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ACUTE METABOLIC PRESENTATIONS  in ADULTS Dr. Peter Galloway, Royal Hospital for Sick Children / Glasgow Royal Infirmary, G...
<ul><li>2% of all live births have an inherited metabolic disorder </li></ul><ul><li>Most common well known in adult clini...
Certain diseases usually appear at specific ages  But Age at Presentation depends on degree of enzyme deficiency and chall...
Classification <ul><li>Based on  compound  e.g. fructose </li></ul><ul><li>Essential fructosuria,  </li></ul><ul><li>Fruct...
Clinical <ul><li>Perhaps best developed by Jean-Marie Saudebray. </li></ul><ul><li>Four groups of clinical circumstances <...
Screening <ul><li>There are no  screening  methods  </li></ul><ul><li>covering all disorders. </li></ul>
Adult Metabolic Clinic GRI <ul><li>Present Range includes: </li></ul><ul><li>CHO – Galactosaemia 15 </li></ul><ul><li>FAT ...
CRITICAL ACUTE PRESENTATIONS <ul><li>Ornithine TransCarbamylase Deficiency </li></ul><ul><li>Maple Syrup Urine Disease </l...
<ul><li>Cases which were all previously well till they presented as described. </li></ul>
<ul><ul><ul><ul><ul><li>23 YEAR OLD FEMALE  </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>(PARA 2+0) </li></ul></u...
19 year old female <ul><li>Camping day two – first day smoking hash and drinking </li></ul><ul><li>Following morning - vom...
<ul><li>Post-Mortem - Microvesicular fatty infiltration  of liver and heart. </li></ul><ul><li>Acyl Carnitines or urine we...
MCAD <ul><li>First reported in 1983 </li></ul><ul><li>Technically difficult in Glasgow till 1989 </li></ul><ul><li>CLASSIC...
<ul><li>LM  DOB 28-11-83 </li></ul><ul><li>Fractured radius in 1986 at 1700 admitted to Stobhill and transferred GRI </li>...
<ul><li>However LM’s elder brother  </li></ul><ul><ul><ul><ul><ul><li>DOB  23-3-76 </li></ul></ul></ul></ul></ul><ul><li>1...
MCAD <ul><li>Incidence    1 in 10,000 to 1 in 15,000 </li></ul><ul><li>5 TH  Don’t present – hence ethical difficulties <...
 
<ul><li>23 year old male presented with second D.V.T. </li></ul><ul><li>6’ 2” tall </li></ul><ul><li>Wide span </li></ul><...
Cystathionine    synthase deficiency- clinical picture <ul><li>ocular abnormalities  </li></ul><ul><ul><li>lens dislocati...
Methionine Diet Homocysteine Cystathionine Cysteine 5-10 MTHF 5 MTHF THF MS BHMT Dimethylgycine Betaine S-Adomet S-AdoHom ...
VASCULAR  EVENT <ul><li>NATURAL EVENT </li></ul><ul><li>· 30% VE before 20 </li></ul><ul><li>· 50% VE before 30 </li></ul>...
 
<ul><li>13 year old male developed nausea, vomiting and anorexia. </li></ul><ul><li>Day 2 - seen by GP prescribed Stemetil...
<ul><li>On admission,  irritable, shouting and disorientated. </li></ul><ul><li>Apyrexial with no papilloedema, or focal n...
<ul><li>C.T. Normal </li></ul><ul><li>Observed overnight becoming less responsive with increased muscular tone and dilated...
<ul><li>On admission, ammonia 750   mol/L </li></ul><ul><li>Treated with emergency haemodialysis and given intravenous gl...
<ul><li>A liver biopsy was obtained pre-mortem confirming ornithine transcarbamylase (OTC) activity to be 11% of normal. <...
Ornithine transcarbamylase deficiency <ul><li>Presents over a  wide age range </li></ul><ul><li>Majority <2 years, often <...
