Inherited Neurometabolic disorders updated

Neurometabolic

1. Inherited Neurometabolic disorders Dr. Husnea Ara Khan Assistant Professor Department of Paediatric Neurology National Institute of Neurosciences & Hospital, Dhaka

2. Learning bite What are inherited neurometabolic disorders Prevalence Pattern of inheritance Pathophysiology Classification Clue to suspicion Clinical presentation Outline of Investigation Outline of treatment Preventive measure

3. Introduction Individually rare but collectively common. Approximately 1 in 1000 > 600 IEM have been described Inherited neurometabolic disorders (INMD) are single gene disorders in which there is a block at some point in the metabolic pathway by defective enzyme, co-factor or transport.

4. Importance to know IEM Rare, but in an aggregate significant burden of pediatric morbidity. Some are treatable. Early diagnosis of treatable IEM and timely intervention either prevent or ameliorate the permanent neurological impairment. Genetic counseling Prenatal diagnosis

5. Pattern of Inheritance Mostly (90%) are Autosomal recessive Others- Autosomal dominant X-linked recessive X-linked dominant Mitochondrial X-linked recessive IEM Hunter disease Adrenoleukodystrophy Lesch-Nyhan syndrome UCD (OTC def) Menkes disease Others ‘HALUM’ Autosomal dominant Glut-1 deficiency disorders Cystinuria

6. Age of onset Can present in all periods of life From the neonatal period to the adult AGE Neonate Birth Early infancy Adolescent Childhood Early age of onset - severity Age of onset is important in determining a possible cause

7. Where is defect Mutation of single gene Defect in enzyme/ Transport protein Block metabolic pathway Abnormal metabolite

8. Pathophysiology Accumulation of toxic product Energy deficiency Storage Normal individual A= Substrate B=End product C=Toxic metabolities Enzyme Cofactors Excess substrate ‘A’ Accumulation of toxic product Storage of ‘A ’ C Alternate pathway Energy deficiency A B A Enzyme Cofactors B Small molecule (OA, UCD. Aminoacidopathy ) Complex molecule Mitochondrial

9. Types of substrate Protein Carbohydrate Fat Aminoacid NH3 Aminoacidopathy carbon skeletal OA UCD Fatty acid oxidation disorder (FAOD) Galactosaemia Fructosaemia GSD Phenylketonuria Homocystinuria Cystinuria Hartnap Disease *MSUD Propionic aciduria (PA) Methylemelonic aciduria Isovaleric aciduria Gluteric aciduria Multiple carboxylase deficiency

10. Course of disease Organic aciduria Aminoacidopathy Urea cycle disorder Fatty acid oxidation disorder Lysosomal disorders Peroxisomal disorders Mitochondrial Relapse & remission relation to infection , food, fasting Good response to symptomatic therapy Independent of intercurrent events

11. Classification May be classified based on either Pathology Age of onset Mode of onset Clinical symptoms

12. According to pathology Disorder of Small molecule (Intoxication) Disorder of Large molecule (Storage) Disorder of cerebral energy metabolism Others (Unclassified) Aminoacidopathy Urea cycle disorders Organic aciduria Fatty acid &,Ketone Disorders of metabolism of CHO Purines & pyrimidines Vitamines & minerals Biogenic amine neurotransmitter (AA Disorders of Lysosome & peroxisome Congenital disorders of glycosylation (CDG) Disorders of lipid metabolism Mitochondrial disorders Creatine metabolism disorders GLUT-1 deficiency Disorders of pyruvate metabolism

13. Variable Small molecule Large molecule Energy deficient Pathophysiology Toxic accumulation Affect cellular organellae leading to storage of macromolecule Energy failure- production / utilization Age of onset Mostly neonate Usually latter Variable Mode of onset Sudden, catastropic Gradual Acute Progression Episodic attack Slowly progressive Progressive Facial dysmorphism Usually not yes Usually not Provokating factor yes No yes Symptom free interval yes No No Antenatal period Usually uneventful Rarely present from antenatal period May present from fetal life Treatment Mostly treatable Some ERT available Difficult to treat

14. Classification by age of onset NKH Pyridoxine deficiency disorder Pyridoxal-5 phosphate def Folinic acid deficiency Sulfite oxidase / Molybdenam cofactor def Organic aciduria except GA type1 MSUD UCD GLUT-1 defi Biotinidase defi Glutaric aciduria PKU Menkes Neurotransmitter disorders Leigh disease NPC type C Lesch-nyhan disease Biotin thiamin responsive Basal ganglia disorder NCL GM1 gangliosidosis Homocystinuria Wilson Neonatal onset Early infancy (1-12 month ) Late infancy to early childhood (1-5 yrs ) Late childhood to adolescent (5-15 yr )

