fumarates and Intellectual-Disability

A 5-year-old girl with a previous diagnosis of cerebral palsy, nonprogressive psychomotor retardation, and hypotonia was found to excrete excessive fumaric acid in urine. Fumarate hydratase activity in skin fibroblasts was 10% of the control value. This case underscores the clinical heterogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy.

Topics: Cerebral Palsy; Child, Preschool; Diagnostic Errors; Female; Fumarate Hydratase; Fumarates; Humans; Intellectual Disability; Metabolism, Inborn Errors; Muscle Hypotonia; Succinates; Succinic Acid

A male infant, whose parents were first cousins, presented at 6 mo of age with hypotonia, microcephaly, and delayed development. He was found to have large amounts of fumaric and succinic acids present in the urine. In lysed cultured skin-fibroblast preparations, the activity of fumarase was found to be 22.7% of that in controls. Cell fractionation by homogenization and by digitonin treatment indicated that the residual activity in the cells of the patient was primarily located in the mitochondrial fraction rather than in the cytosolic fraction. Isoelectric focusing of fibroblast extracts showed that six bands of fumarase activity were discernible in control cell lines, two of them cytosolic with pI's of 5.53 and 5.60 and four of them mitochondrial with a pI of 5.65-6.8. In contrast, isoelectric focusing of fibroblast extracts from the fumarase-deficient patient showed only a single band of activity with a pI corresponding to the mitochondrial type seen in the controls. Immunoprecipitation of proteins with rabbit antifumarase antibody in (35S)-methionine-labeled fibroblasts indicated that a protein of correct size (Mr = 44,000 daltons) corresponding to fumarase was synthesized in similar amounts in both the patients and controls. It is proposed that in the patient's cells a single active species of fumarase that is mitochondrial in location is synthesized. Since it is known that mitochondrial and cytosolic fumarases are encoded by the same gene but differ slightly in amino acid sequence, it is possible that a point mutation might explain these findings.

Topics: Abnormalities, Multiple; Cells, Cultured; Consanguinity; Cytosol; Fibroblasts; Fumarate Hydratase; Fumarates; Humans; Infant; Intellectual Disability; Isoelectric Focusing; Isoenzymes; Male; Microcephaly; Mitochondria; Muscle Hypotonia

Two siblings are described who present with fumaric aciduria, a hitherto unreported organic aciduria. The results of our analytical investigations using gas chromatography/mass spectrometry, and the clinical presentation of the patients, are consistent with the notion that the fumaric aciduria is caused by an inherited defect which leads to a net secretion of fumaric acid by the renal tubules.

Topics: Adult; Female; Fumarates; Humans; Intellectual Disability; Male; Renal Tubular Transport, Inborn Errors; Speech Disorders

Topics: Chronic Disease; Fumarates; Gluconeogenesis; Humans; Hyperventilation; Infant; Intellectual Disability; Ketoglutaric Acids; Lactates; Malates; Muscle Tonus; Psychomotor Disorders; Pyruvate Carboxylase Deficiency Disease; Succinates; Vitamins

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Centrifugation; Cerebral Cortex; Dinitrophenols; Fumarates; Glucose; Glutamates; Hexokinase; Humans; Intellectual Disability; Keto Acids; Male; Mitochondria; Oxidative Phosphorylation; Oxygen Consumption; Phenylpyruvic Acids; Pyruvates; Rats; Succinates; Tissue Extracts

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Ammonia; Animals; Arginine; Child; Child, Preschool; Diet Therapy; Female; Fumarates; Hair; Humans; Infant; Intellectual Disability; Lyases; Male; Rats