Mitochondrial disease and endocrine dysfunction

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases

Pseudohypoparathyroidism type I-b with neurological involvement is associated with a homozygous PTH1R mutation

Pseudohypoparathyroidism type 1b (PHP1b) is characterized by hypocalcemia, hyperphosphatemia, increased levels of circulating parathyroid hormone (PTH), and no skeletal or developmental abnormalities. The goal of this study was to perform a full characterization of a familial case of PHP1b with neurological involvement and to identify the genetic cause of disease. The initial laboratory profile of the proband showed severe hypocalcemia, hyperphosphatemia and normal levels of PTH, which was considered to be compatible with primary hypoparathyroidism. With disease progression the patient developed cognitive disturbance, PTH levels were found to be slightly elevated and a picture of PTH resistance syndrome seemed more probable. The diagnosis of PHP1b was established after the study of family members and blunted urinary cAMP results were obtained in a PTH stimulation test. Integration of whole genome genotyping and exome sequencing data supported this diagnosis by revealing a novel homozygous missense mutation in PTH1R (p.Arg186His) completely segregating with the disease. Here, we demonstrate segregation of a novel mutation in PTH1R with a phenotype of PHP1b presenting with neurological symptoms, but no bone defects. This case represents the extreme end of the spectrum of cognitive impairment in PTH dysfunction and defines a possible novel form of PHP1b resulting from the impaired interaction between PTH and PTH1R

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI

Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes

Introduction There are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2, PDGFB, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods We performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2, PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification

Rare association of Fahr’s disease with multiple myeloma: A case report

Fahr’s disease or Fahr’s syndrome is a rare neurological disorder characterized by abnormal calcified deposits in the basal ganglia and cerebral cortex. 47 years male who presented to us with progressive ataxia and Parkinsonian symptoms was found to have extensive bilateral calcifications including bilateral basal ganglia in CT scan of the brain. The secondary causes of intracranial calcifications were ruled out to make a clinical diagnosis of Fahr’s disease. While investigating for chronic low back pain with anemia and renal failure, high ESR and serum protein electrophoresis showing M band was detected. On further investigation, the bone marrow study confirmed the diagnosis of multiple myeloma. There are only few case reports of association of Fahr’s disease and multiple myeloma in literature. The case is being reported here in view of rarity

Fahr’s syndrome with seizure presentation

Fahr's disease (FD) or Fahr’s syndrome is characterized by basal ganglia calcification with clinical manifestations in the form of neuropsychiatric disorders, neurological symptoms, and cognitive symptoms. FD commonly affects young to middle aged adults. The etiology of this syndrome does not identify a specific agent. Clinical manifestations of this disease incorporate a wide variety of symptoms. The diagnostic criteria of Fahr’s Syndrome consist of bilateral calcification of basal ganglia, progressive neurologic dysfunction, absence of biochemical abnormalities, infectious, traumatic, and a significant family history. Medical imaging techniques for the diagnosis consist of computed tomography (CT), magnetic resonance imaging (MRI), and plain radiography of the skull. This paper presents a case of Fahr’s syndrome in a 60-year-old married prisoner with antisocial personality and seizures. Furthermore, CT and MRI scans showed bilateral symmetric calcifications in the basal ganglia calcification (BGC) and dentate nuclei, cerebellum, and centrum semiovale

Serum calcium and magnesium abnormalities in patients with status epilepticus: a single centre tertiary care experience

Electrolyte imbalances frequently cause seizures, and these seizures may be the sole presenting symptom. Seizures are especially common in patients with sodium disorders, hypocalcemia, and hypomagnesemia. Successful management of patient seizures begins with the establishment of an accurate diagnosis of the underlying electrolyte disturbance, because rapid identification and correction of the disturbance is necessary to control seizures and prevent permanent brain damage. Objectives: To delineate the percentage of people with status epilepticus having calcium and magnesium deficiencies at admission. Methods: The study was carried out from April 2013 to October 2013 at Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan. Seventy patients diagnosed with status epilepticus were enrolled in the study and frequencies of serum calcium & magnesium abnormalities were measured and compared. Results: Calcium level was low in 29 (41.4%) patients. Magnesium level was low only in 7 (10%) patients. Both calcium & magnesium levels were low in 7 (10%) patients. Among the known epileptics, 16 (76.1%) were on regular antiepileptic treatment. Among those on antiepileptic drugs, 8 (50%) had low calcium levels while 6 (37.5%) had low magnesium levels. Conclusion: Serum calcium level was lower in nearly half while magnesium in nearly 2/5th of the previously diagnosed epileptics who presented in status. Among those on antiepileptic drugs, 50% had low calcium levels while 37.5% had low magnesium levels. It is suggested that all epileptic patients, especially those on long term AEDs, should at least be worked up once in detail for electrolyte abnormalities as timely identification and correction can help reduce the morbidity and mortality associated with future status epilepticus

