pyrophosphate and Seizures

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5'-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the

Topics: Alkaline Phosphatase; Animals; Anxiety; Bone and Bones; Calcification, Physiologic; Depression; Diphosphates; Disease Models, Animal; Gene Expression; Humans; Hypophosphatasia; Mutation; Seizures; Severity of Illness Index; Tooth; Vitamin B 6

Topics: Atropine; Cats; Cell Respiration; Cholinesterase Inhibitors; Diphosphates; Dogs; Isoflurophate; Organophosphate Poisoning; Parathion; Phosphorus; Poisons; Research; Respiration; Seizures; Toxicology

Tissue non-specific alkaline phosphatase (TNSALP) is an enzyme that is tethered to the cell membrane by glycosylphosphatidylinositol (GPI) and converts inorganic pyrophosphate to inorganic phosphate. Inorganic phosphate combines with calcium to form hydroxyapatite, the main mineral in the skeleton. When TNSALP is defective, conversion of inorganic pyrophosphate to inorganic phosphate is impaired and the skeleton is at risk of under-mineralization. Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) is one of more than 20 genes in the GPI-biosynthesis family. Pathogenic variants in PIGN have been identified in multiple congenital anomalies-hypotonia-seizures syndrome (OMIM 614080), although a metabolic bone disease or skeletal fragility phenotype has not been reported. We describe a female child with multiple congenital anomalies-hypotonia-seizures syndrome due to a compound heterozygous pathogenic variant in PIGN who sustained a low-trauma distal femur fracture at age 7.4 years. We hypothesized that the GPI synthesis defect may result in metabolic bone disease from inadequate anchoring of TNSALP in bone and initiated asfotase alfa, a human bone-targeted recombinant TNSALP-Fc-deca-aspartate peptide, as it could bypass the PIGN genetic defect that possibly caused her skeletal fragility. Asfotase alfa was begun at 8.5 years. Baseline X-rays revealed mild rachitic findings of wrists and knees, which resolved by 5 months of treatment. Bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) showed mild improvement in spine, hip and total body less head after 16 months of treatment, while radius declined. She sustained additional low trauma fractures at right tibia and left humeral neck at 11 and 15 months into treatment, which healed quickly. Calcium, phosphorus, and parathyroid hormone levels have remained within the normal range over the 18 months of treatment. For adverse effect, she experienced a rash and discomfort in the first week of treatment which resolved with ibuprofen and diphenhydramine. She also developed subcutaneous fat atrophy. Overall, in this child with a compound pathogenic variant in PIGN, off-label use of asfotase alfa has been generally well tolerated with minimal side effects and resolution of rickets, but she continues to remain skeletally fragile.

Topics: Alkaline Phosphatase; Bone and Bones; Bone Diseases, Metabolic; Calcinosis; Calcium; Calcium, Dietary; Child; Diphosphates; Female; Fracture Healing; Humans; Hypophosphatasia; Muscle Hypotonia; Osteoporotic Fractures; Seizures

We describe the pattern of early childhood seizures within a family with autosomal dominant chondrocalcinosis (CCAL, which causes adult-onset arthritis). All affected family members with CCAL experienced seizures in early childhood, usually, but not always, associated with fever. Similarities exist to the syndrome of generalized epilepsy with febrile seizures plus (GEFS+). A mutation within the ANKH gene on chromosome 5p has been found previously in this family; other patients with familial CCAL (but without seizures) have mutations in the same gene. ANKH codes for a transmembrane protein involved in the regulation of extracellular pyrophosphate ion levels, although its precise mechanism of action remains unclear. It is highly expressed in the brain, and its expression may be influenced by seizure activity. The mutation within this family creates a premature initiation codon, adding four amino acids to the N-terminus of the protein. We postulate that this may lead to a gain of function, causing seizure susceptibility as well as chondrocalcinosis. Mutations within this gene may underlie other forms of genetic epilepsy and febrile seizures.

Topics: Arthritis; Child, Preschool; Chondrocalcinosis; Codon, Initiator; Diphosphates; Epilepsy, Generalized; Female; Gene Expression; Genetic Predisposition to Disease; Humans; Infant; Male; Membrane Proteins; Mutation; Pedigree; Phosphate Transport Proteins; Seizures; Seizures, Febrile

Topics: Calcitonin; Calcium; Calcium Radioisotopes; Consanguinity; Craniofacial Abnormalities; Diphosphates; Female; Hepatomegaly; Hospitalization; Humans; Hypocalcemia; Infant; Infant, Newborn; Intestinal Absorption; Male; Osteopetrosis; Parathyroid Hormone; Pedigree; Phosphorus; Seizures; Splenomegaly; Water-Electrolyte Balance

Topics: Animals; Cholinesterase Inhibitors; Cholinesterases; Defecation; Diphosphates; Erythrocytes; Exophthalmos; Insecticides; Male; Mastication; Mice; Paralysis; Phosphates; Pupil; Rabbits; Respiration; Salivation; Seizures; Sulfides; Tremor

Topics: Aging; Animals, Newborn; Carisoprodol; Diphosphates; Hexobarbital; Insecticides; Liver; Meprobamate; Metabolism; Microsomes; NADP; Oxidoreductases; Pentobarbital; Pharmacology; Rats; Research; Seizures; Strychnine; Toxicology