Metabolic emergencies in neurology

1. Metabolic emergenciesin neurology David Dufresne, MD R2, Child neurology Montreal Children’s Hospital September 1st, 2010

2. Presentation plan • Objectives • Basic theory and acute clinical presentation of inborn errors of metabolism • The urea cycle and its potential defects • Initial evaluation and management • Quebec’s neonatal screening program

3. Objectives • Recognition of acute neurological presentations of metabolic disease • Investigations, with focus on treatable disorders • Emergency management – general principles • Rapid overview of provincial screening program

4. BB Tremblay-Gagnon Later named either Pierre-Olivier (or Louis-Philippe) No consanguinity Unremarkable FMHx Term BB boy, GDM, otherwise unremarkable pregnancy Prolonged labor, c-section for failure to progress after 22 hours APGAR 3-5-6, bag and mask ventilation by pediatrician on call, eventually intubated BW 5 kg Cord gas (venous) 6.9/80/10/-17 Neurology called by NICU on DOL 2 Profound hypotonia, no suction, lethargy since birth, now multifocal myoclonic jerks Afebrile, BP 70/40, HR 145, general exam reveals jaundice DOL 1: Venous lactate 19 Improving metabolic acidosis Hypoglycemic – requires IV D10 Elevated liver enzymes Poor urine output, high BUN Normal CBC Bilirubin below phototherapy level Cultures taken at 2 hours of life still not growing anything BB Smith Later named John No consanguinity Unremarkable FMHx Term BB boy, severe gestational HTN, father talks of platelets that were too low Prolonged labor, c-section for profound fetal decceleration (1-2 minutes) APGAR 8-9-10, no resuscitation needed BW 3.6kg Cord gas 7.2/45/20/-3 Initially well, breastfed twice but then mother transferred to ICU Transferred to NICU at 36 hours of life for progressive lethargy and hypotonia, now not drinking at all, very poorly responsive Neurology called for multifocal myoclonic jerks AVSS, general exam reveals hepatomegaly, jaundice DOL 2 Increasing liver enzymes Hypoglycemic, NICU nurse inserting IV to run standard aminoacid solution with 10% dextrose Normal CBC Bilirubin below phototherapy level Normal BUN and urine output Urine analysis unremarkable, no ketones Blood, urine and CSF cultures pending Clinical cases July 1st, 8:05 am – 1st MCH rotation for a brand new R2 Ped. neurology R3 is sick, you and a very motivated M3 are alone, no staff in sight... You get called for two consults!

5. Basic theory • Inborn error of metabolism (IEM): • Genetic defect precluding normal functioning of one particular pathway • Most commonly enzymatic defect, but sometime problem arises from faulty transporter and such • Normal functioning of enzymatic pathway => S1± … ±Sx =Zxyz=> P1±… ±Px

6. Basic theory • Inborn error of metabolism (IEM): • Symptoms result from accumulation of substrate, lack of product or both S1± … ±Sx ≠> P1±… ±Px • Usually 2nd to enzymatic defect, but also transporter, anomaly organelle superstructure, etc.

7. Basic theory Cellular biology 101: obviously, photosynthesis is not pertinent for human pathologies, but unfortunately the rest is… 2003 International Union of Biochemistry and Molecular Biology

8. Clinical presentation patterns • IEMs can be divided in groups according to pathophysiology • Different disorders from same group have some phenotypical similarities • Approach to treatment also similar within group • Categories not totally exclusive – defect in enzyme X can produce symptom by accumulation of substrate AND lack of product • Atypical presentation possible, depending on endogenous and environmental factors

9. Clinical presentation patterns • Typical presentations • Group 1: Disorders of intoxication • Group 2: Disorders of energy metabolism • Group 3: Disorders involving complex molecules • Group 4: Vitamin-responsive encephalopathy

10. Clinical presentation patterns • Group 1: Disorders of intoxication • Accumulation of metabolite to toxic level: ammonia, AA, OA, CHO, metals, porphyrins • Usually no interference with embryo-fetal life • Acute, episodic or chronic presentation, usually after symptom-free interval • Patient presenting after exogenous intake or endogenous release eg. catabolic state • Varying end-organ involvement depending on specific metabolite and end-organ susceptibility

11. Clinical presentation patterns • Group 1: Disorders of intoxication • Variable presentation (especially disorders of metal transport and porphyrias) • Frequent neonatal presentation after initial ‘‘honeymoon’’ phase • Lethargy / irritability • Weak suck • Seizure • Eventual coma • ± hepatic, cardiac or renal failure • Occasionally, episodic or late catastrophic presentation from infancy to adulthood