15. Classification according to clinical symptoms Micro /macrocephaly Ophthalmology Hearing defect Cardiac abnormality Hepatposplenomegaly Abnormal odor of body Skin & hair abnormalities <2 years of age >2 years of age Acute encephalopathy Epilepsy Hypotonia Developmental delay Congenital anomalies Facial dysmorphism Movement disorders Ataxia Recurrent stroke Cognitive and motor regression Psychiatric manifestation Neurological Non-neurological

16. Suspicion to INMD Parental consanguinity Suggestive family history Recurrent abortions, stillbirths Affected sibs/ family members Abnormal development Regression Plateau Delay Deterioration after a period of apparent normalcy Recurrent or persisting vomiting, lethargy Unusual body odour Encephalopathy following minor infection Seizure of unexplained causes Facial dysmorphism Developmental & family history Presenting complaints Unexplained or not responding to the treatment of common disorders

17. Triggers for decompensation Increased protein load UCD MSUD OA Prolonged Fasting FAOD CHO metabolism FAOD CHO metabolism Mitochondrial Prolonged Exercise Protein diet Inadequate Calorie Fever, fasting infection Exercise, Stress Trauma, surgery Infection OA Mitochondrial

18. Clinical Presentation

19. Extraneurological presentation

20. Abnormal odour Phenylketonuria Glutaric aciduria type2 Isovaleric aciduria Maple syrup urine disease Maple syrup Musty Tomcat urine Boiled cabbage Tyrosinemia Multiple carboxylase deficiency Sweaty feet

21. Skin & Hair changes in NMD Skin changes Hair changes Hypopigmentation Phenylketonuria, homocystinuria, Menkes disease Hyperpigmentation ALD Perioral eruption- MCD Eczema Biotinidase deficiency Hartnup disease MCD Seborrheric dermatitis Menkes disease angiokeratomas Fabry disease, lysosomal disorders, Ichthyosis Refsum disease Kinky hair Menkes disease Trichorrhexis nodosa Arginase deficiency Aloplacia Biotinidase deficiency Hypertrichosis Mitochondrial Disorders

22. Angiokeratomas in Fabry disease Trichorrhexis nodosa (a beaded appearance of fragile hair ) Aloplacia & rashes in biotinidase def

23. Eyes in INMD: Clue to diagnosis Chery red spot Taysach disease Niemann pick disease-A&B GM1 Gangliosidosis Sialidosis Galactosaemia Len dislocation MPS(except type II and III) Mitochondrial Corneal clouding Sulfite oxidase deficiency Homocystinuria Optic Atrophy Retinitis pigmentosa Mitochondrial disease NCL B.T. Poll-The et al. https://doi.org/10.1016/j.ejpn.2011.03.005

24. Abnormal eye movement in INMD Niemann pick type-C Mitochondrial disorder Oculogyri crisis External ophthalmoplegia Vertical gaze palsy Horizontal +Vertical gaze palsy Gaucher disease AADC Paroxysmal eye-head movements Glut-1 deficiency Hsin -Pei Wang et al. https://doi.org/10.1016/j.jfma.2021.09.003

25. Neurological Presentation

26. Acute encephalopathy With Metabolic acidosis Without Metabolic acidosis Organic aciduria Congenital Lactic acidosis Fatty acid oxidation Maple syrup urine disorder NKH UCD Molybdenum cofactor deficiency Sulfite oxidase deficiency Encephalopathy Behaviour change Lethargy, irritability, coma Metabolic acidosis : Altered level of consciousness Coma Hypotension Kussmall respiration (increased depth> rate)

27. Epilepsy Beyond 1month <1 month Nonketotic hyperglycenia Pyridoxine responsive epilepsy Pyridoxal 5-phosphate dependent Folinic acid deficiency Molybdenum co-factor deficiency Sulfite oxide deficiency Glut-1 deficiency Biotinidase deficiency NCL & Other PME Mitochondrial Organic aciduria GM2 gangliosides Taysach disease Clinical clue: Myoclonic seizure Atypical absence Refractory to AED Unexplanied seizure Na-valproate worsens epilepsy in- UCD NKH Mitochondrial disorder Glutaric aciduria Most are treatable

