Metabolic Disorders

An Introduction To

INBORN ERRORS OF

METABOLISM

By:

Dina Abdelazim Ghoraba

Organic Acid Disorders Disease Mutated Gene

Cytogenetic Location Deficient Protein/Enzyme

Propionic acidemia

PCCA 13q32

Propionyl-CoA Carboxylase PCCB 3q21-q22

MMAB 12q24

MUT 6p12.3 Methylmalonyl CoA mutase Methylmalonic acidemia MLYCD 16q24 Malonyl CoA decarboxylase

Methylmalonic aciduria MUT 6p12.3 Methylmalonyl CoA mutase

Methylmalonic aciduria and Homocystinuria

Cobalamin deficiency

cblA MMAA 4q31.21 Adenosylcobalamin (AdoCbl) cblB MMAB 12q24

cblE MTRR 5p15.31 Methionine synthase reductase cblG MTR 1q43 Methionine synthase

cblF LMBRD1 6q13 Protein for cobalamin transport and

metabolism

Methylmalonic aciduria and Homocystinuria

(Cobalamin C and D deficiency)

cblC MMACHC 1p34.1 proteinfor cobalamin (vit B12)

uptake

cblD MMADHC 2q23.2 proteinfor cobalamin metabolism

Holocarboxylase synthetase deficiencies

HLCS 21q22.1 Holocarboxylase synthetase

Biotinidase Deficiency BTD 3p25 Biotinidase

Isovaleric acidemia IVD 15q14-q15 isovaleryl-coenzyme A

Glutaric aciduria (Type I)

GCDH/ ACAD5

19p13.2 Glutaryl-CoA dehydrogenase

3-Metheylglutaconic aciduria

(Type I, II, III, IV, V)

AUH 9q22.31 3-methylglutaconyl-CoA DNAJC19 3q26.33 Protein in energy metabolism

OPA3 19q13.32 Protein in energy metabolism TAZ Xq28 Tafazzins

3-Hydroxyisobutyric aciduria/2-ethyl3-hydroxypropionic aciduria

ALDH6A1 14q24.3 Methylmalonate semialdehyde

dehydrogenase

Malonic aciduria MLYCD 16q24 Malonyl CoA Decarboxylase

Methylmalonic aciduria SUCLA2

13q12.2-q13.3

Beta subunit of succinate-CoA ligase

SUCLG1 2p11.2 Alpha subunit of succinate-CoA

ligase 3-Methylcrotonyl CoA Carboxylase deficiency

(3-hydroxyisovaleric aciduria/ 3-Methylcrotonyl glycinuria)

MCCC1 3q27 3-Methylcrotonoyl-coenzyme A carboxylase

MCCC2 5q12-q13

D-2-hydroxyglutaric aciduria D2HGDH 2q37.3 D-2-Hydroxyglutarate

dehydrogenase

L-2-hydroxyglutaric aciduria L2HGDH 14q21.3 L-2-Hydroxyglutarate

dehydrogenase 2-oxoadipic aciduria

2-hydroxyadipic aciduria 2-aminoadipic aciduria

2-Oxoadipic acid dehydrogenase

4-hydroxybutyric aciduria ALDH gene

family

ALDH4A1 1p36 Succinic semialdehyde

dehydrogenase ALDH5A1 6p22 ALDH7A1 5q31

2-methyl 3-hydroxybutyric aciduria/2-methyl-acetoacetic

aciduria/ tiglylglycinuria ACAT1 11q22.3

Mitochondrial Acetoacetyl CoA thiolase

(2-methyl-acetoacetic acid 3-oxothiolase

Amino Acids Disorders Disease Mutated Gene

Cytogenetic Location Deficient Protein/Enzyme

Oculocutaneous Albinism

I TYR 11q14-q21 Tyrosinase

II OCA2 15q P protein MC1R 16q24.3 Melanocortin 1 receptor

III TYRP1 9p23 tyrosinase-related protein 1 IV SLC45A2 5p13.2 Protein in Melanocyte

Alkaptonuria HGD 3q13.33 homogentisate oxidase

Phenylketonuria (PKU) PAH 12q22-q24.2 phenylalanine hydroxylase

Hyperphenylalaninemia/ Defective metabolism of

Tetrahydrobiopterin (BH4)

GCH1 14q22.1-q22.2 GTP cyclohydrolase PCBD1 10q22 4 alpha-carbinolamine

PTS 11q22.3 6-pyruvoyltetrahydropterin

synthase QDPR 4p15.31 quinoid dihydropteridine reductase

Homocystinuria CBS 21q22.3 Cystathionine beta-synthase

Homocystinuria due to n(5,10)-

methylenetetrahydrofolate reductase

MTHFR 1p36.3 N(5,10) Methylenetetrahydrofolate

reductase

Maple Syup urine disease/ Branched chain Oxoaciduria

BCKDHA 19q13.1-q13.2 branched-chain alpha-keto acid

dehydrogenase BCKDHB 6q14.1

DBT 1p31 DLD 7q31-q32 dihydrolipoamide dehydrogenase

Oculocutaneous Tyrosinemia Type II TAT 16q22.1 Tyrosine aminotransferase

Tyrosimnemia type III Type III HPD 12q24-qter 4-hydroxyphenylpyruvate

dioxygenase Hepatorenal Tyrosinemia Type I FAD 15q23-q25 fumarylacetoacetate hydrolase

Nonketotic hyperglycemia Glycin encephalopathy

AMT 3p21.2-p21.1 glycine cleavage enzyme

Aminomethyltransferase

GLDC 9p22 glycine dehydrogenase

Disorder of Carbohydrate Metabolism Disease Mutated Gene

Cytogenetic Location

Deficient Protein/Enzyme

Galactosemia Type I GALT 9p13

Galactose-1-phosphate uridylyltransferase

Type II GALK1 17q24 Galactokinase 1 Type III GALE 1p36-p35 UDP-galactose-4-epimerase

Glycogen storage disease (GSD)

Glycogenosis type I:

A G6PC 17q21 glucose-6-phosphatase,

catalytic subunit also called ( Von Gierke disease)

B

SLC37A4 11q23.3-6p21.3

glucose-6-phosphate transporter

T2b-Translocase C

D

Glycogenosis type II: Pompe/ Lysosomal α-glucosidase

deficiency GAA 17q25.2-q25.3

acid alpha-(1,4)glucosidase (acid maltase)

Glycogenosis type III: Amylo- 1,6-glucosidase (debrancher) deficiency

A

AGL 1p21 amylo-1,6-glucosidase

4-alpha-glucotransferase B C D

http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l232240

Hyperammonemia and Disorders of The Urea Cycle Disease

Mutated Gene



Ornithine transcarbamylase deficiency OTC Xp21.1 ornithine

transcarbamylase

Carbamyl phosphate synthetase I deficiency CPS1 2q35 carbamoyl phosphate

synthetase I

Citrullinemia ASS1 9q34.1

argininosuccinate synthase 1

SLC25A13 7q21.3 Citrin

Argininosuccinic aciduria ASL 7cen-q11.2 argininosuccinate lyase

Argininemia ARG1 6q23 Arginase

(HHH) syndrome

Hyperornithinemia,Hyperammonemi, Homociltrullinuria

SLC25A15 13q14 ornithine translocase

mitochondrial ornithine transporter

Lysinuric protein intolerance SLC7A7 14q11.2 y+L amino acid transporter 1

Hyperornithinemia Gyrate atrophy of the choroid and retina

OAT 10q26 ornithine

aminotransferase

Disorders of Fatty Acid Oxidation Disease Mutated Gene



Carnitine transporter deficiency SLC22A5 5q31 OCTN2 (carnitine transporter)

Carntine translocase deficiency SLC25A20 3p21.31 carnitine-acylcarnitine

translocase Carnitine palmitoyl transferase I

deficiency CPT1A 11q13.2

carnitine palmitoyl transferase I

Medium chain acyl CoA dehydrogenase deficiency

(MCAD) ACADM 1p31

Medium-chain acyl CoA dehydrogenase

Very long chain acyl CoA dehydrogenase (VLCAD)

deficiency ACADVL 17p13.1

very long-chain acyl CoA dehydrogenase

Long chain L-3-hydroxyacyl CoA dehydrogenase (LCAD)

deficiency- trifunctional protein deficiency

HADHA 2p23 long-chain 3-hydroxyacyl

dehydrogenase/ mitochondrial trifunctional protein

Short-chain acyl CoA dehydrogenase (SCAD)

deficiency ACADS 12q24.31

short-chain acyl CoA dehydrogenase

Short-chain hydroxyacyl CoA dehydrogenase (SCHAD)

deficiency HADH 4q22-q26

3-hydroxyacyl CoA dehydrogenase

Multiple acyl CoA dehydrogenase deficiency (MADD)/ Glutaric aciduria typeII Ethylmalonic-adipic

aciduria

ETFA 15q23-q25 Electron transfer flavoprotein

ETFB 19q13.3

ETFDH 4q32-q35 Electron transfer flavoprotein

dehydrogenase

3-Hydroxy-3-methylglutaryl CoA lyase deficiency

HMGCL 1p36.1-p35 3-hydroxymethyl-3-

methylglutaryl CoA lyase

The Lactic Acidemias and Mitochondrial Disorders Disease Mutated Gene



Pyruvate carboxylase deficiency PC 11q13.4-q13.5 pyruvate carboxylase

Fructose 1,6-diphosphatase deficiency

FBP1 9q22.3 fructose-1,6-bisphosphatase 1

Pyruvate dehydrogenase

complex (PDHC)

deficiency

PDP1 8q22.1 pyruvate dehyrogenase

phosphatase catalytic subunit 1

E1 PDHA1 Xp22.1

E1-alpha subunit Pyruvate

decarboxylase PDHB 3p21.1-p14.2

E1-beta subunit

E2 DLAT 11q23.1 dihydrolipoamide acetyltransferase

E3 DLD 7q31-q32 Dihydrolipoyl dehydrogenase

X PDHX 11p13 component X of the pyruvate

dehydrogenase complex Lactic acidemia and defective

activity of pyruvate, 2-oxoglutarate and branched chain

oxoacid dehydrogenase

OGDH 7p14-p13 2-oxoglutarate dehydrogenase

complex

See also DLD, BCKDHA, BCKDHB and SLC25A19

Mitochondrial encephalopathy, lactic acidosis and stroke-like

episodes (MELAS)

MT-ND1

Mitochondorial DNA (mDNA)

NADH dehydrogenase 1 MT-ND5 NADH dehydrogenase 5 MT-TH transfer RNA tRNAHis MT-TL1 tRNALeu(UUR) MT-TV tRNAVal

Myoclonic epilepsy and ragged red fiber (MERRF) disease

MT-TK


tRNALys MT-TL1 tRNALeu(UUR) MT-TH tRNAHis MT-TS1 tRNASer(UCN)

Neurodegeneration, ataxia and renitis pigmentosa (NARP)

MT-ATP6 Mitochondorial DNA (mDNA)

MT-ATP6 protein (one subunit of ATP synthase).