<ul><li>Any sudden  change in catabolic state can precipitate  an attack such as pregnancy, post partum,. after starting t...
UREA CYCLE <ul><li>Stop protein intake </li></ul><ul><li>Give oral emergency regime – CHO and arginine 1.5 gm qds if NH3 >...
 
 
Recurring Encephalopathy <ul><li>Female who at 7 was involved in a RTA suffering a ruptured ureter which was replumbed int...
<ul><li>Presented with poor balance, shaky hands, confusion and slurred speech ’93 – Diagnosis - non-specific illness. </l...
<ul><li>Jan ’97 – further unspecified metabolic encephalopathy - ? Hashimoto’s encephalopathy despite ab negative, but res...
<ul><li>2003 – 3 discrete episodes of neurological dysfunction –   transient right leg hemiparesis for 1 hour, right arm f...
<ul><li>Dialysed and promptly improved. </li></ul><ul><li>Attempted low protein diet and lactulose. </li></ul><ul><li>Furt...
Aminogenic Coma following UTEROSIGMOIDOSTOMY <ul><li>Papers- </li></ul><ul><li>Lancet , Feb 26, 1972 – p496 </li></ul><ul>...
 
<ul><li>16 year old whose behaviour became bizarre.  Admitted to psychiatric ward for assessment of potential schizophreni...
<ul><li>She had an enlarged spleen. </li></ul><ul><li>What signs are present in her eyes ? </li></ul>
Psychiatric Disorders <ul><li>A wide variety of disorders have presented with behavioural disturbances, personality and ch...
<ul><li>Problems Possible Diagnoses   Biochemical Test </li></ul><ul><li>Schizophrenia-like OCT Deficiency Ammonia & plasm...
 
<ul><li>31 year old para 2+0 suffered severe hyperemesis from  7 / 40  to  13 / 40 .  </li></ul><ul><li>Treatment with int...
<ul><li>Given intravenous parentrovite by accident. </li></ul><ul><li>Progressively improved. </li></ul><ul><li>Diagnosis ...
<ul><li>Any unexplained lactic acidosis in a person on artificial diets. </li></ul><ul><li>Consider THIAMINE </li></ul>
 
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Transcript of "Acute Metabolic Presentations comep oct 2010"

  1. 1. ACUTE METABOLIC PRESENTATIONS in ADULTS Dr. Peter Galloway, Royal Hospital for Sick Children / Glasgow Royal Infirmary, Glasgow
  2. 2. <ul><li>2% of all live births have an inherited metabolic disorder </li></ul><ul><li>Most common well known in adult clinics </li></ul><ul><li>e.g. Haemochromatosis, FH </li></ul><ul><li>500 + Intermediate disorders of metabolism </li></ul><ul><ul><ul><li>PKU 1 in 7500 (UK 1 in 12k) </li></ul></ul></ul><ul><ul><ul><li>MMA 1 in 50,000 </li></ul></ul></ul><ul><ul><ul><li>Homocystinuria 1 in 350,000 </li></ul></ul></ul><ul><ul><ul><li>NAGS deficiency 1 in 5 million </li></ul></ul></ul>
  3. 3. Certain diseases usually appear at specific ages But Age at Presentation depends on degree of enzyme deficiency and challenges an individual faces Complete absence – very poor prognosis. Even with families with same defect, very different age of presentation
  4. 4. Classification <ul><li>Based on compound e.g. fructose </li></ul><ul><li>Essential fructosuria, </li></ul><ul><li>Fructose 1, 6 bisphosphatase; </li></ul><ul><li>Hereditary fructose intolerance </li></ul><ul><li>Based on organelle e.g. lysosomes </li></ul><ul><li>GSD II-Pomp é disease </li></ul><ul><li>I cell disease </li></ul>
