Inborn errrors of metabolism

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Huge presentation to be used as a reference. One of the NIMHANS Bangalore seminars.

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An approach to Metabolic diseases in Children :

An approach to Metabolic diseases in Children Dr. Pratheep Joseph Kottam Assistant Professor in Neurology MOSC Medical College, Kolenchery, Kerala, India

Topics:

Topics Introduction Clinical Classification Clinical approach Biochemical approach Radiological approach Management

INTRODUCTION Inborn errors of metabolism :

INTRODUCTION I nborn errors of metabolism Archibald Garrod - concept of inborn errors of metabolism (IEM) (1908) Croonian Lectures and Huxley Lecture (1927) - at Charing Cross Hospital in London. IEM - heterogeneous group of disorders Abnormalities of the synthesis, transport, and turnover of dietary and cellular components. Individually uncommon Significant cause of morbidity and mortality.

INTRODUCTION Inborn errors of metabolism :

Approximately 1 per 1000 individuals born. Estimated 20% of all deaths from genetic diseases. Hereditary neurological or storage disorders account for 38%. INTRODUCTION Inborn errors of metabolism Gregory M Pastores; 2008;Vol II:1761-1783.

What is a metabolic disease? :

What is a metabolic disease? Garrod’s hypothesis product deficiency substrate excess toxic metabolite A D B C

Mechanism of deficient enzyme activity:

Mechanism of deficient enzyme activity Mutations in the primary gene sequence for the protein with loss of activity Abnormal processing - posttranslational modification defects Mistaken intracellular localization. Defects of a structural or transport protein Gregory M Pastores; 2008;Vol II:1761-1783.

PATTERN OF INHERITANCE Inborn errors of metabolism :

PATTERN OF INHERITANCE Inborn errors of metabolism 90% of IEMs - autosomal recessive. Of the remaining 10%, - two thirds are X-linked and one third autosomal dominant traits. Autosomal dominant – AIP, Familial hypercholestrolemia X- linked traits – Fabry`s disease, Lesch-Nyhan syndrome, OTC def Maternal inheritance – Mitochondrial Gregory M Pastores; 2008;Vol II:1761-1783.

Clinical Classification of IEM:

Clinical Classification of IEM Category 1 - Only one functional system or only one organ or anatomic system Category 2 - Metabolic pathway common to a large number of cells / organs or restricted to one organ

Category 2 divided into 3 groups :

Category 2 divided into 3 groups Group 1 . Diseases of Complex molecules – Lysosomal & peroxisomal disorders Group 2 . Accumulation of toxic compounds proximal to metabolic block Amino acidopathies Organic acidurias Congenital urea cycle defects, and Sugar intolerances. Group 3 - Energy deficiency disorders - liver, muscle, brain or myocardium Glycogenosis Gluconeogenesis defects Congenital lactic acidemias Fatty acid oxidation defects Mitochondrial respiratory chain disorders.

Clinical Classification of IEM… Inborn errors of metabolism :

Clinical Classification of IEM… Inborn errors of metabolism Two large categories: Category 1 . only one functional system or only one organ or anatomic system. Symptoms are uniform, Correct diagnosis is usually easy to guess even when the basic biochemical lesion gives rise to systemic consequences. Saudubray JM, Charpentier C ; 2001:1327–403.

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Category 2 . Metabolic pathway common to a large number of cells / organs or restricted to one organ Humoral and systemic consequences. Symptoms are very diverse. CNS - advanced disease Clinical Classification of IEM Inborn errors of metabolism Saudubray JM, Charpentier C ; 2001:1327–403.

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Diagnosis - difficult - secondary abnormalities. Most inborn errors of intermediary metabolism Diseases of intracellular trafficking Lysosomal disorders. Saudubray JM, Charpentier C ; 2001:1327–403. Clinical Classification of IEM Inborn errors of metabolism

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The second category - three groups Group 1 . Diseases - Complex molecules Lysosomal and peroxisomal disorders Symptoms are permanent, progressive, independent of intercurrent events, and unrelated to food intake. Clinical Classification of IEM Inborn errors of metabolism Saudubray JM, Charpentier C ; 2001:1327–403.

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Group 2 . Accumulation of toxic compounds proximal to the metabolic block. Amino acidopathies, Organic acidurias, Congenital urea cycle defects, and Sugar intolerances. A symptom-free interval is followed by clinical signs of intoxication & recurrent metabolic disturbances. Late in onset and intermittent. Clinical Classification of IEM Inborn errors of metabolism Saudubray JM, Charpentier C ; 2001:1327–403.

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Diagnosis is easy - chromatography of plasma and urine amino acids or organic acids. Treatment involves removing the toxin. Clinical Classification of IEM Inborn errors of metabolism Saudubray JM, Charpentier C ; 2001:1327–403.

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Group 3 “ Energy deficiency” disorders - liver, myocardium, muscle, or brain. Glycogenosis, gluconeogenesis defects, congenital lactic acidemias, fatty acid oxidation defects, and mitochondrial respiratory chain disorders. Overlapping clinical spectrum Accumulation of toxic compounds & deficiency in energy production. Clinical Classification of IEM Inborn errors of metabolism Saudubray JM, Charpentier C ; 2001:1327–403.

Clinical Classification of IEM-Pathophysiological Basis:

Disorders involving “complex molecules” lysosomal storage disorders (LSDs), peroxisomal diseases, congenital defects of glycosylation ( CDG ), and defects of cholesterol synthesis Disorders involving “small molecules” amino acidurias, organic acidurias, hyperammonemias, lactic acidemias D isorders associated with “disruption of cellular energy metabolism” mitochondrial respiratory-chain defects, disorders of carbohydrate metabolism, disorders of fatty acid oxidation [FAO] Clinical Classification of IEM-Pathophysiological Basis Gregory M Pastores; 2008;Vol II:1761-1783.

LYSOSOMAL STORAGE DISEASES:

LYSOSOMAL STORAGE DISEASES Sphingolipidosis MPS Glycoprotein degradation disorders Type II Glycogenosis (Pompe Disease) Menkes John H:2006;29-141

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GM1 gangliosidosis Tay-Sach’s disease Sandoff’s disease Gaucher’s disease Niemaan-Pick’s disease Fabry`disease Sphingolipidosis Menkes John H:2006;29-141

Peroxisomal disorders:

Peroxisomal disorders Adrenoleukodystrophy Refsum disease Acyl-CoA oxidase deficiency Bifunctional protein deficiency Rhizomelic chondrodysplasia punctata Mevalonate kinase deficiency Glutaric aciduria type 3 Menkes John H:2006;29-141

Aminoacid disorders:

Aminoacid disorders Phenylketonuria Maplesyrup urine disease Tyrosinemia Homocystinuria Non – ketotic hyperglycinemia Urea cycle disorders Sulfite oxidase deficiency Menkes John H:2006;29-141

ORGANIC ACIDURIAS:

ORGANIC ACIDURIAS Propionic Acidemia (Ketotic Hyperglycinemia) Methylmalonic Aciduria Isovaleric Aciduria Glutaric Acidurias Menkes John H:2006;29-141

Urea cycle defects :

Urea cycle defects N -Acetylglutamate synthetase deficiency Carbamoylphosphate synthetase deficiency Ornithine transcarbamylase deficiency Citrullinemia Argininosuccinic aciduria Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Menkes John H:2006;29-141

DISORDERS OF CARBOHYDRATE METABOLISM AND TRANSPORT:

DISORDERS OF CARBOHYDRATE METABOLISM AND TRANSPORT Galactosemia Fructose Intolerance Glucose Transporter 1 Deficiency Syndrome (De Vivo Disease) Menkes John H:2006;29-141

Glycoprotein degradation disorders :

Glycoprotein degradation disorders Mannosidosis Fucosidosis Sialidosis type I & II Aspartyl glucosaminuria Sialic acid storage disease ( Salla disease ) Menkes John H:2006;29-141

DISORDERS OF METAL METABOLISM:

DISORDERS OF METAL METABOLISM Wilson Disease (Hepatolenticular Degeneration) Menkes Disease (Kinky Hair Disease, KHD) Aceruloplasminemia Menkes John H:2006;29-141

Others…:

Others… DISORDER OF PURINE AND PYRIMIDINE METABOLISM- Lesch-Nyhan Syndrome- Porphyrias- Acute intermittent porphyria Mitochondrial disorders- MELAS MERRF NARP MNGIE Leigh disease Kearns-Sayre Menkes John H:2006;29-141

CLINICAL APPROACH:

CLINICAL APPROACH

Difficult diagnosis ??:

Difficult diagnosis ?? Symptoms are protean, nonspecific and may not be obvious. Specialty laboratories and results do not return promptly. Clinicians - dismiss this category of diseases as being too rare. Scared that one need to memorize the biochemical pathways. Diagnosis does not require extensive knowledge of biochemical pathways or of individual metabolic diseases. An understanding of the clinical manifestations of IEM’s provides the basis for knowing when to consider the diagnosis.

