Metabolic disorders in neurology
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This document provides an overview of neurometabolic disorders, including: 1. It discusses Garrod's hypothesis and how metabolic disorders can be classified into groups related to intoxication, energy metabolism, and complex molecules. 2. The different presentations of neurometabolic disorders are outlined, including encephalopathy, liver disease, cardiac issues, and predominant neurological symptoms. 3. Guidance is provided on when to suspect a neurometabolic disorder and how to conduct initial investigations including metabolic screening tests and MRI patterns. 4. Specific white matter leukoencephalopathies are examined in detail including their genetics, organelle involvement, and distinguishing imaging features.
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Metabolic disorders in neurology
- 2. Neuro-Metabolic disorders By Mohammed E. Mahdy, Msc
- 3. Objectives • Introduction • How to suspect neurometabolic disorder? • MRI • Leukodystrophies • Mitochondrial
- 9. • enzyme • substrate normal product •
- 10. • enzyme • substrate product •
- 11. • enzyme • substrate normal product • toxic
- 13. Metabolic disorders can classified into: I Intoxication II Energy metabolism III Complex molecules
- 14. Group I intoxication • Acute or progressive intoxication from accumulation of toxic compounds proximal to metabolic block. • Example : phenylketonuria • Common features: • * fetal life not affected • * symptom free interval • * may be acute ( coma, liver failure, vomiting, thrombo-embolic) • * may be chronic ( developmental delay, cardiomyopathy)
- 15. Group I intoxication • * provoked by fever, intercurrent illness, food intake • * presentation often late and intermittent • * diagnosis straightforward relies on plasma and urine levels • * most are treatable ( stop or add certain foods, cleansing drugs carnitine, penicillamine, dialysis).
- 16. Group II energy metabolism • Failure of energy production or utilization • In ( liver, muscle, myocardium, brain, others) • Mitochondrial or cytoplasmic • Common features: • * exercise intolerance and fatigue • * hypoglycemia • * hyperlactinemia
- 17. Group II energy metabolism • * hepatomegaly • * hypotonia • * myopathy • * cardiomyopathy • * S U E D I ( sudden unexpected death in infancy) • * diagnosis more difficult needs enzymatic levels, biopsies, cell culture • * treatment more difficult in mitochondrial than cytoplasmic
- 18. Group III complex molecules • Lysosomes and peroxisomes • Common features: • * permenent • * progressive • * not provoked • * most are non treatable
- 19. Neurometabolic disorders Different classifications • • Clinical syndrome • • Cellular organelle involved • • Biochemical studies • • Genetic mutation
- 20. The Daunting Differential List: • Transient Hyperammonemia of Newborn • Inborn Errors of Metab: • Organic Acidemias • Fatty Acid Oxidation def • Urea Cycle Defects • Amino Acidurias • Non-ketotic Hyperglycinemia • Molybdenum Cofactor Deficiency • Sulfite Oxidase Deficiency • Metal Storage Disorders: • Cholesterol Disorders: • Leukodystrophies, other… • Mitochondrial Disorders • Glycogen Storage Disorders • Hyperinsulinism • Carbohydrate Disorders • Lysosomal Disorders • Mucopolysaccharidoses (X-linked Hunter’s, Hurler’s) • Gaucher disease • Tay-Sachs Disease • Peroxisomal Disorders • Zellwegar’s (Cerebro-Hepato- renal) • X-linked Adrenoleukodystrophy
- 21. Small molecule disease Carbohydrate Protein Lipid Nucleic Acids Organelle disease Lysosomes Mitochondria Peroxisomes Cytoplasm
- 22. when do you suspect a neurometabolic disorder ?? • An infant or child presented with any of the following: • * progressively deteriorating neurological or developemental disorder • * diffuse neurological involvement • * family history • * dysmorphic features • * progressive childhood ataxias • * dystonias or other movement disorders • * childhood epilepsies specially if myoclonic
- 23. • * cognitive decline • * spinal deformity • * other organ dysfunction ( liver, heart, GIT) • * MRI features
- 24. Assessment: • Detailed H+P • Describe sz • Fevers -Milestones -FHx -Mom’s GsPs • Physical Exam: • Vitals • Level of alertness • Abnl activity/mvmts • CV- perfusion • Dysmorphology, hair, smell, eyes- cornea • Abdo- HS megaly • Neuro- DTRs, tone, etc • Skin- bruise, pigment, color
- 25. In most instances physical findings do not suggest a specific diagnosis; however, certain findings may direct the reader to further explore specific underlying etiologies: • Macrocephaly; • Abnormal dentition: POLR3-related leukodystrophy or oculodentodigital dysplasia (ODDD) • Palatal myoclonus in adults: Alexander disease • Xanthomas: cerebrotendinous xanthomatosis (CTX) • Abnormalities of skin pigmentation: X-linked adrenoleukodystrophy (X-ALD) • Ichthyosis: Sjögren-Larsson syndrome • Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC)
- 26. Disorders with Macrocephaly and Leukoencephalopathy on MRI
- 27. with Cataract • Galactosemia • Homocystinuria • Cerebrotendinous xanthomatosis
- 28. Coarse facies • Mucopolysaccharidosis • Sialidosis • GM1 gangliosidosis • Zellweger’s
- 31. Kinky hair • Menke’s syndrome • Multiple carboxylase deficiency • Arginosuccinic aciduria
- 32. Menke’s ***** Wilson ????
