Metabolics, Rehab Flashcards

Question

Maple syrup urine disease - general

Answer 1

= branched chain ketoaciduria 1. Genetics + pathogenesis a. Caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) – the second enzyme of the metabolic pathway of the three branched-chain amino acids (leucine, isoleucine and valine) b. Defect in the enzyme system involved in decarboxylation of leucine, isoleucine and valine (BCKAD) c. AR mutation, 1/200,000 2. Clinical features a. Classic MSUD i. Most common form ii. Mutations in genes for E1alpha, E1beta and E2  <3% residual enzyme activity iii. Newborns develop ketonuria within 48 hours of birth – irritability, poor feeding, vomiting, lethargy and dystonia iv. Neurological abnormalities develop by day 4 1. Alternating lethargy and irritability 2. Dystonia, rigidity and opisthotonos 3. Apnoea 4. Seizures 6. Unusual odour (maple syrup, urine and ears) v. Metabolic intoxication 1. Exacerbation of previously controlled disease 2. Triggered by increased catabolism of endogenous protein (intercurrent illness, exercise, injury, surgery, fasting) 3. Clinical manifestations – epigastric pain, vomiting, anorexia, and muscle fatigue 4. Neurological signs – hyperactivity, sleep disturbance, stupor, decreased cognitive function, dystonia, ataxia 5. Death can occur if not treated c. Intermittent MSUD i. Second most common type ii. Affected patients have normal growth and development iii. Present with ketoacidosis during episodes of catabolic stress – intercurrent illness or protein intake iv. Signs of neurotoxicity develop – ataxia, lethargy, seizures, coma v. Death may occur 3. Investigations a. NORMAL glucose, NORMAL ammonia, pH normal b. Strongly positive urinary dipstick test for ketones c. DNPH test – add reagent to urine and precipitates d. Plasma branched chain amino acids = ↑ leucine, isoleucine and valine e. ↑ urinary alpha-hydroxyacids and alpha-ketoacids 4. Treatment a. Diet low in branched chain amino acids i. Reduce natural protein ii. BCAA free formula b. Dialysis to remove toxic metabolites c. Liver transplantation

Answer 2

1. Key points a. The early steps in the degradation of the branched chain amino acids (valine, leucine, and isoleucine) are similar b. Intermediate metabolites are all organic acids [non-amino organic acids] i. Examples = lactate, pyruvate, beta-hydroxy butyrate, methylmalonic acid c. Deficiency in any causes organic acids proximal to the enzymatic block to accumulate  collect in body fluids  excreted in the urine d. Elevated organic acids blocks the urea cycle resulting in hyperammonaemia 2. Clinical manifestations a. Most acidaemias become apparent in newborn period or early infancy b. Present first 1-2 weeks of life – poor feeding, vomiting, floppiness, hypotonia, increased lethargy which progresses to coma c. After an initial period of being well children develop a life-threatening episode of metabolic acidosis characterised by a widened anion gap d. Presenting episode may be mistaken for sepsis e. Children susceptible to metabolic decompensation during episodes of catabolism (eg. illness, trauma, prolonged fasting) 4. Investigations a. Metabolic acidosis with widened anion gap (>25 mmol/L) b. Mild-moderate hyperammonemia c. Elevated ketones d. Hypoglycaemia e. Bone marrow suppression common – results in pancytopaenia f. Urine = elevated organic acids g. Acylcarnitine = all organic acids are esterified to carnitine forming acylcarnitine 5. Common conditions a. Methylmalonic acidaemia (MMA) b. Propionic acidaemia (PA) c. Isovaleric acidaemia (IVA) d. 3-methylcrotonylglycinuria (3-MCG) e. GA-1 6. Treatment principles a. Decrease substrate – low protein diet b. Enhance enzyme activity – biotin, B12 (MMA) c. Disposal of toxic metabolites – carnitine (propionic acidaemia) i. Carnitine binds to organic acids then can be excreted in the urine

Answer 3

1. Key points a. Urea cycle = pathway by which nitrogen (produced from amino acid catabolism) is converted to urea for excretion b. 5 enzymes involved in urea cycle i. All can have mutations ii. OTC most common – characterised by low citrulline + orotic acid 2. Clinical manifestations a. Vomiting b. Lethargy c. Encephalopathy/ coma 3. Investigations a. Hyperammonemia b. Respiratory alkalosis (elevated ammonia stimulates central respiratory drive -> hyperventilation) c. Ketosis d. Liver dysfunction

Answer 4

1. Key points a. Most common inborn error of urea synthesis 2. Genetics + Pathogenesis a. X linked deficiency of OTC enzyme – located in mitochondrial matrix, coded for by Xp21.1 b. Expressed in liver + intestine c. Hyperammonemia i. Ammonium binds with glutamate to form glutamine, which has osmotic effect causing cerebral oedema 3. Clinical manifestations a. Usually lethal in neonatal period i. Severe in affected males – history of deaths in male siblings ii. May manifest in carrier females b. Protein aversion c. Recurrent vomiting, decreased GCS, lethargy and coma d. Acute / chronic encephalopathy 4. Investigations a. Hyperammonaemia (> 1000 mmo/L) b. Additional metabolic markers i. Low citrulline ii. Elevated orotic acid c. No metabolic acidosis (may have respiratory alkalosis as ammonia drives tachypnoea) d. No urinary ketones e. Deranged LFTS/ coagulopathy 5. Treatment a. Decrease substrate availability = low protein diet b. Promote anabolism = increase calories by protein free formula c. Replace deficient metabolites = arginine or citrulline d. Increase disposal of toxic metabolites = sodium benzoate (binds glycine which contains nitrogen) e. Rapid removal of toxic metabolites = haemofiltration f. Liver transplantation