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Considering the possibility!

When to Suspect IEM in a neonate:

Family GENES F- family history- undiagnosed neonatal deaths or unexplained severe illness in childhood G- groups of congenital anomalies or obvious dysmorphism: disorders of energy metabolism that are active in fetal life E- extreme or exceptional presentation of common conditions: infant presents with unusually severe reaction to infection or metabolic stress Whehlan et al When to Suspect IEM in a neonate

When to Suspect IEM in a neonate:

N- neurologic symptoms: unexplained encephalopathy E- extreme or unusual pathology: infant with unusual smell of body or urine S - surprising lab values: Finding a low blood urea in a neonate with respiratory alkalosis in a symptomatic neonate may offer a clue to the diagnosis of urea cycle defect Whehlan et al When to Suspect IEM in a neonate

Clues - History:

Positive family history Consanguinity Failure to thrive Vomiting / Diarrhoea Develpomental delay Seizures Respiratory distress/ apnea Jaundice Unusual odor Clues - History

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Frequent infections Progressive paraparesis Progressive Hemiparesis Behavioral disturbance Dystonia Clues – History –cont….

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Infancy Late infancy & childhood ENLARGING HEAD WITHOUT HYDROCEPHALUS: 1. Canavan’s 6. Menke’s 2. Tay - sach’s 7. MPS-I 3. Adrenoleukodystrophy 4. Krabbe’s 5. Infantile Gangliosidosis 8.Multiple sulfatase deficiency 9. Glutaricaciduria, type II Clues from examination - Head Am Fam Physician 2006;73:1981-90 .

Microcephaly:

Microcephaly Phenyketonuria Propionic aciduria Hyperarginemia HMG Co-A lyase def Congenital disorders of glycosylation Rudolph's pediatrics By Colin David Rudolph

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DYSMORPHIC FEATURES: Infancy Late infancy & childhood 1. GM1 ganglisidosis. 6. Mannosidosis 2. Lowe’s 7. Fucosidosis 3. Zellweger’s 4. MPS 5. Mucolipidosis Clues from examination 8. Glutaric aciduria type 2 9. Multiple carboxylase def Am Fam Physician 2006;73:1981-90 .

ZELLWEGER’S SYNDROME:

ZELLWEGER’S SYNDROME

Hurler schei syndrome:

Hurler schei syndrome Sanfillippo syndrome Minford A,Arumugam R, Illustrated signs in clinical paediatrics,1 st edition.New York:Churchil Livingstone;1998.1-72

Clues from SKIN examination:

Clues from SKIN examination Angiokeratomas Coarse skin Eczema Icthyosis Gum hypertrophy Papular nevi Pellagra like rash Skin lesions Trichorrexis nodosa Xanthoma Am Fam Physician 2006;73:1981-90 .

Clues from SKIN examination:

Infancy Late infancy & childhood ALTERATION OF SKIN: DISORDER SIGN 1. PKU Eczema 2. Arginosuccinic aciduria Trichorrexis nodosa 3. Hartnup Pellagra like rash 4. MPS, Mucolipidosis Coarse skin 5. Fabry’s, Fucosidosis Angiokeratoma 6. Refsum’s, Multiple sulfatase Icthyosis 7. Cerebrotendinous xanthomatosis Xanthoma Clues from SKIN examination Am Fam Physician 2006;73:1981-90 .

Clues from SKIN examination:

Infancy Late infancy & childhood ALTERATION OF SKIN: A. PHOTOSENSITIVITY: Cockayne’s, porphyria B. PAPULAR NAEVI: Fabry’s Clues from SKIN examination Am Fam Physician 2006;73:1981-90 .

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Mucosal angiokeratomas umbilical angiokeratomas . Dermatology Online Journal 2004:10 (1): 20.

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Type 1GM1 Gangliosidosis-Cutaneous Melanosis

Ichthyosis:

Ichthyosis generalised dark, large scaling Harlequin ichthyosis (HI) with constriction of the fingers Eur J Dermatol 2006; 16 (4): 349-59

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Infancy Late infancy & childhood HYPERTROPHIC GUMS: Mucolipidosis Mannosidosis COLORLESS FRIABLE KINKY HAIR: Menke’s kinky hair disease Argininosuccinic aciduria Multiple carboxylase deficiency Giant axonal neuropathy Clues from Gums and Hair

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GUM HYPERPLASIA in I CELL DISEASE

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Scalp with scanty, hypopigmented, browny, stubby, shiny, curly hair and alopecia MENKY’S KINKY HAIR DISEASE J Child Neurol. 2007;22:452-455 .

MENKY’S KINKY HAIR DISEASE:

J Child Neurol. 2007;22:452-455 . Normal control hair shaft Variation of shaft size atrophic medulla Multiple twists MENKY’S KINKY HAIR DISEASE

Trichorrhexis nodosa:

Trichorrhexis nodosa Microscopic analysis of the hair shaft showing breaks located at nodes in the hair (trichorrhexis nodosa) and longitudinal breaks. trichorrhexis nodosa Argininosuccinicaciduria , Menkes' kinky hair syndrome

Pili torti with monilethrix :

Pili torti with monilethrix short and brittle hairs that appear flattened and twisted beaded appearance of the hair due to periodic thinning of the shaft.

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Infancy Late infancy & childhood BEAKED THORACOLUMBAR VERTEBRA: 1. GM1 ganglisidosis. 2. MPS. 3. Mucolipidosis 4. Mannosidosis 5. Fucosidosis Clues from Investigations

EYE as a window to IEM:

EYE as a window to IEM Cataracts Corneal opacity Macular cherry red spot Retinitis pigmentosa Ectopia lentis Optic atrophy Am Fam Physician 2006;73:1981-90 .

OPHTHALMIC SIGNS Infancy Late infancy & childhood :

OPHTHALMIC SIGNS Infancy Late infancy & childhood CATARACT 1. Galactosemia 2. Lowe’s 3. Zellweger’s 4.Marinesco- Sjogren’s 5. Fabry’s 6. Mannosidosis 7. Wilson` 8. Menkes 9. Cerebrotendinous xanthomatosis 10. Systemic carnitine defeciency 11.MPS Am Fam Physician 2006;73:1981-90 .

KF Ring in Wilson:

KF Ring in Wilson

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OPHTHALMIC SIGNS Infancy Late infancy & childhood CORNEAL CLOUDING: 3. 1. Lowe’s syndrome 2. Infantile GM1 gangliosidosis 3. MPS 4. Mucolipidosis 5. Fabry’s Am Fam Physician 2006;73:1981-90 .

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"Whorled" Corneal Opacity Cornea verticillata 2001: 3733-3774 . 2001: 3733-3774 . Desnick RJ, 2001: 3733-3774

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OPHTHALMIC SIGNS Infancy Late infancy & childhood CHERRY RED SPOT: 1. Tay-Sach’s 2. Sandoff’s 3. Infantile Niemann-Pick’s 4. Juvenile GM2 5. MLD 6. sialidosis Eye as a window to IEM 7.Mucolipidosis I ,III 8. Multiple sulfatase defeciency Am Fam Physician 2006;73:1981-90 .

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Macular cherry red spot

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OPHTHALMIC SIGNS Infancy Late infancy & childhood RETINAL PIGMENTARY DEGENERATION : 1. NCL. 7. Abetalipoproteinemia 2. GM2 gangliosidosis 8. Refsum’s 3. Dystonic lipidosis 4. Juvenile GM2. 5. MPS. 6. Mucolipidosis 9. Carbohydrate def glycoprotein syndrome Eye as a window to IEM Am Fam Physician 2006;73:1981-90 .

Ectopia lentis:

Ectopia lentis Homocystinuria Isolated sulfite oxidase def Molybdenum cofactor def Gregory M Pastores; 2008;Vol II:1761-1783.

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OPHTHALMIC SIGNS Infancy Late infancy & childhood OPTIC ATROPHY: 1. Leigh’s 7. NCL. 2. Multiple sulfatase def. 8. MLD. 3. Sandoff’s 9. Homocystinuria 4. Neimann-Pick 10. Juvenile GM2 5. Menke’s 6. Krabbe’s Eye as a window to IEM Am Fam Physician 2006;73:1981-90 .