- 33. Menke’s ***** Wilson ???? Copper transporting ATPase High copper ATPase 7B ATPase 7 A
- 34. Cherry red spot • Tay-Sachs (GM2 gangliosidosis) • Niemann-Pick • Gaucher’s • Sialidosis
- 35. Abnormal odour (urine, body) • Musty : PKU • Caramel : Maple syrup urine disease • Cat urine: multiple carboxylase deficiency
- 36. Patterns of Presentation: 1. Encephalopathy with or without metabolic acidosis. 2. Acute liver disease: 3. Dysmorphic features. 4. Cardiac disease. 5. Diarrhea 6. Hepatomegaly +/- Splenomegaly 7. Predominant Neurological symptoms
- 38. Encephalopathy with or without metabolic acidosis: • Encephalopathy, seizures,and tone abnormalities are predominant presenting features of -organic acidemias, -urea cycle defects, and -congenital lactic acidosis. • Intractable seizures are prominent in -pyridoxine dependency, -non-ketotic hyperglycinemia, -molybdenum co-factor defect, and -folinic-acid responsive seizures.
- 39. Predominant Neurological Symptoms: a. Psychomotor delay: -Aminoacidopathies -Organic acidemias -CNS storage diseases b. Ataxia: -Hartnup dis -Urea cycle disorders -Pyruvate decarboxylase deficiency c. Extrapyramidal signs: - Wilsons disease d. Hypotonia : - Zellweger synd -Mitochondrial myopathies -Muscle carnitine deficiency
- 40. First line investigations (metabolic screen): • The following tests should be obtained in all babies with suspected IEM. • 1) Complete blood count: (neutropenia and thrombocytopenia seen in propionic and methylmalonic academia) • 2) Arterial blood gases and electrolytes • 3) Blood glucose • 4) Plasma ammonia (Normal values in newborn: 90-150 mg/dl or 64-107 mmol/L) • 5) Arterial blood lactate (Normal values: 0.5-1.6 mmol/L) • 6) Liver function tests, • 7) Urine ketones, • 8) Urine reducing substances, • 9) Serum uric acid (low in molybdenum cofactor deficiency).
- 43. Screening : blood • Glucose • Lactate • PH • Ammonia • Amino acids
- 44. Screening : refractory seizures in infancy • Urine : sulphite, aminoadipic semialdehde • Blood: biotinidase, pyridoxine • CSF: pipecolic acid
- 45. MRI ???? Hypo or demyelination • 1st Confluent or multifocal • 2nd Associated findings • 3rd
- 46. A→B. thyroid hormone cell transporter deficiency C. GM1 gangliosidosis with hypomyelination accompanied by early loss of white matter volume D. Persistent and severe hypomyelination seen in a school-aged child with Pelizaeus-Merzbacher disease E. Cerebellar atrophy seen in POLR3-related leukodystrophy (4H syndrome); F. Basal ganglia involvement seen in H-ABC syndrome; Hypomyelination with atrophy of BG and cerebellum
- 49. A. Diffuse cerebral involvement in an individual with megalencephalic leukodystrophy with subcortical cysts B. Primarily frontal involvement in a child with Alexander disease; C. Primarily parieto-occipital involvement in a child with X-linked adrenoleukodystrophy; D. Primarily temporal involvement in an individual with Aicardi-Goutières syndrome; E. Primarily subcortical involvement in Kearns- Sayre syndrome; sparing of the white matter in the periventricular region. F. Primarily periventricular involvement in an individual with metachromatic leukodystrophy; subcortical fibers are spared; G. Primarily brain stem involvement in an individual with adult polyglucosan body disease H. Primarily cerebellar and middle cerebellar peduncle involvement in an individual with autosomal dominant adult-onset leukodystrophy I. Large, asymmetric lesions in hereditary diffuse leukoencephalopathy with spheroids (HDLS);
- 50. A. White matter rarefaction and cysts on FLAIR imaging in vanishing white matter disease B. Calcium deposits and hemosiderin deposits visible on CT in Aicardi-Goutières syndrome; C. Contrast enhancement on T1-weighted imaging within abnormal white matter in X- linked adrenoleukodystrophy; D. Cortical gray matter lesions in POLG-related disorders; E. Cerebellar abnormalities seen in the dentate nucleus in L-2-hydroxyglutaric aciduria; F. Thinning of the corpus callosum (particularly of the genu) in hereditary spastic paraplegia 11; arrow indicates thin corpus callosum with anterior beaking G. Non-calcifying basal ganglia lesions in Alexander disease; H. Typical brain stem involvement in AD adult- onset leukodystrophy (ADLD); I. Spinal cord involvement in LBSL; Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