Answer 5

1. Key points a. Beta oxidation of fatty acids is used to produce energy in periods of starvation/illness, completely oxidized to CO2 and H2O, producing ketone bodies B-hydroxybutyrate and acetoacetate b. Most identified on newborn screening – otherwise dx on urine organic acids, acetyl carnitine profile 2. Common features (liver, muscle, heart) a. Hepatic b. Cardiac i. Acute or chronic hypertrophic or dilated cardiomyopathy ii. Pericardial effusion often accompanies the hypertrophic cardiomyopathy and is often responsible for death c. Muscle i. Moderate to severe hypotonia or recurrent rhabdomyolysis ii. Gross myoglobinuria not observed until CK >30,000 IU/L 3. Investigations a. Hypoglycaemia with LOW ketones b. LFTS may be deranged c. May have hyperammonemia and a metabolic acidosis d. Secondary carnitine deficiency may occur – acylcarnitine profile (Guthrie card) 4. Management a. Give sugar when sick (oral or IV) b. Low long chain fat diet + MCT supplement c. Avoid fasting 5. Common conditions a. VLAD b. SCAD c. MCAD d. Carnitine uptake defects

Answer 6

1. Key points a. Most common fatty acid oxidation defects b. Mortality rate 20-25% at first presentation c. Abnormal neurodevelopmental outcome in 33% of survivors 2. Genetics a. AR mutation in the ACADM gene: enzyme needed to oxidize MCDA  acetyl CoA 3. Clinical manifestations a. Onset 3 months – 5 years b. Hypoglycaemia during periods of fasting c. NO acidosis d. Lethargy, encephalopathy, liver dysfunction 4. Investigations a. Newborn screening b. ↑ medium chain fatty acids c. Secondary carnitine deficiency 5. Treatment a. Avoid fasting b. Treatment with carnitine, IV hydration, dextrose