Optic atrophy:

Optic atrophy Adrenoleukodystrophy Canavan` disease Hyperornithemia with gyrate atrophy Gregory M Pastores; 2008;Vol II:1761-1783.

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Primary Optic atrophy chalky white disc with discrete margins. Optic atrophy

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Hyperornithinemia with Gyrate atrophy of the retina Siblings with Gyrate atrophy and hyperornithinemia: A.Girl 6yrs old: Spastic paraplegia,seizures B.Boy 12 yrs :Defective vision,spastic parapresis A B

Clues from Abnormal eye movements :

OPHTHALMIC SIGNS Infancy Late infancy & childhood OPHTHALMOPLEGIA: 1. Maple syrup urine disease 2. Leigh’s 7. Abetalipoproteinemia 3. Hartnup 8. Tangier’s 4. Juvenile GM1 ganglisidosis 5. Neimann -Pick’s 6. Juvenile Gaucher’s Clues from Abnormal eye movements

Clues from Abnormal eye movements :

OPHTHALMIC SIGNS Infancy Late infancy & childhood Conjunctival TELANGIECTASIA : Fabry ` disease IMPAIRMENT OF VERTICAL GAZE: 1.Niemann-Pick’s C 2.Juvenile dystonic lipidosis 3.Leigh disease, 4.Kearns-Sayre syndrome RAPID PENDULAR NYSTAGMUS: 1. Palizeus - Merzbacher 3. Lesch-Nyhan’s 2. Krabbe’s 4. Late infantile Gaucher Clues from Abnormal eye movements

PowerPoint Presentation:

Conjunctival telangiectasia Sausage-like and markedly dilated conjunctival vessels are typical in patients with Fabry disease. Leonld skorin jr,The Optometrist's Role in Diagnosing and Managing Fabry Disease. PRIMARY CARE OPTOMETRY NEWS November 2007

Other important features:

Infancy Late infancy & childhood DEAFNESS: 1. MPS 2. Cockayne’s BULBAR ABNORMALITIES : 1. Gaucher’s 4. Juvenile GM1 2. Leigh’s 5. Wilson’s 3. Sandoff’s Other important features

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Infancy Late infancy & childhood HEPATOSPLENOMEGALY 1. Infantile Gaucher’s. 7. Fucosidosis 2. Infantile Niemann-Pick 8. Sialidosis. 3. Sandoff’s 4. Multiple sulfatase defeciency 5. MPS. 6. Mucolipidosis Examination of abdomen Am Fam Physician 2006;73:1981-90 .

HEPATOSPLENOMEGALY :

HEPATOSPLENOMEGALY Von Gierks disease Gauchers disease Minford A, Arumugam R, Illustrated signs in clinical paediatrics,1 st edition.New York:Churchil Livingstone;1998.1-72

Other important features:

Infancy Late infancy & childhood INTRACTABLE SEIZURES: Alper’s disease. INTERMITTENT HYPERVENTILLATION : 1. Leigh’s 2. Congenital lactic acidosis ACOUSTICO MOTOR OBLIGATORY STARTLE; 1. Tay-Sach’s 2. Krabbe’s Other important features

Other important features:

EXTRAPYRAMIDAL SIGNS: Infancy Late infancy & childhood 1. Late infantile Neimann-Pick 2. Juvenile dystonic lipidosis. 3. Sanfillipo’s Other important features

Other important features:

MARKED RIGIDITY, OPISTOTONUS & TONIC SPASMS: Infancy Late infancy & childhood 1. Krabbe’s 2. Infantile Gaucher’s 3. Alper’s Other important features

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Clinical classification of IEMs adapted from Saudubray and Cherpentier, 1995.

ACUTE ENCEPHALOPTHY :

ACUTE ENCEPHALOPTHY Presents early in life SYMPTOMS: Recurrent vomiting Poor feeding Lethargy Dehydration Seizures Coma Rapidly progressive course Due to accumulation of small molecules

ACUTE ENCEPHALOPATHY:

ACUTE ENCEPHALOPATHY CONDITIONS: Organic aciduria Aminoacidopathies Lactic acidosis Urea cycle disorders Non ketotic hyperglycinemia Sulfite oxidase deficiency Clinical picture is uniform Diagnosis rests on laboratory tests

CHRONIC ENCEPHALOPATHY :

CHRONIC ENCEPHALOPATHY Late infancy, children, adolescents SYMPTOMS: Spasticity Ataxia Dementia Visual or hearing loss Affection of other organ systems Gradually progressive Due to accumulation of large molecules

CHRONIC ENCEPHALOPATHY:

CHRONIC ENCEPHALOPATHY Chronic progressive encephalopathy Clinical features are less stereotyped Affect other organ systems: Liver, Heart, Kidney Routine metabolic screen less useful. Diagnosis on : Clinical clues Neuroimaging Neurophysiological tests.

CHRONIC ENCEPHALOPATHY:

CHRONIC ENCEPHALOPATHY Lysosomal storage diseases NCL Fatty acid oxidation disorders Peroxisomal disorders .

LYSOSOMAL STORAGE DISEASES SPHINGOLIPIDOSIS:

LYSOSOMAL STORAGE DISEASES SPHINGOLIPIDOSIS Diagnosis: No screening test Diagnosis by age of onset & clinical clues Confirmation by enzyme assay in leucocytes & fibroblasts

LYSOSOMAL STORAGE DISEASES MUCOPLYSACHHARIDOSIS:

LYSOSOMAL STORAGE DISEASES MUCOPLYSACHHARIDOSIS Diagnosis: Clinical clues: Coarse facies Skeletal abnormalities Hepatosplenomegaly Diagnosis by urine MPS & specific enzyme assay

LYSOSOMAL STORAGE DISEASES GLYCOPROTEIN STORAGE DISEASES:

LYSOSOMAL STORAGE DISEASES GLYCOPROTEIN STORAGE DISEASES Clinical features of both MPS & lipidosis Mannosidosis Fucosidosis Sialidosis type I & II Aspartyl glucosaminuria Diagnosis: Quantitative analysis of urine oligosaccharides Specific enzyme assay

CHRONIC ENCEPHALOPATHY NEURONAL CEROID LIPOFUSCINOSIS:

CHRONIC ENCEPHALOPATHY NEURONAL CEROID LIPOFUSCINOSIS 4TYPES Present in early infancy, juvenile or adolescent age group Suspect: MR Myoclonic seizures Ataxia Blindness due to macular degeneration Diagnosis: Demonstration of typical inclusion bodies in Electron microscopy. on bodies in EM

CHRONIC ENCEPHALOPATHY FATTY ACID OXIDATION DISORDERS:

CHRONIC ENCEPHALOPATHY FATTY ACID OXIDATION DISORDERS Systemic carnitine deficiency Palmitoyl transferase deficiency Acyl Co A dehydrogenase deficiency HMG CoA lyase deficiency Manifestations: Muscle weakness, pain & rabdomyolysis Coma & hypoglycemia triggered by infection, stress & fasting Diagnosis: Detection of urine oligosaccharides Specific enzyme assay

CHRONIC ENCEPHALOPATHY PEROXISOMAL DISORDERS:

CHRONIC ENCEPHALOPATHY PEROXISOMAL DISORDERS . Types:Due to defective peroxisomal function Adrenoleucodystrophy Zellweger syndrome Adrenomyeloneuropathy Infantile Refsum’s Rhizomelic Chondrodysplasia punctata Clinical features: Encephalopathy Dysmorphism Hypotonia Seizures Deafness & blindness Diagnosis: Elevated levels of VLCFA in serum & fibroblasts.

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Initial findings include Poor feeding Vomiting Lethargy Convulsion Coma Metabolic disorder infection ObtainPlasma NH3 high normal Obtain ABG normal Acidosis Normal Urea cycle defects Organic acidemias Aminoacidopathies/ galactosemias Clinical approach to a newborn with metabolic disorder Rajvani Iraj,Nelson Textbook of Paediatrics,18 th edition.Philadelphia:Saunders;2008.Vol I:527-566 .

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Refusal of feeds Vomitting Acidosis Dehydration Neutropenia Hypoglycemia Ketosis No Ketosis No skin manifestations Skin manifestations No odor Characteristic odor Methyl malonic acidemia Propionic acidemia Ketothiolase deficiency MSUD Isovaleric acidemia 3-Hydroxy-3methylglutaricaciduria Acyl CoA dehydrogenase deficiency Multiple Carboxylase Deficiency Clinical approach to infants with organic acidemia Rajvani Iraj,Nelson Textbook of Paediatrics,18 th edition.Philadelphia:Saunders;2008.Vol I:527-566 .