12. Clinical presentation patterns • Group 1: Disorders of intoxication • DDx: • Urea cycle disorders - ammonia • e.g. OTC deficiency, CPS deficiency • CHO intolerance – specific sugar • e.g. galactosemia, hereditary fructose intolerance • Aminoacidopathies – various aminoacids • e.g. maple sirup urine disease, PKU • Organic acidurias – various organic acids • e.g. propionic aciduria, methylmalonic aciduria • Disorders of metal transport - metal • e.g. hemochromatosis, Wilson’s, Menkes’ • Porphyrias – porphyrins and precursors • e.g. acute intermittent porphyria

13. Clinical presentation patterns • Group 2: Disorders of energy metabolism • Mitochondrial or cytoplasmic defect • Often associated with prominent lactic acidosis • Mitochondrial usually more severe than cytoplasmic energy metabolism disorder • Some of them interfere with embryo-fetal development – possible dysmorphisms

14. Clinical presentation patterns • Group 2: Disorders of energy metabolism • Mitochondrial metabolism defects: • Especially prone to decompensating in periods of high metabolic demand • Some drugs are toxic to mitochondrias (eg:VPA, barbiturates) • Frequently untreatable • Exceptions are FAODs, ketone metabolism disorders • Various cofactors used as mitochondrial “booster” – variable results • Variable presentations of mtDNA-transmitted disorders • Heteroplasmy accounts for different severity and variable organ involvement of mtDNA defect • More or less random involvement of nervous system, liver, kidneys, heart or skeletic muscle, depending of specific disorder • DDx: • Congenital lactic acidemias • Pyruvate metabolism, Krebs’ cycle • Respiratory chain disorders • Fatty acid oxydation defects • Disorders of ketogenesis or ketolysis

15. Clinical presentation patterns • Group 2: Disorders of energy metabolism • Cytoplasmic energy metabolism disorders: • More homogenous presentation with a similar defect than mtDNA defects • Fasting hypoglycemia, hepatopathy vs myopathy / exercise intolerance • DDx: • Glycogen storage disorders and other disorders of glucose metabolism • Also chronic, progressive intoxication-type disease • Persistent hyperinsulinism • Creatine deficiency syndrome

16. Clinical presentation patterns • Group 3: Disorders involving complex molecules • Chronic, progressive diseases due to disturbance in synthesis or destruction of complex molecules • Dysmorphism, various organ involvement • Symptoms independents of intercurrent events or nutritional intake – some neonatal presentations, but most less acute than other disorders • Includes lysosomal storage disorders (sphingolipidoses, mucopolysaccharidoses, cystinosis), peroxysomal disorders (Zellweger, x-ALD, Refsum, etc), congenital disorders of glycosylation and others • Diagnosis often fastidious, involving enzyme assays and genetic tests • Few, if any, acute presentation – new patients usually present with subacute or chronic symptoms • Some amenable to treatment • Enzyme replacement therapy • Bone marrow transplant • Substrate reduction occasionally gives modest (but more often disappointing eg: Lorenzo oil) results

17. Clinical presentation patterns • Group 4: Vitamin-responsive epileptic encephalopathies • Neonatal/infantile epileptic encephalopathies • Usually refractory to standard therapy • Some AEDs actually inhibit GLUT1, leading to worsening • Pyridoxine (Vit. B6) responsive seizures • Typically, perinatal onset, refractory seizures – but described as late as 18 months at onset • Defect in lysine catabolism leads to increased inactivation of pyridoxal-phosphate • Concomitant accumulation of alpha-aminoadipic-semialdehyde and pipecolic acid can be detected in urine – but depends on test availability • Pyridoxal-phosphate responsive seizures • Similar to Vit.B6 responsive seizures • With microcephaly + hypotonia • Pyridox(am)ine 5’-phosphate oxydase (PNPO) deficiency ± more severe Vit. B6 responsive seizures

18. Clinical presentation patterns • Group 4: Vitamin-responsive epileptic encephalopathies • Folinic acid responsive seizures • Extremely rare, classically diagnosed with CSF markers • One case series has found several patient to have same genetic defect and biochemical markers as pyridoxine responsive seizures • (Gallagher RC, Van Hove JLK, Scharer G, Hyland K, Plecko B, Waters PJ, et al. Folinicacid-responsive seizures are identical to pyridoxine-dependentepilepsy. Ann Neurol. 2009;65:550–6) • Biotidinase deficiency (biotin responsive seizures) • Waxing and waning symptoms – probably diet related • Association of neurological symptoms (lethargy, hypotonia, seizures, ataxia, eventual GDD, leukoencephalopathy, hearing and visual loss) and dermatological manifestation (eczematous or erythematous rash, alopecia, keratoconjunctivitis); eventual organic aciduria • GLUT1 transporter deficiency • GDD, complex motor disorder, slow and slurred speech, hypotonia and ataxia +/- spasticity • Hypoglycorrhachia • Good response to ketogenic diet • Usually improving by adulthood • Avoid inhibitors of GLUT1 (phenobarbital, chloral hydrate, diazepam, methylxanthines, R-OH, green tea) • Carbamazepine or phenytoin well tolerated if additional AED required