Answer 7

``` Peroxisomal biogenesis disorders (PBD) i.e. transport disorders - Zellweger syndrome - Adrenoleukodystrophy - Refsum's disease - Rhizomelic chondrodysplasia punctate Single peroxisomal enzyme deficiencies - X linked adrenoleukodystrophy - D-bifunctional protein deficiency ``` Inheritance: AR except for X-ALD • Peroxisomes = organelles involved in breakdown of fatty acids, present in all cells except erythrocytes • Functions o Lipid metabolism  Synthesis of plasmalogens (for cell walls)  Oxidation of VLCFA****** o Cholesterol + bile acid synthesis • Generally suggested by elevated VLCFA (except RCDP) • No specific management except for refusm which can be treated with phytanic acid (vitamin A) restriction Clinical Manifestations of PBD • Neurological = seizures, hypotonia, neurodegeneration, structural brain abnormalities, psychomotor retardation • Facial dysmorphism • ENT = hearing loss, cataracts, pigmentary retinopathy • Hepatomegaly/ liver dysfunction • Adrenal insufficiency • Bony abnormalities = punctate epiphyseal changes, osteopenia • Death o Early infancy = ZS o Late infantile = NALD o Second decade = IRD First line investigation is VLCFA

Answer 8

1. Key points a. Progressive disorder of CNS associated with adrenal cortical failure*** 2. Genetics + pathogenesis a. X linked b. Mutation in ATP-binding cassette subfamily D, member 1 (ABCD1) located in the peroxisomal membrane c. Results in accumulation of unbranched saturated VLCFA in neural tissue and adrenal glands 3. Phenotype - some only develop neuro sx, others only adrenal insufficiency a. Addison disease only b. Cerebral ALD = childhood onset (most common) i. Usually 4-8 years with insidious cognitive decline ii. More neurological deficits with time c. Adrenomyeloneuropathy (adult onset) 4. Clinical manifestations a. Neurological dysfunction PRECEDES adrenal insufficiency in 85% b. Onset between 5-10 years c. Behaviour change is the most common initial complaint – usually hyperactivity, then poor school performance e. Ataxia, loss of vision and hearing and progression to persistent vegetative state is the typical clinical pattern f. Seizures g. Adrenal insufficiency (males with adrenal insufficiency should have VLCFA checked to ensure dx is not missed) 6. Investigations a. Adrenal insufficiency b. Evidence of demyelination i. CSF protein elevated ii. CT or MRI showing white matter abnormalities c. ↑ serum level of VLCF C26: C22 ratio 7. Treatment a. Treat adrenal insufficiency with steroids b. Lower VLCF = Dietary restriction, Erucic acid (Lorenzo’s oil) c. Immune modulation d. BMT (nonverbal IQ predictive of prognosis, not recommended if < 80, need to be free of nervous system involvement) e. Gene therapy 8. Prognosis = death within 10 years

Answer 9

1. Genetics a. AR b. Mutations in multiple PEX genes associated with peroxisome biogenesis -> unable to import proteins into peroxisomes efficiently 2. Clinical manifestations a. Wide clinical spectrum i. Dysmorphic - macrocephaly, prominent forehead, hypertelorism, large fontanelle ii. FTT b. Neurological i. Severe mental retardation/ GDD then regression ii. Hypotonia iii. Seizures iv. Sensorineural deafness v. Brain malformations e.g. polymicrogyria c. Eye abnormalities - retinopathy, cataracts 3. Investigations a. MRI = polymicrogyria, unmyelinated white matter b. ↑ VLFCA, elevated phytanic acid levels - confirmatory enzymology on fibroblasts Rx - supportive/nil effective 4. Prognosis a. Death in infancy

Answer 10

1. Genetics + pathogenesis a. Inability to degrade phytanic acid, due to PEX 1/6/7 mutations 2. Clinical features a. Survive to infancy b. Moderate dysmorphism: epicanthal folds, flat nasal bridge, low set ears c. Severe ataxia and developmental delay (peripheral neuropathy) d. Sensorineural hearing loss e. Small hypoplastic adrenals f. Characteristic rash 3. Investigations a. Elevated phytanic acid levels

Answer 11

Lipid metabolism overview • Dietary fat transported from the small intestine as chylomicron • Chylomicrons deliver free fatty acids around the body • Liver utilizes remnant proteins to synthesize VLDLs • VLDLs broken down to IDLs and LDLs • HDLs involved in VLDL and chylomicron metabolism and cholesterol transport – mops up excess cholesterol / chylomicrons in the circulation • Apolipoproteins: are constituent proteins involved in metabolism Disorders of Lipoprotein Abnormality 1. Hyperlipidemia a. Familial hypercholesterolemia = most common hyperlipidaemia, monogenic autosomal codominant disorder with mutations of the LDL receptor -> elevated LDL cholesterol levels in the blood - early ischaemic heart disease - xanthomas - diet and exercise mainstay of rx, then statins (teratogenic) c. Familial combined hyperlipidemia = AD condition with moderate elevation of LDL, trigs, ↓ HDL – no specific genetic mutation identified 2. Hypertriglyceridemia - rare - defective chylomicron removal or overproduction of VLDL Conditions with Low Cholesterol 1. Abetalipoproteinemia a. AR disorder of apoenzyme B - triglyceride transfer protein involved in transfer of nascent chylomicrons and VLDL -> absent chylomicrons, VLDL, LDL and apoB b. Fat malabsorption, diarrhoea and FTT c. Blood film = acanthocytosis

Answer 12

Most common sterol biosynthesis defect - a group of disorders characterised by limb defects, major organ dysplasia, and skin abnormalities. Due to block of penultimate step of cholesterol biosynthesis, so cholesterol is low and 7-dehydrocholesterol is high. Features - dysmorphic (microcephaly, narrow frontal area, upturned nose, ptosis) - syndactyly of second and third toes - genital anomalies - learning disability - renal anomalies - faltering growth - feeding difficulties - sunlight sensitivity Ix - as above, low cholesterol, high 7-dehydrocholesterol Rx - Suportive - cholesterol supplementation