  5. 5. Clinical <ul><li>Perhaps best developed by Jean-Marie Saudebray. </li></ul><ul><li>Four groups of clinical circumstances </li></ul><ul><li>Acute symptoms in neonatal period. </li></ul><ul><li>Late onset, acute and recurrent symptoms (such as coma, ataxia, vomiting, acidosis) </li></ul><ul><li>Chronic and general symptoms (mainly digestive and neurological) </li></ul><ul><li>Specific and permanent symptoms indicative of IEM (cataract etc.) </li></ul>
  6. 6. Screening <ul><li>There are no screening methods </li></ul><ul><li>covering all disorders. </li></ul>
  7. 7. Adult Metabolic Clinic GRI <ul><li>Present Range includes: </li></ul><ul><li>CHO – Galactosaemia 15 </li></ul><ul><li>FAT – MCAD 3 , LCHAD 1 , beta-Ketothiolase 1 </li></ul><ul><li>AA – PKU 66 , MSUD 1 , MMA 3 ( Cobalamin defects 2 ), UREA CYCLE (OTC 4 / NAGS 1 ), IVA 3 HOMOCYSTINURIA 10 , OAT 1 , TYROSINAEMIA II 1 </li></ul><ul><li>BIOTINIDASE 1 </li></ul><ul><li>METALS – WILSON’S 1 </li></ul><ul><li>ORGANELLE – FABRY 9 , REFSUM 3 , MPS I/II/IV/VI 4 </li></ul><ul><li>CHOLESTEROL SYNTHESIS – SLO 1 </li></ul><ul><li>TRIMETHYLAMINURIA 10 </li></ul>
  8. 8. CRITICAL ACUTE PRESENTATIONS <ul><li>Ornithine TransCarbamylase Deficiency </li></ul><ul><li>Maple Syrup Urine Disease </li></ul><ul><li>MethylMalonic Aciduria </li></ul><ul><li>Beta-ketothiolase </li></ul><ul><li>LCHAD </li></ul>
  9. 9. <ul><li>Cases which were all previously well till they presented as described. </li></ul>
  10. 10. <ul><ul><ul><ul><ul><li>23 YEAR OLD FEMALE </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>(PARA 2+0) </li></ul></ul></ul></ul></ul><ul><li>Three presentations of nausea, vomiting and abdominal pain associated with depressed consciousness. </li></ul><ul><li>Biochemically acidosis with one confirmed episode of hypo-glycaemia (glucose 2.4 mmol/l). </li></ul><ul><li>No toxicology or infection. </li></ul><ul><li>Following drinking heavily, presented more severely and had a cardiac arrest. </li></ul>
  11. 11. 19 year old female <ul><li>Camping day two – first day smoking hash and drinking </li></ul><ul><li>Following morning - vomiting and intermittently disorientated </li></ul><ul><li>Drowsy, normal reflexes but slightly ataxic. </li></ul><ul><li>CT was normal </li></ul><ul><li>Observed overnight suddenly becoming restless </li></ul><ul><li>15 minutes later found apnoeic and pulseless </li></ul>
  12. 12. <ul><li>Post-Mortem - Microvesicular fatty infiltration of liver and heart. </li></ul><ul><li>Acyl Carnitines or urine were pathognomic of MCADD </li></ul><ul><li>Sibling assessment required </li></ul>
  13. 13. MCAD <ul><li>First reported in 1983 </li></ul><ul><li>Technically difficult in Glasgow till 1989 </li></ul><ul><li>CLASSICALLY presents aged 2-3 years. </li></ul><ul><li>Hypoglycaemia. </li></ul><ul><li>Increased NEFA. </li></ul><ul><li>Relative hypoketosis (3OH Butyrate). </li></ul><ul><li>Specific urinary glycines. </li></ul><ul><li>Specific plasma acylcarnitines. </li></ul>
  14. 14. <ul><li>LM DOB 28-11-83 </li></ul><ul><li>Fractured radius in 1986 at 1700 admitted to Stobhill and transferred GRI </li></ul><ul><li>Operation 10am next morning </li></ul><ul><li>15:40 extended position, repetitive axial jerks and non-communicative. </li></ul><ul><li>Yorkhill – Glucose 0.6 mmol/l, </li></ul><ul><li>NH 3 173 umol/l </li></ul><ul><li>Urine ketones +++ </li></ul>
