Acute Metabolic Presentations comep oct 2010
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Acute Metabolic Presentations comep oct 2010 Acute Metabolic Presentations comep oct 2010 Presentation Transcript

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