28. GM2 gangliosidosis ( Taysach disease) Sulfite-oxidase deficiency NKH

29. Hypotonia Arginase deficiency MLD, ALD, Krabbe Biotinidase deficiency Sulfite oxidase deficiency Molybdenum cofactor deficiency Hypertonia/ spasticity Pompe disease Mitochondrial disorders NKH Sulfite oxidase deficiency Molybdenum cofactor deficiency Motor pathways The motor findings in INMD are almost bilaterally symmetrical except- Mitochondrial disorders & disorders of neurotransmitter metabolism These are spastic CP mimickers

30. With myopathy With Neuropathy Mitochondrial disorder Pompe disease GSD III, V Primary carnitine deficiency MLD Krabbe Mitochondrial disorder CDG Serin deficiency syndrome Refsum disease

31. Zellweger syndrome Dysmorphic Facies CDG Hurler PDH deficiency Zellweger syndrome MPS CDG PDH deficiency Menkes GM I ganglioside The presence of dysmorphism may suggest especially large molecule disorder

32. Abnormal Head size Microcephaly Macrocephaly PKU Alpers syndrome (POLG1 mutation) Sulfite oxidase deficiency Molybdenum cofactor deficiency Methylene tetrahydrofolate reductase deficiency GLUT 1 deficiency Menkes disease Krabbe diease Glut 1 deficiency NCL Glutaric aciduria type 1 Tay- Sach disease Sandhoff’s disease Alexander Canavan MPS

33. Ataxia Progressive ataxia Vitamin-E deficiency Abetalipoproteinaemia Refsum disease Cerebrotendinous Xanthomatosis NPC GM2 gangliosidosis Gaucher type3 Mitochondrial disorder NCL Maple syrup urine disease Urea cycle disorder Hartnap disease Episodic ataxia

34. Dystonia <2 year 2-5 years >5 years Glut-1 deficiency AADC Glutaric aciduria type-1 Leigh disease Organic aciduria Leigh disease Biotin-thiamine responsive BG disease PKAN Lesch Nyhan disease Organic aciduria NPC Wilson disease NBIA Mitochondrail disorder Dystonia With abnormal eye movement Paroxysmal eye-head movement Glut1 deficiency Oculogyri crisis AADC Vertical gaze palsy NPC Horizontal gaze palsy Gaucher disease Tay- sach disease Ophthalmoplegia Mitochondrial disorders

35. Psychiatric manifestations Phenylketonuria Urea cycle disorders Lesch Nyhan syndrome Creatine deficiency disorders Cerebral folate deficiency Carnitine transport deficiency Purine & pyrimidine disorders Wilson disease X-ALD MPS ALD Mitochondrial Hearing loss Visual loss MLD ALD Krabbe

36. Recurrent stroke / stroke-like episodes Late stroke Early stroke Organic aciduria Congenital disorder of glycosylation Urea cycle disorder Homocystinuria Melas, MERRF Cerebrotendinous Xanthomatosis Age of onset Follow vascular territory Homocystinuria Fabry disease Cystinosis Cerebrotendinous xanthomatosis OA CDG UCD MELAS NO Yes Mechanism of metabolic stroke : Unknown Neuronal dysfunction due to endothelial dysfunction, tendency to hypercoagulation cerebral perfusion dysfunction due to aggregation of metabolites and secondary neurotoxicity without rupture or obstruction of larger brain vessels Differential of recurrent stroke: AHC Hemiplegic migraine Moya Moya Metabolic stroke

37. Difference between vascular & and metabolic stroke Variable Vascular stroke Metabolic stroke H/O consanguinity, sib death Usually not present Usually present Follow the vascular territory Yes Usually not except homocystinuria, Fabre disease Onset Sudden Acute Precipitated by stressor like fever, infection Usually not Yes Associated with other abnormalities, such as epileptic seizures, ataxia, migraine, coma Usually not Frequenty Tendency to recur May be Characterized by reversibility and a tendency to recur

38. Cardiomyopathy Mitochondrial disorder FAOD Pompe disease (GSD II) Propionic acidemia Congenital disorder of glycosylation GSD type III & IV

39. Diagnosis

40. History Clinical Examination Extra neurological features (Skin, hair, eye cardiac, organomegaly) Presenting features Investigation Head to toe examination Neurological Age of onset, Family history H/O consanguinity Sib death, recurrent abortion Clue to diagnosis Family history is the fundamental to the evaluation of children with metabolic disorders 3 degree pedigree is important for family history Diagnosis

41. Head to toe examination This Photo by Unknown Author is licensed under CC BY-NC OFC Eyes, ear Dysmorphism Cardiac Skin survey DTR, Tone, Power Organomegaly Planter response Cognition