Hypoglycemia in Mitochondrial Disorders

INTRODUCTION: The electron transport chain (ETC) in mitochondria functions to produce energy in the form of adenosine triphosphate (ATP). Defects in the mitochondrial or nuclear DNA that codes for components of the ETC lead to mitochondrial disorders (MTDs). MTDs are multi-system conditions affecting the heart, muscles, and especially brain. The endocrine system is commonly affected in MTDs, and diabetes and hyperglycemia are established secondary diagnoses. Rates of non-iatrogenic hypoglycemia have not been studied in individuals with MTDs. This study aims to investigate the frequency of hypoglycemia in patients with MTDs. METHODS: Individuals diagnosed with a ‘definite’ or ‘probable’ MTD according to the modified Walker criteria at The University of Texas, Mitochondrial Center of Excellence were included in this study. Exclusion criteria included diagnosis of diabetes or adrenal insufficiency or past or present use of hydrocortisone or prednisone. Patient charts were reviewed retrospectively for blood glucose values. Individuals with at least two values were recorded. Patients were classified as neonatal (≤28 days of life) or non-neonatal (\u3e28 days of life) at the time of measurement. Data analysis included descriptive statistics, mixed-model regression, and two-sample tests of proportion. All data analysis was done using Stata® (v.13, College Station, TX). Statistical significance was assumed at p\u3c0.05. RESULTS: Of the 116 patients included in this study, 22 (18.97%) experienced at least one episode of hypoglycemia. This is significantly higher (pp\u3c0.05). CONCLUSION: Patients with MTD are more likely to experience hypoglycemia compared to the general population with especially low blood glucose readings during the neonatal period. This demonstrates hypoglycemia may be contributing to the high rate of neurological symptoms reported in MTDs and supports that MTDs should be on the differential diagnosis in cases of hypoglycemia, especially during the neonatal period. Additional and earlier monitoring of blood glucose could reduce negative outcomes such as decreased cognitive outcome, developmental delays, seizures, or brain damage in patients with MTDs

Clinical Features of Pediatric Idiopathic Intracranial Hypertension and Applicability of New ICHD-3 Criteria

Idiopathic intracranial hypertension (IIH) is characterized by intracranial pressure >28 cmH2O in the absence of identifiable causes. Aim of this paper is to describe the clinical phenotype of pediatric IIH and to analyze the applicability of ICHD-3 criteria in comparison to the ICHD-2. We conducted a retrospective analysis of full clinical data of pediatric patients diagnosed with IIH between January 2007 and June 2018. Diagnostic evaluation included neuroimaging (all patients) and ultrasound-based optic nerve sheath diameter measurement (9 patients). Diagnosis of IIH was verified according to both ICHD-2 and ICHD-3 criteria for headache attributed to IIH, to verify the degree of concordance. We identified 41 subjects with suspected IIH; 14 were excluded due a diagnosis of secondary IH or lack of data. We therefore selected 27 subjects (age 4-15 years, mean 11). All patients presented with headache and bilateral papilloedema. Headache was daily in 22% cases, with diffuse gravative pain in 41%. In 4%, pain was exacerbated by cough, stress or tension. The most common presentation symptoms, in addition to headache, were blurred vision or diplopia (70%), vomiting (33%), and dizziness (15%). Twenty patients (74%) were obese. In 6 patients (22%) neuroimaging showed empty sella. Optic nerve sheath distension was detected in 6 out of 9 patients. Regarding the applicability of the ICHD-2 criteria, 18/27 (71%) patients have criterion A; 24/27 (89%) criterion B; 27/27 (100%) criterion C; 27/27 (100%) criterion D. When the ICHD-3 criteria were used, 27/27 (100%) fitted criterion A; 24/27 (89%) criterion B; 27/27 (100%) criterion C; and 27/27 (100%) criterion D. Our study suggests that, as compared with the ICHD-2, the new ICHD-3 criteria for headache attributed to IIH are better satisfied by pediatric patients with IIH. This is mainly due to the fact that qualitative headache characteristics are no longer considered in ICHD-3. Although the risk of under-rating the symptom of headache in IIH should not be disregarded, in pediatric population headache characteristics are usually less defined than in adults and obtaining a precise description of them is often very difficult

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders