metabolic x 2 Flashcards
What are the mutations that lead to the same phenotype as Methylmalonic acid metbolic disease
mut0, mut−, cblA, cblB, and cblD
How many 3-Methylglutaconic acidurias are there and what are they?
There are 5: A group of disorders characterised by excretion of 3-methylglutaconic acid.
I is an inborn error of leucine catabolism; 3-methylglutaconyl- CoA hydratase deficiency: slowly progressive leukoencephalopathy (adulthood)
II: barth syndrome: x linked cardiomyopathy, growth retardation, neutropenia, phospholipid metabolism (TAZ gene)
III: costeff syndrome; optic atrophy, extrapyramidal signs, spasticity,
IV - unclassified
V: DCMA syndrome: cardiomyopathy with conduction deficits and nonprogressive cerebellar ataxia
What is Canavan disease? and what is the enzyme + gene associated?
A Leukodystrophy. A disorder of Progressive psychomotor retardation, progressive epileptic encephalopathy, macrocephaly, leukodystrophy (particularly subcortical U fibres) optic atrophy, enzyme: Aspartoacylase. Diagnosis: Organic aciduria (Nacetyltaspartic acid) Gene ASPA
What role do the sulphur amino acids (methionine and homocysteine) play in metabolism and what are the major diseases?
Sulphur amino acids play a central role in cytosolic methylation transfer required for a range of functions including the synthesis of creatine, choline and adrenaline as well as DNA methylation.
Disorders may be due to primary disorders of cobalamin (Vitb12) or folate metabolism.
- isolated hyperthmethioninaemia
- A-Adenosylhomocysteine hydrolase deficiency
- Methionine synthase deficiency
- Mild hyperhomocysteinaemia
- classical homocystinuria
- Sulphite oxidase deficiency and molybednum cofactor deficiency
What are the disorders of Histidine, tryptophan and lysine metabolism and the pathophysiology?
The terminal amino group of lysine is transferred to 2-oxoglutarate (producing glutamatae).
1. glutaric aciduria type I
2. Histidinaemia - no treatment
3. Tryptophanaemia - incidental finding; Tx: nicotinamide
mostly asymptomatic
Disorders of Serine, glycine and glycerate metabolism are rare. Describe the biochemistry
Serines: microcephaly, psychomotor retardation, seizures.
Glycine: inability to convert glucose to serine and glycine or to turn NH3 into glucose.tx: L-serine.
1. Non ketotic hyperglycinaemia: severe epileptic encephalopathy, hypotonia, progresive neurological symptoms, neonatal onset; issue with the glycine cleavage system, so can’t use glycine to make glucose
- enzyme studies: lymphocytes, liver.
mutations: GLDC, AMT and GCSH.
-treatment : dextromethorphan (5020mg/day), sodium benzoate aiming to normalise plasma glycine levels; folinic acid. poor prognosis. treat with L-serine
what is the physiology of amino acid transport?
several specific transport systems ensure virtually complete (re) absorption of amino acids in the gut and kidneys. The calculation of renal tubular re-absorption shows values >96-99% for most amino acids. Genetic defects of these transport systems are sometimes asymptomatic and are detected only through elevation of the respective amino acids in urine with normal or low levels in plasma. the inability of these systems to work leads to deficiencies and crystallisation in the urine/kidney
What is a disorder of amino acid synthetase deficiency?
Glutamine synthetase deficiency: brain malformations, multiple organ failure in neonates, static encephalopathy, recurrent hyperammonaemia
What is a common feature of disorders of peptide metabolism?
frequent infections and skin manifestations
- Prolidase deficiency
- Carnosinaemia
- homocarnosinosis
What are the 7 major types of disorders of carbohydrate metabolism
- galactose and fructose
- gluconeogenesis/glycogenolysid
- glycogen storage disease
- glycerol metabolism
- pentose metabolism
- glucose transport
- congenital hyperinsulinism
what are the major fx of galactose and fructose metabolic diseases?
inability to intake lactose or fructose. The presence of reducing substances in the urine is an important first clue to the diagnosis.
What is hereditary fructose intolerance?
symptoms commence after weaning or supplementary fructose containing food: vomiting, apathy, coma, progressive liver dysfunction, hepatosplenomegaly, hypoglucaemia, rernal tubular dysfunction, FTT, aversion to fructose containing food/sweets
dx: renal tubular damage (increasing glucose, albumin, AA, reducing substnces in urine)
What are the symptoms , genetics diagnostic fx and treatment of Galactosaemia
symptoms after start of milk feeds (3rd or 4th day); vomiting, diarrhoea, jaundice, distubrances of liver function (most sensitive reduced IBR), development of bilateral cataracts, sepsis (gram neg organisms), hepatic and renal failure.
enzyme deficiency GALT (galactose-1-phosphate uridyltransferase). varients: Duarte
diagnosis: newborn screening - GALT activity, galactitol, renal tubular damage
Tx: galactose restricted diet throughout life
What are the cataracts associated with galactokinase deficiency due to?
build up of galactitol in the lens
What are the characteristics of UDP-galactose epimerase deficiency?
like classical galactosaemia
What are the disorder of gluconeogenesis?
recurrent hypoglycaemia with lactic acidosis +/- ketosis.
