Chapter 5 – Biochemical Testing for Metabolic Movement Disorders




Abstract




Strategies in the biochemical testing for movement disorders depend on the available laboratory test panels and clinical description of the patient. Clinical signs and symptoms may already provide a hint for the selection of biochemical investigations.





Chapter 5 Biochemical Testing for Metabolic Movement Disorders


Nenad Blau and Georg F. Hoffmann



Introduction


Strategies in the biochemical testing for movement disorders depend on the available laboratory test panels and clinical description of the patient. Clinical signs and symptoms may already provide a hint for the selection of biochemical investigations. Therefore, a precise clinical definition of the movement disorder is of great importance [1–4]. The term “movement disorders” refers to a group of neurological conditions that cause abnormally decreased or increased movements, which may be voluntary or involuntary. For example, ataxia often results from dysfunction of the part of the brain that controls coordinated movement, the cerebellum. Cerebellar dysfunction may cause uncoordinated or clumsy balance, speech, or limb movements, among other symptoms. Chorea is characterized by repetitive, brief, irregular, somewhat rapid, involuntary movements that typically involve the face, mouth, trunk, and limbs. Dystonia involves sustained involuntary muscle contractions with twisting, repetitive movements. It may affect the entire body (generalized dystonia) or one part of the body (focal dystonia). Myoclonus causes lightning-quick jerks of a muscle or a group of muscles. Parkinsonism describes a group of conditions that has symptoms similar to those of Parkinson disease, characterized by dystonia, tremor, stiffness (rigidity), slow decreased movement (bradykinesia), or imbalance. Spasticity is characterized by increased muscle contractions causing stiffness or tightness of the muscles that may interfere with movement, speech, and walking. Tremor causes involuntary rhythmic shaking of the hands, head, or other parts of the body. Further signs and symptoms of movement disorders may include reduced muscle tone, repetitive hand movements, disturbed eye movements, irregular breathing, and gait abnormalities. Movement disorders in children are mainly divided into three subgroups: ataxia, hyperkinetic/dyskinetic movement disorders (which include dystonia, chorea, athetosis, myoclonus, tremors, tics, and stereotypies), and hypokinetic movement disorders, which include parkinsonism.


Our ability to unravel and diagnose movement disorders due to metabolic diseases is still hampered by the fact that neurological symptoms and disease courses greatly overlap with non-metabolic diseases and that not all diseases presenting with abnormal movements fit the description of classic movement disorders.



Clinical and Biochemical Background


We used the large database approach, to select inborn errors of metabolism (IEMs) with signs and symptoms associated with movement disorders. IEMbase (www.iembase.org) [5] is a knowledgebase tabulating 1,441 IEMs (as of February 2020), categorized according to the recently proposed nosology [6]. IEMbase lists age-matched biochemical and clinical phenotypes for each of the diseases and generates a list of matching diagnoses. With the resulting list, users can generate differential diagnosis charts, suggested biochemical test panels, and targeted gene panels in order to pursue concurrent biochemical and genetic/genomic investigations for a rapid diagnosis.


Signs and symptoms associated with movement disorders listed in the IEMbase are summarized in Box 5.1. They are assigned to 7 groups: (1) ataxia, (2) dystonia, (3) chorea/athetosis, (4) myoclonus, (5) tremor, (6) hypokinetic–rigid syndrome, and (7) other signs and symptoms. The most common symptoms in the 208 selected IEMs were ataxia (73%), dystonia (47%), chorea/athetosis (24%), hypokinetic–rigid syndrome (17%), tremor (15%), and myoclonus (14%) [7].




Box 5.1 Signs and symptoms of disturbed movements associated with 208 IEMs. Data source: IEMbase (www.iembase.org).





  1. 1. Ataxia




    • Truncal ataxia



    • Cerebellar ataxia



    • Spasticity (diplegia, tetraplegia, paraplegia, paresis, paraparesis)




  2. 2. Dystonia




    • Oculogyric crises




  3. 3. Chorea/athetosis



  4. 4. Myoclonus



  5. 5. Tremor



  6. 6. Hypokinetic–rigid syndrome




    • Akinesia



    • Bradykinesia



    • Hypokinesia






  1. 7. Other signs and symptoms




    • Hyperekplexia



    • Stereotyped fencing and/or bicycling movements



    • Paroxysmal exercise-induced dyskinesia



    • Midline hand movements



    • Myokymia



A total of 208 inherited metabolic diseases were identified to present with the above-mentioned signs and symptoms of movement disorders (Box 5.2). This list is by far not complete, due to a continuously rising number of newly described diseases and better phenomenological delineation of diseases.




Box 5.2 Inherited metabolic diseases presenting with movement disorders and their classification in corresponding metabolic pathways. Diseases with movement disorder as a primary or prominent feature are highlighted in bold.




