Intermittent Late-Onset Acute Presentation:

Intermittent Late-Onset Acute Presentation Recurrent attacks of coma, strokes, or vomiting with lethargy, ataxia, or psychiatric symptoms Metabolic acidosis Ketosis Hyperlactacidemias Hypoglycemia Hypoketotic hypoglycemias due to inborn errors of ketogenesis Reye syndrome Sudden infant death syndrome Recurrent attacks of dehydration Exercise intolerance and recurrent myoglobinuria Abdominal pain (recurrent attacks) Cardiac disorders (acute cardiac failure, heartbeat disorders) Bone crisis

Progressive Neurologic Symptoms:

Progressive Neurologic Symptoms Progressive neurologic and mental deterioration Early in infancy (1 to 12 months) Late infancy to early childhood (1 to 5 years) Late childhood to adolescence (5 to 15 years) Onset in adulthood (15 years to more than 60 years) Extrapyramidal signs (dyskinesia, dystonia, choreoathetosis, parkinsonism) Deafness Hypotonia in the neonatal period and in early infancy Hyperventilation attacks

Clinical Findings Characteristic of an Inborn Error of Metabolism:

ACUTE METABOLIC ENCEPHALOPATHY SUBACUTE PROGRESSIVE EPILEPTIC ENCEPHALOPATHY CHRONIC ENCEPHALOPATHY WITH MULTIPLE ORGAN INVOLVEMENT CHRONIC ENCEPHALOPATHY WITHOUT MULTIPLE ORGAN INVOLVEMENT MSUD Glycine cleavage defects Mitochondrial disorders L-AAD def Organic acidemias Pyridoxine dep /def CDG Glutaric aciduria Urea cycle defects Sul Ox/Mb cofactor def Peroxisomal disorders GTP cyclohydrolase def Electron chain defects Folinic acid-responsive defects Lysosomal storage disorders PKU OXPHOS defects Menkes' disease Cholesterol biosynthesis defects SSADH def Fatty acid oxidation defects COX def CPT II def L-AAD def MTP defects GLUT I def AICAR/SAICAR Serine biosynthesis defects Creatine def MECP2 Clinical Findings Characteristic of an Inborn Error of Metabolism

NEUROMETABOLIC DISEASES CLASSIFICATION:

NEUROMETABOLIC DISEASES CLASSIFICATION Grey matter disease Vs White matter disease

GREY OR WHITE MATTER DISEASE:

GREY OR WHITE MATTER DISEASE

GREY MATTER DISEASES:

GREY MATTER DISEASES With visceromegaly Without seizures With Dysmorphism Without visceromegaly Without Dysmorphism With multifocal seizures With cherry red spot No cherry red spot With cherry red spot No cherry red spot

GREY MATTER DISEASE:

GREY MATTER DISEASE WITH VISCEROMEGALY WITHOUT VISCEROMEGALY

GREY MATTER DISEASE:

WITH DYSMORPHISM GREY MATTER DISEASE WITH VISCEROMEGALY WITHOUT DYSMORPHISM GM1 Gangliosidosis MPS Multiple sulfatase deficiency Mannosidsis Fucosidosis I cell disease Zellweger’s disease Gaucher’s disease Niemann-Pick disease Sandoff’s disease

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WITH MULTIFOCAL SEIZURES WITH VISCEROMEGALY WITH DYSMORPHISM WITHOUT DYSMORPHISM GM1 Gangliosidosis MPS Multiple sulfatase deficiency Mannosidosis Fucosidosis I cell disease Zellweger’s disease WITHOUT SEIZURES GM1 Ganglliosidosis Sialidosis Zellweger’s Lowe’s I cell disease MPS MPS Multiple sulfatase deficiency Mannosidosis Fucosidosis

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WITH MULTIFOCAL SEIZURES WITH VISCEROMEGALY WITH DYSMORPHISM WITHOUT DYSMORPHISM WITHOUT SEIZURES GM1 Ganglliosidosis Sialidosis Zellweger’s Lowe’s I cell disease MPS Multiple sulfatase deficiency Mannosidsis Fucosidosis CHERRY RED SPOT NO CHERRY RED SPOT CORNEAL CLOUDING NO CORNEAL CLOUDING GM1 Gangliosidosis Sialidosis Zellweger’s Lowe’s MPS Mannosidosis I cell disease Multiple sulfatase deficiency Fucosidosis

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WITH CHERRY RED SPOT WITH VISCEROMEGALY WITH DYSMORPHISM WITHOUT DYSMORPHISM NO CHERRY RED SPOT Gaucher’s Niemann -Pick MEGELENCEPHALY NO MEGELENCEPHALY BULBAR SIGNS NO BULBAR SIGNS Sandoff’s Niemann -Pick Gaucher’s Niemann-Piock Gaucher’s Niemann-Pick’s Sandoff’s Niemann-Pick Sandoff’s

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WITH CHERRY RED SPOT WITHOUT VISCEROMEGALY NO CHERRY RED SPOT NCL Menke’s MEGELENCEPHALY NO MEGELENCEPHALY ABNORMAL HAIR NO ABNORMAL HAIR Tay-Sach’s Sialidosis Menke’s NCL Tay-Sach’s Sialidosis Tay-Sach’s NCL Sialidosis type I Menke’s disease

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WHITE MATTER DISEASE Canavan,s disease Alexander’s Adrenoleucodystrophy Palizeus Merzbacher CNS AFFECTION CNS &PNS AFFECTION Canavan’s disease Alexander’s disease Palizeus –Merzbacher Adrenoleucodystrophy MLD Krabbe’s Neuroaxonal dystrophy Cockayne,s Adrenomyeloneuropathy MACROCEPHALY NO MACROCEPHALY Canavan’s dis. Alexander’s Palizeus-Merzbacher Adrenoleucodystrophy Visual loss No visual loss Adrenal defeciency No adrenal def.

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WHITE MATTER DISEASE CNS AFFECTION CNS &PNS AFFECTION Canavan’s disease Alexander’s disease Palizeus –Merzbacher Adrenoleucodys trophy MLD Krabbe’s Neuroaxonal dystrophy Cockayne,s Adrenomyeloneuropathy opisthotonus Hypotonia Photodermatitis Krabbe’s MLD Cockayne’s

BIOCHEMICAL APPROACH :

BIOCHEMICAL APPROACH

Biochemical approach :

Biochemical approach Blood: Ammonia, lactate, pyruvate, VLCFA Urine : To detect aminoaciduria, MPS CSF Tissue Biopsy Skin, nerve, muscle, brain Enzyme Deficiency In cultured fibroblasts

Blood Profile :

Blood Profile Complete blood count: Propionic and Methyl Malonic Acidemia-Neutropenia and Thrombocytopenia Arterial blood gases and electrolytes Blood glucose Plasma ammonia Plasma lactate Liver function tests Serum uric acid -low in molybdenum cofactor deficiency

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TESTS CLINICAL UTILITY Ammonia Urea cycle defects, organic acidemia Carnitine , plasma or serum total and free ( unesterified ) urine levels Deficiency may develop in carnitine transport defects, disorders of fatty acid oxidation and branched chain amino acid metabolism, and valproic acid treatment Acylcarnitine profile Normal plasma acyl/free carnitine ratio: <0.25 Ceruloplasmin Decreased in Wilson's and Menkes' disease, aceruloplasminemia Cholesterol Low plasma levels in Smith- Lemli - Opitz syndrome, cerebrotendinous xanthomatosis ; Free fatty acids (FFA); ketone bodies (KB): 3-hydroxybutyrate, acetoacetate Disorders of fatty acid oxidation and ketolysis ; Lactate Defects of glycogen metabolism, gluconeogenesis and fatty acid oxidation defects involving the electron transport chain, Krebs cycle, and pyruvate dehydrogenase Lactate/ pyruvate ratio (NI: <20:1) provides insight into oxidation-reduction status (increased in OXPHOS defects; normal in PDHC deficiency) Normal blood lactate < 1.8 mmol /L Normal CSF lactate < 2.2 mmol /L Commonly Requested Tests for the Evaluation of a Patient Thought to Have an Inborn Error of Metabolism