Answer 13

1. Pathology a. Lysosomes usually required to degrade macromolecules such as mucopolysaccharides, gangliosides, glycoproteins into smaller molecules that can be recycled b. Disorders = inability to degrade some of these molecules, buildup of precursor products 2. Universal features a. Coarse features + hair b. Hepatosplenomegaly – EXCEPT Tay Sachs, marked in Gaucher’s c. CNS abnormalities – all are progressive + classically result in regression iii. Retinitis pigmentosa iv. Bony changes v. Macrocephaly 3. Classification a. Mucopolysaccharidoses (1-7) b. Sphingolipidoses i. Gaucher ii. Gangliosidoses (1, 2 (Tay Sachs, Sandhoff), Krabbe) iii. Metachromatic leukodystrophy iv. Niemann-Pick v. Fabry c. Neuronal cerebral lipidoses d. Glycoproteinoses i. Mannosidosis ii. Sialidosis 4. Investigations a. Elevated urine GAGs (glycosaminoglycans) b. White cell enzyme test – for lysosomal enzyme activity

Answer 14

Mucopolysaccharidoses = glycosaminoglycans - structural molecules integral to connective tissues e.g. cartilage. Degradation occurs w/i lysosomes -> deficiency in enzymes produces mucopolysaccharidoses. All AR except MPSII which is X-linked Patients appear normal at birth and present with developmental delay in the first year. Features become more obvious with time. Hurler syndrome is the classic MPS - storage affects body and CNS - enzyme deficiency is alpha-iduronidase - Scheie disease is a milder variant - features: coarse faces, macroglossia, hirsutism, corneal clouding, ENT problems, otitis media, dysostosis multiplex, cardiomyopathy, hepatosplenomegaly, hernias, stiff joints, developmental delay - dx: urine GAGs and white cell enzymology - rx: bone marrow transplantation , enzyme replacement therapy, supportive care

Answer 15

* Sphingolipids = a component of cellular membranes * Sphingolipidoses = disorders with abnormal catabolism of sphingolipids, leading to intracellular storage of lipid substrates * All autosomal recessive EXCEPT Fabry (X-linked) * Classic cause of early developmental regression ``` • Include 1. Gaucher 2. Gangliosidoses  GM1 ganagliosidoses  GM2 gangliosidoses  Krabbe disease 3. Niemann-Pick 4. Metachromatic leukodystrophy 5. Fabry ``` Typical features include psychomotor retardation, neurological degeneration including epilepsy, ataxia and spasticity, +/- hepatomegaly.

Answer 16

A sphingolipidoses Glucocerebrosidase deficiency results in the accumulation of cerebroside in the visceral organs +/- the brain depending on the type. Most have no neuro disease. Most common Ashkenazi Jewish inherited condition Type 1 - most common 80-90% - non-neuropathic - splenomegaly>hepatomegaly - anaemia, bleeding tendancy - skeletal pain, deformities, osteopenia - abdominal pain (splenic infarcts) Type 2 - most severe - NO bony disease - acute neuropathic - severe CNS involvement, rapidly progressive - convergent squinting and horizontal gaze palsy - hepatosplenomegaly Type 3 - subacute neuropathic - convergent squint and horizontal gaze palsy - splenomegaly>hepatomegaly - slow neurological deterioration Dx - elevated ACE and acid phosphatase - BMA may reveal Gaucher cells (crumpled tissue-paper cytoplasm) - white cell enzymes for glucocerebroside give the definitive diagnosis Rx - ERT in type 1 and 3 - BMT - splenectomy - no effective treatment for type 2

Answer 17

A subtype of the general metabolic group of disorders "gangliosidoses" (GM2 - a type of ganglioside) 1. Genetics a. Most common in Ashkenazi Jews b. AR, carrier rate up to 1/30 in Jewish population c. HEXA gene mutation on 15 q23-24 i. ↓ serum hexosaminidase A = ganglioside accumulation d. Prenatal testing to assess beta-hexosaminidase levels 2. Clinical manifestations a. Onset 3-6 months – hyperacusis, exaggerated startle b. Regression 4-6 months c. Early hypotonia -> spasticity d. Blindness (cherry red spot - universal) e. Macrocephaly + seizures – second year of life f. Coarse facies No hepatosplenomegaly compared with Sandhoff*** 3. Natural history a. Usually pass away by 2-4 years secondary to aspiration pneumonia 4. Investigations a. Hexosaminidase A – alpha polypeptide gene (HEXA) mutation

Answer 18

A GM2 gangliosidosis/metabolic disorder 1. Genetics = HEXB gene mutation on chr 5q13 2. Clinical manifestations a. Very similar to TSD  loss of developmental milestones, seizures, blindness b. Doll like facies c. Hepatosplenomegaly*** (differentiates from Tay-Sachs) d. Cardiac involvement e. Usually pass away by 3-4 years 3. Diagnosis = ↓ serum hexominidase A and B in leukocytes

Answer 19

(Google) Leukodystrophy refers to a group of conditions that mainly affect the white matter of the brain and the spinal cord. The white matter is the wiring network of the brain. It links the brain to the spinal cord and rest of the body. Leukodystrophies affect myelin production or breakdown.

Answer 20

Globoid Cell Leukodystrophy 1. Key points a. Type of demyelinating sphingolipidoses 2. Genetics + Pathogenesis a. AR disorder b. Deficiency of galactocerbrosidase beta galactosidase leading to demyelination and formation of globoid cells 3. Classification a. Infantile onset i. Present first 3-4 months ii. Rapidly progressive v. Regression, irritability, spasticity, opisthotonos + absent deep tendon reflexes b. Juvenile onset and adult onset also 4. Investigations a. ↓ galactocerebrosidase b. MRI brain i. Symmetrical atrophy of grey + weight matter + periventricular change c. NCG = slowing of motor and sensory conduction d. Histology = globoid cells + demyelination 5. Treatment a. Enzyme replacement type 1 6. Prognosis a. Death in 2-5 years b. Older onset has more benign course

