Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Characterization of Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism

Summary: Hypoparathyroidism (hypoPT) and pseudohypoparathyroidism (Ps-hypoPT) are rare diseases, characterized by low levels of parathyroid hormone [PTH] and plasma calcium or high plasma PTH and low plasma calcium, respectively. A recently study by the investigators' group, identified 123 living persons with idiopathic hypoPT and 62 living persons with Ps-hypoPT, only few of these have been genetic tested.
  The aim of the study is to perform a detailed clinical and genetic characterization of Danish patients with idiopathic hypoPT and Ps-hypoPT. Patients will be examined by questionnaires, biochemistry, scans, bone biopsies and genetic tests. Furthermore the investigators aim to perform family tracing for the hereditary forms. The prevalence of magnesium depletion will be assessed as well.
  In addition to providing new information on symptoms, co-morbidity, and prognosis for this group of patients, the investigators presume that the study may improve their understanding on calcium homeostasis and bone metabolism in general.

Detailed description: Background:
  Hypoparathyroidism (HypoPT) is a group of rare clinical disorders characterized by hypocalcaemia and hyperphosphatemia with inappropriate low levels of parathyroid hormone (PTH). Due to the lack of PTH, the renal production of 1α,25-dihydroxycholecalciferol (1,25(OH)2D) is reduced. Most often, HypoPT is caused by accidental removal of the parathyroid glands during neck surgery (postsurgical hypoPT). However, in rare in-stances HypoPT is caused by autoimmune disorders with immune mediated destruction of the parathyroid glands, or a variety of genetic mutations, including the CATCH-22 (DiGeorge) Syndrome, familial isolated HypoPT or an activating mutation in the gene encoding the calcium-sensing receptor (CaSR), termed autosomal dominant hypocalcaemia (ADH).
  The CaSR is not only found in the parathyroid glands, but is also expressed by other tissue including the renal tubules. Low plasma levels of ionised calcium (Ca2+) are registered by the calcium sensing receptors (CaSR) located e.g. in the cell membranes of the parathyroids and in the renal tubules. Low levels of Ca2+ increases the release of PTH from the parathyroids, which normalises plasma Ca2+ and decrease P-phosphate. Lack of PTH decreases the renal synthesis of 1,25-dihydroxycholecalciferol, witch in combination with low PTH decreases bone turnover. Although, large-scale meta-analysis of genome wide association data incorporating 150 candidate genes did not link the CaSR to bone mineral density or osteoporotic fracture risk, no specific data are available on whether BMD in patients with an activating mutation in their CaSR gene (ADH patients) differs from the general population. The largest case series of patients with ADH so far reported included 25 patients and did not report BMD within this group.
  Calcium is of importance to many physiological processes, including cardiovascular functioning. The CaSR has been suggested to be of importance in the regulation of blood pressure and a Batter's like phenotype has been reported in patients with ADH. Although the recent study by the investigators' group did not show an increased cardiovascular morbidity in patients with postsurgical hypoPT, no data are available on blood pressure regulation or indices of atherosclerosis in patients with idiopathic hypoPT.
  PseudoHypoPT is due to PTH resistance in the target organs, causing hypocalcemia with inappropriate high PTH concentrations. The phenotype in type 1 is known as Albrights's hereditary osteodystrophy, (AOH) (maternal 2 of 8 allele). Pseudo-pseudoHypoPT is characterized by AOH, but without the typical biochemical findings (pater-nal allele). PseudoHypoPT type 2 has typical biochemical changes but no characteristic phenotype. Discrepant results have been reported on effects on bone mineral density (BMD), as some studies has shown a decreased BMD (hyperparathyroid bone disease), whereas other studies have shown that BMD actually may be increased.
  Untreated, hypoPT is characterized by an increased neuromuscular irritability including weakness, muscle cramps, paraesthesias of the lips, tongue, fingers and feet, loss of memory, headaches and uncontrollable cramping muscle movements of the wrists and feet (carpopedal spasm). Other symptoms may be spasm of the facial muscles (Chovstek´s Sign) and the contraction of the muscle produced by ischemia (Trousseaus Sign).
