Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Citrullinemia, a rare inborn error of metabolism, is characterized by a deficiency of argininosuccinic acid synthetase that results in large increases in plasma ammonia, citrulline, and glutamine, with normal acid-base balance. The neurologic symptoms vary from poor feeding, vomiting, and irritability to hypotonia, apnea, and death. The most common pathologic findings at autopsy are cerebral edema and focal neuronal necrosis. We describe a case of fulminant citrullinemia in an infant in whom the major pathologic findings included diffuse cerebral edema and a lack of overt metabolic derangement characteristic of neonates with a urea cycle defect. Our case differs from the classic presentation of citrullinemia in that subarachnoid hemorrhage was identified early in the clinical course. We report the first observation of subarachnoid hemorrhage in an infant with a urea cycle defect.
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PMID:Perinatal pathology casebook. 886 47

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
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PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

It is widely appreciated that health food beverages are not appropriate for infants. Because of continued growth, children beyond infancy remain susceptible to nutritional disorders. We report on 2 cases of severe nutritional deficiency caused by consumption of health food beverages. In both cases, the parents were well-educated, appeared conscientious, and their children received regular medical care. Diagnoses were delayed by a low index of suspicion. In addition, nutritional deficiencies are uncommon in the United States and as a result, US physicians may be unfamiliar with their clinical features. Case 1, a 22-month-old male child, was admitted with severe kwashiorkor. He was breastfed until 13 months of age. Because of a history of chronic eczema and perceived milk intolerance, he was started on a rice beverage after weaning. On average, he consumed 1.5 L of this drink daily. Intake of solid foods was very poor. As this rice beverage, which was fallaciously referred to as rice milk, is extremely low in protein content, the resulting daily protein intake of 0.3 g/kg/day was only 25% of the recommended dietary allowance. In contrast, caloric intake was 72% of the recommended energy intake, so the dietary protein to energy ratio was very low. A photograph of the patient after admission illustrates the typical features of kwashiorkor: generalized edema, hyperpigmented and hypopigmented skin lesions, abdominal distention, irritability, and thin, sparse hair. Because of fluid retention, the weight was on the 10th percentile and he had a rotund sugar baby appearance. Laboratory evaluation was remarkable for a serum albumin of 1.0 g/dL (10 g/L), urea nitrogen <0.5 mg/dL (<0.2 mmol/L), and a normocytic anemia with marked anisocytosis. Evaluation for other causes of hypoalbuminemia was negative. Therapy for kwashiorkor was instituted, including gradual refeeding, initially via a nasogastric tube because of severe anorexia. Supplements of potassium, phosphorus, multivitamins, zinc, and folic acid were provided. The patient responded dramatically to refeeding with a rising serum albumin and total resolution of the edema within 3 weeks. At follow-up 1 year later he continued to do well on a regular diet supplemented with a milk-based pediatric nutritional supplement. The mortality of kwashiorkor remains high, because of complications such as infection (kwashiorkor impairs cellular immune defenses) and electrolyte imbalances with ongoing diarrhea. Children in industrialized countries have developed kwashiorkor resulting from the use of a nondairy creamer as a milk alternative, but we were unable to find previous reports of kwashiorkor caused by a health food milk alternative. We suspect that cases have been overlooked. Case 2, a 17-month-old black male, was diagnosed with rickets. He was full-term at birth and was breastfed until 10 months of age, when he was weaned to a soy health food beverage, which was not fortified with vitamin D or calcium. Intake of solid foods was good, but included no animal products. Total daily caloric intake was 114% of the recommended dietary allowance. Dietary vitamin D intake was essentially absent because of the lack of vitamin D-fortified milk. The patient lived in a sunny, warm climate, but because of parental career demands, he had limited sun exposure. His dark complexion further reduced ultraviolet light-induced endogenous skin synthesis of vitamin D. The patient grew and developed normally until after his 9-month check-up, when he had an almost complete growth arrest of both height and weight. The parents reported regression in gross motor milestones. On admission the patient was unable to crawl or roll over. He could maintain a sitting position precariously when so placed. Conversely, his language, fine motor-adaptive, and personal-social skills were well-preserved. Generalized hypotonia, weakness, and decreased muscle bulk were present. Clinical features of rickets present on examination included: frontal bossing, an obvious rachitic rosary (photographed), genu varus, flaring of the wrists, and lumbar kyphoscoliosis. The serum alkaline phosphatase was markedly elevated (1879 U/L), phosphorus was low (1.7 mg/dL), and calcium was low normal (8.9 mg/dL). The 25-hydroxy-vitamin D level was low (7.7 pg/mL) and the parathyroid hormone level was markedly elevated (114 pg/mL). The published radiographs are diagnostic of advanced rickets, showing diffuse osteopenia, frayed metaphyses, widened epiphyseal plates, and a pathologic fracture of the ulna. The patient was treated with ergocalciferol and calcium supplements. The published growth chart demonstrates the dramatic response to therapy. Gross motor milestones were fully regained within 6 months. The prominent neuromuscular manifestations shown by this patient serve as a reminder that rickets should be considered in the differential diagnosis of motor delay. (ABSTRACT TRUNCATED)
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PMID:Severe nutritional deficiencies in toddlers resulting from health food milk alternatives. 1133 66

