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.
what are diseases of lysosomal metabolism?
Genetic defects of lysosomal enzymes usually caude the accumulation of incompletely catabolised substrates within the organelle and progressive impairment of the function of affected cell systems. The cell and consequently the whole organ ‘swells’ causing organomegaly/
how do you diagnose disorders of lysosomal metabolism?
Sx: chronic progression of symptoms without acute metabolic crisi
in thh neonatal period: hydrops fetalis, hypotonia, dysmorphia, hypotonis, preogressive orgaomegaly, coarse facial features, skeletal changes
ataxia, hyperexcitability, spasticity, cherry red spot.
Invx: skeleton, parenchymous organs, eyes, vacuoles in leukocytes, glycosaminoglycans and oligosaccharides in the urine, enzymes in leukocytes and fibroblasts, chitotriosidase in serum.
Mucopolysaccharidoses
lysosomal storage disorder
disorder of the breakdown of glycosaminoglycans
- appear normal at birth, progressive connective tissue (facial dysmorphism, skin changes) skeletsal deformities, growth restritriction, bone dysplasia, contracutres), as well as hepatomegaly and often hernias. progressive psychomotor retardation, with loss of acquired skills , corneal clouding and deafness. Tx: enzyme replacement therapy (MPSI, II, VI) HSCT in presynaptic patients with severe MPS1 and MPS VI
MPS I
lysosomal storage disorder
Mucopolysaccharidoses: Hurler-Scheie: recurrent URTIs, slowing growth, psychomotor development, progressive hepatosplenomegaly, dysmoprphism, cardiac disease, cornal clouding, death 5-10 years. Enzyme replacement tx
MPS2
lysosomal storage disorder Mucopolysaccharidoses Hunter x-chromosomal IDS gene - joint contractures and restrictive airway disease, cardiac disease, skeletal deformities, progressive cognitive decline; fstal within 10-20 years. no corneal clouding. Enzyme replacement (iduronate-2-sulphatase)
MPS3-5
lysosomal storage disorder
Mucopolysaccharidoses
sanfillippo: encephalopathy with minor organ involvement, seizures, behavioural disturbance
Morquio: atlanto-axial instability
oligosaccharidoses
are disorders in the breakdown of complex carbohydrate side chains of glycosylated proteins.; resemble MPS but less common. diagnosis: urinary excretion of oligosaccharieds (also in tay sachs, sandoff) Tx: symptomatic, HSCT
Sphingolipodoses
major compounds of cellular membranes (ceramide - sphingosine and LCFA) which serves as a hydrophobi ancho on the outside of the cell.
clin: progressive psychomotor retardation, neurological problems, specifically epilepsy as well as ataxia and/or spasticity. hepatosplenomegaly is not uncommon, dysmorphism, macula spot, foam cells in the bone marrow or vaculated lymphocytes. Neurological and neuroradiological findings are not always specific.
GM1:
GM1: gangliocidosis
Acid B-galactosidase removes galactose from GM1 gangliosides - GLB1 and GM1 gene.
TI: neonatal hypotonia, sometimes edema, facial dysmorphism, arrest of neurological development - decerebration, death before age 2. Type II: late infantile/juvenile presentation with ataxia, no dysmorphism, mild bone changes, no hepatosplenomegaly. Dx: vacuolared lymphocytes; oligosaccharides/ GAG
GM2
GM2: gangliocidosis: Tay sachs and sandhoff
- infantile: 4-6 months, hypotonia, cherry red spot, blindness, spastic tetrapareesis, decerebration, macrocephaly.
Late infantile: ataxia, incoordination, dysarthria, myoclonus.
vacuolated lymphocutes or elevated urinary oligosaccharides.
Metachromatic leukodystrophy
lysosomal storage disorder
gene: ARSA
central and peripheral demyelination (tiger stripes on MRI), spasticity, neuropathy, loss of skills, fatal age 3-6. dx: increased CSF protein, HSCT
Krabbe
lysosomal storage disorder Globoid cell leukodystrophy Galactosylceramidase. GALC gene central and peripheral demyelination, startle reaction, fever, spasticiy - fatal before age 2. increased csf protein decreased nerve conduction. tx: HSCT may be effective
Gaucher
lysosomal storage disorder
Non neuronopathic form, manifestation in infancy to adulthood with visceral, haematological and skeletal symptoms.
- hepatosplenomegaly, anaemia, thrombocytopenia,bleeding tendency, acute abdomen (splenic infarctions, acute bone crises, osteonecrosis, osteopenia, fractures, growth rsstriction, lung fibrosis, normal intelligence, no CNS involvement
II - Acute neuronopathic form - rapidly progressing in infancy, brainstem dysfunction (opthalmoplegia, dysphagia, spasticity, hepatosplenomegaly. fatal within 2 years.