Progressive external ophthalmoplegia, Autosomal

dominant, type 2 (PEOA2)

SLC25A4 leads to

deletion in mtDNA

genes

4q35

carrier protein that translocates ADP from the

mitochondrial matrix into the cytoplasm

Kearns-Sayre syndrome (KSS)/ progressive external

ophthalmoplegia, Autosomal dominant, type1 (PEOA1)

POLG leads to deletion in mtDNA

genes 15q2

catalytic subunit of mitochondrial DNA polymerase gamma

C10orf2 10q24 Twinkle and Twinky proteins

progressive external ophthalmoplegia, Autosomal

dominant type 4(PEOA4)

POLG2 leads to deletion in mtDNA

genes 17q

processivity subunit of the mitochondrial DNA polymerase gamma

Mitochondrial DNA depletion syndromes: mitochondrial DNA polymerase deficiency (MDDS)

Pearson syndrome

MT-ND5, MT-ND4, MT-ND4L, MT-ND3,


(Deletion)

NADH dehydrogenase (complex I)

MT-ATP6, MT-ATP8 ATP synthase subunits

(complex V)

MT-CO3 Cytochrome c oxidase subunit

3 (complex IV) MT-TL2 tRNA leucine 2 (CUN) MT-TS2 tRNA serine 2 (AGU/C) MT-TH tRNAHis MT-TR tRNA arginine MT-TG tRNA glycine

http://ghr.nlm.nih.gov/gene/MT-TK

http://ghr.nlm.nih.gov/gene/MT-TL1

http://ghr.nlm.nih.gov/gene/MT-TH

http://ghr.nlm.nih.gov/gene/MT-TS1

Hepatocerebral

Toddler form/Alpers-Huttenlocher

syndrome

DGUOK 2p13 deoxyguanosine kinase

MpV17 2p23.3 mitochondrial inner membrane protein

POLG 15q2 catalytic subunit of mDNA

polymerase gamma

Myopathic Infantile C10orf2 10q24 Twinkle and Twinky proteins Toddler TK2 16q22-q23.1 thymidine kinase

Peroxisomal Disorders Disease Mutated Gene



x-linked Adrenoleukodystrophy

ABCD1 Xq28 adrenoleukodystrophy protein

(ALDP) Peroxisomal biogenesis Disorders (PBD)

Refsum disease PHYH 10p13 phytanoyl CoA hydroxylase PEX7 6q23.3 peroxisomal biogenesis factor 7

Infantile refsum disease (IRD) Infantile phytanic acid storage

diseases

PEX1 7q21.2 peroxisomal biogenesis factor 1

PEX2 8q21.1 peroxisomal biogenesis factor 2 PEX26 22q11.21 peroxisomal biogenesis factor 26

Zellweger syndrome (ZWS)

PEX1 7q21.2 peroxisomal biogenesis factor 1 PEX5 12p13 peroxisomal biogenesis factor 5

PEX2 8q21.1 peroxisomal biogenesis factor 2 PEX3 6q23-q24 peroxisomal biogenesis factor 3 PEX6 6p21.1 peroxisomal biogenesis factor 6

PEX12 Chr.17 peroxisomal biogenesis factor 12 PEX14 1p36.2 peroxisomal biogenesis factor 14 PEX26 22q11.21 peroxisomal biogenesis factor 26

Neonatal adrenoleukodystrophy (NALD)

PEX5 12p13 peroxisomal biogenesis factor 5 PEX1 7q21.2 peroxisomal biogenesis factor 1

PEX10 1p36.35 peroxisomal biogenesis factor 10 PEX13 2p15 peroxisomal biogenesis factor 13 PEX26 22q11.21 peroxisomal biogenesis factor 26

Disordersof Purine Metabolism

Disease Mutated Gene Cytogenetic

Location Deficient

Protein/Enzyme Lesch-Nyhan disease and non-lesch-Nyhan variants of HPRT (Kelley-Seegmiller syndrome)

HPRT1 Xq26.1 Hypoxanthine

phosphoribosyltransferase 1

Adenine phosphoribosyl-transferase deficiency

(APRTD) /2,8-dihydroxyadenine

urolithiasis

APRT 16q24 Adenine

phosphoribosyltransferase

Adenine phosphoribosylpyrophosphate

(PRPP)synthetase superactivity

PRPS1 Xq21.32-q24 phosphoribosyl pyrophosphate synthetase 1(PRPP synthetase

1)

Adenosine deaminase deficiency

ADA 20q13.12 Adenosine deaminase

Adenylosuccinate lyase deficiency

ADSL 22q13.1 Adenylosuccinate lyase

Mucopolysaccharidoses Disease

Mutated Gene



1 Mucopolysaccharidois type I; α-L-iduronidase deficiency

Mucopolysaccharidois type IH (MPS I-H)/Huler disease

IDUA 4p16.3 alpha-L-iduronidase Mucopolysaccharidois type IS (MPS I-

S)/Scheie disease Scheie and Huler-Scheie diseases/

Mucopolysaccharidosis IS and IHS/α-iduronidase deficiency

2 Hunter disease/

Mucopolysaccharidosis Type II/ Iduronate sulfatase deficiency

IDS Xq28 I2S enzyme

( Iduronate sulfatase)

3 Mucopolysacchaideosis type III (MPS III); Sanfilippo disease

Mucopolysacchaideosis type IIIA (MPS IIIA)

SGSH 17q25.3 Heparpn-N-sulfamidase

Mucopolysacchaideosis type IIIB (MPS IIIB)

NAGLU 17q21 alpha-N-acetylglucosaminidase

Mucopolysacchaideosis type IIID (MPS IIID)

GNS 12q14 N-acetylglucosamine-6-

sulfatase

Mucopolysaccharidosis type IIIC (MPS IIIC)

HGSNAT 8p11.1 heparan-alpha-glucosaminide

N-acetyltransferase

4 Mucopolysaccharidosis type IV (MPS IV); Morquio syndrome/ Keratan sulfaturia

MPS IV type A GALNS 16q24.3 N-acetylgalactosamine 6-

sulfatase

MPS IV type B GLB1 3p21.33 beta-galactosidase

5

Maroteaux-lamy disease/ Mucopolysaccharidosis VI (MPS VI)/

N-acetylgalactosamine-4-sulfatase deficiency

ARSB 5q11-q13

arylsulfatase B

(N-acetylgalactosamine-4-

sulfatase deficiency)

6 Sly disease/β-glucuronidase

deficiency/ Mucopolysaccharidosis VII (MPS VII)

GUSB 7q21.11 β-glucuronidase

7 Mucopolysaccharidosis type IX (MPS

IX)/hyaluronidase deficiency. HYAL1 3p21.3-p21.2 lysosomal hyaluronidase

Disordersof Cholestrol and Neutral Lipid Metabolism Disease

Mutated Gene



Familial Hypercholestrolemia

APOB 2p24-p23 Apolipoprotein B-48

Apolipoprotein B-100.

LDLR 19p13.3 low-density lipoprotein

receptor

LDLRAP1 1p36-p35 Protein helps to remove

cholesterol from the bloodstream

PCSK9 1p32.3 protein that regulates cholesterol level in the

bloodstream Mevalonic aciduria MVK 12q24 Mevalonic acid kinase

Lipoprotein lipase deficiency LPL 8p22 Lipoprotein lipase

Lysosomal Storage Disorders

Disease Mutated Gene Cytogenetic

Location Deficient

Protein/Enzyme Fabry disease GLA Xq22 α-galactosidase A

GM1 gangliosidosis/ β-galactosidase deficiency

GLB1 3p21.33 β-galactosidase

Tay-Sachs disease/ Hexosaminidase A deficiency

HEXA 15q24.1 beta-hexosaminidase A

Sandhoff disease/ GM2 gangliosidosis/

Hexosaminidase A and B deficiency/

hex-B subunit deficiency

HEXB 5q13 Subunit of β-hexosaminidase A

and β-hexosaminidase B

GM2 activator deficiency/ GM2 gangliosidosis- deficiency

of the activator protein GM2A 5q33. GM2 ganglioside activator

Gaucher disease GBA 1q21 β-glucocerebrosidase Niemann-Pick disease

type A and B SMPD1 11p15.4-p15.1 acid sphingomyelinase

Niemann-Pick type C disease/ Cholestrol processing

abnormality

NPC1 18q11-q12 Protein plays a role in the movement of cholesterol and

other types of lipids (fats) across cell membranes.

NPC2 14q24.3

Krabbe disease galactosylceramide lipiosis

Globoid cell leukodystrophy GALC 14q31

Galactosylceramide β-galactosidase

Wolman disease / cholesteryl ester storage disease

LIPA 10q23.2-q23.3 lysosomal acid lipase

Fucosidosis FUCA1 1p34 α-L-fucosidase α-Mannosidosis MAN2B1 19cen-q13.1 α-mannosidase Galactosialidosis CTSA 20q13.1 cathepsin A

Metachromatic leukodystrophy(MLD)

ARSA 22q13.31-qter Arylsulfatase A PSAP 10q21-q22 Prosaposin

Multiple sulphatase deficiency (MSD)

SUMF1 3p26.1 sulfatase modifying factor 1

Disordersof Transport and Mineral Metabolism Disease

Mutated Gene



Cystinuria Type II SLC3A1 2p16.3

transporter protein complex Type I SLC7A9 19q13.1

Type III Cystinosis CTNS 17p13 cystinosin

Hartnup disease (HND) SLC6A19 5p15.33

system B(0) transmembrane

protein

(neutral amino acids

transporters)

Histidinuria Histidine transporter

Menkes disease ATP7A Xq21.1 protein regulates copper (Cu++)

levels in the body

Wilson disease ATP7B 13q14.3 Copper (Cu++) -transporting

ATPase 2

Miscellaneous Disease

Mutated Gene



Congenital disorders of glycosylation, type Ia(CDG-Ia)

PMM2 16p13 Phosphomannomutase (PMM)

Other forms of Congenital disorders of glycosylation Group I: Defects in the generation or transfer of the dolicholpyrophosphate-linked oligosaccharide

Ia PMM2 16p13.3-p13.2 Phosphomannomutase 2 Ib PMI 15q22-qter Phosphomannose Isomerase

Ic hALG6 1p22.3 Dolichyl-P-Glc:Man9GlcNAc2-PP-

dolichyl α1,3-Glucosyltransferase

Id hALG3 3q27 Dolichyl-P-Man:Man5GlcNAc2-PP

dolichyl a1,3-Mannosyltransferase Ie DPM1 20q13.13 Dolichol-P-Man synthase 1 If MPDU1 17p13.1-p12 Dolichol-P-Man Utilization Defect

Ig hALG12 22q13.33 Dolichyl-P-Man7GlcNAc2-PP-dolichyl

α1,6-Mannosyltransferase

Ih hALG8 11q14 Glc1Man9GlcNAc2-PP-dolichy α3-

glucosyltransferase

Ii hALG2 9q22 GDP-Mannose:Man1GlcNAc2-PP-

dolichyl 1,3-Mannosyltransferase

Ij DPAGT1 11q23.3 UDP-GlcNAc:dolichol-P GlcNac-1-

phosphate transferase Ik hALG1 16p13.3 β1,4-mannosyltransferase IL hALG9 11q23 α1,2-mannosyltransferase Ix Unknown genetic basis

Group II: Defects in processing of N-glycans

IIa MGAT2 14q21 UDP-GlcNAc: 6-D-mannoside 1,2-GlcNAc

transferase II (GnT II) IIb GCS1 2p13-p12 α1,2-Glucosidase I IIc FUCT1 11 GDP-fucose transporter I

IId B4GALT1 9p13 UDP-Gal:N-acetylglucosamine β

-1,4-galactosyltransferase I

IIe COG7 16p Conserved oligomeric Golgi complex

subunit 7 IIx Unknown genetic basis

α1- Antitrypsin deficiency SERPINA1 14q32.1 α1- Antitrypsin Canavan disease

aspartoacylase deficiency ASPA 17p13.3 Aspartoacylase

Glutamyl-ribose-5-phosphate storage disease/ ADP-ribosyl- protein lyase deficiency Ethylmalonic encephalopathy ETHE1 19q13.31 Enzyme involved in energy production

Disorders of creatine metabolism

GAMT 19p13.3 guanidinoacetate methyltransferase CRTR Xq28 Creatine transporter

Sanjad-Sakati syndrome Kenny-Caffey

TBCE 1q42-q43 Tubulin specific chaperone E

Al Aqeel-Sewairi syndrome Multicentric osteolysis, Nodulosis, Arthropathy

(MONA)/ MMP-2 deficiency

MMP2 16q13-q21 matrix metallopeptidase 2

http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l244460

SUMMARY OF:

Organic Acid Disorders

Disease Name : PROPIONIC ACIDEMIA Alternate name(s) (PROPIONYL-CoA CARBOXYLASE DEFICIENCY; KETOTIC HYPERGLYCINEMIA) Acronym PA Classification: Organic Acid Disorder Genetic Information:

Inheritance: Autosomal recessive Gene and Location : PCCA gene- 13q32

PCCB gene- 3q21-q22 Common Mutations: PCCB gene has several common mutations in different

Populations OMIM# .232050; #606054; .232000

Statistical Information:

Population Incidence:

In US the incidence is estimated to be 1:100,000.