Prader-Willi syndrome is an uncommon multisystem genetic disorder caused by defects of chromosome 15 (15qll-ql3), often due to deletions or uniparental disomy The syndrome is characterized by neonatal hypotonia, dysmorphic facial features, short stature, motor and mental disabilities, behavioral changes, hyperphagia, precocious obesity and hypogonadotropic hypogonadism. We present a 17 year-old woman, with a previous genetic diagnosis of Prader-Willi syndrome and BMI of 74 Kg/m(2), that was admitted in anasarca, with marked cyanosis, dyspnea and oliguria. She presented high levels of blood urea, creatinine and aminotransferases, in addition to hyperkalemia and hyperuricemia. She had been in regular use of fluoxetine during the last six months, and evolved with severe high blood pressure and respiratory failure, which needed intensive care support. Moreover, sequels and clear signs of recent self-injuries were observed in her trunk, forearms and hands. The findings of morbid obesity, anasarca, self-injury, hyperuricemia and hypoxemia in Prader-Willi syndrome are emphasized.
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PMID:Morbid obesity in an adolescent with Prader-Willi syndrome. 1954 50

HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations.
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PMID:HERC1 mutations in idiopathic intellectual disability. 2832 26

BACKGROUND The urea cycle converts amino acids to urea and is excreted by the kidneys. Ornithine carbamoyltransferase (OTC) deficiency is a rare X-linked urea cycle disorder which results in hyperammonemia. Diagnosis is made based on a clinical presentation of poor feeding, hypotonia, biochemical profile, and genetic testing. Another genetic cause for hyperammonemia is hyperammonia hyperinsulinemia (HAHI) syndrome. A mutation coding for glutamate dehydrogenase (GDH) results in increased alpha-keto glutarate and ATP, triggering the secretion of pancreatic insulin. However, unlike OTC deficiency, these patients are asymptomatic but do have symptoms of hypoglycemia. The purpose of this article is to present the case of a 66-year-old woman with an unusual late-onset of OTC deficiency compounded with an underlying HAHI syndrome with co-disease management. CASE REPORT A 66-year-old female with a history significant for transient ischemic attack (TIA) and urea cycle disorder was admitted for new adverse symptoms. Further evaluation revealed hyperammonemia and hypoglycemia. Despite standard previous treatment for her underlying urea cycle disorder, high ammonia levels and hypoglycemia persisted. The contradicting values with continued hypoglycemia regardless of dextrose treatment was suspicious for underlying HAHI. Further genetic testing during her admission revealed a deletion in GLUD-1 gene concurrent with diagnosis of HAHI. After co-diagnosis was established, effective management required medications for both disorders in concordance with dietary restriction. CONCLUSIONS This is an extremely rare case of OTC deficiency, with a vague presentation in an elderly female. Exploring compounding genetic disorders in the presence of one that is already established and early recognition are crucial for prompt diagnosis and management.
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PMID:Management of Ornithine Carbamoyltransferase Deficiency with Underlying Hyperammonia Hyperinsulinemia Syndrome. 3133 45

Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter-conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter-conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however-with the exception of urea cycle defects-abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism-rather than individual glutamate and glutamine levels-the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.
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PMID:Inborn errors of enzymes in glutamate metabolism. 3160 91


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