Answer 21

1. Key points a. Rare autosomal recessive lysosomal storage disease b. Results in progressive demyelination of the central and peripheral nervous system Autosomal recessive 4. Clinical manifestations a. Late infantile onset (6 months to 2 years) = 80% i. Early signs = regression of motor skills, gait difficulties, seizures, ataxia, hypotonia, extensor plantar responses, optic atrophy ii. Other features = hypotonic extremities, deep tendon reflexes absent or diminishes iii. Progressive deterioration in motor skills – unable to stand iv. Deterioration in intellectual function – speech slurred and dysarthric v. Prognosis – death within 5 to 6 years 5. Investigations a. Nerve conduction studies – marked slowing b. Brain MRI – symmetrical white matter lesions with a periventricular predominance c. Lysosomal enzyme screen – ARSA activity in leukocytes < 10% d. ↑ urinary excretion of sulfatides 6. Treatment a. BMT b. Gene therapy

Answer 22

Eponymous name for the sphingomyelinoses - types A and B are biochemically and genetically distinct from type C. A (infantile) - feeding difficulties - hepatomegaly>splenomegaly - cherry-red spot - lung infiltrates - neurological decline, deaf, blind, spasticity - death w/i 3 years B (visceral) - milder course w/o neurological involvement - HSM - pulmonary infiltrates - ataxia - hypercholesterolaemia C (lysosomal cholesterol export defect) - conjugated hyperbilirubinaemia (earliest sign) - HSM - neurological deterioration - dystonia - cherry-red spot - vertical ophthalmoplegia Dx - BMA for Niemann-Pick disease cells, white cell enzymes, genotyping - cholesterol studies on fibroblasts and genotyping for type C Rx - supportive

Answer 23

Alpha-galactosidase deficiency -> storage of glycolipids in blood vessel walls, heart, kidney and autonomic spinal ganglia. X LINKED*** recessive Clinical features - onset late childhood/adolescence - severe pain in extremities (acroparaesthesia) - angiokeratoma (bathing-trunk area) - corneal opacities - cardiac disease - cerebrovascular disease - nephropathy - normal intelligence Dx - maltese crosses (birefringent lipid deposits) in urine - white cell enzymes Rx - ERT now reduces pain and stabilises renal function - death in 5th decade

Answer 24

Grey matter disorder. These disorders are characterised by storage of pigments that are similar to ceroid and lipfuscin. Originally thought to be related, genetic analysis has shown them to be separate disorders. 1. Key points a. Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders b. Characterised by progressive intellectual and motor deterioration, seizures and early death c. Lipopigment is deposited in neuron and some visceral tissues d. Disorders are classified by age of onset and rapidity of progression e. Most types occur AFTER 2 years f. Most of the disorders are characterised by dementia and blindness i. Seizures are common in the late infantile form Infantile - onset 8-18mo - myoclonus, ataxia, extrapyramidal features, visual impairment slight - death by 5 Late infantile - 18mo-4yrs - epilepsy (occurs first), marked ataxia, late visual deficit Juvenile (Batten disease) - 4-7yrs - visual failure (first), later dementia - death 15-30yrs Adult - onset adulthood - slow cognitive decline, normal vision - death slow 5. Investigations a. Enzyme assay activity b. Molecular genetic testing c. Ophthalmology d. Electronic microscopic findings of skin, conjunctiva or rectum e. MRI = cerebral atrophy 6. Treatment - symptomatic and palliative only

Answer 25

* Carbohydrates can exist as monosaccharides (glucose, galactose, fructose, sucrose) , disaccharides or polysaccharides (eg glycogen) * Carbohydrates are broken down into monosaccharides which are eventually broken down to pyruvate, which is converted to CO2 + H20 via mitochondria oxidation * Glycogen is the form of carbohydrate storage, largely in the liver and muscle * Disorders of carbohydrate can involve problems with glycogen storage, defective metabolism of galactose/ fructose or pyruvate ``` • Classification o CHO intolerance disorders  Galactosaemia  Galactokinase deficiency  Hereditary fructose intolerance o Disorders of CHO production or utilization  Glycogen storage disease  Disorders of gluconeogenesis ``` ``` • Common features o Hypoglycaemia with ketosis o Metabolic acidosis o Liver dysfunction o Non-glucose reducing substances in urine ```

Answer 26

Glucose is stored as glycogen in liver, muscles, and kidneys. GSDs result from defects of lycogen breakdown. Hepatic forms p/w hepatomegaly and hypoglycaemia, muscle forms p/w weakness and fatigue. 1. Key points a. Numbered in order of recognition b. I, II, III and IX are the most common in children c. V is most common in adolescents/ adults (McArdle) 2. Clinical manifestations a. Hypoglycaemia + lactic acidosis b. Hyperuricaemia and hyperlipidemia c. Hepatomegaly d. Increased CK e. Facies = fat cheeks (cherubic facies), thin extremities, protuberant abdomen f. FTT + short stature g. Recurrent infections + IBD (GSD IB) h. Subtype specific features: i. Type Ib = neutropenia/ impaired neutrophil function ii. Type II = Pompe  a muscle glycogenosis iii. Type III = liver and muscle problems iv. Type V = sore muscles 3. Investigations a. Lactic acidosis b. Hypoglycaemia c. Elevated uric acid d. High cholesterol + TG e. Deranged LFTs f. +/- high CK 4. Treatment a. Largely relates to management of sugars – eg administration of corn starch overnight b. Liver transplantation potential cure c. Can be complicated by liver and renal disease