19. The urea cycle disorders • Urea cycle: main pathway for removal of ammonia produced during AA deamination • Converts ammonia to urea in the liver • NH3 production increased in period of increased catabolism eg: • Fasting • Infection / surgery / anesthesia • Large protein load • Puerperium • Etc. • Urea cycle disorders: • Inability to properly detoxify ammonia • Cumulative prevalence varies according to source • Possibly relatively common – range 1:8000 to 1:25 000 live born • Mostly autosomal recessive – OTC X-linked dominant with variable expression due to random X inactivation

20. The urea cycle disorders Glutamine synthetase deficiency NAGS deficiency Carbamoyl PO4 synthetase deficieny OTC deficiency Citrin deficiency HHH syndrome Arginosuccinate synthetase deficiency Saudubray et al, Inborn Metabolic Diseases, 4th edition Arginase deficiency Arginosuccinate lyase deficiency

21. The urea cycle disorders • Clinical presentation • As in other Group 1 disorders • Normal antenatal development • Initial ‘‘Honeymoon phase’’ post-natally • Symptoms triggered by endogenous or exogenous substrate load • Hyperammonemia, initial respiratory alkalosis • Catastrophic presentation in periods of catabolic stress • High incidence of neurological impairment after severe decompensation • Some patients are highly sensitive to VPA - beware! • Thought to be related to close relationship between urea cycle and TCA cycle

22. The urea cycle disorders • Clinical presentation • Severity of disease related to degree of enzymatic impairment • Typically presents neonatally, in late infancy, puberty and sometime adulthood • Neonatal presentation: poor feeding and vomiting, irritability/lethargy, tachypnea followed by eventual central hypoventilation, seizures, autonomic instability, hypotonia, loss of normal reflexes, eventual cerebral or pulmonary hemorrhage • Infantile presentation: Usually less acute, with anorexia, NoVo, lethargy, failure to thrive and poor development; progression to encephalopathy with intercurrent illness • Adolescence/adulthood: Precipitated by illness, fasting, puerperium, anorexia, malaise, NoVo, H/A, ataxia, followed by fluctuating LOC, occasionnal focal deficits and resolution or death by cerebral oedema if not corrected • Arginase deficiency associated with more indolent course of progressive spastic diplegia, dystonia ataxia and seizures, not always presenting episodes of acute encephalopathy

23. Initial investigations • Basics – ABCs, then H&P • History • Past medical history – especially NYD syndromes • Good antenatal / perinatal history is essential • LCHAD associated with maternal HELLP or acute fatty liver of pregnancy • Infantile E.Coli sepsis associated with galactosemia • Family history • Origin • Consanguinity • SIDS, other perinatal death (eg: neonatal sepsis), unexplained infantile/childhood death • Neurological impairment, especially if unexplained • HPI • Circumstances leading to presentation • Fasting, injury/illness, surgery, weaning of breastmilk/introduction of new foods • Physical • As usual, plus special attention to • Vitals and general status, height, weight, head circumference • Dysmorphisms, skin/hair anomalies, dysraphism • Organomegaly • Smell (patient, urine)

24. Initial investigations • Basic investigations • ‘‘Shotgun’’ approach • Many disorders progress rapidly and leave deficits • Need to exclude treatable disorders rapidly • If within neonatal period, obtain provincial screening results (CHUS/CHUL) • Some tests are run in reference centers – can call for stats • Plasma • Blood gas, including • lactate, glucose, lytes, AG • Liver enzymes • BUN, Creat • CBC • Blood culture • Amino acids • Ammonia • Sample needs to be put drawn from free flowing vessel (no capillary sample), w/o tourniquet, put in chilled tube, on ice and processed ASAP • ±Pyruvate • Also needs special processing, check w/ lab • ± Acylcarnitine profile • FAOD and others • Urine • Analysiswithketones • Organicacids • Culture • In doubt, draw more and freeze to use later, samples are more valuableduring acute episode

25. Initial investigations • Additional investigations • According to clinical suspicion • Genetics consult highly recommended • Urine • Oroticacid • Reducing substances • Plasma • VLCFA • Peroxysomal disorders • Carnitine • Uric acid • Homocysteine • Insulin • CK • Liver synthetic function • Coags, albumin • Inflammatory markers • ESR, CRP • CSF • Cell count • Biochemistry • Cultures • Aminoacids • Lactate, pyruvate • Processsampleadequately, drawserum, call lab • Neurotransmitters and metabolites