  15. 15. <ul><li>However LM’s elder brother </li></ul><ul><ul><ul><ul><ul><li>DOB 23-3-76 </li></ul></ul></ul></ul></ul><ul><li>1990 suffered knee operation </li></ul><ul><li>Became hypoglycaemic afterwards ! </li></ul><ul><li>Younger brother DOB 10-5-90 </li></ul><ul><li>MCAD diagnosed within first year so hypoglycaemia rapidly corrected during episode of gastroenteritis in infancy </li></ul>
  16. 16. MCAD <ul><li>Incidence  1 in 10,000 to 1 in 15,000 </li></ul><ul><li>5 TH Don’t present – hence ethical difficulties </li></ul><ul><li>5 TH Die </li></ul><ul><li>5 TH Left with handicap </li></ul><ul><li>2 / 5 Fine </li></ul><ul><li>Relative hypoketotic hypoglycaemia where encephalopathy may precede hypoglycaemia </li></ul>
  17. 18. <ul><li>23 year old male presented with second D.V.T. </li></ul><ul><li>6’ 2” tall </li></ul><ul><li>Wide span </li></ul><ul><li>High arched palate </li></ul>
  18. 19. Cystathionine  synthase deficiency- clinical picture <ul><li>ocular abnormalities </li></ul><ul><ul><li>lens dislocation </li></ul></ul><ul><ul><li>glaucoma, optic atrophy, retinal problems </li></ul></ul><ul><li>skeletal abnormalities </li></ul><ul><ul><li>osteoporosis </li></ul></ul><ul><ul><li>arachnodactyly </li></ul></ul><ul><ul><li>Marfanoid habitus </li></ul></ul><ul><ul><li>pes cavus </li></ul></ul><ul><ul><li>scoliosis and genu valgum </li></ul></ul><ul><li>CNS symptoms </li></ul><ul><ul><li>mental retardation +/- seizures </li></ul></ul><ul><ul><li>psychiatric disturbances </li></ul></ul><ul><li>thromboembolism </li></ul>
  19. 20. Methionine Diet Homocysteine Cystathionine Cysteine 5-10 MTHF 5 MTHF THF MS BHMT Dimethylgycine Betaine S-Adomet S-AdoHom MTHFR CBS B12 B6 B6 SO 4 2-
  20. 21. VASCULAR EVENT <ul><li>NATURAL EVENT </li></ul><ul><li>· 30% VE before 20 </li></ul><ul><li>· 50% VE before 30 </li></ul><ul><li>· Long-term therapy in Dublin, Australia and the Netherlands. </li></ul><ul><li>· In 84 patients reduction from 53 expected VE to 5 (mean age 48.8; </li></ul><ul><li>range 30-60) </li></ul>
  21. 23. <ul><li>13 year old male developed nausea, vomiting and anorexia. </li></ul><ul><li>Day 2 - seen by GP prescribed Stemetil </li></ul><ul><li>Day 3 – irritable, drowsy, disorientated and ataxic </li></ul><ul><li>PMH - Fell off a swing fracturing his right arm 1 month before. </li></ul>
  22. 24. <ul><li>On admission, irritable, shouting and disorientated. </li></ul><ul><li>Apyrexial with no papilloedema, or focal neurological signs. </li></ul><ul><li>Urgent LP – clear CSF with no cells and normal protein/glucose </li></ul><ul><li>Sodium 146 mmol/L, Bicarbonate 22 mmol/L, Urea 5.0 mmol.L, Glucose 7.4 mmol/L, CRP <10 mg/l and AST 45 iu/L. </li></ul>
  23. 25. <ul><li>C.T. Normal </li></ul><ul><li>Observed overnight becoming less responsive with increased muscular tone and dilated pupils. </li></ul><ul><li>He was transferred to a regional paediatric ITU unit. </li></ul>
