Ca&Bone

[A de novo heterozygous R551K point mutation and an A986S polymorphism in a patient with neonatal severe primary hyperparathyroidism]

CSÁKVÁRY Violetta, TÓTH Miklós, PATÓCS Attila, VARGA Ibolya, OROSZLÁN György, RÁCZ Károly

NOVEMBER 20, 2004

Ca&Bone - 2004;7(04)

[INTRODUCTION - Familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism are caused by inactivating mutations of the calcium-sensing receptor (CaSR) gene. We report the case of a now 9.5 years old boy who presented with the clinical syndrome of neonatal severe hyperparathyroidism. PATIENT AND METHODS - At the age of 2 days the patient developed respiratory distress. Clinical studies revealed increased serum calcium (3.1 mmol/l), non-suppressed serum parathyroid hormone level (48.3 pg/ml) and severe undermineralization of bones, as well as periosteal calcification in the distal part of both femurs suggesting fractures during the intrauterine life. Parathyreoidectomy was not performed.At the age of 6 years normal mental and physical development, persisting hypercalcemia without clinical symptoms, normal skeletal morphology, absence of new bone fractures, and absence of renal stones or nephrocalcinosis were documented, and the patient has remained completely symptom-free until his present age of 9.5 years. Sequence analysis of the entire coding region (exons 2-7) of the CaSR gene in peripheral leukocyte DNA revealed a heterozygous mutation at codon 551 (AGG→AAG) predicting a change of arginine to lysine (R551K). In addition, a known heterozygous polymorphism at codon 986 (GCC→TCC) was found in the proband and in his father. CONCLUSION - Our patient seems to represent the fourth reported case of neonatal severe primary hyperparathyroidism with a heterozygous de novo mutation of the CaSR gene. In addition, this case provides new evidence that with time the disease of neonatal severe hyperparathyroidism may spontaneously turn into a symptomless, benign condition resembling familial hypocalciuric hypercalcemia.]

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Ca&Bone

[Comparison of osteodensitometric and quantitative bone ultrasound parameters among patients with pseudopseudohypoparathyroidism, pseudohypoparathyroidism type Ia and primary hyperparathyroidism]

CSUPOR EMŐKE, SZABOLCS István, FERENCZ VIKTÓRIA, GÓTH Miklós, IVÁN Gabriella, GYŐRI Gabriella, KOVÁCS LÁSZLÓ, TÓTH EDIT, MÉSZÁROS SZILVIA, HORVÁTH CSABA

[INTRODUCTION - Parathyroid hormone (PTH) excretion is increased both in primary hyperparathyroidism (pHPT) and in pseudohypoparathyroidism type Ia (PHP Ia). Pseudo-pseudohypoparathyroidism (P-PHP) is considered to be the normocalcemic form of pseudohypoparathyroidism type Ia. Our aim was to assess bone mineral content and bone quality as well as to determine whether these parameters are related to PTH levels in the above mentioned disorders. PATIENTS AND METHOD - 10 patients with pseudopseudohypoparathyroidism (P-PHP, age: 41.6 ±5.4 ys) were compared to 10 patients with primary hyperparathyroidism (pHPT) and to 10 healthy subjects, matched for age and gender. Moreover, nine patients with pseudohypoparathyroidism type Ia (PHP, age: 34.2 ±5.43 ys) were compared to nine age- and gender-matched patients with primary hyperparathyroidism and to nine healthy controls, respectively.The occurrence of previous bone fractures was recorded and bone mass was measured (by dual photon absorptiometry on the axial bones and by single photon absorptiometry on the forearm). Quantitative ultrasound (QUS) examination was performed both on the calcaneus by broadband ultrasound attenuation (BUA, dB/MHz) and speed of sound (SOS, m/s) measurements and on the proximal phalanges by amplitude-dependent speed of sound (AdSOS, m/s) measurements. In addition, some laboratory parameters of calcium metabolism were tested. RESULTS - No difference was found between PHP Ia and pHPT in bone mass.The lowest value was observed at the radius. Among the QUS parameters, pathologically low AdSOS was found at the phalanges in PHP Ia and it was lower than in pHPT patients, whereas at the calcaneus BUA showed a similar tendency. Bone mass did not significantly differ between P-PHP and healthy controls, it was decreased, however, at the forearm in the patients. Pathological AdSOS was found in P-PHP, which was lower than in pHPT. SOS at the calcaneus was lower in P-PHP than in pHPT, though it was not considered pathological. Laboratory results were typical for the diseases and the radiological examinations confirmed the diagnosis. Bone fractures occurred in three and two patients with PHP Ia and P-PHP, respectively, while no fractures were recorded in the pHPT and healthy groups. CONCLUSION - Bone loss among patients with PHP Ia is considered to be the impact of PTH excess on bone tissue.The deterioration of bone quality and architecture may play a role in the development of bone fractures.]