  In long standing congenital cases there may be cataract and malformations of the teeth's. Due to high blood phosphorous levels intracranial calcifications (basal ganglia) may be seen by X-ray. Renal stones and renal failure may develop either because of the disease or its treatment. Studies have shown that postsurgical hy-poPT is associated with a reduced quality of life (QoL).
  Aim:
  The aim of the project is to perform a detailed clinical and genetic characterization of Danish patients with idiopathic hypoparathyroidism, including pseudohypoparathyroidism. Patients will be examined as detailed in the section on methods, and genetic tests will be performed in patients who have not been tested previously. Furthermore the investigators aim to perform family tracing for the hereditary forms.
  Design:
  A cross-sectional descriptive study on patients with idiopathic hypoparathyroidism, autosomal dominant hypocalcaemia and pseudohypoparathyroidism, including family tracing for inherited forms.
  Materials and methods:
  Study subjects:
  All patients with non-surgical hypoPT in Denmark will be invited by letter to participate in the study. Patients who accept participation will undergo a detailed examination in terms of:
  -  Questionnaire/ interviews:
  -  Quality of life: To study the participants health related quality of life the WHO's 5 Well-Being Index, the Physical Activity Scale (PAS), and the SF-36v2 will be used in a Danish version.
  -  Biochemistry incl. genetics
  -  24hours urine:
  -  Cardiovascular indices: Blood pressure is measured in sitting position twice after minimum 5 minutes of rest. The presence of atherosclerosis is assessed by tonometry measuring pulse wave velocity and central aortic pressure using the SphygmoCor System.
  -  Muscle function- and postural stability: Isometric maximum voluntary muscle strength on the dominant hand side is measured using a dynamometer connected to a computer (Good Strength TM, Meititur Ldt, Finland) (25;26). Muscle strength is assessed at knee and elbow flexion and extension. Similarly, grip strength on the dominant hand is measured. Balance function is assessed by measuring the dynamic stability on a stadiometer (Meititur Ltd, Finland). Two smaller physical tests are also performed, "Repeated chair stand test" and "Timed Up and Go-test".
  -  Osteodensitometry: Bone mineral content (BMC) and areal bone mineral density (aBMD) is assessed by Dual-Energy X-ray absorptiometry" (DXA) using a Hologic Discovery scanner. Measurements are performed at the lumbar spine (L1-L4), hip region, forearm, and the whole body. Furthermore, body composition (lean and fat-tissue mass) will be determined by DXA. Volumetric total, cortical, and trabecular bone mineral density (vBMD) at the lumbar spine (L1+L2) and at the hip are assessed using quantitative computer tomography (QCT) (Mid-ways Software Inc., Austin Texas, USA). Bone microarchitecture is assessed by high resolution peripheral quantitative computer tomography (HRpQCT)-scans of the right forearm and tibia using an XtremeCT scanner (Scan-co Medical).
  -  Bone biopsies: a bone biopsy will be obtained from the iliac crest for histomorphometric analyses. Prior to the biopsy, intravital tetracycline double marking will be performed.
  -  Family tracing: Investigations on first degree relatives will be performed in patients with known inherited forms of hypoPT as well as in patients with hypoPT of unknown origin. At first, family members will have plasma levels of calcium and PTH measured. If results show signs of hypoPT, the relatives will be examined as the index persons themselves (as detailed in this protocol).
  Statistics:
  Differences between study groups are assessed using Fisher's Exact Test for categorical variables and a two-sample t-test or Mann-Whitney U-test for continuous variables, as appropriate. Sample size calculation are as detailed in the section on hypothesis.
  Ethical considerations:
  The general protocol has been approved by the Central Denmark Region Committees on Biomedical Research Ethics.
  Perspective:
  HypoPT is a rare disease and only few data are available on this group of patients. In addition to providing new information on symptoms, co-morbidity, and prognosis for this group of patients, the investigators presume that the study may improve their understanding on mechanisms of importance to calcium homeostasis and bone metabolism in general.

Eligibility: Inclusion Criteria:
  -  Diagnosed with either:
  Idiopathic hypoparathyroidism, pseudohypoparathyroidism or autosomal dominant hypocalcaemia
  -  Participants must be able to read and understand Danish
  Exclusion Criteria:
  -  None

Relevance to patient case: not relevant