Ethnic Incidence: In Saudi Arabia the frequency is 1:2000 to 1:5000; Greenland. Inuit population incidence is about 1:1000.

Disease Information:

Major Phenotypic Expression

Recurrent episodes of ketosis, acidosis and dehydration, progressive to coma; neutropenia, thrombocytopenia; osteoporosis; hyperglycinemia; propionic acidemia; methylcitraturia; and deficiency of propionyl CoA carboxylase.

Symptoms Onset: Most patients present in newborn period, others have presented later in life.

Symptoms: In the newborn period, symptoms include severe metabolic acidosis manifested by refusal to feed, vomiting, lethargy, hypotonia and seizures. Another neonatal presentation may be hyperammonemia similar to a urea cycle defect with less metabolic acidosis. A few patients have presented later in life with acute encephalopathy, episodic ketoacidosis or with developmental retardation without ketosis or acidosis. Immune deficiency with signs mimicking sepsis can be another presenting feature.

Physical Findings: Short stature and failure to thrive are common in these children as are osteoporosis and skin lesions. Pancreatitis is a complication seen in this and other organic acidurias. May have dystonia or seizures as well as central hypotonia and abnormal EEGs.

Treatment: Treatment regimens are complicated with a diet restricted in protein and use of a special formula deficient in the amino acids that feed into propionate metabolism L-carnitine may be a useful therapeutic adjunct to replete intracellular and extracellular stores of free carnitine. Oral antibiotic therapy may be useful as well to decrease gut production of propionate or use of a laxative to increase gut motility. Continuous overnight feedings may be helpful in decreasing betaoxidation and the release of odd-chain fatty acids since it theoretically will inhibit lipolysis. Liver transplant protects against acute metabolic decompensation but not completely and the biochemical correction is incomplete with continuously elevated metabolites.

Natural History without Treatment :

The usual course is severe neurological damage to coma and death, although a few asymptomatic adults have been reported. Some have progressed to cardiomyopathy similar to seen with beriberi. This incidence is unknown as is the etiology.

Natural History with Treatment :

Even with treatment, developmental delay, seizures, dystonia, cerebral atrophy, and EEG abnormalities are common in survivors. Increased protein intake, intercurrent illness or other stress precipitates repeated episodes of decompensation. Necrosis of the basal ganglia and/or metabolic stroke can result from these crises. Bone marrow suppression occurs frequently and may be secondary to build-up of toxic metabolites. Common laboratory findings are neutropenia, thrombocytopenia, and hypogammagobulinemia. Pancytopenia usually manifests 2-3 days after the acute metabolic presentation. There is a high frequency of infections among affected children.

Metabolic Information:

Missing Enzyme

Name : Propionyl-coenzyme A carboxylase

Function: Conversion of propionyl CoA to D-methylmalonyl CoA.

Location:

Affected Amino acid Pathway(s):

Isoleucine, Valine, Methionine, Threonine

Metabolite Changes: MS/MS Profile: C3 (propionyl carnitine)- elevated

C3:C2 ratio >0.4 Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Propionic acid, 3-OH propionic acid, methyl citric acid, propionyl glycine in urine Propionyl carnitine, increased glycine in blood

Prenatal Testing: Prenatal diagnosis is possible by measuring propionyl CoA carboxylase activity in amniocytes or by DNA analysis if a mutation has been identified in the family or there is a common mutation in the family’s ethnic group.

Miscellaneous Information: Thrombocytopenia is frequent during acute illnesses and resolves when the patient is doing well. Elevation of C3 acylcarnitine on newborn screening does not differentiate between propionic or methylmalonic aciduria. Anecdotally patients are treated with thiamine are purported to have less problems with lactic acidosis and cardiomyopathy.

Disease Name : METHYLMALONIC ACIDURIA (MUT TYPE)VITAMIN B-12 NON-RESPONSIVE. Alternate name(s)

Methylmalonic aciduria due to methylmalonic CoA mutase deficiency, Methylmalonic aciduria due to MCM deficiency; MMA due to MCM deficiency; MCM deficiency; complementation group mut0; methylmalonyl CoA mutase, included; mut -, included)

Acronym MMA Classification: Organic Acid Disorder Genetic Information:

Inheritance: Autosomal recessive Gene and Location :

MUT gene-6p12.3 MCM genes- 6q21.2

Common Mutations:

In MCM gene: not known In MUT gene: Mutations were found in all codingexons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations

OMIM# .251000 Statistical Information:

Population Incidence:

1:48,000 live births.

Ethnic Incidence:

No known population at increased risk.



Recurrent episodes of ketosis, acidosis, vomiting, and dehydration; anorexia, failure to thrive; hepatomegaly; osteoporosis; neutropenia; thrombocytopenia; hyperglycinemia; elevated concentrations of methylmalonic acid (MMA) in blood and urine; and defective activity of methylmalonyl CoA mutase.

Symptoms Onset:

Severe mut0 deficiency accounts for two-thirds of the mutase patients. Eighty percent become ill during the first week of life, 90 percent present by end of first month. Infants with the less severe mut- may present later than the first month. A very few may remain asymptomatic or present much later in life depending on the residual enzyme activity and the metabolic stressors.

Symptoms: Most common signs and symptoms are lethargy, failure to thrive, recurrent vomiting, dehydration which leads to profound metabolic acidosis, respiratory distress, hypotonia and death if not recognized. Complications of acute episodes can include metabolic stroke, extrapyramidal signs, dystonia and bilateral lucencies of globus pallidus. Survivors may have significant neurological damage. Renal failure may appear during childhood. Clinical spectrum is wide, ranging from fatal neonatal disease to asymptomatic individuals. Patients do not have to have clinical crises in order to have neurological or other organ compromise.

Physical Findings:

Most patients have no obvious dysmorphic features. Some patients, in whom there is known consanguinity, have had associated birth defects, congenital heart defects, hydronephrosis and facial dysmorphisms.

Disease Information (Continued)

Treatment: Treatment regimens include a protein-restricted diet and OH-Cbl injections as soon as diagnosis of MMA is suspected. While mutase deficient infants are not generally responsive to OH Cbl, this may still be beneficial. Carnitine supplementation is needed to replete intracellular and extracellular stores of free carnitine, and oral antibiotic therapy may be useful, as well, to decrease gut production of propionate. Precursors of propionate and methylmalonate are methionine, threonine, valine, isoleucine, odd-chain fatty acids and cholesterol. Unfortunately the body makes the majority of the odd-chain fatty acids and cholesterol so they cannot be limited solely by manipulating the diet. However, using special formulas that are deficient in these amino acids can decrease the problematic metabolic precursors. Liver transplant or combined liver/kidney transplant are options for metabolic control. The liver

http://omim.org/entry/251000

transplants have significant perioperative risk and there is documentation of neurological problems after transplant despite improved biochemical parameters. The renal transplants have shown good response with drop in methylmalonic acid levels. However, any type of transplant is limited because MMA enzyme is in all tissues and the transplants do not affect the levelsmade in the cerebral spinal fluid and brain.


Variable depending on the enzyme defect and the patient. Some will die as a neonate, others will survive with deficits and a few others will remain asymptomatic.


About 60% of patients die within the first year of life and of those that survive, 40% are distinctly developmentally impaired. Age of onset of symptoms can help prognosticate – those with later onset tend to have a more benign course. Liver and liver/kidney transplant are one treatment option. However, liver transplants have significant preoperative risk and there is documentation of neurological problems after transplant despite improved biochemical values. Renal transplants have shown good response with drops in methylmalonic acid levels, normalization of the diet and absence of acute episodes of metabolic decompensation. However, the effect of any type of transplant is limited because the MMA enzyme is in all tissues and the transplants do not affect the levels made in the cerebro-spinal fluid and brain.


Missing Enzyme

Name : Methylmalonyl-CoA mutase Function: Catalyzes methylmalonyl-CoA to succinyl-CoA Location: Liver, kidneys, cerebrospinal fluid, brain


Isoleucine, valine, methionine, threonine

Metabolite Changes:

Increased methylmalonic acid in blood and urine.

MS/MS Profile: C3 (propionyl carnitine)- elevated. C3/C2 ratio – elevated. Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Methylmalonic acid in blood and urine Propionic acid, 3-OH propionic acid, methyl citrate in urine Acyl carnitines, increased glycine in blood

Prenatal Testing:

Possible via enzyme assay on amniocytes or CVS.

Sites of Reference:

www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?251000 http://ghr.nlm.nih.gov/condition=methylmalonicacidemia%20and%20

Disease Name : METHYLMALONIC ACIDURIA, VITAMIN B-12 RESPONSIVE (MMA CBL A & B) Alternate name(s) (Methylmalonic Aciduria, Vitamin B12-responsive, due to defect in synthesis of

adenosylcobalamin, cblA complementation type; Methylmalonic aciduria, cblA type; MMAA; Methylmalonic aciduria, vitamin B12-responsive, due to defect in synthesis of adenosylcobalamin, cblB complementation type)

Acronym MMA Cbl A & B Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : Cobalamin A disease- MMAA gene - 4q31.1-q31.2 Cobalamin B disease- MMAB gene - 12q24

Common Mutations: No known common mutations. OMIM# #251100; #251110

Statistical Information: Population Incidence: Unknown. Ethnic Incidence: No known population at increased risk.

Disease Information: Major Phenotypic Expression Recurrent episodes of ketosis, acidosis, vomiting, and dehydration; anorexia, failure to thrive; hepatomegaly; osteoporosis; neutropenia; thrombocytopenia; hyperglycinemia; elevated concentrations of methylmalonic acid (MMA) in blood and urine; and defective activity of methylmalonyl CoA mutase.

Symptoms Onset: Ranges from presentation in the first week of life to asymptomatic.

Symptoms: Episodic ketoacidosis accompanied by lethargy and coma can lead to death. In survivors, developmental and growth retardation, spastic quadriparesis, dystonia and seizures are common. Neutropenia, thrombocytopenia and osteoporosis are common complications.