42. Specific clue NPC Cataplexy, dystonia, upgaze palsy Intractable epilepsy, severe diaper rash, aloplecia Increased intrauterine fetal movement Neonatal hiccup Biotidinase deficiency Pyridoxin deficiency NKH NKH

43. Clinical pointers to further evaluation in children with cerebral palsy mimics Absence of definite perinatal injury Developmental regression A positive family history Inadequately explained oculomotor disturbances Involuntary movement disorder & ataxia PS bindu . Pediatric neurology neurometabolic disorders: A diagnostic approach. Indian Journal of practical pediatrics April 2016

44. Investigation

45. Laboratory Radiological EEG Specific test Genetic test First tier 2 nd tier 3 rd tier

46. Laboratory Radiological EEG First tier inv CBC, LFT Basic metabolic screening Urine metabolic Screening Laboratory Basic metabolic screening FBS ABG Blood lactate Blood ammonia Urinary ketone & other metabolites Hypoglyceamia FAOD GSD 1 OA Urinary reducing substance Urinary Ketone Galactosaemia No Yes No Yes FAOD OA, MSUD Mitochondrial Ketosis Metabolic acidosis Yes No CBC- Neutropenia , thrombocytopenia (PA, MMA)

47. Plasma NH3 OA Mitochondrial FAOD Ketosis No ketosis Acidosis High Blood PH, CO2 Normal No ketosis UCD Normal Blood PH,CO2 Normal Suspecting INMD PKU, NKH

48. At a glance High plasma ammonia Organic aciduria Mitochondrial disorders Metabolic acidosis Ketosis PKU, NKH No metabolic acidosis No ketosis No acidosis No Ketosis Urea cycle disorder Metabolic acidosis No ketosis Normal Ammonia FAOD Normal/High plasma ammonia Normal/High plasma ammonia

49. Urine metabolic screening Disorder Ferric Chloride DNPH Reducing Substance Nitruproside MPS spot test PKU + + - - - OA + + - - - Aminoaciduria - + - - - Homocystinuria - - - + Galactosaemia - - + - - MPS - - - - +

50. Laboratory Radiological EEG First titer inv Pattern recognition Pattern recognition in MR imaging and clinical clues help to narrow the differential, tailor subsequent investigations Characteristic MRI findings in INMD Bilaterally symmetrical except- Mitochondrial disorders & disorders of neurotransmitter White matter involvement Deep grey nuclei (basal ganglia, thalami, dentate fastigial nuclei, substantia nigra with or without brainstem involvement , red nuclei) brain tissue volume loss or edema Tips: Amino acid disorders (i.e., MSUD and NKH) predominantly involve white matter tracts ; Organic acid disorders usually involve deep gray matter ; Energy production/lactic acidosis disorders may involve both deep grey and white matter

51. Cortical gray matter Malformation Atrophy Swelling of cortex Urea cycle disorder MSUD MELAS Molybdenum co-factor deficiency Menkes disease NCL Alper syndrome Mitochondrial disorder Pachygyria - Pyruvate dehydrogenase deficiency Glutaric aciduria type 2 Cerebellar abnormalities- CDG, NKH Lissencephaly- Serine defects, Mitochondrial

52. Putamen Propionic aciduria Leigh disease GA type1, SOD Wilson disease Thalamus Krabby Bilateral & symmetrical BG lesion Globus pallidus MMA, IVA PDH deficiency PKAN Deep gray matter

53. Suspected mitochondrial disorders CoQ def Leigh syndrome MELAS Cavitating Predominant cortex Predominant BG lesion Predominant White matter Predominant brainstem POLG 1 Non Cavitating Respiratory chain defect MINGE SURF 1 mutation POLG related mutation

54. Glutaric aciduria Type 1 Fronto -temporal atrophy Bifrontal chronic subdural hemorrhages reduced diffusion in the lentiform nuclei and thalami Axial T2WI Axial T1WI DW1

55. Propionic aciduria Methylmelonic aciduria

56. Maple syrup urine disease Intramyelinic edema in the myelinated white matter tracts. Involved regions include the globi pallidi , internal capsules, thalami, and optic radiations and the cerebellum, brainstem tracts, and optic chiasm .