Answer 27

Acid maltase deficiency d. Deficiency results in abnormal glycogen deposition in skeletal/ cardiac/ smooth muscle/ central and PNS Really a lysosomal storage disorder with accumulation of glycogen in lysosomes Infantile form - severe hypotonia, weakness, hyporeflexia - macroglossia, respiratory failure, feeding difficulties - ECG -> giant QRS complexes - vacuolated lymphocytes are seen on the blood film - hepatomegaly Dx - confirmatory enzymology is performed on fibroblasts Rx - enzyme replacement? Prog - death w/i 1 year

Answer 28

1. Pathogenesis a. Deficiency I galactose 1 uridyl transferase  cannot break down lactose/ galactose 2. Clinical manifestations a. Presents < 2 weeks of life b. Jaundice – prolonged, worse following milk ingestion c. FTT d. Hepatomegaly, liver failure e. E.coli sepsis f. Lenticular cataracts 3. Investigations a. Urine reducing substances, Galactoscreen b. NOT part of newborn screening test - Gal-1-PUT assay not suitable if has had transfusion 4. Treatment = soy formula, lactose/ galactose restriction

Answer 29

X-linked disorder of purine metabolism Caused by hypoxanthine-guanine phosphoribosyl-transferase deficiency Features - motor: hypotonia, dystonia, choreoathetosis, spasticity, bulbar disorders (speech and feeding difficulties) - growth faltering - hyperuricaemia (stones, nephropathy, gout) - compulsive self-injury - cognitive impairment 1. Key points a. Triad of features i. Motor dysfunction resembling cerebral palsy ii. Cognitive and behavioural disturbances iii. Uric acid overproduction – hyperuricaemia b. Often mis-diagnosed with choreoathetoid CP c. Persistent self-injurious behaviour (biting the fingers, hands, lips and cheek, banging the head or limbs) = hallmark of disease Dx - elevated urate and hypoxanthine in urine (plasma urate may be normal due to renal clearance) - enzymology of red cells or fibroblast studies Rx - allopurinol and liberal fluids reduce renal complications - MDT approach essential - low purine diet (limited evidence)

Answer 30

1. Key points a. Prevalence 30 per million Copper excess (Menkes = copper deficiency) 2. Genetics + Pathogenesis a. Autosomal recessive Excessive accumulation of copper in nervous system and liver due to lack of binding globulin (ceruloplasmin) 3. Clinical a. Heterogenous clinical manifestations i. Hepatic - may present in acute liver failure with haemolysis ii. +/- neurological and psychiatric symptoms b. Neurological presentation – affect BG (30% p/w neuro symptoms only) i. Parkinsonism ii. Pseudosclerotic iii. Dystonia iv. Chorea c. Kaiser-Fleischer rings usually present when there is neurological involvement 4. Investigations a. MRI – copper pigment in thalami and BG 5. Treatment a. Reduce ingestion = nuts, seeds, liver, shellfish b. Chelators i. D-penicillamine*** ii. Trientine iii. Tetrathiomolybdate c. Uptake inhibition = zinc

Answer 31

= kinky hair disease Copper deficiency (low copper low ceruloplasmin) X-linked 2. Pathogenesis a. Mutation of the transport protein mediating copper uptake from the intestine – encoded by ATP7A gene b. Inactivating mutation  severe copper deficiency  progressive neurological deterioration and early death Features - onset in neonatal period or early infancy (healthy for first 2-3mo) - hypothermia, poor weight gain - hair is sparse and brittle - progressive cerebral infarction occurs, leading to seizures and neurological impairment 5. Investigations a. ↓ copper due to impaired intestinal copper absorption b. ↓ Caeruloplasmin c. Genetic – ATP7A mutation 6. Treatment a. Copper-histidine complex – not consistently effective b. Supportive Prog - death w/i 2 years

Answer 32

1. Key points a. Heterogenous group of clinical syndromes caused by genetic lesions that impair energy production b. Signs and symptoms reflect the vulnerability of the nervous system, muscles and other organs (kidney, liver, heart) to deficiency c. Often multifocal signs that are intermittent or relapsing-remitting, often in association with intercurrent illness 2. Physiology a. Respiratory chain catalyses oxidation of fuel molecules, transfers electrons to molecular O2 to form ATP i. Organic acids, fatty acids and amino acids broken down to acetyl-CoA ii. Acetyl Co A catalyses metabolism of oxaloacetate  citrate iii. Citrate can then enter Krebs cycle b. Defects in any of these pathways tends to produce a lactic acidosis i. Inheritance of the disease is maternal – but both sexes are equally affected Phenotypic expression of an mtDNA mutation depends on the relative proportions of mutant and wild type genomes – with a minimum critical number of mutant genomes being necessary for expression (threshold effect)  the critical number of mutant mtDNAs required varies depending on the ii. vulnerability of the tissue to impairments of oxidative metabolism

Answer 33

5. Clinical manifestations a. Signs and symptoms of brain and muscle dysfunction i. Seizures ii. Weakness iii. Ptosis + external ophthalmoplegia iv. Psychomotor regression v. Hearing loss vi. Movement disorders + ataxia b. Lactic acidosis c. Cardiomyopathy d. Diabetes mellitus e. Liver disease 6. Suspect if a. Multisystem involvement b. Multiple-neurological involvement i. Vision/hearing/ataxia/seizures/neuropathy c. Signs and symptoms that come and go d. MRI lesions that may change over time i. Grey and white matter e. Investigations i. Often need liver and muscle biopsies to make a diagnosis ii. Blood and CSF lactate may be normal 7. Investigations a. Metabolic acidosis b. Lactic acidosis c. Hypoglycaemia d. Deranged LFTs 8. Treatment a. Mitochondrial vitamin cocktail b. High fat die c. Supportive measures – seizure control, feeding d. Palliative care