Ca&Bone

[Biochemical processes of the bone in patients treated with clodronate for metastatic prostate cancer]

GERVAIN Mihály, BEZZEGH Attila, PREKOPP Gábor, VANIK Miklós, FÉL Pál, VARGA Béla, BORSI László, PÁSZTOR Imre, KORÁNYI Sándor, PINTÉR Erzsébet

[INTRODUCTION - The bone remodelling process of 81 patients with metastatic prostate cancer was analyzed and correlated to PSA levels. PATIENTS AND METHODS - The patients were recruited from 9 collaborating urology departments. Levels of β-CrossLaps, BALP, urine calcium and urine phosphate were measured. All patients were treated identically (TUR plus an LH-RH analogue or MAB), according to GCP guidelines. After the appearance of metastasis, the patients also received a bisphosphonate compound (clodronate). RESULTS - Bone degradation and formation showed a correlation both in living and deceased patients, indicating that the two processes are not independent. A progressive decrease in the PSA level was associated with a decrease in the β-CrossLaps level. CONCLUSION - In addition to PSA, β-CrossLaps and BALP, two markers of bone metabolism, might prove good predictors of metastasis formation and of response to therapy. Evaluation of the markers relative to agedependent osteoporosis can further improve their predictive value.]

Ca&Bone

[The pathophysiological role of the cell surface calcium-sensing receptor New clinical entities and drugs, potential therapeutic targets]

TÓTH Miklós

[The extracellular calcium-sensing receptor (CaSR) was recognized and cloned a decade ago. It is a G-proteincoupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. Diseases known as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism and autosomal dominant hypocalcemia are the consequences of naturally occurring mutations of the CaSR. However, the spectrum of the CaSR diseases became more complex with the recognition of both hypo- and hypercalcemic states caused by anti-CaSR autoantibodies. Activating anti-CaSR autoantibodies have been implicated in the pathogenesis of isolated idiopathic hypoparathyroidism and of hypoparathyroidism associated with autoimmune polyglandular syndromes. Inactivating CaSR autoantibodies may cause fluctuating hypercalcemic disorder that resembles primary hyperparathyroidism. The CaSR recently became one of the most intensively investigated target of potential new drugs. Cinacalcet has been approved for the treatment of secondary hyperparathyroidism associated with chronic renal insufficiency and for the management of inoperable or metastatic parathyroid carcinoma.The CaSR may be one of the main molecular target of strontium ranelate, wich is a new antiosteoporotic compound.]

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Ca&Bone

[The pathophysiological role of the cell surface calcium-sensing receptor New clinical entities and drugs, potential therapeutic targets]

TÓTH Miklós

[The extracellular calcium-sensing receptor (CaSR) was recognized and cloned a decade ago. It is a G-proteincoupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. Diseases known as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism and autosomal dominant hypocalcemia are the consequences of naturally occurring mutations of the CaSR. However, the spectrum of the CaSR diseases became more complex with the recognition of both hypo- and hypercalcemic states caused by anti-CaSR autoantibodies. Activating anti-CaSR autoantibodies have been implicated in the pathogenesis of isolated idiopathic hypoparathyroidism and of hypoparathyroidism associated with autoimmune polyglandular syndromes. Inactivating CaSR autoantibodies may cause fluctuating hypercalcemic disorder that resembles primary hyperparathyroidism. The CaSR recently became one of the most intensively investigated target of potential new drugs. Cinacalcet has been approved for the treatment of secondary hyperparathyroidism associated with chronic renal insufficiency and for the management of inoperable or metastatic parathyroid carcinoma.The CaSR may be one of the main molecular target of strontium ranelate, wich is a new antiosteoporotic compound.]

Clinical Neuroscience

Late simultaneous carcinomatous meningitis, temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting with mono-symptomatic vertigo – a clinico-pathological case reporT

JARABIN András János, KLIVÉNYI Péter, TISZLAVICZ László, MOLNÁR Anna Fiona, GION Katalin, FÖLDESI Imre, KISS Geza Jozsef, ROVÓ László, BELLA Zsolt