1. Fructose-1, 6 bisphosphatase deficiency (increased lactate, pyruvate, ketones; Tx: oral or IV glucose and insulin.
Phophoenolpyruvate carboxykinase deficiency:
Describe glycogen storage disorders
disorders of glycogen degredation, glycolysis, glucose release and glycogen synthesis.
Liver: hypoglycaemia, hepatomegaly, growth retardation (GSD, I, IV, VI, IX 0)
Muscle: exercise intolerance, muscle cramps
mixed/generalised: cardiomyopathy, liver/muscle involvement.
What are the disorders of glucose transport?
GLUT1 deficiency; GLUT 2 deficiency, SGLT1 deficiency, SGLT2 deficiency
What is Fanconi-Bickel disease
Glycogen storage disease type XI; Glucose transporter 2 (GLUT2 and SLC2A2 gene)
renal fanconi syndrome -> rickets, aminoaciduria, glucosuria, small statue, malabsorption, hepatomegaly, nephromegaly. Fasting hypoglycaemia with no response to glucacon. Tx: frequent feeds
Congenital Hyperinsulinsism
neonatal hypoglycaemia: congenital hyperinsulinism due to KATP channel mutations; other disorders assoc. with congenital hyperinsulinism.
what disorders are associated with congenital hyperinsulinism?
glucokinase activating mutations
hyperinsulinism-hyperammonaemia syndrome
exercise induced hyperinsulinaemis hypoglucaemia
short chain hydroxacyl-CoA dehydrogenase (SCHAD) deficiency
phosphomannose isomeraase deficiency
Beckwith-Wiedermann syndrome
What is the biochemistry of Fatty acid oxidation disorders?
mitochondrial oxidation of fatty acids is one of the major sources of cellular energy, providing up to80% of total energy requirements during fasting. mostly present during prolonged fasting for surgery, or infection, vomiting - hypoketotic hypoglucaemic come. otherwise accumulation of toxic long chain acylcarnitines, particularly in long chain fatty acid oxidation and the carnitine shuttle may affect skeletal muscle and become manifest in adolescence or early adulthood as chornic rela excretion od acylcarnitines can lead to a deficiency.
Diagnosis of FFAOD?
- serum FFAs and ketones
- hypoglycaemia (ammonis, lactate, CK, myoglobin)
- carnitine status (serum) free total carnitine
acylcarnitines
organic acids
enzume studies
molecular studies
treatment of FFAOD
avoid fasting acute: high dose glucose (10mg/kg/min), keep bgl >5.5mmol/l no IV lipids LCFAD: dialysis, exhange transfusion. long term: medium chain triglycerides
What is the clinical fx, diagnosis and management of MCAD
The most common FFA disorder 1:6000). Reye like often reapidly progressive metabolic crisis after 8-12-16 hours fasting, during ordinary illness, after surgery etc. Lethargy, nauea, vomiting, often with normal bsl.
Diagnosis: high acylcarnitines (c8, c6), urineL c6-10 dicarboxylic acids, hexanolglycine.
avoid fasting, normal feeding levels are safe when the child is well. low dose carnitine if free carnitine is low.
VLCAD, carnitine transporter deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase, LCHAD,
clinical fx: cardiomyopathy, liver disease, hepatomealy, SIDS.
Tx: dietary therapy: medium chain triglycerides, decreased long chain fatty acids, frequent meals, avoid fasting, carnitine sup may be harmful
What is Smith-Lemli-Opitz
craniofacial dysmorphism (microcephaly, micrognathis, anteverted nostrils, ptosis); syndactly of 2nd and 3rd toes, renal, cardiac, gastrointerstinal and midline malformations including holoprosencephaly, genital malformations. Defect in the last step of cholesterol biosynthesis. Diagnosis: sterols (plasma, fibroblast cultures) Tx: cholesterol (50-100mg/kg), simvastating. Frozen plasma can be given as an emergency source of LDL cholsterol
GLUTATHIONE SYNTHETASE DEFICIENCY
which is a result of generalized deficiency of the enzyme, severe acidosis and massive 5-oxoprolinuria are the rule
- Glutathione Synthetase Deficiency
- GLUTATHIONEMIA (γ-GLUTAMYL TRANSPEPTIDASE DEFICIENCY)
- Congenital Glutamine Deficiency
What are the acute neuropathic porphorias?
acute episodes of severe abdominal pain, limb pain, sympathetic overactivity (tachycardia, hypertension, tremor), vomiting, constipation, electrolyte imblance, mental disturbance, development of peripheral neuropathy, weakness, seizures.
pathogenesis: accumulation of highly neurotoxic 5-aminolaevulinic acid + porphobilinogen deaminase (or amnionlaevulate dehydrogenase) triggers: cyp450 inducers, hormones, nutritional factors, smoking, alcohol, stress.
diagnosis: high porphonlinogen. Tx: ICU, analgesia, iv glucose, haemin, avoid triggers.