  24. 26. <ul><li>On admission, ammonia 750  mol/L </li></ul><ul><li>Treated with emergency haemodialysis and given intravenous glucose, sodium benzoate (  glycine) sodium phenyl butyrate (  glutamate) and arginine. </li></ul><ul><li>Ammonia kept less than 80  mol/l, but EEG very poor. </li></ul>
  25. 27. <ul><li>A liver biopsy was obtained pre-mortem confirming ornithine transcarbamylase (OTC) activity to be 11% of normal. </li></ul>
  26. 28. Ornithine transcarbamylase deficiency <ul><li>Presents over a wide age range </li></ul><ul><li>Majority <2 years, often <2 weeks </li></ul><ul><li>Second age peak occurs 12-15 years in males </li></ul><ul><li>Other cases have presented in their 30s. </li></ul><ul><li>eg focal neurological signs (loss of vision). </li></ul><ul><li>Have met uncle age 62 with genetic defect! </li></ul>
  27. 29. <ul><li>Any sudden change in catabolic state can precipitate an attack such as pregnancy, post partum,. after starting total parenteral nutrition for ulcerative colitis, or fracturing your hip. </li></ul>
  28. 30. UREA CYCLE <ul><li>Stop protein intake </li></ul><ul><li>Give oral emergency regime – CHO and arginine 1.5 gm qds if NH3 > 100 umol/l </li></ul><ul><li>Monitor ammonia levels </li></ul><ul><ul><li>60-100 umol/l watch and repeat 4 hourly </li></ul></ul><ul><ul><li>>120-150 umol/l start iv therapy </li></ul></ul><ul><ul><li>>350 umol/l may need ITU for dialysis. </li></ul></ul>
  29. 33. Recurring Encephalopathy <ul><li>Female who at 7 was involved in a RTA suffering a ruptured ureter which was replumbed into her sigmoid colon. </li></ul><ul><li>Followed up till 1963 (age 18) and then lost to follow up until 1983 – though had had 3 successful pregnancies </li></ul>
  30. 34. <ul><li>Presented with poor balance, shaky hands, confusion and slurred speech ’93 – Diagnosis - non-specific illness. </li></ul><ul><li>June ’96 collapsed in street, GCS 5 admitted to ITU hyperventilating. CT scan mild atrophy. Improved. </li></ul><ul><li>Diagnosis – encephalopathy of unknown cause ?drugs, ? Wenicke given parentrovite </li></ul><ul><ul><ul><li>Multiple investigations including rbc transketolase </li></ul></ul></ul>
  31. 35. <ul><li>Jan ’97 – further unspecified metabolic encephalopathy - ? Hashimoto’s encephalopathy despite ab negative, but response to steroids </li></ul><ul><li>Dec ’98 – GPs letter starts ‘ metabolic encephalopathy secondary to metabolic acidosis in connection with urinary diversion’ </li></ul><ul><li>Feb ’00 – confused, laughing inappropriately, dyspraxic, demeanour different </li></ul><ul><ul><li>Treated empirically with antibiotics and returned to normal </li></ul></ul>
  32. 36. <ul><li>2003 – 3 discrete episodes of neurological dysfunction – transient right leg hemiparesis for 1 hour, right arm for 30 mins and right leg for 30 mins over 2 weeks with visual blurring and headache. </li></ul><ul><li>All in carotid territory so given vertebral/carotid doppler, echo and MRI </li></ul><ul><li>2005 – further non-specific encephalopathy </li></ul><ul><li>Broader work up suggested by SGH SHO </li></ul><ul><li>What single test would you advise? </li></ul><ul><li>Check AMMONIA </li></ul><ul><li>Level 327 umol/l </li></ul>
  33. 37. <ul><li>Dialysed and promptly improved. </li></ul><ul><li>Attempted low protein diet and lactulose. </li></ul><ul><li>Further episodes promptly treated with dialysis (four times). </li></ul><ul><li>Given Ileal conduit (2007)– different person, with no further episodes </li></ul>