Physical Findings: No dysmorphisms. Disease Information (Continued)

Treatment: Treatment regimens include a protein-restricted diet and OH-Cbl injections as soon as diagnosis of MMA is suspected. While mutase deficient infants are not generally responsive to OH Cbl, this may still be

http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?251000

http://ghr.nlm.nih.gov/condition=methylmalonicacidemia%20and

beneficial. Carnitine supplementation is needed to replete intracellular and extracellular stores of free carnitine, and oral antibiotic therapy may be useful, as well, to decrease gut production of propionate. Precursors of propionate and methylmalonate are methionine, threonine, valine, isoleucine, odd-chain fatty acids and cholesterol. Unfortunately the body makes the majority of the odd-chain fatty acids and cholesterol so they cannot be limited solely by manipulating the diet. However, using special formulas that are deficient in these amino acids can decrease the problematic metabolic precursors. Liver transplant or combined liver/kidney transplant are options for metabolic control. The liver transplants have significant perioperative risk and there is documentation of neurological problems after transplant despite improved biochemical parameters. The renal transplants have shown good response with drop in methylmalonic acid levels. However, any type of transplant is limited because MMA enzyme is in all tissues and the transplants do not affect the levelsmade in the cerebral spinal fluid and brain.


Variable depending on the enzyme defect and the patient. Some will die as a neonate, others will survive with deficits and a few others will remain asymptomatic.


About 60% of patients die within the first year of life and of those that survive, 40% are cblA- They have the best prognosis because the biochemical and clinical abnormalities reverse in about 90 percent of patients when they are provided pharmacological doses of hydroxy-cobalamin (OH-cbl) injections. cblB- Equal fractions of affected patients are alive and well, alive and impaired or deceased. Age of onset of symptoms can help prognosticate, those with later onset tend to have a more benign course. About 40 percent of these patients will respond with a drop in MMA level when given pharmacological doses of OH-cbl injections.


Missing Enzyme

Name : Cobalamin A (cblA) deficiency: defect in the mitochondrial cobalamin reductase. These patients are unable to make adenosylcobalamin. Cobalamin B (cblB) deficiency: defect of mitochondrial cobalalamin adenosyltransferase and the patients are unable to make adenosylcobalamin.

Function: Cobalamin is a cofactor for the formation of deoxyadenosylcobalamin, (the cofactor for the mutase enzyme)

Location: Mitochondria Affected Amino acid Pathway(s): Isoleucine, valine, methionine, threonine Metabolite Changes: Increased methylmalonic acid in blood and urine. MS/MS Profile: C3 (propionyl carnitine) - elevated.

C3/C2 ratio – elevated. Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Methylmalonic acid in blood and urine Propionic acid, 3-OH propionic acid, methyl citrate in urine Acyl carnitines, increased glycine in blood

Prenatal Testing: Possible via enzyme assay on amniocytes or CVS. Sites of Reference: www.ncbi.nlm.nih.gov/htbin-

post/Omim/dispmim?251000 http://ghr.nlm.nih.gov/condition=methylmalonicacidemia%20and%20

Disease Name : VITAMIN B12 METABOLIC DEFECT WITH METHYLMALONIC ACIDEMIA AND HOMOCYSTINURIA (MMA CBL C, D,F)

Alternate name(s) (Combined deficiency of methylmalonyl CoA mutase and Homocysteine: Methyltetrahydrofolate methyltransferase; cblC; Vitamin B12 metabolic defect,type 2; Methylmalonic acidemia and Homocystinuria; cblD; Vitamin B12 lysosomal release defect; Cobalamin, defect in lysosomal release of vitamin B12 storage disease; cobalamin F disease; cblF; Methylmalonic aciduria due to Vitamin B12-release defect)

Acronym MMA Cbl C,D & F Classification: Organic Acid Disorder Genetic Information:

Inheritance: Autosomal recessive Gene and Location : Cobalamin C (cblC) disease- MMACHC gene – 1p34.1





Cobalamin D (cblD) disease- MMADHC gene – 2q23.2 Cobalamin F (cblF) disease- LMBRD1 gene – 6q13

Common Mutations: No known common mutations.

OMIM# cblD- #277410; cblC- .277400; cblF- #277380


Population Incidence: Unknown, cobalamin C deficiency is the most common and less than 100 patients have been identified.

Ethnic Incidence: No known population at increased risk. Disease Information:


Megaloblastic anemia; failure to thrive; retinopathy (cblC), developmental delay; excretion of homocystine and methylmalonic acid; and defective activities of both methylmalonyl CoA mutase and methionine synthase.

Symptoms Onset: In a study of 50 patients with cblC disease, 44 had onset in the first year of life and six had onset after six years of age. The median age of onset was one month and ranged from birth to 14 years. Patients in the cblD group generally do not have clinical problems until later in life. In cblF disease, the patient may have signs or symptoms of the disorder at birth or shortly afterwards.

Symptoms: CblC disease: Early onset patients have feeding problems; hypotonia; failure to thrive; seizures; microcephaly; developmental delay; cortical atrophy; hydrocephalus; nystagmus; pigmentary retinopathy; decreased visual acuity; bone marrow dysfunction and some have presented with renal failure and hemolytic uremic syndrome. Late onset patients present in childhood or adolescence with acute neurological changes: decreased cognitive performance; confusion; dementia; delirium; myelopathy; and tremor. Only one late-onset patient had pigmentary retinopathy. The hematology abnormalities are seen in late-onset patients. They may have progressive neurological deficits in spite of appropriate treatment. In cblD disease in general there are no clinical problems until later in life. Often they present with behavior pathology; mental retardation and neuromuscular symptoms. They do not tend to have bone marrow dysfunction. The cblF patients tend to be small for gestational age at birth and present with the metabolic ketoacidosis from methylmalonic acidemia. They have poor feeding, growth retardation, and persistent stomatitis or rashes. Some patients have been noted to have minor facial anomalies, dextrocardia and macrocytosis. It has been found to be a cause of sudden death. One patient, each with hypertrophic cardiomyopathy and glomerulosclerosis, have been noted in the literature.

Physical Findings: There are no particular dysmorphisms specific for any of the three types but dysmorphisms are found frequently, except the cblF patients have more minor facial anomalies reported.


Treatment: Treatment includes a protein-restricted diet, supplement with OH-Cbl and betaine in order to bypass the defect in the cobalamin synthesis.

Natural History without Treatment : Clinical course ranges from sudden death to severe psychosis and developmental delay. Varies among family members.

Natural History with Treatment : Early diagnosis and prompt institution of therapy may be the only way to change the outcome of these patients, which has been dismal thus far. It is not clear that treatment changes the natural history but may help to decrease some of the psychiatric complications, and hopefully, avoid some of the skin rashes and other secondary complications, like the pigmentary retinopathy and renal involvement.


Missing Enzyme

Name , Function Location

Precise defect in cblC and cblD is not known, but is thought to involve an early step in intracellular metabolism of cobalamin. In cblF disease there is impaired efflux of free cobalamin from lysosomes.



Metabolite Changes: Increased methylmalonic acid and Homocystine in blood and urine. MS/MS Profile: C3 (propionyl carnitine)- elevated.

C3/C2 ratio – elevated.

Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Methylmalonic acid in blood and urine Total homocysteine in plasma and urine

Prenatal Testing: Enzyme assay is available on chorionic villi or amniocytes in known families at risk.

Miscellaneous Information: Differentiation between types is based on complementation studies of skin.

Disease Name : GLUTARIC ACIDURIA TYPE I Alternate name(s) (GA I; GLUTARIC ACIDURIA I; GLUTARYL-CoA DEHYDROGENASE DEFICIENCY) Acronym GA I Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : GCDH gene- 19p13.2 Common Mutations: No common mutation, with the exception of the above

mentioned populations. OMIM# .231670

Statistical Information: Population Incidence: 1:40,000 in Caucasians; 1:30,000 in Sweden; 1:300 in Old Order Amish.

Ethnic Incidence: 1/10 carrier frequency among certain inbred populations, particularly the Old Order Amish in Pennsylvania and the Ojibway Indians in Canada.

Disease Information: Major Phenotypic Expression

Megalencephaly; acute encephalitis-like crises; neurodegenerative disorder with spasticity, dystonia, choreoathetosis, ataxia and dyskinesia; seizures, increased signal on imaging of caudate and putamen and frontotemporal atrophy; glutaric aciduria and 3-hydroxyglutaric aciduria; and deficient activity of glutaryl CoA dehydrogenase.

Symptoms Onset: Infancy, typically 2-37 months. Symptoms: Seventy percent of patients have macrocephaly at or shortly

after birth. There may be soft neurologic signs like jitteriness, irritability, and truncal hypotonia in the newborn period. There are several different clinical presentations: 1) Affected infants appear normal and then suffer an acute metabolic crisis, usually 6-18 months (90 percent of acute crises in first 24 months of life), with subsequent neurological findings that improve slightly then remain static. Changes in the basal ganglia in particular, atrophy of the caudate and putamen develop within a few days or weeks of encephalopathic episode; 2) Infants have a period of normal development, acute crisis and subsequent neurological findings similar to those above, but then progress slowly with recurrent episodes of ketosis, vomiting, hepatomegaly and encephalopathy when the child develops infections; 3) Approximately 25 percent of infants gradually develop motor delay, hypotonia, dystonia and dyskinesis during the first few years of life without any apparent acute crisis; and 4) Individuals can be completely asymptomatic without any crises and normal development. This has been documented via carrier testing and identification of five percent of affected Amish without symptoms. Some of these adults have now been diagnosed with white matter changes.

Physical Findings: Macrocephaly, cerebral palsy, dystonia.

Treatment: Prompt treatment of catabolic events with fever control, IVF, glucose, insulin and carnitine may prevent neurologic symptoms in patients without striatal damage at diagnosis. The effect of treatment with riboflavin and diet restriction of lysine and tryptophan is less clear. Hospital admission is mandatory for IV fluids with any vomiting or febrile illness. Patients appear to do better if started on high-dose IV carnitine during illnesses.


Presymptomatic diagnosis has proven to have a better outcome than identifying patients after their first encephalopathic event.

Natural History with Even with prospective treatment up to thirty five percent of patients will have neurological

Treatment : insult and disability. Metabolic Information: Missing Enzyme Name : Glutaryl-coenzyme A dehydrogenase

Function: Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA.

Location: Mitochondria; liver, kidney and fibroblasts and Leukocytes

Affected Amino acid Pathway(s): Lysine, hydroxylysine, tryptophan Metabolite Changes: Increased Glutaric acid, 3-OH-glutaric acid in urine

Glutarylcarnitine in blood MS/MS Profile: C5-DC (glutaryl carnitine)- elevated- can be missed

in some patients. Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Glutaric acid, 3-OH-glutaric acid in urine Glutarylcarnitine in blood

Prenatal Testing: Yes. Enzyme activity in CVS and amniocytes. Miscellaneous Information: Neuroradiographic findings of frontal-temporal

atrophy and/or arachnoid cysts before the onset of symptoms. Infants with GA I are prone to suffer acute subdural hemorrhages and retinal hemorrhages after minor head trauma, i.e. commonly around the first birthday when starting to walk. This can be misdiagnosed as child abuse. In this population, 20-30 percent of patients have “chronic” subdural effusions and hematomas identified on neuroimaging studies; these are always found in the presence of atrophy and extra cerebral fluid. At least two patients with GA I have developed rhabdomyolysis after fairly mild infections.