  1. 1. Disorders of nitrogen-containing compounds




    1. (a) Disorders of pyrimidine metabolism:




      • CAD trifunctional protein deficiency




    2. (b) Disorders of purine metabolism:




      • Phosphoribosyl pyrophosphate synthetase 1 superactivity



      • Phosphoribosyl pyrophosphate synthetase 1 deficiency



      • Purine nucleoside phosphorylase deficiency



      • Adenylosuccinate lyase deficiency



      • Hypoxanthine–guanine phosphoribosyltransferase deficiency




    3. (c) Disorders of creatine metabolism:




      • Guanidinoacetate N-methyltransferase (GAMT) deficiency



      • Creatine transporter deficiency




    4. (d) Disorders of glutathione metabolism:




      • Gamma-glutamylcysteine synthetase deficiency



      • Glutathione synthetase deficiency, severe




    5. (e) Disorders of ammonia detoxification:




      • Ornithine transcarbamylase deficiency



      • Argininosuccinate synthetase deficiency



      • Argininosuccinate lyase deficiency



      • Arginase deficiency



      • Hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome



      • Mitochondrial ornithine transporter deficiency




    6. (f) Disorders of amino acid transport:




      • Hartnup disease




    7. (g) Disorders of monoamine metabolism




      • Tyrosine hydroxylase deficiency



      • Aromatic L-amino acid decarboxylase deficiency



      • Dopamine transporter deficiency



      • Dopamine–serotonin vesicular transport defect




    8. (h) Disorders of phenylalanine and tetrahydrobiopterin metabolism:




      • Phenylalanine hydroxylase deficiency (classic PKU)



      • Autosomal-recessive GTPCH1 deficiency



      • Autosomal-dominant GTPCH1 deficiency (Segawa disease)



      • 6-Pyruvoyl-tetrahydropterin synthase deficiency



      • Sepiapterin reductase deficiency



      • Dihydropteridine reductase deficiency



      • DNAJC12-deficient hyperphenylalaninemia




    9. (i) Disorders of sulfur amino acid and sulfide metabolism




      • Methionine adenosyltransferase I/III deficiency



      • Classic homocystinuria



      • Sulfite oxidase deficiency



      • Ethylmalonic encephalopathy




    10. (j) Disorders of branched-chain amino acid metabolism




      • Maple syrup urine disease type 1a



      • Maple syrup urine disease type 1b



      • Maple syrup urine disease type 2



      • Dihydrolipoamide dehydrogenase deficiency



      • Isovaleric acidemia



      • Methylglutaconic aciduria type 1



      • Mitochondrial short-chain enoyl-CoA hydratase deficiency



      • 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency



      • 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency



      • Propionic acidemia PCCA



      • Propionic acidemia PCCB



      • Methylmalonyl-CoA epimerase deficiency



      • Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency



      • Combined malonic and methylmalonic aciduria



      • Malonic aciduria




    11. (k) Disorders of lysine metabolism:




      • Glutaric aciduria type 1 (GA-1)




    12. (l) Disorders of proline and ornithine metabolism:




      • Pyrroline-5-carboxylate synthase deficiency




    13. (m) Disorders of beta- and gamma-amino acids:




      • Beta-ureidopropionase deficiency



      • Gamma-aminobutyric acid (GABA) transaminase deficiency



      • Succinic semialdehyde dehydrogenase deficiency




    14. (n) Disorders of glutamate metabolism:




      • Glutamate aspartate transporter deficiency




    15. (o) Disorders of serine metabolism:




      • Phosphoglycerate dehydrogenase deficiency




    16. (p) Disorders of glycine metabolism:




      • Glycine encephalopathy due to glycine decarboxylase deficiency



      • Glycine encephalopathy due to aminomethyltransferase deficiency



      • Hyperekplexia due to glycine transporter 2 defect




    17. (q) Disorder of asparagine metabolism:




      • Asparaginase deficiency






  1. 2. Disorders of vitamins, cofactors, metals, and minerals




    1. (a) Disorders of cobalamin metabolism:




      • Imerslund–Gräsbeck syndrome



      • cblC disease



      • Methylcobalamin synthesis defect – cblD variant 1



      • Methionine synthase deficiency – cblG



      • cblX disease





    1. (b) Disorders of folate metabolism:




      • Hereditary folate malabsorption



      • Folate receptor alpha deficiency



      • Methylenetetrahydrofolate reductase deficiency



      • Dihydrofolate reductase deficiency





    1. (c) Disorders of biotin metabolism:




      • Biotinidase deficiency



      • Holocarboxylase synthetase deficiency





    1. (d) Disorders of thiamine metabolism:




      • Thiamine pyrophosphokinase deficiency



      • Mitochondrial thiamine pyrophosphate transporter deficiency





    1. (e) Disorders of nicotinamide adenine dinucleotide (NAD) metabolism:




      • Mitochondrial NAD kinase 2 deficiency



      • NAXE deficiency





    1. (f) Disorders of pantothenate metabolism:




      • Pantothenate kinase-associated neurodegeneration (PKAN)



      • Coenzyme A synthase deficiency





    1. (g) Disorder of pyridoxine metabolism:




      • Pyridoxine-dependent epilepsy



      • Pyridox(am)ine phosphate oxidase deficiency





    1. (h) Disorder of vitamin E metabolism:




      • Alpha–tocopherol transfer protein deficiency





    1. (i) Disorders of molybdenum metabolism:




      • Molybdenum cofactor deficiency





    1. (j) Disorders of copper metabolism:




      • Wilson disease



      • Menkes disease





    1. (k) Disorders of iron metabolism:




      • Neuroferritinopathy



      • Aceruloplasminemia





    1. (l) Disorders of manganese metabolism:




      • SLC30A10 deficiency



      • SLC39A14 deficiency



      • SLC39A8 deficiency





    1. (m) Disorders of zinc metabolism:




      • Birk–Landau–Perez syndrome





    1. (n) Disorders of selenium metabolism:




      • Selenocysteine synthase deficiency






  1. 3. Disorders of carbohydrates




    1. (a) Disorders of carbohydrate transport and absorption:




      • Glucose transporter 1 (GLUT1) deficiency





    1. (b) Disorders of galactose metabolism:




      • Classic galactosemia





    1. (c) Disorders of the pentose phosphate pathway and polyol metabolism:




      • Ribose-5-phosphate isomerase deficiency





    1. (d) Disorders of gluconeogenesis:




      • Pyruvate carboxylase deficiency





    1. (e) Disorders of glycolysis:




      • Triosephosphate isomerase deficiency






  1. 4. Mitochondrial disorders of energy metabolism




    1. (a) Disorders of pyruvate metabolism:




      • Pyruvate dehydrogenase (PDH) deficiency





    1. (b) Disorders of the Krebs cycle:




      • Mitochondrial aconitase deficiency



      • Succinyl-CoA ligase beta subunit (SUCLA2) deficiency



      • Succinyl-CoA ligase alpha subunit (SUCLG1) deficiency



      • Fumarase deficiency



      • Mitochondrial malate dehydrogenase deficiency



      • Plasma membrane citrate transporter deficiency





    1. (c) Disorders of metabolite repair:




      • L-2-hydroxyglutaric aciduria





    1. (d) Disorders of mitochondrial carriers:




      • Aspartate–glutamate carrier 1 deficiency




    2. (e) Disorders of mitochondrial complex subunits and assembly:




      • Leigh syndrome (various genes)



      • Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (various genes)



      • Myoclonic epilepsy with ragged red fibers (MERRF; various genes)



      • Neuropathy, ataxia, and retinitis pigmentosa (NARP)




    3. (f) Disorders of mitochondrial DNA depletion:




      • POLG deficiency



      • MPV17 deficiency



      • Twinkle mitochondrial DNA helicase deficiency



      • FBXL4 deficiency




    4. (g) Disorders of mitochondrial translation factors:




      • C12orf65 release factor deficiency




    5. (h) Disorders of mitochondrial tRNA incorporation and recycling:




      • Mitochondrial aspartyl-tRNA synthetase deficiency



      • Mitochondrial methionyl-tRNA synthetase deficiency



      • Mitochondrial tryptophanyl-tRNA synthetase deficiency





    1. (i) Disorders of mitochondrial fusion:




      • OPA1 deficiency



      • Costeff syndrome



      • MSTO1 deficiency





    1. (j) Disorders of mitochondrial phospholipid metabolism:




      • MEGDEL syndrome





    1. (k) Disorders of mitochondrial protein import:




      • DNAJC19 deficiency



      • Mohr–Tranebjaerg syndrome





    1. (l) Disorders of mitochondrial protein quality control:




      • Mitochondrial processing peptidase alpha deficiency



      • Caseinolytic peptidase B (CLPB) deficiency



      • Sacsin deficiency



      • AFG3L2 deficiency



      • Parkin deficiency





    1. (m) Primary coenzyme Q10 deficiencies:




      • COQ2 deficiency



      • COQ6 deficiency



      • COQ8A deficiency






  1. 5. Disorders of lipids




    1. (a) Disorders of ketone body metabolism:




      • Beta-ketothiolase deficiency





    1. (b) Disorders of fatty acid synthesis and elongation:




      • Mitochondrial enoyl-CoA reductase deficiency



      • ELOVL4 deficiency



      • ELOVL5 deficiency





    1. (c) Disorders of the fatty alcohol cycle:




      • Sjögren–Larsson syndrome





    1. (d) Disorders of intracellular triglyceride metabolism:




      • Chanarin–Dorfman syndrome



      • Celia’s encephalopathy





    1. (e) Disorders of non-mitochondrial phospholipid metabolism:




      • Phosphatidylserine flippase ATP8A2 deficiency



      • PLA2G6-associated neurodegeneration (PLAN)



      • PNPLA6 deficiency



      • PHARC syndrome





    1. (f) Disorders of non-lysosomal sphingolipid metabolism:




      • Fatty acid hydroxylase-associated neurodegeneration



      • GBA2 deficiency





    1. (g) Disorders of palmitoylation:




      • CLN1 disease





    1. (h) Disorders of lipoprotein metabolism:




      • Apolipoprotein B deficiency (familial hypobetalipoproteinemia)



      • Abetalipoproteinemia





    1. (i) Disorders of cholesterol biosynthesis:




      • Mevalonate kinase deficiency





    1. (j) Disorders of bile acid synthesis:




      • Oxysterol 7α-hydroxylase deficiency



      • Cerebrotendinous xanthomatosis



      • Alpha-methylacyl-CoA racemase deficiency



      • Peroxisomal branched-chain acyl-CoA oxidase deficiency






  1. 6. Disorders of tetrapyrroles




    1. (a) Disorders of heme metabolism:




      • Recessive porphobilinogen deaminase deficiency



      • Coproporphyrinogen oxidase deficiency



      • Congenital methemoglobinemia due to CYB5R3 deficiency






  1. 7. Storage disorders




    1. (a) Disorders of autophagy:




      • Beta-propeller protein-associated neurodegeneration (BPAN)



      • SNX14 deficiency





    1. (b) Neuronal ceroid lipofuscinoses:




      • CLN2 disease



      • CLN4 disease



      • CLN5 disease



      • CLN7 disease



      • CLN8 disease



      • CLN10 disease



      • CLN11 disease



      • ATP13A2 deficiency



      • CLN13 disease



      • CLN14 disease





    1. (c) Sphingolipidoses:




      • Gaucher disease



      • Gaucher disease-like disorder due to saposin C deficiency



      • GM1 gangliosidosis



      • Beta-hexosaminidase alpha subunit deficiency (Tay–Sachs disease)



      • Beta-hexosaminidase beta subunit deficiency (Sandhoff disease)



      • Krabbe disease



      • Metachromatic leukodystrophy



      • Multiple sulfatase deficiency



      • Combined saposin deficiency





    1. (d) Oligosaccharidoses:




      • Sialidosis



      • Galactosialidosis



      • Alpha-mannosidosis



      • Beta-mannosidosis



      • Fucosidosis





    1. (e) Disorders of lysosomal cholesterol metabolism:




      • Niemann–Pick disease type C (NPC)





    1. (f) Disorders of lysosomal transport or sorting:




      • Salla disease



      • Action myoclonus–renal failure syndrome






  1. 8. Disorders of peroxisomes




    1. (a) Disorders of peroxisomal fatty acid oxidation:




      • X-linked adrenoleukodystrophy (X-ALD)



      • Peroxisomal acyl-CoA oxidase deficiency



      • D-Bifunctional protein deficiency



      • Sterol carrier protein-2 deficiency



      • Refsum disease (classic, adult)





    1. (b) Disorders of peroxisomal biogenesis:




      • Zellweger spectrum disorders – peroxin deficiencies






  1. 9. Congenital disorders of glycosylation




    1. (a) Disorders of N-linked glycosylation:




      • Phosphomannomutase 2 deficiency



      • DPAGT1-CDG



      • ALG1-CDG



      • RFT1-CDG



      • ALG6-CDG



      • ALG13-CDG





    1. (b) Disorders of glycosylphosphatidylinositol biosynthesis:




      • PIGG-CDG



      • PIGN-CDG



      • PGAP1-CDG



      • PGAP3-CDG





    1. (c) Disorders of glycolipid glycosylation:




      • ST3GAL5-CDG



      • B4GALNT1-CDG





    1. (d) Disorders of dolichol metabolism:




      • DPM1-CDG



      • MPDU1-CDG



      • Steroid 5 alpha-reductase 3 deficiency





    1. (e) Glycosylation disorders of vesicular trafficking:




      • TRAPPC11-CDG



      • COG4-CDG



      • COG5-CDG



      • COG8-CDG



      • GOSR2-CDG





    1. (f) Disorder of deglycosylation:




      • N-glycanase 1 deficiency



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Oct 19, 2020 | Posted by in NEUROLOGY | Comments Off on Chapter 5 – Biochemical Testing for Metabolic Movement Disorders

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