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Very-long-chain fatty acid (VLCFA) Disorders of peroxisomal metabolism Phytanic acid Elevated in Refsum's disease and rhizomelic chondrodysplasia punctata Uric acid Elevated in Lesch-Nyhan syndrome and other defects of purine metabolism and glycogen storage disorders; Decreased in molybdenum cofactor deficiency and defects of pyrimidine metabolism CSF: Plasma ratio Glucose <0.35 Glucose transport defect Glycine >0.6 Nonketotic hyperglycinemia ; low in plasma and CSF glycine levels in 3-phosphoglycerate dehydrogenase deficiency; markedly elevated plasma glycine in patients with organic acidemias (MMA, PA, IVA) Serine <0.2 Serine deficiency syndromes (3-phosphoglycerate dehydrogenase and phosphoserine phosphatase deficiency) Commonly Requested Tests for the Evaluation of a Patient Thought to Have an Inborn Error of Metabolism

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GROUP Blood gases Ketones Lactic acid Ammonia Disorders Type I with ketosis - + - - MSUD Type II Ketosis + acidosis + + - - Organic aciduria Type III Lactic acidosis + + + - Lactic acidosis Type IV Hyperammonemia without ketoacidosis - - - + Urea cycle disorders Type V Without ketoacidosis,without hyperammonemia - - - - NKH Sulfite oxidase deficiency Peroxisomal

ACUTE ENCEPHALOPATHY:

ACUTE ENCEPHALOPATHY FINAL CONFIRMATION: Detection of organic acid, aminoacid, & sulfites in urine Detection of specific enzyme deficiency in WBC and fibroblasts Clinical distinction between various diseases coming under each category is not possible. e

Differential diagnosis of Acute encephalopaty:

Differential diagnosis of Acute encephalopaty Ann Ind Acad Neurol 2008;11;1-14

URINE EXAM :

URINE EXAM

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Urine ketones Urine reducing substances Urine amino acids and organic acids: by gas chromatography mass spectrometry (GCMS)- for diagnosis of organic acidemias Urinary orotic acid- in cases with hyperammonemia for classification of urea cycle defect

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Metachromatic granules in urine

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Infancy Late infancy & childhood XV. UNUSUAL ODOURS; 1. PKU Musty odour 2. Tyrosinemia Rancid butter 3. Maple syrup urine Maple syrup 4. Isovaleric acidemia Sweaty feet 5. Glutaric acidemia Sweaty feet 6. Hydroxy methyl glutaryl Cat’s urine NEUROLOGICAL STIGMATA HELPING DIFFERENTIAL DIAGNOSIS

URINE METABOLIC SCREEN:

URINE METABOLIC SCREEN Disorder Ferric chloride DNPH Sugar Nitroprusside CTAB PKU + + - - - Galactosemia - - + - - Organic aciduria + + - - - Aminoaciduria - + - - - Homocystinuria - - - + - MPS - - - - +

ACUTE ENCEPHALOPATHY URINE FERRIC CHLORIDE TEST:

ACUTE ENCEPHALOPATHY URINE FERRIC CHLORIDE TEST PKU HISTIDINEMIA MSUD PROPIONIC & METHYL MALONIC ACIDEMIA Emarald green Greenish Navy blue purple brown

CSF Analysis :

CSF Analysis DISORDER LEVELS IN CEREBROSPINAL FLUID BH4 BH2 NEOP HVA 5HIAA 3OMD GTP-CH deficiency (Segawa disease) ↓ N ↓ ↓ ↓ N Septiapterin reductase deficiency ±↓ N ↓ ↓ N Tyrosine hydroxylase deficiency N N N ↓ N N AADC deficiency N N N ↓ ↓ ↑ Hyland K. 2003, Ann Neurol:54: 6.S13-17.

Enzyme assay :

Enzyme assay Disorders of Complex molecules Biotinidase assay- in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia) GALT (galactose 1-phosphate uridyl transferase ) assay- in cases with suspected galactosemia (hypoglycemia, cataracts, reducing sugars in urine).

TISSUE BIOPSY :

TISSUE BIOPSY

Biopsy of Skin , Conjunctivae, Lymphocytes :

Biopsy of Skin , Conjunctivae, Lymphocytes Most lipidoses, - late infantile and juvenile neuronal ceroid lipofuscinosis Lafora disease Neuroaxonal dystrophy Mucolipidosis Sanfilippo syndromes Fabry disease Menkes John H:2006;29-141

Muscle biopsy :

Muscle biopsy Late infantile and juvenile neuronal ceroid lipofuscinosis Familial myoclonus epilepsy Mitochondrial disorders Menkes John H:2006;29-141

Peripheral Nerve biopsy :

Peripheral Nerve biopsy Metachromatic leukodystrophy Globoid cell leuko dystrophy Infantile neuroaxonal dystrophy Fabry disease Refsum disease Tangier disease Menkes John H:2006;29-141

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Granular myelin breakdown Hematoxylin & Eosin Granular myelin breakdown Masson’s trichrome stain

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NORMAL Increased endoneurial collagen secondary to fibre loss

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Metachromatic material accumulating in schwann cells

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Kulchitsky Pal stain – uniform loss of myelinated fibres NORMAL

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Thinly myelinated fibres + granular myelin breakdown and remodeling Active myelin breakdown Normal

Bone-marrow biopsy :

Bone-marrow biopsy Lysosomal storage diseases Niemann-Pick diseases Gaucher diseases G M1 gangliosidosis Mucopolysaccharidoses Mucolipidoses

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GAUCHER CELL IN BONE MARROW

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NIEMANN-PICK CEELL IN BONE MARROW

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Infancy Late infancy & childhood VACUOLATED LYMPHOCYTES: 1. Niemann –Pick 2. Generalised GM1 3. MPS. 4. Mucolipidosis 5. Mannosidosis 6. Fucosidosis Clues from investigations

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VACUOLATED LYMPHOCYTES

Liver Biopsy :

Liver Biopsy Glycogen storage diseases Fructose 1,6-diphosphatase deficiency Non-ketotic hyperglycinemia Lysinuric protein intolerance Primary hyperoxaluria type 1 Wilson disease Menkes disease Niemann-Pick diseases

 An approach to inherited metabolic disorders with chronic encephalopathy:

An approach to inherited metabolic disorders with chronic encephalopathy

Hyperammonemia:

Hyperammonemia

Hyperammonemia:

Hyperammonemia Enzyme defects in urea cycle OTC deficiency CPS-I deficiency NAGS deficiency AS deficiency AL deficiency Arginase deficiency Fatty acid oxidation defects : Acyl-CoA dehydrogenase deficiency Systemic carnitine deficiency Congenital lactic acidosis: Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Mitochondrial diseases

Hyperammonemia:

Organic acidemias: Isovaleric acidemia Propionic acidemia Methylmalonic acidemia Glutaric acidemia type II Multiple carboxylase deficiency Beta-ketothiolase deficiency Dibasic amino acid transport defect Lysinuric protein intolerance Hyperammonemia-hyperornithinemia -homocitrullinuria (HHH) Hyperammonemia

Hyperammonemia:

Drugs Valproate 5-Fluorouracil Salicylates Liver diseases : Acute or chronic liver diseases cystic fibrosis, Wilson disease, biliary atresia, AAT deficiency. Renal diseases :Urinary tract infections with Proteus mirabilis, Staphylococcus or Corynebacterium Reye's syndrome, Parenteral hyperalimentation Transient hyperammonemia of the newborn Hyperammonemia

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Barbara K. Burton, Pediatrics 1998;102 ;e69:1-9

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Obtain Plasma Amino Acids Specific amino acid elevation No specific amino acid elevation Obtain urine oroticacid High Normal or low Obtain plasma citrulline OTC deficiency Low Normal or elevated CPS/ NAG synthetase deficiency Transient Hyperammonemia Obtain ABG Acidosis No acidosis Citrullinemia Argininemia Argininosuccinic acidemia HHH syndrome Clinical approach to a newborn with symptomatic hyperammonemia

An approach to diagnosis of hyperammonemia in older children:

An approach to diagnosis of hyperammonemia in older children

Metabolic acidosis:

Metabolic acidosis

Evaluation of metabolic acidosis with increased anion gap:

Evaluation of metabolic acidosis with increased anion gap

Hypoglycemia:

Hypoglycemia

Etiology of hypoglycemia:

Etiology of hypoglycemia Fasting period : Fattyacid oxidation defects Fructose 1,6 biphosphatase def Ketogenesis and Ketolytic defects Tyrosinemia1 Resp chain disorders Ann Ind Acad Neurol 2008;11;1-14

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Immediate postprandial : Sulfonylurea 1 defect Inward rectifier potassium channel defect Glutamate dehydrogenase defeciency Glucokinase gene defects Shortchain 3 hydroxy acyl co-A dehydrogenase def Few hours after meals: Glycogenosis 1 and 3 Glycogen synthase def Resp chain disorders Ann Ind Acad Neurol 2008;11;1-14