Disease Name : GLUTARIC ACIDURIA TYPE II Alternate name(s) Glutaric Aciduria Type II; Ethylmalonic-Adipic Aciduria;

Multiple Acyl CoA dehydrogenase deficiency (MADD); Electron Transfer Flavoprotein Dehydrogenase Deficiency; Etf/Etf Qo Deficiency

Acronym GA2, GAII, MAD, MADD Classification: Fatty Acid Oxidation Defect and Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : ETF alpha subunit: 15q23-25 ETF beta subunit 19q13.3 ETFDH gene – 4q32-q35

Common Mutations: No common mutation, with the exception of the above mentioned populations.

OMIM# .231680; .130410; .231675; #231680 Statistical Information: Population Incidence: Not a rare disease but incidence is unknown.

Ethnic Incidence: No known population at increased risk. Disease Information: Major Phenotypic

Expression Overwhelming neonatal illness with metabolic acidosis, acrid odor, hypoketotic hypoglycemia and hyperammonemia; dysmorphic features; polycystic kidneys; massive urinary excretion of lactic and glutaric acids and increased concentrations of many other organic acids including ethylmalonic acid, butyric acid, methylbutyric acid, isobutyric and isovaleric acids and deficiency of electron transfer flavoprotein (ETF) or its dehydrogenase (ETF-QO). Later onset, milder variants referred to as ethylmalonic-adipic aciduria, may first present in the neonatal period or adulthood with episodic illness characterized by vomiting, hypoglycemia and lipid storage myopathy.

Symptoms Onset: Newborn to adult. Symptoms: Three different phenotypes that stay consistent within

families: Neonatal onset withcongenital anomalies: Infants often premature, present during the first 24-48 hrs of life with hypotonia, hepatomegaly, hypoglycemia, metabolic acidosis, sweaty feet odor, kidneys often palpably enlarged and cystic, facial dysmorphisms, rocker-bottom feet, muscular defects of the anterior abdominal wall and anomalies of the external genitalia (hypospadias and

chordee). Virtually all die within the first week of life. Neonatal onset without anomalies: Infants develop problems within the first few days of life with hypotonia, tachypnea, metabolic acidosis, hepatomegaly, hypoglycemia and sweaty feet odor. The few who have survived beyond the first week of life have died within a few months usually with severe cardiomyopathy. A few others have been hypoglycemic as newborns and later developed typical episodes of Reye syndrome-like illness and have survived somewhat longer. Mild or late onset is extremely variable in its course and age at presentation but typically include episodes of hypoketotic hypoglycemia and hepatic dysfunction. There is progressive lipid storage myopathy and carnitine deficiency, and few had progressive extrapyramidal movement disorders similar to GAI. There are reports of asymptomatic adults.

Physical Findings: In the congenital form the above described dysmorphisms.


Treatment: Treatment of the severe neonatal presentations is not effective. Mainstay therapies include avoidance of fasting, a diet low in fat and protein and high in carbohydrates. Riboflavin supplementation in the milder cases has been curative in some cases. Additional supplements of glycine and L-carnitine have been used.


Variable, depending on age at presentation and severity of symptoms.


Treatment may not help infants with congenital or early onset, especially if there is cardiomyopathy. For individuals with the milder late onset type, therapy may prevent some of the neurological findings and the carnitine deficiency. One infant diagnosed at birth through newborn screening was alive and well at 4 years of age.


Missing Enzyme: Name, Function and Location

Electron Transfer Flavoprotein (ETF) or ETF-ubiquinone oxidoreductase in the mitochondria, affects the acyl-CoA dehydrogenases of the various chain lengths.

MS/MS Profile: C4; C5; C6; C8; C10- multiple elevations. C6 hexanoyl carnitine- mild elevations. C8 octanoyl carnitine- elevated. C16; C18:1- multiple elevations.


2-OH glutaric aciduria

Prenatal Testing: Yes, analyte analysis of amniotic fluid or enzyme analysis of amniocytes.

Miscellaneous Information: Urine organic acids may only be abnormal during acute episodes. The finding of 2-OH glutaric aciduria is useful as a diagnostic point as it distinguishes between GA I and GA II. Been implicated as a cause of SIDS. Mothers have been reported with HELLP syndrome.

Disease Name : ISOVALERIC ACIDEMIA/ACIDURIA Alternate name(s) (Isovaleric acid CoA dehydrogenase deficiency) Acronym IVA, IVD Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : IVD gene -15q14-q15 Common Mutations: At least five different classes of mutations have been

identified. OMIM# #243500

Statistical Information: Population Incidence: Uncertain, 1/230,000. Ethnic Incidence: No known population at increased risk.


Episodic overwhelming illness with vomiting, ketosis, acidosis and coma; characteristic odor; neutropenia and thrombocytopenia; isovaleric acidemia; urinary excretion of isovalerylglycine and 3-hydroxyisovaleric acid; C5 and C5/C3 acylcarnitine profile; and deficiency of isovaleryl CoA dehydrogenase.

Symptoms Onset: Usually within the first 14 days of life in the acute form and later in the chronic form.

Symptoms: Infants with the acute neonatal form present after a few days of normalcy with poor feeding, vomiting, severe metabolic ketoacidosis, progressing to coma and death. Dehydration, hyperammonemia, hypocalcaemia, hepatomegaly and hyper/hypoglycemia are often present. Depressed bone marrow function with neutropenia, thrombocytopenia and pancytopenia can lead to infection and/or cerebral hemorrhage. Most, but not all, will have the characteristic odor of “sweaty socks” which comes from the accumulation of isovaleryl acid. The chronic intermittent form presents later in infancy or childhood with episodes of metabolic acidosis as described above, usually associated with an intercurrent illness or increased protein load. Pancreatitis has occurred in a number of patients. The different forms can occur in the same family, so are not related to genotype.

Physical Findings: No particular dysmorphisms. Disease Information (Continued)

Treatment: Avoidance of fasting, low-protein diet with restricted leucine intake, in combination with glycine and carnitine supplements. Glycine and carnitine allow for the nontoxic removal of excess isovaleric-CoA. Patients will often self-select a low protein diet.


About 50 percent of patients with the acute neonatal form will die in their first episode. Survivors may have neurological damage, although several patients have had complete neurological recovery. Patients with the chronic form may have neurological damage, but most have normal growth and development. Death from acidotic episodes can occur at any age.


Intellectual prognosis depends on early diagnosis and treatment and subsequently on long-term compliance. If treated appropriately most will have normal development.


Missing Enzyme

Name , Function and Location

Isovaleryl-CoA dehydrogenase is the first step in branched chain organic acid metabolism of leucine.



Metabolite Changes: Urinary isovaleryl glycine, 3-hydroxysoraline acid, increased isovaleric acid in blood. During acute attacks, 4-hydroxyisovaleric acid, mesaconic acid, and methylsuccinic acid, isovalerylglycine and 3-hydroxyisovaleric acid are present.

MS/MS Profile: C5 (isovaleryl/ 2-methylbutyryl carnitine) - elevated. Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

3-OH isovaleric acid, isovaleryl glycine in urine

Prenatal Testing: Prenatal diagnosis is possible via assay of isovalerylglycine in the amniotic fluid and/or by enzyme assay of chorionic villi.

Miscellaneous Need to differentiate from 2-methylbutyryl dehydrogenase deficiency.

Disease Name : BIOTINIDASE DEFICIENCY Alternate name(s) Multiple Carboxylase Deficiency, Late-Onset;

Multiple Carboxylase Deficiency, Juvenile-Onset; Acronym Btd Deficiency Classification: Organic Acid Disorder

Genetic Information:

Inheritance: Autosomal recessive Gene and Location : BTD Gene on 3p25 Common Mutations: None known. OMIM# #253260; .609019


Population Incidence: The incidence is estimated to be 1 in 60,000 live births. Ethnic Incidence: No known population at increased risk.



Seizures, ataxia, hypotonia, alopecia, periorificial cutaneous eruption, episodic metabolic acidosis, hearing loss, loss of vision, developmental delay; lactic acidemia, propionic acidemia, excretion of 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, methylcitric acid and 3-hydroxypropionic acid in urine; and defective activity of biotinidase.

Symptoms Onset: Generally appear in infancy or early childhood. Symptoms: The symptoms of biotinidase deficiency are variable with

respect to age of onset, frequency, and severity. Signs and symptoms may include seizures, skin rash, hair loss, hypotonia, ataxia, hearing loss, optic nerve atrophy, developmental delay,

and metabolic acidosis, which can result in coma and death. Physical Findings: Variable, but can include seizures, skin rash, hair loss,

hypotonia, ataxia, hearing loss, optic nerve atrophy, and developmental delay.

Disease Information: Treatment: Acute symptoms will completely disappear with administration of pharmacological doses of biotin, usually 10 mg per day. The hearing loss and vision problems can resolve over time as well. Usually there are no biotinidaserelated problems occurring once treatment is started. Lifelong treatment is recommended for all individuals with biotinidase deficiency.


Depending on the severity of the defect. Severe or total biotinidase deficiency presents early in life and progresses to neurological signs with rash and if the patient is severely stressed can lead to death from metabolic acidosis. Partial deficiency may have problems in cases of severe metabolic stress, but that is speculative.


If on biotin supplementation, unlikely to have any problems according to the literature.


Missing Enzyme: Name , Function and Location

Biotinidase is an enzyme in the serum that recycles biotin, an essential cofactor, from a bound form so that it can be used by the body. In the absence of the enzyme, the body becomes biotin deficient.

NBS profile: Decreased fluorescence on enzyme assay. Prenatal Testing: Possible, but not offered clinically. Miscellaneous Screening results are affected by blood transfusions. Newborn

screening specimen should always be collected prior to a transfusion. Test is not dependent on timing or type of feeding. The enzyme activity may be affected if the sample is delayed in the mail or exposed to high temperatures. Family studies are indicated when an affected newborn is identified.

Disease Name : HOLOCARBOXYLASE DEFICIENCY Alternate name(s) Holocarboxylase Synthetase Deficiency;

Multiple Carboxylase Deficiency, Neonatal Form Acronym MCCD Classification: Organic Acid Disorder


Inheritance: Autosomal recessive Gene and Location: HLCS gene - 21q22.1 Common Mutations: Some with increased frequency in different populations. OMIM# .253270

Statistical Information: Population Incidence: 1 in 87,000 live births. Ethnic Incidence: No known population at increased risk.



Erythematous, scaly eruption; alopecia; episodic, potentially lethal attacks of vomiting, ketosis, acidosis, and dehydration progressive to coma; lactic acidemia; organic aciduria including 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, methylcitric acid and 3-hydroxypropionic acid; defective activity of the propionyl CoA, 3-methylcrotonyl-CoA and pyruvate carboxylases; and defective activity of holocarboxylase synthetase.

Symptoms Onset: Anytime from birth to 15 months of age. Symptoms: Infants generally present with food refusal, vomiting, breathing

problems, hypotonia, seizures and lethargy. Severe metabolic/lactic acidosis, organic aciduria, mild hyperammonemia and variable hypoglycemia can lead to coma and death if not treated. Survivors can have neurological damage. Patients may have skin rash and alopecia at later stages.

Physical Findings: The skin rash and alopecia. Otherwise, no particular dysmorphisms.