26. Initial investigations • Additional investigations • As clinically warranted • EEG • Neuroimaging • ECG • CXR • Echocardiogram

27. Initial management • ABCs first • Strongly consider ICU setting • Consult genetics if available – this is their field • Eliminate the insulting agent – in case of new patient, need to eliminate as much as possible • NPO • Promote anabolism - High parenteral caloric intake • Low lipids (fatty acid oxydation defects, ketone body metabolism, etc) • Low proteins (UCD, aminoacidopathies, organic acidurias) • Low complex sugar (galactosemia, hereditary fructose intolerance, etc.) • D10% infusion, initial rate 150% maintenance • However, risk of worsening in congenital lactic acidemias • If not worsening with dextrose, control hyperglycemia with insulin • Eliminate offending drugs, control fever, infection, etc. • Ondansetron might be useful – pathology itself as well as drugs used make patient nauseous

28. Initial management • Substrate removal • Ammonia • Na-phenylacetate (phenylbutyrate if n/a), Na-benzoate • L-arginine – promotes continuation of urea cycle • Extracorporeal detoxification if NH3 >500 • Carbaglu if OTC or CPS suspected • Organic acids • Carnitine helps restore CoA and excrete organic acid as acylcarnitine • Also, secondary carnitine loss in many other disorders, and might improve status in congenital lactic acidemia • Vitamin cocktail for various disorders (Q10, biotin, thyamine, riboflavin, etc.) • Electrolytic and acid-base imbalance managed as usual

29. Specific treatments • Initial protein restriction usually last 24-48 hours • Group 1: Disorders of intoxication • Initial management with IV dextrose +/- insulin • Lipids to be started after FAOD ruled-out • MCTs in long-chain fatty acid oxydation defect • Strict Ins and Outs, daily weight • Specific formulas or synthetic essential AA mixtures for aminoacidopathies • Synthetic essential AA also useful in UCD • Group 2 • Requires only normal glucose intake • Except hyperinsulinism • Too much can exacerbate congenital lactic acidosis – start lipids when feasible • Avoid additional mitochondrial toxicity • Group 4 • Consider trial of pyridoxine, pyridoxal-phosphate, folinic acid or biotin if seizures are prominent • Ketogenic diet for GLUT1 deficiency

30. Quebec’s neonatal screening program • 2 arms: • blood (CHUQ - Quebec) • Dried bloodspot from heelprick, before initial departure from hospital • PKU, congenital hypothyroidism, tyrosinemia • Urine (CHUS - Sherbrooke) • Dried urine sent on filter paper, around 21 days of postnatal life • Disorders of amino acid metabolism, organic acidurias, amino acid transport disorders, urea cycle disorders • Research done in detection of some other disorders (eg: Fabry’s disease) • Many more disorders (eg: FAOD) could be tested relatively easily using tandem MS technology; in this respect, most of Canada is lagging behind most industrialized countries

31. Summary • Individual IEMs are quite rare in general population • Combined prevalence, however, is much more significant • By the time neurology is consulted, much has been done to rule-out frequent pathologies – or the patient is critically ill • Suspect neurological manifestation of IEM in • Critically ill neonate without clear evidence in favor of HIE or sepsis, or other evident cause • Any other patient with recurrent episodes of acute encephalopathy, ataxia, vomiting, seizure, LOC • Suspicious familial history (consanguinity, most infantile death, unexplained death later in childhood or adulthood) • Act fast to rule-in/out treatable disorders, while trying for an effective empirical treatment • Involve genetics early, and keep on reading!

32. Tidbits • Good references • Fernandes, Saudubray, Van den Berghe, Walter, Inborn Metabolic Diseases: Diagnosis and Treatment, 2006, ISBN 3540287833 • Good reference, nice revision of involved pathway at the beginning of each chapter, greatest problem is its cost… • Joe T. R. Clarke, A Clinical Guide to Inherited Metabolic Diseases, 2006, ISBN 0521614996 • Like the Fenichel for Child Neurology, provides good approach to differential diagnosis according to clinical picture, but not the reference to learn in depth about a particular disease. • How to contact… • Shebrooke (CHUS): • urine screening program, some standard tests (urine organic acids for example) are also done there and can be done faster if you have a reasonnable reason • 819-346-1110, dial 0 for operator and ask for genetic lab • Quebec (CHUQ) • If you think your patient might have PKU, tyrosinemia or congenital hypothyroidism and is still in the window period where the results might not be in yet • 418-654-2103 (Medical genetic) or 418-525-4444 (general #)

33. Questions or comments?