Although vertigo is one of the most common complaints, intracranial malignant tumors rarely cause sudden asymmetry between the tone of the vestibular peripheries masquerading as a peripheral-like disorder. Here we report a case of simultaneous temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting as acute unilateral vestibular syndrome, due to the reawakening of a primary gastric signet ring cell carcinoma. Purpose – Our objective was to identify those pathophysiological steps that may explain the complex process of tumor reawakening, dissemination. The possible causes of vestibular asymmetry were also traced. A 56-year-old male patient’s interdisciplinary medical data had been retrospectively analyzed. Original clinical and pathological results have been collected and thoroughly reevaluated, then new histological staining and immunohistochemistry methods have been added to the diagnostic pool. During the autopsy the cerebrum and cerebellum was edematous. The apex of the left petrous bone was infiltrated and destructed by a tumor mass of 2x2 cm in size. Histological reexamination of the original gastric resection specimen slides revealed focal submucosal tumorous infiltration with a vascular invasion. By immunohistochemistry mainly single infiltrating tumor cells were observed with Cytokeratin 7 and Vimentin positivity and partial loss of E-cadherin staining. The subsequent histological examination of necropsy tissue specimens confirmed the disseminated, multi-organ microscopic tumorous invasion. Discussion – It has been recently reported that the expression of Vimentin and the loss of E-cadherin is significantly associated with advanced stage, lymph node metastasis, vascular and neural invasion and undifferentiated type with p<0.05 significance. As our patient was middle aged and had no immune-deficiency, the promoting factor of the reawakening of the primary GC malignant disease after a 9-year-long period of dormancy remained undiscovered. The organ-specific tropism explained by the “seed and soil” theory was unexpected, due to rare occurrence of gastric cancer to metastasize in the meninges given that only a minority of these cells would be capable of crossing the blood brain barrier. Patients with past malignancies and new onset of neurological symptoms should alert the physician to central nervous system involvement, and the appropriate, targeted diagnostic and therapeutic work-up should be established immediately. Targeted staining with specific antibodies is recommended. Recent studies on cell lines indicate that metformin strongly inhibits epithelial-mesenchymal transition of gastric cancer cells. Therefore, further studies need to be performed on cases positive for epithelial-mesenchymal transition.

Clinical Neuroscience

Alexithymia is associated with cognitive impairment in patients with Parkinson’s disease

SENGUL Yildizhan, KOCAK Müge, CORAKCI Zeynep, SENGUL Serdar Hakan, USTUN Ismet

Cognitive dysfunction (CD) is a common non-motor symptom of Parkinson’s disease (PD). Alexithy­mia is a still poorly understood neuropsychiatric feature of PD. Cognitive impairment (especially visuospatial dysfunction and executive dysfunction) and alexithymia share com­mon pathology of neuroanatomical structures. We hypo­thesized that there must be a correlation between CD and alexithymia levels considering this relationship of neuroanatomy. Objective – The aim of this study was to evaluate the association between alexithymia and neurocognitive function in patients with PD. Thirty-five patients with PD were included in this study. The Toronto Alexithymia Scale–20 (TAS-20), Geriatric Depression Inventory (GDI) and a detailed neuropsychological evaluation were performed. Higher TAS-20 scores were negatively correlated with Wechsler Adult Intelligence Scale (WAIS) similarities test score (r =-0.71, p value 0.02), clock drawing test (CDT) scores (r=-0.72, p=0.02) and verbal fluency (VF) (r=-0.77, p<0.01). Difficulty identifying feelings subscale score was negatively correlated with CDT scores (r=-0.74, p=0.02), VF scores (r=-0.66, p=0.04), visual memory immediate recall (r=-0.74, p=0.01). VF scores were also correlated with difficulty describing feelings (DDF) scores (r=-0.66, p=0.04). There was a reverse relationship bet­ween WAIS similarities and DDF scores (r=-0.70, p=0.02), and externally oriented-thinking (r=-0.77,p<0.01). Executive function Z score was correlated with the mean TAS-20 score (r=-62, p=0.03) and DDF subscale score (r=-0.70, p=0.01) Alexithymia was found to be associated with poorer performance on visuospatial and executive function test results. We also found that alexithymia was significantly correlated with depressive symptoms. Presence of alexithymia should therefore warn the clinicians for co-existing CD.

Clinical Neuroscience

[The role of sleep in the relational memory processes ]

CSÁBI Eszter, ZÁMBÓ Ágnes, PROKECZ Lídia

[A growing body of evidence suggests that sleep plays an essential role in the consolidation of different memory systems, but less is known about the beneficial effect of sleep on relational memory processes and the recognition of emotional facial expressions, however, it is a fundamental cognitive skill in human everyday life. Thus, the study aims to investigate the effect of timing of learning and the role of sleep in relational memory processes. 84 young adults (average age: 22.36 (SD: 3.22), 21 male/63 female) participated in our study, divided into two groups: evening group and morning group indicating the time of learning. We used the face-name task to measure relational memory and facial expression recognition. There were two sessions for both groups: the immediate testing phase and the delayed retesting phase, separated by 24 hours. 84 young adults (average age: 22.36 (SD: 3.22), 21 male/63 female) participated in our study, divided into two groups: evening group and morning group indicating the time of learning. We used the face-name task to measure relational memory and facial expression recognition. There were two sessions for both groups: the immediate testing phase and the delayed retesting phase, separated by 24 hours. Our results suggest that the timing of learning and sleep plays an important role in the stabilizing process of memory representation to resist against forgetting.]