Biochemical evaluation of hypoglycaemia:

Biochemical evaluation of hypoglycaemia

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Ann Ind Acad Neurol 2008;11;1-14

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DISORDER ENZYME DEFICIENCY PRIMARY METABOLIC INDICATOR AMINO ACIDOPATHY Phenylketonuria/Hyperphenylalaninemia Phenylalanine hydroxylase (and variants) Phe Maple syrup urine disease Branched chain oxo- (or keto) acid dehydrogenase Leu/Ile, Val Homocystinemia Cystathionine β-synthase Met Hypermethioninemia Methionine- S -adenosyltransferase Met Citrullinemia Argininosuccinate synthetase Cit Argininosuccinic aciduria Argininosuccinate lyase Cit Tyrosinemia type I Fumarylacetoacetate hydrolase Tyr ORGANIC ACIDEMIA Glutaric acidemia type 1 Glutaryl-CoA dehydrogenase C5DC Propionic acidemia Propionyl-CoA carboxylase C3 Methylmalonic acidemia Methylmalonyl-CoA mutase C3 Metabolic Disorders Detected Through Tandem Mass Spectrometry Gregory M Pastores; 2008;Vol II:1761-1783.

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Isovaleric acidemia Isovaleryl-CoA dehydrogenase C5 3-hydroxy-3-methylglutaryl CoA lyase deficiency C5OH 3-methylcrotonylcarboxylase deficiency C5OH FATTY ACID OXIDATION DEFECTS Medium-chain-acyl-CoA dehydrogenase deficiency C8, C10, C10:1, C6 [*] Very-long-chain acyl-CoA dehydrogenase deficiency C14:1, C14, C16 Short chain acyl-CoA dehydrogenase deficiency C4 Multiple acyl-CoA dehydrogenase deficiency C4, C5, C8, C12, C14, C16, C5DC Carnitine palmitoyltransferase deficiency C16, C18:1, C18 Carnitine/acylcarnitine translocase deficiency C160H, C18:1OH, C18OH Very-long-chain hydroxyacyl-CoA dehydrogenase deficiency C16OH, C18:1OH, C18OH Trifunctional protein deficiency C16OH, C18:1OH, C18OH DISORDER ENZYME DEFICIENCY PRIMARY METABOLIC INDICATOR Metabolic Disorders Detected Through Tandem Mass Spectrometry Gregory M Pastores; 2008;Vol II:1761-1783 .

RADIOLOGICAL APPROACH:

RADIOLOGICAL APPROACH

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Mitochondrial disorders Pyruvate dehydrogenase deficiency + + + + + Fumarase deficiency + + + + Fatty acid oxidation Carnitine palmitoyltransferase deficiency + Glutaric acidemia 2 + + + Amino aciduria Maternal PKU + Nonketotic hyperglycinemia + + Organic aciduria + 3-hydroxyisobutyric aciduria + + 3-hydroxybutyl-CoA deacylase deficiency + DISEASE PACHYGYRIA/LISSENCEPHALY POLYMICROGYRIA CORTICAL HETEROTOPIA CEREBELLAR DYSPLASIA OLIVARY NUCLEI DYSPLASIA DYSGENETIC CORPUS CALLOSUM Gregory M Pastores; 2008;Vol II:1761-1783.

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Cholesterol metabolism Smith-Lemli-Opitz syndrome + + + + + Glycoprotein metabolism Congenital disorder of glycosylation type 1 + atrophy + Trace element metabolism Menkes' kinky hair disease + + + DISEASE PACHYGYRIA/LISSENCEPHALY POLYMICROGYRIA CORTICAL HETEROTOPIA CEREBELLAR DYSPLASIA OLIVARY NUCLEI DYSPLASIA DYSGENETIC CORPUS CALLOSUM Gregory M Pastores; 2008;Vol II:1761-1783.

Inborn Errors of Metabolism Associated with Abnormal Brain Development and Encephaloclastic Lesions :

Inborn Errors of Metabolism Associated with Abnormal Brain Development and Encephaloclastic Lesions DISEASE NEURAL TUBE DEFECTS HOLOPROSENCEPHALY CEREBELLAR MALFORMATIONS HYPOPLASTIC TEMPORAL LOBES Mitochondrial disorders Respiratory chain enzyme deficiency + Fatty acid oxidation Glutaric acidemia II [*] + + Folic acid metabolism Methylenetetrahydrofolate reductase deficiency + Organic aciduria Glutaric aciduria [†] + Ethylmalonic aciduria + Gregory M Pastores; 2008;Vol II:1761-1783.

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DISEASE PACHYGYRIA/LISSENCEPHALY POLYMICROGYRIA CORTICAL HETEROTOPIA CEREBELLAR DYSPLASIA OLIVARY NUCLEI DYSPLASIA DYSGENETIC CORPUS CALLOSUM Peroxisomal disorders Zellweger's syndrome + + + + + + Infantile Refsum's disease + + Neonatal pseudo-ALD + + + Bifunctional enzyme deficiency + + + + + Chondrodysplasia punctata + Gregory M Pastores; 2008;Vol II:1761-1783.

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Smith- Lemli - Opitz syndrome + Glycoprotein metabolism Congenital disorder of glycosylation type + Trace element metabolism Menkes' kinky hair disease + DISEASE NEURAL TUBE DEFECTS HOLOPROSENCEPHALY CEREBELLAR MALFORMATIONS HYPOPLASTIC TEMPORAL LOBES Inborn Errors of Metabolism Associated with Abnormal Brain Development and Encephaloclastic Lesions Gregory M Pastores; 2008;Vol II:1761-1783.

White matter versus gray matter:

White matter versus gray matter Disorders of Cortical gray matter cortical thinning prominent cortical sulci. white matter : ↓ volume and mild hyperintensity on FLAIR and T2 due to Wallerian degeneration of axons Disorders of deep gray matter FLAIR hyperintensity and prolonged T1 and T2 relaxation in acute phase Short T2 relaxation times in a more chronic stage

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Disorders primarily affecting white matter Marked signal abnormality before any volume loss is apparent. Inflammatory component in the early stages : edema Necrosis and cavitation of the affected regions and subsequent ex - vacuo dilatation of the ventricles ALD and fibrinoid leukodystrophy (Alexander disease) start locally and advance over time to involve adjacent areas.

Disorders causing T2 or FLAIR hyperintensity of the corpus striatum :

Disorders causing T2 or FLAIR hyperintensity of the corpus striatum Wilson disease Glutaric aciduria type I Molybdenum co-factor deficiency Propionic academia Leigh syndrome

Disorders causing T2 or FLAIR hyperintensity of the globi pallidi :

Methylmalonic academia Succinic semialdehyde dehydrogenase deficiency Urea cycle disorders Pyruvate dehydrogenase (E2) deficiency Isovaleric academia Disorders causing T2 or FLAIR hyperintensity of the globi pallidi

Leukodystrophies with early involvement of deep white matter and sparing of subcortical white matter :

Krabbe disease (globoid cell leukodystrophy) Metachromatic leukodystrophy GM2 gangliosidoses Lowe syndrome (oculocerebrorenal syndrome) Mucolipidosis type IV Leukodystrophies with early involvement of deep white matter and sparing of subcortical white matter

Leukodystrophies with globus pallidus involvement :

Leukodystrophies with globus pallidus involvement Canavan disease Methylmalonic academia L-2-Hydroxyglutaric aciduria Maple syrup urine disease

Leukodystrophies with striatal (caudate and putaminal) involvement :

Leigh syndrome MELAS Other mitochondrial leukoencephalopathies Propionic academia Glutaric acidemia type I Isolated sulfite oxidase deficiency Childhood hypoglycemia Leukodystrophies with striatal (caudate and putaminal) involvement

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Acute hyperammonemic encephalopathy T2-weighted axial image Diffusion-weighted apparent diffusion coefficient (ADC) mapping infantile citrullinemia Pediatr Neurol 2009;41:139-142.

Acute hepatic encephalopathy:

Acute hepatic encephalopathy Bindu PS, Sinha S, Taly AB, Christopher R, Kovoor JME.Pediatr Neurol 2009;41:139-142 .

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MRI OF Proximal Urea Cycle Disorder Bindu PS, Sinha S, Taly AB, Chandrasekhar HS, Christopher R,Arunodaya GR, Shetty T. J Child Neurol. 2007;22:238-239.

