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