Disease Information Treatment: Majority of cases respond readily to biotin supplementation. Biotin increases the functional activation of the carboxylase enzymes.


Repeated bouts of acidosis, skin rashes, failure to thrive, coma, developmental delay and death.


Children with holocarboxylase synthetase deficiency, treated with biotin, have normal growth and development. However, some only partly respond to therapy and one has been reported to be unresponsive to biotin therapy.

Metabolic Information: Missing Enzyme: Name , Function and

Holocarboxylase synthetase (HS) attaches biotin to the four carboxylase enzymes (pyruvate carboxylase; propionyl CoA

Location carboxylase; beta-methylcrotonyl CoA carboxylase; acetyl CoA carboxylase) in order to activate them. Deficiency of HS results in functional deficiencies of all the carboxylase enzymes.

MS/MS profile: C3 (propionyl carnitine) - elevated. C5-OH (3-hydroxyisovaleryl carnitine) - elevated.

Prenatal Testing: Enzyme assay of the carboxylase enzymes on amniocytes.

Disease Name : MALONYL-COA DECARBOXYLASE DEFICIENCY Alternate name(s) Malonic Aciduria Acronym MA Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : MLYCD, MCD genes on 16q24 Common Mutations: No known common mutations. OMIM# #248360

Statistical Information: Population Incidence: Rare, less than 20 reported cases. Ethnic Incidence: No known population at increased risk.

Disease Information: Major Phenotypic

Expression Patients have been described with and without deficiency of malonyl CoA decarboxylase. Each may have a variable phenotype. Both display developmental delay, seizures, episodic metabolic acidosis with ketosis, hyperammonemia, hypoglycemia and lactic acidemia, and a pattern of organic aciduria in which methylmalonic acid, citric acid cycle intermediates, 3-hydroxy-3-methylglutaric acid and dicarboxylic acids are dominated by malonic aciduria.

Symptoms Onset: Age of presentation ranges from three days to 13 years old. Symptoms: All patients have had developmental delay and 20-40 percent

have other symptoms, including hypotonia, hypoglycemia, metabolic acidosis, cardiomyopathy (hypertrophic and/or dilated), diarrhea, vomiting, ketosis, seizures, lactic acidemia, microcephaly and low cholesterol.

Physical Findings: Single report of micropenis and renal dysplasia in a patient with malonic aciduria. Another with epicanthal folds and long face.

Disease Information Treatment: Carnitine, high-carbohydrate diet, and decreased fatty acids in diet. Efficacy of treatment has not been determined.


One patient died as a neonate and two died in infancy. Symptoms tend to be worse with stressors like illness or fasting. A patient in her 20’s has severe cognitive impairment and spastic quadriparesis.


Unknown, no known prospectively treated patients.

Metabolic Information: Missing Enzyme: Name , Function and Location

Enzyme is present in both peroxisomes and mitochondria. Malonyl CoA decarboxylase breaks down malonyl CoA to acetyl CoA.

MS/MS profile: C3-DC (malonyl carnitine)- elevated. Prenatal Testing: Theoretically possible via enzyme analysis on amniocytes or

CVS. Miscellaneous Information:

The malonic acid and malonyl-CoA are thought to be toxic to the brain cells and cause the neurological symptoms.

Disease Name : 3-METHYLGLUTACONIC ACIDURIA TYPE I Alternate name(s) 3-Methylglutaconyl-CoA Hydratase Deficiency Acronym MGA Type I Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : AUH gene on 9q22.31 Common Mutations: Nonsense mutation (R197X) and a splice-site mutation

(IVS8-1GrA) OMIM# #600529, .250950


Retardation of speech and mental development, fasting hypoglycemia, metabolic acidosis, excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid, and defective activity of 3-methylglutaconyl CoA hydratase. The gene is known as AUH; it was previously shown to code for an AU specific RNA-binding protein; it is now known to have 3-methylcrotonyl CoA hydratase activity.

Symptoms Onset: Childhood and infancy

Symptoms: Birthweight Low (Small For Gestational Age), Cerebellar

Atrophy Or Hypoplasia, Chorea Or Athetosis, Coma,

Hypoglycemia, Mental Retardation, Metabolic Acidosis,

Motor Retardation, Optic Atrophy, Organic Aciduria,

Paraparesis/Paraplegia, Respiratory Distress, Seizuresm

Delayed Speech Development, AbnormalSpeech

Development. Physical Findings: No Dwarfism.

Disease Information Treatment: Low-protein diet. Metabolic Information: Missing Enzyme:


3-methylglutaconyl-CoA hydratase, one of the key enzymes of leucine degradation

MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)-elevated. Affected Amino acid Pathway(s):

Leucine


Urinary elevation in levels of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid.

Prenatal Testing:

Disease Name : 3-METHYLGLUTACONIC ACIDURIA TYPE II Acronym MGA Type II Classification: Organic Acid Disorder Genetic Information: Inheritance: X- linked

Gene and Location : TAZ gene- xq28 Common Mutations: OMIM# #302060

Statistical Information: Population Incidence: rare (>20 male patients) X-linked Ethnic Incidence:

Disease Information: Major Phenotypic Expression Barth syndrome of cardiomyopathy, neutropenia, recurrent infections, shortness of stature, excretion of 3-methylglutaconic and 3-methylglutaric acids, normal activity of 3-methylglutaconyl CoA hydratase, and an X-linked pattern of inheritance. This mitochondrial disease is caused by mutations in the tafazzin gene (TAZ).

Symptoms Onset: Adolescent, Child, Infant, Newborn Symptoms: Cardiomegaly, Cardiomyopathy, Chorea Or Athetosis

Dysmorphism, Early Death, Failure To Thrive, Feeding Difficulties, Poor Feeding, Growth Retardation, Hearing Defect, Deafness, Hypertonia, Spasticity, Hypothermia, Hypotonia, Infections (Severe Or Recurrent), Lactic Acidosis, Myopathy, Neutropenia (Decreased Neutrophils), Optic Atrophy, Organic Aciduria and Seizures

Physical Findings: Dysmorphisms. Treatment: L-carnitine, panthotenic acid Metabolic Information: Missing Enzyme:


mutations in the taffazin gene (TAZ), alteration in cardiolipin remodeling, normal hydratase

MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)-elevated. Prenatal Testing: Possible mutation analysis for at risk pregnancies.

Disease Name : 3-METHYLGLUTACONIC ACIDURIA TYPE III

Alternate name(s) Optic Atrophy Plus Syndrome; Iraqi-Jewish 'Optic Atrophy Plus'; Costeff Syndrome

Acronym MGA Type III

Classification: Organic Acid Disorder

Genetic Information: Inheritance: Autosomal recessive

Gene and Location : OPA3 gene on 19q13.2-q13.3

Common Mutations: A G-to-C founder mutation has been identified

OMIM# #258501; .606580

http://www.metagene.de/program/s.prg?id=1700










































Statistical Information: Population Incidence: Unknown- only been diagnosed among Jewish kindred

Ethnic Incidence: 1:10,000 among Iraqi Jewish kindred.


Costeff syndrome of optic atrophy and progressive neurodegenerative disease, excretion of 3-methylglutaconic and 3-methylglutaric acids, normal activity of 3-methylglutaconyl CoA hydratase, and mutation in the OPA3 gene.

Symptoms Onset: Presents in infants.

Symptoms: The disease presents with infantile bilateral optic atrophy, choreoathetosis, spastic paraparesis, cerebellar ataxia and nystagmus. Some patients have mental retardation. The course of the disease is non-progressive beyond childhood. Most develop spastic paraparesis by the second decade of life. About one-half of patients have nonprogressive ataxia. Some patients have been noted to have dysarthria. The life span is normal.

Physical Findings: No dysmorphisms.

Disease Information Treatment: There are no effective treatments. Coenzyme Q10 therapy has been tried without any change in the clinical status.


Spastic paraparesis with blindness and possible mental retardation. Possibly some ataxia.


Same as for untreated group.

Metabolic Information: Missing Enzyme:


The basic enzyme defect is unknown but it is a protein involved in energy metabolism.

MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)-elevated.

Prenatal Testing: Possible mutation analysis for at risk pregnancies.

Disease Name : 3-METHYLGLUTACONIC ACIDURIA TYPE IV Acronym MGA, TYPE IV Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : Unknown, likely many genes involved. Common Mutations: No known common mutations. OMIM# #250951

Statistical Information: Population Incidence: Unknown. Ethnic Incidence: No known population at increased risk.


Unspecified group of patients with 3-methylglutaconic aciduria appears to be heterogeneous. 1. Pearson syndrome and mitochondrial DNA deletions 2. Mitochondrial ATP synthase deficiency 3. Progressive encephalopathy 4. Neonatal lactic acidosis, ketosis, hypoglycemia This disease results in an accumulation of cis and trans 3-methylglutaconic acid. Symptoms include anemia, hyperammonemia, mental retardation, optic atrophy, hypotonia and early death.

Symptoms Onset: Presents in the first year of life. Symptoms: Type IV patients have a disparate variety of symptoms with the

only commonality being the mild excretion of 3-MGA in the urine. Patients have a clinically heterogeneous and nonspecific presentation and clinical course. There is variable psychomotor retardation; hypertonicity; hypotonia; optic atrophy; dysmorphic features; seizures; cardiomyopathy and hepatic dysfunction. Others have been noted to have neurodegeneration; deafness; failure to thrive; absence of acidosis.

Physical Findings: No dysmorphisms may have neurological findings.

Treatment: There are no effective treatments. Natural History without Treatment :

Varies from asymptomatic except for organic aciduria to neurodegeneration and deafness.





MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)-elevated. Prenatal Testing: None available, basic biochemical defect is unknown. Miscellaneous Information:

Some patients may have Pearson syndrome hematological disorder, lactic acidemia, and abnormality of the electron transport chain with identified mitochondrial DNA deletions.

Disease Name : 3-METHYLGLUTACONIC ACIDURIA TYPE V Acronym MGA Type V Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : DNAJC19 gene on 3q26.3 OMIM# #610198

Disease Information Symptoms: Ataxia, Cardiac Arrest, Cardiomyopathy, Cryptorchism, Failure To Thrive, Growth Retardation, Hypospadia, Mental Retardation, Optic Atrophy, Seizures

Treatment: There are no effective treatments. Natural History without Treatment :

Spastic paraparesis with blindness and possible mental retardation. Possibly some ataxia.






Elevated levels of 3-Methylglutaconic acid and 3-Methylglutaric acid

MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)-elevated. Prenatal Testing: Possible mutation analysis for at risk pregnancies.

Disease Name : BETA-KETOTHIOLASE DEFICIENCY Alternate name(s) Alpha-methylacetoacetic aciduria, 2-methyl-3-hydroxybutyric academi,

Mitochondrial acetoacetyl-CoA thiolase deficiency, 2- methyl-acetoacetic aciduria, 3-oxothiolase deficiency MAT deficiency, T2 deficiency, 3-oxothiolase deficiency, 3-ketothiolase deficiency, 3-KTD deficiency

Acronym BKD, 3-KTD, Classification: Organic Acid Disorder and Disorder Of Ketone Body Metabolism


Inheritance: Autosomal recessive Gene and Location : ACAT1 gene - 11q22.3-q23.1 Common Mutations: None, in 19 patients identified 24 mutations have

been found. OMIM# .203750, #607809

Statistical Information: Population Incidence: Unknown Ethnic Incidence: No known population at increased risk.