Answer 34

1. Genetics + pathogenesis a. Many enzymes, hormones and proteins require post-translational glycosylation to function normally (complex process of attaching sugars to proteins) occurs in the cytosol, ER and Golgi apparatus d. Inherited in AR manner e. Most common = CDG1a 3. Clinical manifestations a. Onset usually occurs in infancy b. Multisystem disorder c. Neurological i. Developmental delay ii. Hypotonia iii. ‘Malformations’ – cerebellar ‘hypoplasia’ iv. Ataxia v. Seizures vi. Retinopathy vii. Optic atrophy d. Physical i. Big ears ii. Abnormal fat pads iii. Inverted nipples e. Oher i. FTT ii. Hypoglycaemia iii. Protein losing enteropathy 4. Investigations a. Transferrin isoforms screening test - unreliable in first 3/12 b. Assay CDG enzyme or sequence CDG genes (panel or exome)

Answer 35

Syndrome of dementia, autistic behaviour and motor sterotypes seen in GIRLS. Features - normal perinatal period and first year - deceleration of head growth from ~9mo (often first sign) - loss of neurological skills, neurodevelopmental arrest - loss of spoken language - hand wringing, loss of purposeful hand skills*** - hyperventilation - gait apraxia (loss of the ability to execute or carry out skilled movements and gestures) - may develop scoliosis Dx - was clinical - now MeCP2 gene (80%) -> mutations in boys lead to severe neonatal encephalopathy Rx - supportive, nothing specific e. Most patients survive well into adulthood – median age of survival 45 years in 1 study f. Cause of death – cardiopulmonary factors (LRTI, aspiration, asphyxiation, respiratory failure), seizues

Answer 36

a. Traumatic brain injury i. Falls ii. MVA iii. NAI b. Cerebral hypoxia i. Near drowning ii. Post-surgical complications c. Meningitis/encephalitis d. Metabolic/neurology – glutaric aciduria type 1, ADEM e. Stroke – primary, ECMO/Berlin Heart population f. Tumour g. Post-surgical (Epilepsy surgery)

Answer 37

3. Mild head injury a. Constitutes up to 80% of all head injuries b. Majority go on to do well c. May be discharged while still in a confused state and go on to experience significant problems at home and school 4. Concussion a. Blunt head injury, with one or more of the following i. Somatic = headache, vomiting ii. Fatigue = cognitive fatigue iii. Dazed iv. Physical signs = LOC, amnesia, coordination, balance v. Behavioural change vi. Cognitive impairment = slowed reaction time, concentration vii. Sleep disturbance b. Symptoms reflect functional disturbance rather than structural injury c. No abnormality on neuroimaging d. Classification i. Simple = symptoms resolve over 7-10 days ii. Complex = persistent symptoms or specific symptoms iii. Second impact syndrome = when a concussion or mild TBI is sustained before first TBI has resolved iv. Post-concussion syndrome = 3 or more symptoms persist for at least 3 months e. Management i. Education ii. Symptom management = fatigue, headaches, cognitive iii. Return to school = graded iv. Return to sport/contact sport 1. SCAT3 guideline or CanChild Guidelines

Answer 38

a. Definition = period of mental confusion from the time of the TBI when the subject is disoriented in time, place and person and is unable to retain new, continuous memory b. Features i. Disorientation in time and space ii. Defect of perception and inability to synthesis perceptual data iii. Judgement is impaired iv. Thought constantly impeded by perseveration v. Disturbances of speech function vi. Disruption in behaviour, patients may be talkative, drowsy, docile, aggressive, impudent or irritable d. Classification i. <5 min = very mild ii. 5-60 minutes = mild iii. 1-24 hours = moderate iv. 1-7 days = severe v. 1-4 weeks = very severe vi. >4 weeks = extremely severe f. Recovery from PTA i. Marked improvement in behaviour, reduction in agitation, improvement in attention ii. PTA is dynamic process for the patient iii. May shade imperceptibly into a picture of post-traumatic dementia/ chronic memory impairment (CMI) 1. CMI is the single most common residual neuropsychological deficit after severe TBI

Answer 39

8. Trajectory of ABI a. Mild i. Rapid recovery ii. Discharged in a day or two iii. Review ABI clinic in 6/52 iv. 80% plus normal in 3 months b. Moderate i. Cognitive + behavioural difficulties c. Severe i. Inpatient - outpatient rehab ii. 80% residual defect 9. Management overview a. Initial management of severe TBI i. Multidisciplinary inpatient management ii. Medical complications iii. Goals iv. Discharge planning v. Education vi. Re-integration into community vii. Long-term management b. Medical management i. Behaviour = agitation – low stimulation, disinhibition ii. Spasticity/dystonia = splints, medications, botox iii. Nutrition/NGT iv. Bladder/bowel v. Skin vi. Other trauma = fractures, chest, tracheostomy vii. DVT prophylaxis – post-pubescent chidlern Pharmacology a. Spasticity = baclofen, diazepam, tizanidine (central alpha agonist), botox b. Rage/disinhibition = carbamazepine, beta blockers, valproate, risperidone, olanzapine c. Dystonia = trihexyphenidyl (artane), gabapentin d. Inattention, hyperactivity = occasionally methylphenidate e. Fatigue = modafinil (dopamine reuptake inhibitor) f. Endocrine = bisphosphonate (hypercalcaemia) g. Improve awakening in short term = amantadine (dopaminergic)