  34. 38. Aminogenic Coma following UTEROSIGMOIDOSTOMY <ul><li>Papers- </li></ul><ul><li>Lancet , Feb 26, 1972 – p496 </li></ul><ul><li>J Urology , Nov 11, 1984 – p 743-4 </li></ul><ul><li>Yorkhill handbook 2001 </li></ul>
  35. 40. <ul><li>16 year old whose behaviour became bizarre. Admitted to psychiatric ward for assessment of potential schizophrenia. </li></ul><ul><li>She appeared to develop easy bruising. A full blood count showed platelets 20 x 10 9 /dl. </li></ul><ul><li>What is the underlying aetiology? </li></ul>
  36. 41. <ul><li>She had an enlarged spleen. </li></ul><ul><li>What signs are present in her eyes ? </li></ul>
  37. 42. Psychiatric Disorders <ul><li>A wide variety of disorders have presented with behavioural disturbances, personality and character changes, mental regression, psychosis and schizophrenia-like syndrome </li></ul><ul><li>Problems Possible Diagnoses Biochemical Test </li></ul><ul><li>Hyperactivity/ Sanfilippo Urine glycosaminoglycans </li></ul><ul><li>Behavioural </li></ul><ul><li>Disturbance </li></ul><ul><li>Personality changes Krabbe  -Galactocerebrosidase </li></ul><ul><li>Metachromatic Aryl sulphatase A </li></ul><ul><li>leukodystrophy </li></ul><ul><li>Mental regression Neimann-PICK C Possible storage cell in bone marrow. </li></ul><ul><li>Skin fibroblasf Filipin test. </li></ul><ul><li>Adrenoleukodystrophy Very long chain Fatty Acids </li></ul>
  38. 43. <ul><li>Problems Possible Diagnoses Biochemical Test </li></ul><ul><li>Schizophrenia-like OCT Deficiency Ammonia & plasma aminoacids and urine orotate </li></ul><ul><li>Wilson’s Disease Urine copper </li></ul><ul><li> Serum copper-ceruloplasmin </li></ul><ul><li>Leigh Syndrome Plasma lactate/pyruvate </li></ul><ul><li>Methylene tetrahydrofate Urine amino acids, total </li></ul><ul><li>reductase deficiency homocysteine </li></ul><ul><li>Spielmegal-Vogt disease Vacuolated lymphocytes </li></ul><ul><li>Hallervorden Spatz Acanthocytosis with retinitis </li></ul><ul><li>pigmentosa </li></ul><ul><li>Cerebrotendinous Cholestanol </li></ul><ul><li>Xanthomatosis </li></ul><ul><li>Porphyria (AIP) Urine Porphobilinogen </li></ul>
  39. 45. <ul><li>31 year old para 2+0 suffered severe hyperemesis from 7 / 40 to 13 / 40 . </li></ul><ul><li>Treatment with intravenous fluids and rectal anti-emetics. </li></ul><ul><li>At 16 / 40 raised AFP and US confirmed foetal death. Prostaglandin induced abortion. </li></ul><ul><li>2 / 7 later she complained of poor vision. </li></ul><ul><li>On examination, she has brisk reflexes and sustained ankle clonus, horizontal nystagmus, light only in left eye, and swelling and haemorrhages in both eyes. (Optic Papillitis) </li></ul><ul><li>What are the possibilities? </li></ul>
  40. 46. <ul><li>Given intravenous parentrovite by accident. </li></ul><ul><li>Progressively improved. </li></ul><ul><li>Diagnosis - Wernicke’s encephalopathy </li></ul>
  41. 47. <ul><li>Any unexplained lactic acidosis in a person on artificial diets. </li></ul><ul><li>Consider THIAMINE </li></ul>
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