Acute episodes of ketosis and acidosis, vomiting, lethargy, urinary excretion of 2-methyl-3-hydroxybutyric acid, tiglyglycine and 2-methylacetoacetic acid, deficiency of mitochondrial acetoacetyl CoA thiolase (2-methylacetoacetic acid 3-oxothiolase).

Symptoms Onset: Late infancy or childhood. Mean age at presentation is 15 months (range 3 days to 48 months). There are documented cases of asymptomatic patients with enzyme deficiency. Frequency of decompensation attacks falls with age and is uncommon after the age of 10.

Symptoms: Symptoms include intermittent episodes of severe metabolic acidosis and ketosis accompanied by vomiting (often hematemesis), diarrhea and coma that may progress to death. There is great clinical heterogeneity between patients. Infancy is the period of highest risk for decompensation. Death













or neurologic complications can occur. Neurologic damage includes striatal necrosis of the basal ganglia, dystonia and/or mental retardation. Other symptoms include cardiomyopathy, prolonged QT interval, neutropenia, thrombocytopenia, poor weight gain, renal failure and short stature. If neurologically intact, patients are normal between episodes.

Physical Findings: No dysmorphisms Disease Information Treatment: Acute management of the ketoacidosis is

supportive with IV glucose and bicarbonate. Bicarbonate therapy is often required long term. While protein restriction is not usually necessary, protein rich diets and ketogenic diets should be avoided. Carnitine supplementation can be used. The family should monitor urinary ketones to be alert for impending metabolic crisis.


Clinical outcome varies widely with a few patients suffering severe psychomotor retardation or death as a result of their initial attack and others with normal development and no episodes of acidosis.


Despite severe recurrent attacks, appropriate supportive care can result in normal development.


Missing Enzyme:

Name Mitochondrial acetoacetyl-CoA thiolase enzyme

Function Catalyzes the decarboxylation of oxoacids.

Location Converts 2-methylacetoacetyl-CoA to propionyl-CoA and acetyl-CoA.

MS/MS profile: C5:1 tiglycarnitine – elevated C5-OH (3-hydroxy-2-methylbutyryl carnitine) – elevated.


Isoleucine

Metabolite Changes: Increased urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, 2-butanone, and ketone bodies (acetoacetic acid, 3-hydroxybutyric acid).


2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine in urine

Prenatal Testing: Enzyme analysis in amniocytes or CVS tissue. If mutations have been identified, DNA testing is possible

Disease Name : 3-HYDROXY-3-METHYLGLUTARYL-COA LYASE DEFICIENCY Alternate name(s) Hydroxymethylglutaric Aciduria; 3-Hydroxy-3-Methylglutarylcoa

Lyase Deficiency; Hl Deficiency; Hydroxymethylglutaric Aciduria Acronym HMG-CoA lyase deficiency Classification: Defect of ketone metabolism and organic aciduria- Disorder of the last step in

branched chain (leucine) amino acid metabolism and ketogenesis Genetic Information: Inheritance: Autosomal recessive

Gene and Location : HMGCL gene-1pter-p33 Common Mutations: R41Q and F305fs(-2) in Saudi Arabia.

G109T- some Southern European and Mediterranean populations.

OMIM# .246450 # 613898

Statistical Information: Population Incidence: Unknown, rare. Ethnic Incidence: Increased in Saudi Arabia represents 16 percent of all

metabolic disorders. Disease Information: Major phenotypic

expression Hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia; hepatomegaly; a characteristic organic aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric; and deficiency of 3-hydroxy3-methylglutaryl CoA lyase.

Symptoms Onset: About one-third present in neonatal period (two to five days) and about two-third present between three and 11 months. There are reports of asymptomatic individuals detected because of an affected sibling.

Symptoms: Presentation with severe hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, vomiting,



hepatomegaly and hypotonia. Unless recognized this may progress to coma and death in 20 percent of patients. The symptoms resemble Reye’s syndrome. Illness or fasting can precipitate an acute metabolic decompensation as can protein loading, decreased caloric intake and increased glucose needs. White matter changes, MR and epilepsy may occur following hypoglycemic episodes. Macrocephaly has been seen in some patients with severe neurological complications. Between episodes the children are typically normal on exam. Instances of dilated cardiomyopathy with arrhythmia, pancreatitis, nonprogressive deafness and retinitis pigmentosa have been reported. These may be related to neurological damage from the hypoglycemia. On pathology fatty deposits are seen in liver and in the brain, gliosis, spongiosis and increased glycogen in astrocytes

Physical Findings: Macrocephaly has been noted, as has short stature. Otherwise no particular dysmorphisms.

Disease Information Treatment: Avoidance of fasting. Low fat, protein and high carbohydrate diet. Cornstarch supplementation. Carnitine supplementation. Intravenous glucose to treat hypoglycemia during crisis episodes. Crises consist of severe acidosis and hypoglycemia treated with IV glucose and bicarbonate administration.


Recurrent episodes of acute illness usually in response to fasting or to viral infection. White matter changes, MR and epilepsy may occur following hypoglycemic episodes. Twenty percent mortality in unrecognized patients


Normal IQ and development are possible. Severe hypoglycemic episodes may result in seizures and mental retardation. If diagnosed early, treated patients may have normal development


Missing Enzyme:

Name HMG CoA lyase

Function Catalyzes the final step of leucine degradation and plays a role in ketone formation.

Location Liver, fibroblasts and leukocytes MS/MS profile: C5-OH (3-hydroxyisovaleryl carnitine)- elevated.

C6-DC (methylglutaryl carnitine)- elevated. Metabolite Change: 3-hydroxy-3-methylglutaric acid in urine, increased levels of

glutaric and adipic acids may be elevated in urine during crisis, notable absence of ketosis.


Leucine


3-OH-3-methyl glutaric acid, 3-methylglutaconate, 3-OH-isovalerate, 3-methylglutarate, Adipic acid in urine

Prenatal Testing: Prenatal testing has been accomplished by analysis of metabolites in maternal urine at 23 weeks. Enzyme is active in amniocytes and prenatal testing should be possible using this method.

Disease Name : 3-METHYLCROTONYL COENZYME A CARBOXYLASE DEFICIENCY Alternate name(s) Biotin unresponsive 3-Methylcrotonylglycinuria Acronym 3-MCC Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : MCCA 3q25-q27 MCCB 5q12-q13.1

Common Mutations: No known common mutations. OMIM# .210200

Statistical Information: Population Incidence: 1:50,000. Ethnic Incidence: No known population at increased risk.

Disease Information: Major Phenotypic Expression Reye-like episodes of ketoacidosis, hypoglycemia, hyperammonemia and coma; seizures, failure to thrive; excretion of 3-methylcrotonyl glycine and 3-hydroxyisovaleric acid; and deficiency of 3-methylcrotonyl CoA carboxylase. An increasing population of asymptomatic individuals, mostly

adult women discovered because of elevated 3-hydroxyisovalerylcarnitine detected in the neonatal screening blood spots of their infants.

Symptoms Onset: Generally after three months of age but can be variable. Many individuals with no symptoms into adulthood.

Symptoms: Some infants have presented with a Reye-like illness with hypoketotic hypoglycemia, metabolic acidosis and liver dysfunction often precipitated by an intercurrent illness, which has led to fulminant liver failure and death in some cases. Others present with muscle hypotonia and failure-to-thrive in conjunction with recurrent episodes of vomiting and diarrhea. In general, the earlier the presentation the poorer the prognosis.

Physical Findings: No specific dysmorphology. Disease Information Treatment: Leucine-restricted diet with glycine, carnitine and

biotin supplementation. Natural History without Treatment :

Primary manifestations appear to be muscular hypotonia and atrophy, probably of spinal origin. Individuals with Reye-like illnesses may die or suffer neurologic insult during these episodes. As many individuals remain asymptomatic, the etiology of the symptoms is unknown. Newborn screening has led to the detection of several asymptomatic women whose infants had transiently elevated isovalerylcarnitine.


It is uncertain whether treatment modifies disease course. Given asymptomatic individuals, treatment is of questionable value.


Missing Enzyme: Name 3-methylcrotonyl-CoA carboxylase

Function Breakdown of leucine

Location MCC is predominantly localized to the inner membrane of the mitochondria and is known to be highly expressed in kidney and liver.

MS/MS profile: C5:1 (tigyl or 3-methylcrotonyl carnitine) elevated C5-OH (3-hydroxy-2-methylbutyryl carnitine)- elevated

Affected Amino acid Pathway(s): Leucine Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

3-hydroxy-isovaleric acid, 3-methylcrotonyl glycine in urine

Prenatal Testing: May be possible for at-risk pregnancies. Miscellaneous Information:

Heterozygotes (obligate carriers) do not have abnormal metabolites in the urine. For definitive diagnosis, exclusion of multiple carboxylase deficiency, enzyme assay must show a deficit of 3-MCC activity and normal activity of at least one other carboxylase enzyme in leukocytes or fibroblasts.

Disease Name : SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY Alternate name(s) 4-Hydroxybutyric aciduria Acronym SSADH, 4-HBA Classification: Organic Acid Disorder Genetic Information:

Inheritance: Autosomal recessive Gene and Location : ALDH5A1gene- 6p22

ALDH7A1gene-5q31 ALDH4A1gene-1p36

OMIM# .271980, # 610045


Population Incidence: Unknown Ethnic Incidence: Unknown



Mental retardation, ataxia, hypotonia, hyporeflexia, convulsions, hyperkinetic behavior or lethargy bordering on narcolepsy, macrocephaly, excretion of 4-hydroxybutyric acid in the urine, and deficiency of succinic semialdehyde dehydrogenase.

Symptoms Onset: At 11 months Symptoms: Intellectual disability with prominent deficits in expressive

language, hypotonia, nonprogressive ataxia, and hyporeflexia. Elevated free and total GABA and homocarnosine concentrations in CSF

Physical Findings: Macrocephaly (Large Calvaria, >2 SD For Age), Mental Retardation, Microcephaly, Motor Retardation, Myopathy, Ragged Red Fibers, Autistic-Like, Hyperactive Behavior, Restless.

http://www.ncbi.nlm.nih.gov/omim/271980

http://www.ncbi.nlm.nih.gov/omim/610045










Disease Information

Treatment: Include symptomatic therapy with vigabatrine (ᵧ-vinyl- GABA), which is an irreversible inhibitor of GABA transaminase. Doses employed have included 1.5 g/d in a 30 kg patient in whom alertness appeared to improve and hypotonia to decrease.


Missing Enzyme: Name , Function and Location

Succinic Semialdehyde Dehydrogenase in in GABA degradation, it works with the enzyme GABA transaminase to convert GABA to succinic acid.


Elevation of 4-hydroxybutyric acid concentration in urine, plasma and CSF, Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid and significant amounts of dicarboxylic acids in the urine. Increased glycine concentration in urine and plasma and, rarely in CSF

Disease Name : 2-METHYLBUTYRYL-COA DEHYDROGENASE DEFICIENCY Alternate name(s) Short/branched chain acyl-CoA dehydrogenase deficiency,

Methylbutyrylglycinuria Aconym: 2-MBC Classification: Organic Acid Disorder Genetic Information: Inheritance: Autosomal recessive

Gene and Location : SBCAD gene on 10q25-q26

Common Mutations: A common mutation has been identified in the Hmong population – M356V which causes skipping of exon 10 in the SBCAD.

