), (2) discrepancies in the criteria used to classify subjects as psychopaths and (3) consideration of psychopathic subtypes. The available evidence suggests that each of these issues could have a substantial effect on the reliability of imaging data. We propose several strategies for resolving these methodological issues in future studies, with the goal of fostering further progress in the identification of the neural correlates of psychopathy.

Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect.

BACKGROUND: Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, VCX-A (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports suggest that mutations in NLGN4 (neuroligin 4), located at that same region, are involved in autistic disorders and ID. METHODS: In the current case study, we clinically and molecularly describe a pedigree of three generations affected by contiguous gene syndrome that includes features of X-linked ichthyosis and Kallmann syndrome. RESULTS: Molecular analysis revealed the presence of an interstitial deletion spanning approximately 4.5Mb at Xp22.3. The centromeric breakpoint was localized between markers DXS1467 and DXS8051, proximal to KAL-1. The telomeric breakpoint was localized between markers DXS89 and DXS1060, distal to NLGN4. The deletion of VCX-A and NLGN4 in this family prompted us to examine the cognitive functions of our two adult patients using comprehensive intellectual and neurocognitive assessment. Normal intellectual function was found in one patient and mild ID was revealed in the other. Neither patient met any Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for a pervasive developmental disorder such as autism. CONCLUSIONS: These findings suggest that deletion of VCX-A and NLGN4 can result in variable phenotypic features and that normal mental development can be achieved despite this deletion, emphasizing the importance of environmental factors and possible modifier genes.

Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity.

BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) is an autosomal recessive form of complicated HSP mainly characterized by slowly progressive spastic paraparesis and mental deterioration beginning in the second decade of life. The locus for HSP-TCC, designated SPG11, was mapped to chromosome 15q13-15 in some of the affected families from Japan, Europe, and North America, spanning an interval of 17.5 megabases (Mb). OBJECTIVE: To perform a clinical and genetic study of HSP-TCC. DESIGN AND SETTING: Case series; multi-institutional study. PATIENTS: Seven patients with HSP-TCC who belong to 3 consanguineous families of Arab origin residing in Israel. RESULTS: The 7 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain magnetic resonance imaging. After excluding the SPG7 locus, we tested the 3 families for linkage to the SPG11, SPG21/MAST, and ACCPN loci associated with autosomal recessive disorders with TCC. Two families showed evidence for linkage to SPG11 (Z(max) = 5.55) and reduced the candidate region to 13 Mb. CONCLUSIONS: Our findings in HSP-TCC further confirm its worldwide distribution and genetic heterogeneity, and they significantly reduce the candidate SPG11 interval.

Frontotemporal dementia with ubiquitinated neuronal inclusions and visuospatial impairment.

Dementia with ubiquitinated neuronal inclusions has been described only with frontotemporal dementia (FTD). The authors report a patient with progressive FTD accompanied by prominent impairments in visuospatial cognitive functions. Pathology was characterized by ubiquitin-positive intranuclear and cytoplasmic neuronal inclusions. Cortical pathology was widespread and posteriorly accentuated but spared the hippocampal dentate gyrus.

The effect of low protein diet in pregnancy on the development of brain metabolism in rat offspring.

The effect of maternal low protein diet in pregnancy on the function of offspring cerebral cytochrome c oxidase (CcO) was investigated in vitro immediately before and after birth, using fetal and neonatal rat pup forebrain tissue. Pregnant rat dams were fed either a control (C, 18% casein n = 22) or low protein (LP, 9% casein n = 14) diet. Cerebral tissues were harvested from pups the day before (E21) and after (P1) birth. A Clarke electrode chamber was used to determine O(2) consumption in brain tissue homogenate, under baseline conditions with and without the mitochondrial electron transport chain inhibitor myxothiazol and in the presence of incremental doses of the electron donor N',N',N',N'-tetramethyl-p-phenylenediamide (TMPD) with myxothiazol. Maximal stimulated CcO activity was less in LP versus C pups at both E21 (P < 0.001) and P1 (P < 0.05). At E21 only, sensitivity to electron flux (pEC(50)) was greater (P < 0.001) in LP compared to C offspring. In addition, was reduced and pEC(50) was greater after birth (i.e. P1 versus E21) in C (P < 0.001) but not in LP pups. This is the first report of the effects of maternal dietary imbalance in pregnancy on offspring cerebral metabolic function. The effects may form part of a developmental adaptive response to reduce energy consumption and promote perinatal survival, or to confer advantage in a postnatal environment predicted to be nutritionally poor.

Brief assessment of cognitive mental status in Hebrew: Addenbrooke's Cognitive Examination.

We describe a new brief neurocognitive assessment instrument, Addenbrooke's Cognitive Examination, which is built around the shell of the Mini-Mental State Examination but which assesses a wider range of cognitive functions specific to various dementing diseases such as Alzheimer's disease and frontotemporal dementia. A Hebrew-language adaptation of the instrument is also provided.

Early clinical heterogeneity in choreoacanthocytosis.

BACKGROUND: Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene. OBJECTIVE: To describe the early clinical features and possible genotype-phenotype correlation in CHAC. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS AND MAIN OUTCOME METHODS: Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A. RESULTS: Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear. CONCLUSIONS: These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.

Regional cerebral blood flow in patients with mild hypothyroidism.

UNLABELLED: Emotional and cognitive abnormalities are common in adult hypothyroidism. Few studies, however, have evaluated cerebral perfusion and metabolism in this disorder. The aims of this study were to compare regional cerebral blood flow (rCBF) between hypothyroid patients and healthy subjects and assess flow during the euthyroid state after treatment. METHODS: Ten mildly hypothyroid patients, before and after thyroxine treatment, and 10 healthy controls underwent 99mTc-hexamethylpropyleneamine oxime brain SPECT, MRI, and psychometric testing. SPECT images were analyzed using statistical parametric mapping. RESULTS: Compared with controls, rCBF in patients before treatment was lower in right parietooccipital gyri, cuneus, posterior cingulate, lingual gyrus, fusiform, insula, and pre- and postcentral gyri. Perfusion did not normalize on a return to the euthyroid state. CONCLUSION: Decreased rCBF in mild hypothyroidism is found in regions mediating attention, motor speed, memory, and visuospatial processing, faculties affected in hypothyroidism. Follow-up studies are needed to determine the longer-term persistence of perfusion abnormalities in this disorder.

Response perseveration in psychopathic women.

Recent attempts to validate the Psychopathy Checklist-Revised (PCL-R) as a measure of psychopathy in female offenders have been limited by a failure to examine laboratory correlates of the syndrome. We assessed 112 incarcerated women by using the PCL-R and examined their performance on a card perseveration task that has been used to demonstrate response perseveration in psychopathic men. Contrary to prediction, psychopathic women did not perseverate responding when the PCL-R was used either dimensionally or categorically. The authors discuss the implications of the results for the PCL-R and for female psychopathy more generally.