III chronich neuronopathic form (between I and II)
dx: increased acid phosphatase, ‘gaucher cells in bone marrow, chitotriosidase (in serum)
enzyme replacement therapy
Niemann-Pick
lysosomal storage disorder
Type A) Sphingomyelinase deficiency; feeding problems, hypotonia, FTT, lymphadenopathy, neurological deterioration, fatal within 1.5-3 years
Type b - normal intelligence and lifespan
‘niemann-pick cells’ in bone marrow
Type C: disorder of cellular cholesterol trafficking - cholesterol storage with secondary storage of sphingomuelin and glycosphingolipids. NPC1 NPC2 (juvenile - 2-5, progresive ataxia, language delay, behaviour problems, hepatosplenomegaly). Niemann-Pick cells in fibroblasts. Substrate inhibition therapy.
Fabry disease
lysosomal storage disorder
X linked (GLA gene)
manifestation in the first decade, recurrent pain and parasthesia in limbs lasting hours to days. Enzyme replacement
Farber disease
lysosomal storage disorder
ceramidase (ASAH gene)
Painful contractrues/joint deformities, hoarseness, skin nodules, neurodegeneration.
HSCT
ceroid lipofuscinoses
Neuronal ceroid lipofuscinoses - most common neurometabolic disorder
- seizures
-progressive deterioration of cognition
- motor dysfunction
- progressive loss of vision (retinopathy, optic atrophy, nystagmys)
deceleration of head growth, microcephaly
dx: microscopy (skin biopsy, lymphocytes), distinct storage patterns, vacuolated lymphocytes.
peroxisomal biogenesis
PEX mutations
1. Zellweger syndrome: severe hypotonia, seizures, liver dysfunction, jaundice, hepatomegaly, portal hypertension, FTT, dysmorphic, skeletal abnormalities, sensorineural deadness, retinopathy, progressive white matter disease, fatal within a few months. disorders of B oxidation are very similar to biogenesis.
What is the biochemistry of peroxisomal metabolism
b-oxidation of VLCFA, pristanic acid and intermediates of bile acid synthesis: detoxification and oxygen dependent reactions which occurs inside the peroxisomes to protect the cell against free oxygen radicals. various peroxins encoded by PEX genes are required for peroxisome biogenesis.
what are the clinical features of disorders of peroxisomal metabolism?
- neurological abnormalities - hypotonia, encephalopathy, seizures, deafness, retinopathy, cataract, blindness
- skeletal abnormalities - short limbs, calcific stippline
- Dysmorphic features - high forehead, large fontanels, shallow supraorbital ridges, epicanthic folds, micrognathis, minor ear anomalies
- Hepatointestinal dysfunction - neonatal hepatitis, hepatomegaly, cholestasis, cirrhosis etc.
major diagnostic features of disorders of peroxisomal metabolism?
- decreased cholesterol, increased bilirubin, abnormal LFTs
- VLCFA in cerum and increased C26 indicates deficient peroxisomal B oxidation
- Plasmalogens (erythrocytes): reduced in disorders affecting etherlipid biosynthesis
- phytanic acids (deficient a oxidation)
pristanic acids (reduced in a-oxidation)
bile acid intermediates (serum, urine)
enzyme studies, murtation analyses.
Rhizomelic chondrodysplacia punctata
Small stature, proximal shortening, facial dysmorphism microcephaly, congenital cataracts, contractures, spacticity, mental disabilith. Due to deficient ethetphospholipid biosynthesis. See mostly increased phtytanic acid, and decreased pristanic acid.
X-lined adrenoleukodystrophy
x linked; Most common peroxisomal disorder (1:20000).
a) Childhood cerebral form - boys 4-12; school failur, visual/hearing imparirment, intellectual regression, ataxia, adrenal insufficiency, leukodystrophy - decerebration within 2-4 years.
Adrenomyeloneuropathy: AMN, males early adults 20% of females >35 years)
genetics ABCD gene (Xq28), de novo mutations in 7% of affected boys. diagnosis increased hexacosanoic acid (C26:0, VLCFA plasma)
Tx: early HSC transplantation, gene therapy; Lorenzo’s oil (glyceril trioleate + glyceryl Trierucate) may reduce risk for childhood cerebral form.
Refsum disease
clinical: retinitis pigmentosa, polyneuropathy, cerebellar ataxia, deafness, anosmia, icthyosis, skeletal and cardiac symptoms normal intelligence; alpha oxidation defects; phytanic acid restricted diet, plasma pheresis
Acatalasaemia, Primary hyperoxaluria Type 1, Mulibrey nanism
other peroxisomal enxyme deficiencies
Disorders of copper metabolism?
- Wilson disease
2. Menke kinky hair
Features of Wilson disease?
(hepatolenticular degeneration): chronic liver disease, cirrosis, kayser-Fleisher ring, dysarthria, poor coordination, bulbar paralysis, renal problems, haemolysis.
6-8 yrs, disorder of hepatic copper binding P-type ATPase. biochem: serum decreased ceruloplasmin, decreased copper in serum, increased urinary coppe,
Features of Menke kinky hair syndrome?
classical - kinky hair, tissues/bone abnormalities, ataxia, dysarthria.
occipital horn syndrome - laxity of skin and soft tissues; exostosis (occipital horn)
copper deficiency as defective intestinal uptake of Cu. Serum decreased copper and ceruloplasm (protein that carries copper). Tx: early copper-histadine subcutaneous injections (50-150ug/day)
example of Disorders of amino acid transport
- Lysinuric protein intolerance: FTT/diarrhoea, interstitial pneumonia, osteoporosis, renal failure, haemolysis, hyperammonaemia (dx: increased ammonia, LDH, Ferretin), Arginine, lysine, ornithine increased in urine and decreased in plasma. tx: citrulline substitution.