OMIM# .600301 Statistical Information: Population Incidence: Rare; < than 20 patients identified

Ethnic Incidence: As high as 1/500 Disease Information: Major Phenotypic Expression Retardation of speech and mental development,

fasting hypoglycemia, metabolic acidosis, excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid, and defective activity of 3-methylglutaconyl CoA hydratase. The gene is known as AUH; it was previously shown to code for an AU specific RNA-binding protein; it is now known to have 3-methylcrotonyl CoA hydratase activity.

Symptoms Onset: Variable Symptoms:

One patient presented with neonatal onset of

hypotonia, lethargy, apnea and hypoglycemia. At four

years of age, he has developmental delay,

choreoathetoid cerebral palsy and visual deficits.

Another patient presented in the second year of life

with motor delay, muscular atrophy and strabismus.

A sibling identified prenatally and 8 Hmong patients

identified by newborn screening remain

asymptomatic on treatment. At least 4 asymptomatic

relatives of these patients have been described with

gene mutations and/or elevated excretion of 2-

methylbutyrylglycine. Physical Findings: None reported

Disease Information Treatment: Protein restriction, carnitine supplementation, avoidance of fasting.


Ranges from asymptomatic to acute neonatal decomposition with neurological deficits. The limited number of patients makes it difficult to determine the natural history of the disorder. However, the disorder is not thought to be benign in that asymptomatic individuals may not have been exposed to the environmental stressors (i.e. fasting) that can cause symptoms.


Treatment in a symptomatic patient resolved episodic hypoglycemia but the neurologic dysfunction remains. Other patients treated from birth are asymptomatic thus far but the efficacy of the treatment remains to be established.

Metabolic Information: Missing Name 2-methylbutyryl-CoA dehydrogenase

http://en.wikipedia.org/wiki/GABA

http://en.wikipedia.org/wiki/GABA_transaminase

http://en.wikipedia.org/wiki/GABA_transaminase

http://en.wikipedia.org/wiki/GABA

http://en.wikipedia.org/wiki/Succinic_acid

http://www.newbornscreening.info/Pro/organicaciddisorders/2MBC.html

Enzyme: Function Metabolism of L-isoleucine Location Mitochondria

MS/MS profile: Elevated C5 isovaleryl-carnitine Affected Amino acid Pathway(s): L-isoleucine Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Increased 2-methylbutyryl, increased 2- methylbutyrylcarnitine.

Prenatal Testing: Enzyme analysis in amniocytes or CVS

Disease Name : L-2-Hydroxyglutaric Aciduria Classification: Organic Acid Disorder Genetic Information: Inheritance: Rare Autosomal recessive

Gene and Location : L2HGDHgene on 14q22.1 Common Mutations: Unknown OMIM# #236792


Ataxia, hypotonia, tremor, psychomotor retardation, seizures; rarely neonatal expression with apnea; cerebellar atrophy; and L-2-hydroxyglutaric aciduria.

Symptoms Onset: Infancy and childhood Symptoms:

Alopecia, Ataxia, Behavior, Autism Or Autistic-Like,

Blindness, Visual Loss, Visual Impairment, Dysarthria,

Early Death, Extrapyramidal Signs, Hyperpigmentation,

Hypertonia, Spasticity, Hypotonia, Macrocephaly (Large

Calvaria, >2 Sd For Age), Mental Retardation, Organic

Aciduria, Pyramidal Signs, Seizures, Delayed and

AbnormalSpeech Development, Tremor Or Twitching. Physical Findings: None reported

Disease Information Treatment: No Specific Treatment, Anticonvulsants, L-Carnitine, Riboflavin.


Name L-2-hydroxyglutarate dehydrogenase Function Metabolism of Lysine Location Mitochondria


Lysine


Increased L-2-Hydroxyglutaric acid in plasma and urine, Lysine in plasma.

Disease Name : D-2-HYDROXYGLUTARIC ACIDURIA Classification: Organic Acid Disorder Genetic Information: Inheritance: Rare Autosomal recessive

Gene and Location : D2HGDHgene on 2q37.3 Common Mutations: Unknown OMIM# #600721

Disease Information: Major Phenotypic Expression Developmental delay, macrocephaly, seizures, vomiting, cerebral atrophy, and D-2-hydroxyglutaric aciduria.

Symptoms Onset: Infancy and childhood Symptoms: Alopecia, Anemia, Bleeding Tendencies,

Hemorrhages, Blindness, Visual Loss, Visual Impairment, Cardiomegaly, Cardiomyopathy, Corpus Callosum, Agenesis/Hypoplasia, Dysmorphism, Hyperpigmentation, Hypotonia, Infantile Spasms, Irritability, Macrocephaly (Large Calvaria, >2 Sd For Age), Mental Retardation, Metaphyseal Dysplasia, D-2-Hydroxyglutaric acid in urine, CSF and plasma Peripheral, Neuropathy, Seizures, Vomiting

Physical Findings: None reported Disease Information Treatment: No Specific Treatment Metabolic Information: Missing Enzyme: Mitochondrial D-2-hydroxyglutarate

dehydrogenase Diagnostic Analytes by GC/MS and Quantitative amino acid

Increased D-2-Hydroxyglutaric acid in plasma and urine, 2-Oxoglutaric acid in urine.










































analysis

Disease Name : ISOBUTYRYL-COA DEHYDROGENASE DEFICIENCY Alternate name(s) Acyl-CoA dehydrogenase family, member 8 Classification: Organic Acid Disorder/Fatty Acid Oxidation Defect Genetic Information: Inheritance: Presumed autosomal recessive

Gene and Location : ACAD8 gene on 11q25 Common Mutations: No common mutations known OMIM# #604773

Statistical Information: Population Incidence: Rare. 10 cases reported. Ethnic Incidence: None known

Disease Information: Symptoms Onset: 12 months of age Symptoms:

Initial patient presented with dilated cardiomyopathy,

low carnitine and anemia. Was small for age at

presentation, but normal growth resumed with

treatment. Physical Findings: Cardiomyopathy. No dysmorphisms reported.

Disease Information Treatment: Moderate protein restriction. Carnitine therapy. Natural History without Treatment : Unknown. Natural History with Treatment :

Improvement in symptoms of cardiomyopathy and anemia with improved growth and normal development.


Missing Enzyme:

Name Isobutyryl-CoA dehydrogenase Function Metabolism of valine Location Mitochondria

MS/MS profile: C4 butyryl carnitine elevation Affected Amino acid Pathway(s): Valine Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Increased isobutyrylglycine in urine

Prenatal Testing: May be possible by enzyme analysis on amniocytes or CVS. Disease Name : 5-OXOPROLINURIA type A Alternate name(s) Pyroglutamic aciduria Classification: Unclassified Genetic Information: Inheritance: Rare autosomal recessive

Gene and Location : Unknown Common Mutations: No common mutations known OMIM# #260005


Major Phenotypic Expression 5-Oxoprolinuria is a biochemical finding that can arise from two underlying metabolic disorders has two types: A (severe form) and B (milder form)

Symptoms Onset: 12 months of age Symptoms:

Anemia, Cleft Palate, Diarrhea, Failure To Thrive, Hypotonia,

Mental Retardation, Metabolic Acidosis, Microcephaly,

Organic Aciduria, AbdominalPain, Respiratory Distress,

Urolithiasis Treatment: no specific treatment


Name 5-oxoprolinase (Pyroglutamase) Function (ATP-hydrolyzing )ATP + 5-oxo-L-proline + 2 H(2)O

<=> ADP + phosphate + L-glutamate Location Mitochondria


Increased 5-Oxoproline (pyroglutamic acid) in urine and plasma

Disease Name : 5-OXOPROLINURIA type B Alternate name(s) Pyroglutamic aciduria Classification: Unclassified Genetic Information: Inheritance: Rare autosomal recessive

Gene and Location : GSS gene- 20q11.2 Common Mutations: No common mutations known OMIM# #266130

Disease Information: Major Phenotypic Expression 5-Oxoprolinuria is a biochemical finding that can arise from two underlying metabolic disorders has two types: A (severe form) and B (milder form)

Symptoms Onset: Childhood, infancy Symptoms: Anemia, Ataxia, Cerebellar Atrophy Or Hypoplasia

Hyperammonemia, Jaundice, Mental Retardation, Metabolic













http://www.biocheminfo.org/klotho/html/ATP.html

http://www.biocheminfo.org/klotho/html/H2O.html

http://www.biocheminfo.org/klotho/html/ADP.html

http://www.biocheminfo.org/klotho/html/L-glutamate.html








Acidosis, Motor Retardation, Organic Aciduria, Seizures Spastic Diplegia/Quadriplegia,Thromboembolism, Tremor Or Twitching, Vomiting.

Disease Information Treatment: N-acetylcysteine, vitamin C (ascorbate) Metabolic Information: Missing

Enzyme: Name glutathione synthetase Function ATP + gamma-L-glutamyl-L-cysteine + glycine <=> ADP +

phosphate + glutathione


Increased 5-Oxoproline (pyroglutamic acid) in urine and plasma , Proline in plasma

Disease Name : 3-HYDROXYISOBUTYRIC ACIDURIA Alternate name(s) 2-Ethyl-3-Hydroxypropionic Aciduria Classification: Organic Acid Disorder


Inheritance: Rare autosomal recessive Gene and Location : ALDH6A1 gene-14q24.3 Common Mutations: No common mutations known OMIM# #236795


Major Phenotypic Expression Recurrent episodes of ketoacidosis; failure to thrive; lactic acidemia; 3-hydroxyisobutyric aciduria; 2-ethyl-3-hydroxypropionic aciduria; and defective oxidation of valine and -alanine.

Symptoms Onset: 12 months of age Symptoms: Clinodactyly, Dehydration, Dysmorphism,

Early Death, Failure To Thrive, Hypotonia, Ketosis, Lactic Acidosis, Metabolic Acidosis, Microcephaly, Organic Aciduria, Respiratory Insufficiency, Vomiting.


Name methylmalonate semialdehyde dehydrogenase/ 3-hydroxyisobutyrate dehydrogenase

Function Catabolism of valine MS/MS Profile 3-Hydroxyisovalerylcarnitine (C5-OH) Diagnostic Analytes by GC/MS and Quantitative amino acid analysis

Increased 3-Hydroxyisovaleric acid,2-ethyl- 3-Hydroxypropionic acid, 3-Hydroxyisovaleric acid, Ketone bodies and lactic acid in urine and increased lactic acid and alanine in plasma

Disease Name : 2-KETOADIPIC ACIDEMIA Alternate name(s) 2-oxoadipic aciduria, 2-hydroxyadipic aciduria, 2-aminoadipic aciduria Classification: Organic acid disorder


Inheritance: Rare autosomal recessive Gene and Location :

Unknown

Common Mutations:

No common mutations known

OMIM# #245130



Not clear. May be no clinical disease.

Symptoms: Ataxia, hypotonia, mental retardation, metabolic acidosis, no clinical signs or symptoms, Organic aciduria, seizures, skin defects


Name 2-oxoadipic acid dehydrogenase E1 or E2 component Function Metabolism of lysine, Hydroxylysine and tryptophan


Increased in 2-Aminoadipic acid, 2-Hydroxyadipic acid, 2-Hydroxyglutaric acid (L), 2-Ketoadipic acid, N-Acetyl-2-aminoadipic acid in urine and 2-aminoadipic acid in plasma









Metabolic Disorders

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