Lecture 32: What's the condition?

Term
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Severe intellectual disability if untreated & excellent prognosis if treated from birth
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Terms in this set (41)
Severe intellectual disability if untreated & excellent prognosis if treated from birth
PKU & congenital hypothyroidism
Natural history
•Severe intellectual disability
•seizures, tremors
•spasticity
•behavioural problems, irritability
•eczema in childhood
Untreated PKU
Risk tyrosine insufficiency in a treatment of this condition
PKU (by low phenylalanine diet - tyrosine becomes an essential amino acid)
Tyrosine becomes an essential amino acid in this condition
PKU
Detected by IRT-DNA protocol
CF (not all cases detected, though)
Defect in β-cystathionine synthase
Homocystinuria ("classical")
Tx is HSCT (haematopoietic stem cell transplantation) or gene therapy (for a few causes)
SCID
Screening target is glutaryl carnitine (C5DC)
glutaric aciduria type 1
•The majority (75-80%) have the classical disease, presenting during the neonatal period, encephalopathy and cerebral oedema plus poor feeding, ketoacidosis and seizures
Maple syrup urine disease
20% children with undiagnosed may die during first 2 years of life
Sickle cell disease

Usually die of
•Acute infection
•Acute splenic sequestration
•Cerebrovascular accident - stroke
Screening target: methionineHomocystinuriaRisk of vitamin and trace element deficiencies in the Tx of this disorderPKU (Tx w/ low phenylalanine diet - a semi-synthetic diet)Improved outcomes of screening for this condition include being able to - initiate prophylactic penicillin - parental educationSickle cell disease•About 70% of patients have an encephalopathic crisis, most commonly at around 9 months, with 90% by age 2 years precipitated by a non-specific intercurrent illness, gastrointestinal infection or pneumonia. Leads to dystonia and dyskinesia as permanent sequelae. Of symptomatically diagnosed patients about 50% die before the age of 25 years. Survivors usually have severe handicap.Glutaric aciduria Type 1•Screening test: bloodspot C8 and C8/C10 ratioMCADDModulator therapy, including drugs such as ivacaftor, elexacaftor, tezacaftorCF•Without treatment, 25% of patients will die before the age of 30, usually due to thromboembolismHomocystinuria•Screening target: isovaleryl carnitine (C5)Isovaleric acidaemia•Screening target: leucineMSUD•Screening test: bloodspot TSHcongenital hypothyroidism•Clinical effects: usually healthy at birth, the diagnosis is not usually made until the first 2-3 years of life. Myopia followed by dislocation of the lens, osteoporosis, thinning and lengthening of the long bones, mental retardation and thromboembolismHomocystinuria•Autosomal recessive inherited defect of fatty acid oxidation •Body cannot use its own fat reserves to produce energy in periods of fasting or metabolic stress •Hypoglycaemia and metabolic decompensation develop, which may result in seizures, brain damage or deathMCADD•Clinical effects: The disease has a spectrum of clinical phenotypes; •acute neonatal presentations in the first two weeks of life. Infants are initially well, then develop vomiting and lethargy, progressing to coma. •acute presentations at a later age, usually precipitated by an infection. •chronic intermittent presentations, failure to thrive and/or developmental delay, usually within the first year.Isovaleric acidaemia•Group of inherited disorders causing major abnormalities in the immune system •Characterised by recurrent infections usually starting from 3 - 6 months of age •Severity and duration are longer than would be expected, more treatment than usual is required •Poor feeding, chronic diarrhoea, failure to gain weightSCID•Benefits of screening include: •Prevention of early infections •Prevention of inappropriate vaccinations •Early definitive treatmentSCIDTreated with biopterin supplementation (artificial version of sapropterin. Tradename Kuvan)PKULow Phe diet requires careful monitoringPKU•Treatment: avoidance of fastingMCADDInitially most controversial •Doubts about clinical benefits of early treatment •Identification of less severe variants •Identification of heterozygotesCF•defect in branched chain 2-keto acid dehydrogenase complexMSUDPyridoxine responsive and pyridoxine unresponsive forms, in the UK 50% of patients are in each group - predominantly the pyridoxine unresponsive form is picked up by newborn screeningHomocystinuria•Confirmation of diagnosis: •Bloodspot acylcarnitines, urine organic acids, DNA analysisMCADD•Confirm diagnosis with plasma thyroid function tests •no need to measure enzyme or DNACongenital hypothyroidism•Prognosis: good if decompensation avoided. 'Safe' times between meals increases as children grow olderMCADDEventual IQ outcome correlates with blood phe Pathophysiological determinant likely to be brain phe •Neurological damage not reversiblePKU•Confirm diagnosis with plasma phenylalanine measurements •no need to measure enzyme or DNAPKU•deficiency of glutaryl-CoA dehydrogenase, involved in lysine catabolismGlutaric aciduria type 1•a deficiency of isovaleryl-CoA dehydrogenase involved in leucine catabolism.Isovaleric acidaemia•Secondary target: total homocysteineHomocystinuria•Treatment with thyroxine, carefully monitoredCongenital hypothyoidism•Screening test: bloodspot phenylalaninePKU