Answer 40

a. Dysautonomia = paroxysmal autonomic instability i. Central autonomic dysfunction ii. Intermittent storms iii. Hyperthermia, sweating, tachypnoea, tachycardia iv. Increased dystonia v. Treatment 1. Quiet room, cooling 2. Medications = beta blocker, diazepam, clonidine, bromocriptine b. Post-traumatic epilepsy i. Risk 1. Mild = no increased risk 2. Moderate = 1.5-2x increased risk 3. Severe = 2x increased risk ii. Classification = immediate (<1 day), early (1-7d) and late iii. Prevention of PTE using anticonvulsants – phenytoin, Keppra iv. NO effect in preventing late seizures in treated group c. Endocrine i. Posterior pituitary = diabetes insipidus ii. Bone health 1. Prolonged immobility 2. Hypercalcaemia/ osteopenia 3. Heterotopic ossification d. Sensory impairments i. Communication impairments 1. Non-verbal 2. Dysarthria ii. Anosmia iii. SNHL – CNVIII damage iv. Visual impairments 1. Hemianopia 2. Cerebral visual impatient 3. Diplopia, gaze palsy – CNS III, IV, VI

Answer 41

1. Key points a. Also referred to as spinal cord injury and disease (SCID) b. Relatively rare in children c. Huge implications i. Permanent loss of motor and sensory function ii. Dysfunction of bowel and bladder iii. Social and psychological consequences for child d. 50-80% have concomitant TBI 2. Aetiology a. Transection b. Distraction c. Compression d. Bruising e. Haemorrhage f. Ischaemia g. Inflammation 4. Classification a. Quadriplegia = cervical SCI causing dysfunction of arms, legs, bowel and bladder b. Paraplegia = thoracic, lumbar or sacral SCI causing dysfunction of legs, bowel and bladder c. Complete = entire cross-section of SC affected, with loss of all motor and sensory function below level of injury d. Incomplete = spinal cord has been partially injured, with preservation of either motor of sensory function 5. ASIA a. American Spinal Injury Association (ASIA) – created AIS (ASIA impairment scale) b. Constructed to provide standardized method for communication between professionals c. A = complete d. B = sensory incomplete e. C = motor incomplete f. D = motor incomplete (at least half of key muscle functions) g. E = normal

Answer 42

a. Clinical manifestations i. Flaccid paralysis below level of injury ii. Loss of spinal reflexes below level of injury iii. Loss of sensation (pain, touch, P+V, temp) below level of injury iv. Loss of sweating below level of injury v. Loss of sphincter tone and bowel/ bladder dysfunction b. Acute management i. ABC ii. Regular monitoring of vitals iii. Spinal immobilisation 1. Collar, sandbags, forehead strap 2. Early surgical intervention 3. Halo and orthotic devices to maintain correct spinal alignment 4. Use patient slide to move patient, log roll to turn patient 5. No pharmacological agent has been proven to limit damage and optimize function in acute SCI – including steroids

Answer 43

i. Damage to anterior 2/3 spinal cord, usually due to vascular occlusion ii. Features 1. Motor paralysis (corticospinal tract) – variable 2. Loss of pain and temperature (spinothalamic tract) – variable 3. Sparing of the dorsal column – light touch, joint position spared

Answer 44

i. Typically caused by hyperextension causing central cord injury ii. Features 1. Greater motor weakness in the upper limbs than lower limbs (corticospinal tract) 2. Variable loss of sensation, bowel and bladder function (fibres affecting voluntary bowel and bladder function are also centrally located)

Answer 45

i. Least frequent syndrome ii. Aetiology 1. B12 deficiency 2. Syphilis 3. HIV iii. Features 1. Injury to posterior columns resulting in proprioceptive loss (dorsal columns) 2. Spared muscle strength, pain and temperature spared

Answer 46

i. Hemisection of the spinal cord ii. Neurological deficits distal to the level of the lesion vary from the different nerve tracts crossing at different locations iii. Features 1. Ipsilateral flaccid paralysis at the level of the lesion = LMN 2. Ipsilateral spastic paralysis below the level of the lesion = UMN 3. Ipsilateral loss of position sense and vibration sense below the lesion = dorsal column medial lemniscus (decussates in the medulla) 4. Contralateral loss of pain and temperature below the lesion = spinothalamic (decussates in the spinal cord)

Answer 47

i. Conus medullaris syndrome 1. The conus medullaris = terminal segment of the adult spinal cord (L1-L2) 2. Features a. Areflexic bladder + bowel (usually hypertonic) – constipation + retention b. LL weakness (type can vary) ii. Cauda equina syndrome 1. Injuries below the L-1L2 affect the cauda equina 2. Results in lower motor neuron injury 3. Features a. Produces motor weakness and LL atrophy b. Bladder and bowel involvement (atonic) – incontinence c. Impotence d. Absent bulbocavernosus reflex 4. Better prognosis relative to UMN injuries

Answer 48

1. Self-adhesive electrodes are attached to the child’s leg muscles and attached to a stimulator which activates the muscles 2. Can also be used for arms 3. Reverse muscle atrophy 4. Improve local circulation 5. Increase ROM 6. Reduce muscle spasms

Answer 49

i. SCI at T6 and above ii. Clinical manifestations 1. High blood pressure 2. Sweating 3. Headache 4. Flushing above level 5. Bradycardia iii. Complications 1. ICH 2. Seizures iv. Treatment 1. Sit up/elevated head of bed 2. Loosen clothing, stockings, abdominal binders 3. Check BP regularly 4. Remove noxious stimulus = urinary retention***, faecal impaction, ingrown toenail, abdominal pathology, pressure sores, spasticity, fractures (labour) v. Consider medications 1. Nifedipine