- 51. WHITE MATTER DISEASES Leukoencephalopathies • Demyelination Primary : MS Secondary : ADEM, SSPE, HIV Hypertensive • Dysmyelination (Leukodystrophy) Hypodense on CT ; Hypointense in T1WI and Hyper in T2WI MRI cannot distinguish Demyelination from Dysmyelination
- 52. Classification • Genetics • Organelle based Lysosomal : MLD, Krabbe Peroxisomal : ALD Mitochondrial : MELAS, MERRF X-linked Adrenoleukodystrophy Pelizaeus-Merzebacher disease Autosomal recessive Metachromatic Leukodystrophy Krabbe Canavan Cockayne Neonatal ALD Unknown Alexander disease
- 55. Some Discriminating features • Near complete lack of myelination • Frontal Predominance • Occipital Predominance • Macrocephaly • Enhancement • Infarcts • Hyperdense BG • Dysplasia Canavan Disease, PMD Alexander disease X- linked ALD Alexander, Canavan ALD, Alexander MELAS, MERRF, Leigh Krabbe, Aicardie Zellweger
- 56. Metachromatic Leukodystrophy •MC Lysosomal disorder •Arylsulphatase A deficiency •Low levels in urine, leukocytes •Late infantile form MC (6months to 3 yrs) •Pathology: metachromatic granules in brain, kidney, nerves. Symmetric confluent hyperintensity in T2WI in periV & Cerebellar WM.
- 58. KRABBE DISEASE Globoid Cell Leukodystrophy (GLD) AR, Lysosomal Disorder Early infantile form MC Death by 2 yrs Based on age of onset , MRI findings – ≤ 2yrs (early onset) > 2yrs (late onset) Abnormal high signal in T2WI along the corticospinal tracts.
- 59. Late onset GLD
- 60. ADRENOLEUKODYSTROPHY • Peroxisomal disorder • Single enzyme defect – Classic X linked ALD, AMN • Multiple enzyme defects – Zellweger disease, Neonatal ALD • Symmetrical areas of WM abnormalities in pareito-occipital region, extending across splenium • Corticospinal tract involvement • Auditory pathway involvement (LGB) • Contrast enhancement in leading edge of dysmyelination
- 63. ALEXANDER DISEASE Macrocrania •Frontal predominance •Enhancement •Late diffuse cases resemble Canavan.
- 65. CANAVAN DISEASE Macrocrania •Diffuse involvement of WM with swelling •Subcortical U fibers involved early •High signal in Globus pallidus.
- 68. Pelizaeus-Merzebacher Disease X-linked recessive Lack of proteolipid lipoprotein (Lipophilin) Diffuse involvement of the WM with sparing of internal capsule and subcortical U fibers Characteristic sparing of perivascular WM – Tigroid or Leopard skin pattern.
- 70. Mitochondriopathies (Multiorgan Disorders) Skeletal muscle Cardiac muscle Extraocular muscle Liver Retina Lens Central nervous system Peripheral nervous system
- 71. Mitochondrial vs Mendelian genetics?
- 72. Mitochondrial Disorders • Involve both gray matter and white matter Leigh disease (subacute necrotizing encephalo-myelopathy) MERRF (Myoclonic epilepsy with ragged red fibers) MELAS (Mitochondrial Encephalomyelopathy, Lactic Acidosis and Stroke Like episodes) Kearns-Sayre syndrome (KSS)
- 73. Leigh Disease Symmetric hyperintensities in lentiform nucleus & caudate nucleus Periventricular WM and periaquiductal GM often involved
- 75. MELAS and MERRF
- 76. ZELLWEGER’S SYNDROME •Neuronal migration disorders - Heterotopias, pachygyria, polymicrogyria •White matter hypomyelination •Cortical neuronal loss
- 77. Van der Knapp Syndrome • Identified in 1995 • Vacuolating Megalencephalic Leukoencephalopathy with Subcortical Cysts
- 78. • Near complete lack of myelination • Frontal Predominance • Occipital Predominance • Macrocephaly • Enhancement • Infarcts • Hyperdense BG • Dysplasia Canavan Disease, PMD Alexander disease X- linked ALD Alexander, Canavan ALD, Alexander MELAS, MERRF, Leigh Krabbe Zellweger
- 80. Treatment • Dietary Restriction • Supplement deficient product • Stimulate alternate pathway • Supply vitamin co-factor • Organ transplantation • Enzyme replacement therapy • Gene Therapy