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Girl:4mo Dev delay, seizures Boy: 3yrs Dev delay,seizures,abnl odour Maple syrup urine disease,MRI : Diffuse hypomyelination,basal ganglia,thalami,brainstem, cerebellum affected J Child Neurol . 2007;22:911-913 .

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Maple syrup urine disease-Progression in myelination after treatment Pre treatment Post treatment

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Maple syrup urine disease: Neonatal form 14 days old baby girl. Lethargy, vomiting,poor feeding Diffusion weighted images : restricted diffusion in the central part of the centrum semi ovale (A); posterior limb of the internal capsule(B); pons and cerebellar white matter(C) with corresponding ADC maps (D,E,F). T2 weighted images :Elevated signal intensity and swelling of white matter in posterior limb of the internal capsule, thalamus and globus pallidus, (A); midbrain(B); pons and cerebellar white matter (C).

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Phenyl Ketonuria: 4 diffnt patients MRI :white matter changes Periventricular,posterior predominant

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Phenyl Ketonuria : Bilateral symmetrical white matter hyperintensities Pt aged 15 yrs Dev delay,abnormal hair,spastic paraplegia

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MRI : Bilateral putamen,caudate, SN,Periaqueductal gray matter affected 11/2 yr old baby with dystonia, EOM abnormalities,regression Leigh’s disease

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Leigh's disease 7 mo old child: Regression, EOM abnormalities,abnormal respiration MRI : Putamen,thalami,SN,Periaqueductal gray matter affected 15 mo:Leigh's phenotype MRI : Putamen,Subthalamic nucleus,SN,white matter affected

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Glutaric aciduria Type 1 : 4 different patients MRI: Enlarged sylvian fissure, Subdural collection, Basal ganglia involvement

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Boy aged 12yrs : Dev delay, cyclic vomiting, Dystonia Girl aged 15 mo: Recurrent encephalopathy, Dev delay, Hypotonia, Chorea&dystonia Methyl Malonic Acidemia: Medial globus pallidus hyperintensity

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Biotin responsive basal ganglia disease: Bilateral symmetrical caudate and putamen involvement J Child Neurol. 2009;24:750-752 . 9 year old girl: Recurrent encephalopathy, dystonia,Myoclonus

Metachromatic Leukodystrophy :

Metachromatic Leukodystrophy Bilateral confluent areas of high signal intensity in the periventricular white matter. with the sparing of sub-cortical U fibers (arrowheads) . Lack of enhancement in the demyelinated white matter

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Metachromatic Leukodystrophy Pt 1 : B/L symmetrical whitematter changes. Cerebellar white matter affected. Pt 2 . Characterestic radial stripes. Cerebellar white matter not affected

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GM2 gangliosidosis : Thalamic hyperdensity on T1W and hypointensity on T2 Patient 2 : Tay sach’s disease. Hypomyelination with Basal ganglia and thalamic changes

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GM1 gangliosidosis Infantile onset (Type 1) Cutaneous melanosis Beaking of vertebrae White matter chnages on CT. MRI-white matter changes with basal ganglia and thalami involvement. A B C D

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Menkes syndrome : A . Boy 4mo:regression,myoclonic seizures B .Child 7mo:regression,seizures MRI:Atrophy,delayed myelination MRA: Tortuous vessels A B J Child Neurol. 2007;22:452-455.

Canavan disease:

Canavan disease diffuse white matter hyperintensity, including the subcortical, deep, and periventricular white matter. Abnormal hyperintensity is also seen in the globi pallidi and anterior and lateral thalami 10-month-old infant

Globoid cell leukodystrophy (Krabbe disease):

Symmetric high-signal-intensity areas in the deep white matter. The internal and external capsules are also involved . Note the bilateral areas of abnormal signal intensity in the thalami Globoid cell leukodystrophy (Krabbe disease)

Mucopolysaccharidosis:

Mucopolysaccharidosis Hurler disease. T1-weighted MR image shows multiple well-defined areas of low signal intensity in the central and subcortical white matter. Which are Hyperintense on T2-weighted image

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T2 shows symmetric confluent demyelination in the peritrigonal WM & the corpus callosum. (b) On T1, the peritrigonal lesions are hypointense. (C) Gadolinium-enhanced T1 image reveals a characteristic enhancement pattern in the intermediate zone (d) ALD involving the splenium. Adrenoleukodystrophy

Zellweger Syndrome:

Zellweger Syndrome T2-weighted MR image shows extensive areas of diffuse high signal intensity in the white matter s/o pachygyria. On a T1-weighted MR image, the white matter abnormalities demonstrate low signal

Mucolipidosis IV::

Mucolipidosis IV: T1-weighted, multiplanar reconstructed sagittal magnetic resonance imaging showing thin corpus callosum J Child Neurol. 2008;23:1443-1446 10 yr old pt dev delay,MR,regression, Skin biopsy- inclusions s/o ML IV on EM

Principles o f Management of IEM :

Principles o f Management of IEM The appropriate management of IEM depends upon the particular metabolic derangement. Therapeutic strategies may include one or more of the following approaches: substrate reduction (2) removal (or enhanced clearance) of the toxic metabolites; (3) replenishment of depleted metabolites or cofactor supplementation (or both); (4) enzyme (replacement or enhancement) therapy; and (5) cellular replacement (e.g., bone marrow, liver, heart or kidney transplantation) Chakrapani A., Wraith J.E.: Principles of management of the more common metabolic disorders. CurrPaediat 2002 ; 12:117-124.

Principles o f Management of IEM :

Immediate management goals- Reducing energy expenditure promoting anabolism are Each patient requires an individualized approach; Some disorders require more than one management option. The clinical response to most treatment plans may vary, and residual disturbances are common. Patients may remain at risk for metabolic decompensation when stressed by infection, trauma, or surgery. Principles o f Management of IEM

Role of Diet in IEM:

Role of Diet in IEM Special diets require attention to caloric requirements and balanced nutrition. Dietary restriction include the aminoacidopathies: phenylketonuria (PKU), MSUD, and homocystinuria. In classic Refsum's disease, reduction in dietary phytanate results in normalization of the biochemical and clinical phenotype. Some disorders require alternative dietary sources. Administration of medium-chain triglycerides as a lipid source to patients with very-long-chain acyldehydrogenase [VLCAD] and long-chain acyldehydrogenase [LCHAD] deficiency. In Smith-Lemli-Opitz syndrome ,the use of a high-cholesterol diet (± bile acids) improves growth and neurodevelopmental status, although clinical response is variable.

Role of Diet in IEM:

In children with GSDs carbohydrate supplements prevent hypoglycemia and suppress secondary metabolic derangements (e.g., hyperlipidemia and hyperuricemia). In the urea cycle disorders, arginine or citrulline supplements make up for compounds that are not synthesized secondary to the metabolic block. Role of Diet in IEM

Detoxification strategies in IEM-Hyperammonemia:

Detoxification strategies in IEM-Hyperammonemia Failure of dietary manipulation to correct the accumulation Haemodialysis Peritoneal dialysis (PD) Forced diuresis Alternative pathways for the excretion of toxic metabolites Exchange transfusion Low etal 1996

Detoxification strategies in IEM:

Toxic compound Anti dote Hyper ammonia Sodium benzoate, phenylbutyrate,Phenylacetate Isovaleric acidemia Oral Glycine Cystinosis Cysteamine Organic acidemia Carnitine Detoxification strategies in IEM

Management of hyperammonemia :

Management of hyperammonemia Discontinue all protein containing feeds . Adequate calories by intravenous glucose and lipids. Maintain glucose infusion rate 8-10mg/kg/min. Start intravenous lipid 0.5g/kg/day (up to 3g/kg/day). Dialysis is the only means for rapid removal of ammonia. Hemodialysis is more effective and faster than peritoneal dialysis. Peritoneal dialysis may be more widely available and feasible.

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An extracorporeal membrane oxygen pump can be used to drive the hemodialysis machine (ECMO/HD). ECMO/HD is the fastest ammonia removal system. Exchange transfusion is not useful.

Alternative pathways for nitrogen excretion :

Alternative pathways for nitrogen excretion Sodium benzoate (IV or oral)- loading dose 250mg/kg then 250-400mg/kg/day in 4 divided doses Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followed by L-arginine (oral or IV)- 300 mg/kg/day L-carnitine (oral or IV)- 200 mg/kg/day Supportive care: treatment of sepsis, seizures, ventilation.

