ACUTE METABOLIC PRESENTATIONS in ADULTS Dr. Peter Galloway, Royal Hospital for Sick Children / Glasgow Royal Infirmary, Glasgow
May 27, 2015
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-Pompé disease
• I cell disease
ClinicalPerhaps best developed by Jean-Marie
Saudebray.Four groups of clinical circumstances1) Acute symptoms in neonatal period.2) Late onset, acute and recurrent
symptoms (such as coma, ataxia, vomiting, acidosis)
3) Chronic and general symptoms (mainly digestive and neurological)
4) 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 – Galactosaemia15
• FAT – MCAD3, LCHAD1, beta-Ketothiolase1
• AA – PKU66, MSUD1, MMA3 ( Cobalamin defects2),
UREA CYCLE (OTC4 / NAGS1), IVA 3
HOMOCYSTINURIA10, OAT1, TYROSINAEMIA II1
• BIOTINIDASE1
• METALS – WILSON’S1
• ORGANELLE – FABRY9, REFSUM3, MPS I/II/IV/VI4
• CHOLESTEROL SYNTHESIS – SLO1
• TRIMETHYLAMINURIA10
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,
• NH3 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
MCADIncidence 1 in 10,000 to 1 in 15,000
5TH Don’t present – hence ethical difficulties
5TH Die
5TH Left with handicap2/5 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
MSBHMT
Dimethylgycine
Betaine
S-Adomet
S-AdoHom
MTHFR
CBS
B12
B6
B6
SO4 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 109/dl.
What is the underlying aetiology?
She had an enlarged spleen.
What signs are present in her eyes?
Psychiatric DisordersA wide variety of disorders have presented with behavioural disturbances,
personality and character changes, mental regression, psychosis and schizophrenia-like syndrome
Problems Possible Diagnoses Biochemical TestHyperactivity/ Sanfilippo Urine glycosaminoglycansBehaviouralDisturbance
Personality changes Krabbe -GalactocerebrosidaseMetachromatic Aryl sulphatase Aleukodystrophy
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 TestSchizophrenia-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