57. Role of MRS In INMD Non-invasive tool in aiding in diagnosis of neurometabolic disorders In most inherited metabolic disorders, MRS findings are abnormal but not specific for a single disease or syndrome

58. Specific MRS patterns are mainly found in Canavan disease Creatine deficiency NKH Glycin peak at 3.55ppm Decreased Creatine peak at 3.03 ppm Increased NAA peak at 2.01 ppm Mitochondrial disease Lactate double peak at 1.33ppm

59. Laboratory Radiological EEG Burst suppression pattern NKH Pyridoxin dependent epilepsy Organic aciduria Biotinidase deficiency MOCO/ SOD Hypsarrythmia Comb like discharge MSUD PKU Glut-1 deficiency NKH Biotinidase deficiency Pyridoxin deficiency/ PNPO Mitochondrial disorder Organic aciduria

60. 2nd tier test Blood for Tandem mass spectrometry(TMS) Urine for gas chromatography-mass spectrometry (GCMS ) CSF lactate Plama aminoacid & acylecarnitine -Organic aciduria,UCD , Aminoacidopathy , FAOD Organic aciduria Enzyme assay Biotinidase deficiency Lysosomal disorder(Arylsulfatase A def) To be performe in a targeted manner CSF & blood glucose ratio CSF & blood glycine ratio Mitochondrial disorders Glut-1 deficiency NKH

61. Heel prick Applied to filter paper Plasma acyl carnitine profile by TMS FAOD OA Differentiat e HOW Low& odd acylcarnitine are elevated High & even acylcarnitine are elevated C3/C5 C6-C10 & so on TMS

62. Precise Diagnosis Precise therapy Genetic counseling Prenatal diagnosis 3rd tier test Genetictest Sanger sequencing Clinical exome Whole exome When 1 st & 2 nd tire inv fail/ suggestive To confirm the diagnosis

63. Summary History & examination Suggestive Inherited NMD Basic metabolic Screening Suggestive of Organic aciduria Aminoaciduria or UCD MRI of brain with contrast with MRS CSF lactate Blood for TMS Urine for GCMS Mitochondrial Genetic test

64. Treatment

65. Aim of treatment Product Cofactor Gene mutation Enzyme Substrate Removal of toxic products Dietary restriction Enzyme replacement Cofactor replacement Product supplementation Gene therapy Substrate reduction

66. Acute management Supportive care Chronic / maintenance therapy Specific therapy Outline of treatment

67. Acute management Stop oral feed for 1-2 days to prevent catabolism Maintain hydration Correction of dyselectrolytemia Correction of hypoglycemia Treat & prevent Infection Antipyretic for fever Antiseizure drug Start IV fluid with 10 -15 % dextrose Correction of acidosis by Na bicarbonate (0.25-0.5mEq/kg/ hr ) Specific therapy if available Elimination of toxic products By Hemodialysis/Peritoneal dialysis (if NH3 level >600micromole/l) Na-benzoate(250-500mg/kg/day) Supportive/ symptomatic Mx Maintenance therapy

68. Chronic/ maintenance therapy To prevent/ reduce further episode Dietary restriction (Protein) Avoidance of fasting Vitamine / cofactor supplementation Carnitine supplementation Metronidazole in OA: 10mg/kg once daily in 10 consecutive days every month

69. Co-factor / vitamin supplementation Disorder Cofactor/ Vitamin Dose Propionic aciduria Biotin Methylmelonic aciduria Hydroxocobalamine 1mg /day IM/IV Glutaric aciduria type 1 Riboflavin 200-300mg/day Homocystinuria Pyridoxin Vitamin B12 Folic acid MSUD Thiamine Riboflavin 10-200mg/day 200-300mg/day oral TDS Biotinidase deficiency Biotin 5-20mg /day

70. Enzyme replacement Therapy FDA approved Gaucher disease Fabry disease Pompe disease Agalsidase beta Alglucosidase alfa Imiglucerase Velaglucerase NCL-2 MPS I,II, IVA, VI Cerliponase 2

71. Gene therapy Upstaza for AADC FDA approved Eli- cel for cerebral ALD ( Skysona ) late infantile or early juvenile forms of MLD aged 18 months and older Libmeldy for MLD 4-17years EMA approved FDA approved

72. Prevention of recurrence of disease Prenatal diagnosis & newborn screening Aim Indication Previously affected child Carrier parents Chorionic villi sampling <12 weeks of gestation Amniotic fluid (12-16 weeks) Sample collection Prevention Enzyme assay Metabolite Genetic test

73. Key message Most of INMD are autosomal recessive inheritance A high index of suspicion is important for diagnosis Don’t miss treatable INMD Early diagnosis & intervention can improve quality of life

74. Report of urinary metabolites \ Urinary ketonebodies -