- Cystinuria: nepholithiasis; tx is high fluid intake and alkialinsation of the urine.
- Hartnup disease: photodermatitis, cerebellar ataxia; can’t reabsorb neutral amino acids. SLC6A19 gene. Ddx: fanconi syndrome; Tx: nicotinamide/sun protection
- Iminoglycinuria: asymptomatic
what are the ceroid lipofuscinoses?
- Neonatal
- congenital: microcephaly and seizures
infantile (sanravuori-Haltia disease) - Later infantile (Jansky-Bielschowski disease)
- Juvenile form (batten disease, vogt-spielmeyer disease) 4-10 years, often rapid loss of vision - blindness, epilepsy, regression, behavioural distrubances, hallucinations, disturbed sleep patterns, parkinsonian like disease, die early adulthood
what are the groups within this lysosomal metabolism?
- mucopolysaccharisoses (deficient breakdown of glycosaminoglycans)
- oligosaccharidoses (deficient breakdown of carbohydrate side chains from glycoproteins
- sphingolipidoses: deficient breakdown of ceramide- containing membrane lipis
- neuronal ceroid lipofuscinoses
- lysosomal export defects
lysosomes are required for the intracellular breakdown of various molecules and compounds of all sized. They are therefore secreted and taken up by other cells through endocytosis and can be measured in body fluids
What are the branched chain amino acids?
Leucine, Isoleucine and valine
What is the characteristic disorder of Branch-chain keto-acid dehydrogenase deficiency catabolism?
MSUD - the accumulation of the leucine, isoleucine and valine cause the maple syrup smell
What is the Ddx for chronic encephalopathy assoc with the following extra CNS abnormalities?
a) muscle
b) hepatospleno megaly/bone
c) skin/connective tissue
a) mitochondrial
b) Lysosomal storage, Peroxisoma,
c) Homocysteinuria, menkes
which are the only two lyusosomal storage disorders that are not AR in genetic inheritance?
Fabry and hunter (MPS2) are x linked
What are the most common lysosomal storage disorders?
- Gaucher,
- MPS1,
- Metachromatic leukodystrophy,
- MPSIIIa,
- Fabry,
- MPSII,
- Krabbe,
- Pompe,
- MPS IVA,
- Cystinosis,
- TaySachs,
- MPS IIIB,
- Neiman-pickC
What are the major features of lysosomal storage disorders?
Phenotype: macrocephaly, coarse facial fx, macroglossia, corneal clouding, hepatosplenomegaly, inguinal, umbi hernias
ENT: chronic rhinnorhea, recurrent OM, enlarged tonsils, OSA, hearing loss
Cardiac: cardiomyopathy, valvular disease
Respiratory: recurrent lower resp infections, reactive airways disease
Neurodevelopmentals: developmental delay, cognitive impairment, behavioural problems, seizures
Musculoskeletal: dystostosis multiplex, lumbar kyphosis
major manifestation of MPSII radiologically
Metacarpals: proximal pointing
Metacapraps: thick, short with thin cortices
Carpal bones: irregular, hypoplastic
rounded vertebral bodies, anteror beaking, posteriorly thin ribs that widen anteriorly
proximal humerus thin
which MPS respond to Enzyme replacement therapy?
MPS I, II, IVA, VI.
MPS I, II, VI also HSCT
What is Pompe disease?
Glycogen storage disorder type II
deficiency of acid alpha-glucosidase (GAA)
progressive accumulation of lysosomal glycogen - particularly in cardiac, skeletal and smooth muscle.
sx: cardiomyopathy, cardiomegaly, macroglossia, FTT, resp insufficiency, CCF rapidly fatal
What is the most recognisable feature of Lesch-Nyhan disease?
self mutilation of mouth
Very rare x-linked disorder of purine salvage (hypoxanthine phosphoribosyltransferase)
1:400 000
hyperuricaemia
DDx for severe hypotonia
Pompe disease
peroxisomal disorders
mitochondiral respiratory chain disorders
clinical features of mitochondial disorders?
neonatal lactic acidaemia unexplained multiorgan failure skeletal myopathy, exercise intolerance cardiomyopathy hepatopathy, intestinal pseucoobstruction encephalopathy sideroplastice anaemia renal tubulopathy cateract, retinitisc, optic hypoplasia, opthalmoplesia, sensorinerual deafness panreatic insufficiency
what are the key fx of MELAS?
Michochondrial Encephalopathy, Lactic acidosis and stroke like episodes
- recurrent stroke like episodes (confusion, blindness, vomiting, transient blindness, seizures), often recover completely, progressive neuromusc abnormalities
best approximation for basal energy requirement for ages?
6mg/min for fasting child
2mg/kg/min in a fasting adult
this flux decreases as the fasting proglongs
8.3mg/kg/min of 10% glucose @5ml/kg/hour