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Condition Medication Route Dose Caution Most conditions L- carnitine IV/PO 100 mg/kg/d Hyperammonemia Sodium benzoate/sodium phenylacetate /sodium phenylbutyrate IV IV: 0.25 g/kg bolus over 24 h, then infusion of 0.25 g/kg over 24 h Hypernatremia, hypokalemia, acidosis, transient hyperammonemia, confusion, cerebral edema, hypotension Citrullinemia, Argininosuccinate lyase deficiency L- arginine IV <0.2-0.6 g/kg bolus then infusion of 0.25 g/kg over 24 h Acidosis, extravasation, can be harmful in some urea cycle disorders Biotinidase deficiency, multiple carboxylase deficiency Biotin PO 10 g/d Treatments commonly employed in neonates with metabolic disorders

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Stop any "toxic" nutrient e.g., protein, galactose Give high-energy intake usually glucose, orally or intravenously Neonatal intensive care correct tissue perfusion, dehydration, acidosis, hypothermia, anemia, etc. Treat hyperammonemia sodium benzoate, sodium phenylbutyrate , arginine Dialysis haemofiltration/ haemodialysis or peritoneal (bicarbonate based) Insulin to control hyperglycemia and reduce catabolism Vitamins e.g., biotin, hydroxocobalamin or pyridoxine Specific therapy e.g., carnitine , glycine for isovaleric acidemia Management of a suspected metabolic disorder

Acute management of newborn with suspected organic academia :

Acute management of newborn with suspected organic academia Nil per orally and intravenous glucose is provided. Supportive care: hydration, treatment of sepsis, seizures, ventilation. Carnitine: 100 mg/kg/day IV or oral. Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr) Start Biotin 10 mg/day orally. Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of Methylmalonic acidemias)

Management of congenital lactic acidosis :

Management of congenital lactic acidosi s Supportive care: hydration, treatment of sepsis, seizures,ventilation. Avoid sodium valproate. Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2mEq/kg/hr) Thiamine: upto 300 mg/day in 4 divided doses. Riboflavin: 100mg/day in 4 divided doses. Add Co-enzyme Q: 5-15 mg/kg/day L-Carnitine: 50-100 mg/kg orally.

Treatment of newborn with refractory seizures with no obvious etilogy (Suspected metabolic etiology) :

Treatment of newborn with refractory seizures with no obvious etilogy (Suspected metabolic etiology) Seizures persists despite 2 or 3 antiepileptic drugs in adequate doses, consider trial of pyridoxine 100 mg intravenously. If seizures persist despite pyridoxine, give trial of Biotin 10 mg/day and folinic acid 15 mg/day (Folinic acid responsive seizures). Rule out glucose transporter defect: Measure CSF and blood glucose. In Glucose transporter defect, CSF glucose level is equal to or less than 1/3 rd of the blood glucose level. This disorder responds to the ketogenic diet.

Management of asymptomatic newborn with a history of sibling death with suspected IEM :

Management of asymptomatic newborn with a history of sibling death with suspected IEM After baseline metabolic screen, start oral dextrose feeds After 24 hours add medium chain triglycerides. Monitor sugar, blood gases, ketones, ammonia. If all tests normal after 48 hours, add low protein milk. Repeat tests after 48 hours; if negative; start breast feeds. After 48 hours, TMS and urine organic acid tests should be obtained.

Long term treatment of IEM: :

Long term treatment of IEM: Dietary treatment Acceleration of removal of substrate Reaction product replacement Enzyme replacement therapy (ERT): Cofactor replacement therapy

Substrate Reduction Therapy ( SRT ):

Substrate Reduction Therapy ( SRT ) Substrate synthesis inhibitors to block the production of toxic metabolites NTBC (2-nitro-4-trifluoro-methylbenzoyl-1,3-cyclohexanedione) In one study of NTBC in more than 300 patients with tyrosinemia type 1, 95% showed improvement of hepatic and kidney function Grompe ,2001

Substrate Reduction Therapy ( SRT ):

Substrate Reduction Therapy ( SRT ) Based on same action Miglustat is potentially useful in Gaucher's disease type I, Cox etal 2000 Late-onset Tay-Sachs, Sandhoff's disease, G M1 -gangliosidosis and Niemann-Pick disease type C Pastores and Barnett 2005

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COFACTOR DOSE (mg/day) DISORDER Betaine 150 [*] Homocystinuria MTHFR deficiency Biotin 10-20 Propionic aciduria Multiple carboxylase deficiency Hyperlactacidemia due to pyruvate carboxylase deficiency Carnitine 50-100 PO; Branched-chain organic aciduria (MMA, PA, IVA) 400 IV Primary hyperammonemia Hyperlactacidemia Fatty acid oxidation defects Cobalamin (B 12 ) 1-2 Methylmalonic aciduria Folinic acid 10-40 Folinic -responsive seizures Lorenzo's oil (glycerol tiroleate and trierucate) Asymptomatic X-linked adrenoleukodystrophy Pyridoxine (B 6 ) 50-100 Pyridoxine-responsive seizures, hyperoxaluria type 1, aromatic L-amino acid decarboxylase Glutaric aciduria , homocysteinemia Riboflavin (B 2 ) 20-40 Fatty acid oxidation defects Thiamine (B 1 ) 10-50 Maple syrup urine disease Hyperlactacidemia due to pyruvate dehydrogenase deficiency Replenishment of depleted metabolites

Enzyme replacement therapy (ERT):

Gaucher's disease (Hematological and visceral manifestations) Fabry's disease, MPS type I (Hurler-Scheie syndrome), MPS type VI (Maroteaux-Lamy syndrome), and MPS II (the mild variant of Hunter's syndrome) GSD II (Pompe's disease) Niemann-Pick disease type B Pastores and Barnett 2005 Enzyme replacement therapy (ERT)

Cellular replacement:

Cellular replacement Methods : BMT HSCT Found to be useful in MPS I, Gaucher's disease type III Peters etal 2003 X-linked adrenoleukodystrophy Moser 2006 Not useful in MPS II (severe Hunter's syndrome) MPS III (Sanfilippo's syndrome).

Organ transplantation:

Organ transplantation Metabolic defect confining to the single organ eg ;liver or Kidney Liver transplantation Kidney transplantation Crigler-Najjar syndrome, Fabry's disease Hyperoxaluria type I Hyperoxaluria type I OTC deficiency, Tyrosinemia, GSD-IV

Palliative Measures :

Palliative Measures l - dopa improves motor function in patients with tyrosine hydroxylase deficiency. Desmopressin reduces the bleeding tendency during surgery of patients with GSD type 1A (von Gierke's disease). G-CSF administered to patients with GSD IB and neutropenia minimizes the risk of recurrent bacterial infection and gastrointestinal tract ulceration. Corticosteroid and mineralocorticoid replacement are essential in patients with ALD and adrenal insufficiency.

PREVENTION: Genetic counselling and prenatal diagnosis: :

PREVENTION: Genetic counselling and prenatal diagnosis : Most of the IEM are single gene defects, inherited in an autosomal recessive manner, with a 25% recurrence risk. Prenatal diagnosis can be offered – known diagnosis is confirmed in the index . -Chorionic villus tissue or amniotic fluid. Modalities available are: Substrate or metabolite detection: useful in phenylketonuria, peroxisomal defects. Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite.

Neonatal screening::

Neonatal screening: Tandem mass spectrometry - used in some countries for neonatal screening for IEM. Disorders which can be detected by TMS include aminoacidopathies (PKU, MSUD, Homocystinuria, Citrullinemia, Argininosuccinic aciduria, hepatorenal tyrosinemia), fatty acid oxidation defects, organic acidemias (glutaric aciduria, propionic acidemia, methylmalonic acidemia, isovaleric acidemia). The cost of this procedure is high, a potent dis-incentive for resource poor countries like India.

NIMHANS Experience – TMS 2007-2009:

NIMHANS Experience – TMS 2007-2009 Total samples 3815 Methyl Malonic acidemia 21 Glutaric acidemia 20 Phenylketonuria 19 MSUD 13 Propionic acidemia 07 Hyperornithemia 07 Hyperarginenemia 06 Hyperglycinemia 06 Homocystinuria 01 Others 10

Metabolic autopsy:

Metabolic autopsy Infant with suspected IEM when diagnosis is uncertain and death seems inevitable. Blood: 5-10ml; frozen at -20 0 C; both heparinized and EDTA samples to be taken. Urine: Frozen at -20 0 C CSF Skin biopsy: including dermis in culture medium or saline with glucose. Store at 4-8 0 C. Do NOT Freeze. Liver, muscle, kidney and heart biopsy: as indicated. Clinical photograph (in cases with dysmorphism) Infantogram (in cases with skeletal abnormalities)

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