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)

Two female infants with nonketotic hyperglycinemia (NKH) were treated with diazepam for the control of seizures. The first infant had seizures, lethargy, and respiratory distress in the first 24 hours of life. The diagnosis of NKH was made at 3 weeks of age and she was then placed on a regimen of strychnine and a low-protein diet. Strychnine therapy was discontinued after three months of treatment because there was no improvement in the seizure control or in the patient's condition. At 5 months of age the patient was referred to our clinic for further work-up. The second infant had seizures, hypotonia, and respiratory distress shortly after birth. She was treated with phenobarbital and diphenylhydantoin, which had no effect on her seizures. The baby was referred to our clinic at 8 months of age and diagnostic studies revealed NKH. All previous medications were stopped and both infants were placed on diazepam, a competitor for glycine receptors in the CNS. Choline and folic acid were added for one-carbon unit transfer and sodium benzoate to bind excessive glycine. Both infants responded to this treatment with cessation of seizures; they became more responsive and alert, and their EEGs showed remarkable improvement despite the persistence of elevated glycine levels in plasma, CSF, and urine. Diazepam as a competitor for the receptors of glycine may prove helpful in controlling the intractable seizures associated with NKH.
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PMID:Nonketotic hyperglycinemia: treatment with diazepam--a competitor for glycine receptors. 630 Jul 46

Although there are a number of studies and individual case reports concerning the use of benzodiazepines in human pregnancy, the data concerning teratogenicity and effects on postnatal development and behaviour are inconsistent. There is evidence from studies in the 1970s that first trimester exposure to benzodiazepines in utero has resulted in the birth of some infants with facial clefts, cardiac malformations, and other multiple malformations, but no syndrome of defects. Diazepam and chlordiazepoxide are amongst the drugs most frequently implicated in the earlier studies. However, data from later studies provide no clear evidence of significant increase in either the overall incidence of malformations or of any particular type of defect. Many of the women included in these studies has psychiatric illnesses, epilepsy, or diabetes all of which have an intrinsic risk in pregnancy, and some were on multidrug therapy. Medical-obstetric histories and family history of malformations were not always presented in the publications, which makes assessment of risk associated with benzodiazepine use per se difficult. Nevertheless, in most of the studies involving first trimester use of benzodiazepines, the majority of infants were normal at birth and had normal postnatal development. Late third trimester use and exposure during labour seems to be associated with much greater risks to the fetus/neonate. Some, but by no means all infants exposed at this time, exhibit either the floppy infant syndrome, or marked neonatal withdrawal symptoms. Symptoms vary from mild sedation, hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms have been reported to persist for periods from hours to months after birth. This correlates well with the pharmacokinetic and placental transfer of the benzodiazepines and their disposition in the neonate. However, there has been no significant increase in the incidence of neonatal jaundice and kernicterus in term infants. The prolonged use of benzodiazepines throughout pregnancy raised the concern that there may be altered transmitter synthesis and function, leading to neurobehavioural problems in the children. In approximately 550 children who were followed up for various times up to four years of age, there is no increase in either the malformation rate or adverse effects on neurobehavioural development and IQ. Although some of the data indicate that a small number of children were slower to develop during the first year or so, they did exhibit catch up growth and most had developed normally by four years of age. Where developmental deficits persisted, it was not possible to prove a cause-effect relationship with benzodiazepine exposure. These children were often from families where there was maternal illness requiring prolonged drug therapy or where there were social problems. It is important to consider poor environmental and social factors when assessing the possible prenatal influence of the benzodiazepines on the postnatal health and development of the child. There is evidence that clonazepam, clorazepate, diazepam, lorazepam, midazolam, nitrazepam, and oxazepam are excreted into breast milk. The published data indicate that the levels detected in breast milk are low; therefore, the suckling infant is unlikely to ingest significant amounts of the drug in this way. Problems may arise if the infant is premature or has been exposed to high concentrations of drug either during pregnancy or at delivery.
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PMID:The effects of benzodiazepine use during pregnancy and lactation. 788 Nov 98

The Congenital Myasthenic Syndromes (CMS), a group of heterogeneous genetic disorders of neuromuscular transmission, are often misdiagnosed as congenital muscular dystrophy (CMD) or myopathies and present particular management problems. We present our experience of 46 children with CMS, referred to us between 1992-2007 with provisional diagnoses of congenital myopathy (22/46), CMS or limb-girdle myasthenia (9/46), central hypotonia or neurometabolic disease (5/46), myasthenia gravis (4/46), limb-girdle or congenital muscular dystrophy (4/46) and SMA (2/46). Diagnosis was often considerably delayed (up to 18y4 m), despite the early symptoms in most cases. Diagnostic clues in the neonates were feeding difficulties (29/46), hypotonia with or without limb weakness (21/46), ptosis (19/46), respiratory insufficiency (12/46), contractures (4/46) and stridor (6/46). Twenty-five children had delayed motor milestones. Fatigability developed in 43 and a variable degree of ptosis was eventually present in 40. Over the period of the study, the mainstay of EMG diagnosis evolved from repetitive nerve stimulation to stimulation single fibre EMG. The patients were studied by several different operators. 66 EMGs were performed in 40 children, 29 showed a neuromuscular junction abnormality, 7 were myopathic, 2 had possible neurogenic changes and 28 were normal or inconclusive. A repetitive CMAP was detected in only one of seven children with a COLQ mutation and neither of the two children with Slow Channel Syndrome mutations. Mutations have been identified so far in 32/46 children: 10 RAPSN, 7 COLQ, 6 CHRNE, 7 DOK7, 1 CHRNA1 and 1 CHAT. 24 of 25 muscle biopsies showed myopathic changes with fibre size variation; 14 had type-1 fibre predominance. Three cases showed small type-1 fibres resembling fibre type disproportion, and four showed core-like lesions. No specific myopathic features were associated with any of the genes. Twenty children responded to Pyridostigmine treatment alone, 11 to Pyridostigmine with either 3, 4 DAP or Ephedrine and five to Ephedrine alone. Twenty one children required acute or chronic respiratory support, with tracheostomy in 4 and nocturnal or emergency non-invasive ventilation in 9. Eight children had gastrostomy. Another 11 were underweight for height indicative of failure to thrive and required dietetic input. A high index of clinical suspicion, repeat EMG by an experienced electromyographer and, if necessary, a therapeutic trial of Pyridostigmine facilitates the diagnosis of CMS with subsequent molecular genetic confirmation. This guides rational therapy and multidisciplinary management, which may be crucial for survival, particularly in pedigrees where previous deaths have occurred in infancy.
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PMID:Congenital myasthenic syndromes in childhood: diagnostic and management challenges. 1870 67