Metabolic Disorders



Metabolic Disorders





Glycogen Storage Diseases


I. Acid Maltase Deficiency (also known as Pompe disease)



  • Infantile



    • Onset—weeks


    • Clinical features



      • Floppy baby, generalized and bulbar weakness


      • Macroglossia


      • Cardiomegaly


      • Hepatomegaly


      • Death by age 2 years


  • Adult Acid Maltase Deficiency



    • Onset: 20s to 30s age group


    • Clinical presentation



      • Respiratory weakness > limb-girdle weakness


      • Intracranial aneurysms secondary to glycogen in vessels


  • Laboratory Findings



    • Normal ischemic exercise test


    • Increased creatine kinase


  • Electromyography (EMG): myopathy, electrical myotonia without clinical myotonia


  • Inheritance: autosomal recessive (AR)


  • Path: vacuolar myopathy. Accumulation of periodic acid-Schiff (PAS) positive material in lysosomes


II. Muscle Phosphorylase Deficiency (McArdle Disease) Glycogen Storage Disease Type V



  • Onset



    • Childhood with exercise intolerance


    • Adults with cramps


  • Clinical Presentation



    • Premature fatigue, weakness


    • Myalgias


    • Cramps


    • Symptoms resolve with rest


    • Acute muscle necrosis


    • Myoglobinuria (dark urine following exercise)


    • Fixed weakness occurs in one third of patients



  • Laboratory Findings



    • Positive ischemic exercise test (no rise in serum lactate after ischemic exercise)


    • Creatine kinase elevated in 90%


    • Myoglobinuria in 50%


  • EMG: usually normal, may have second-wind phenomenon


  • Inheritance: AR


  • Path



    • Subsarcolemmal glycogen deposits (blebs), which are periodic acid-Schiff (PAS) positive.


    • Intermyofibrillar vacuoles


    • Immunohistochemical stains show absent staining for phosphorylase.


III. Muscle Phosphofructokinase Deficiency (Tauri Disease) Glycogen Storage Disease Type VII.



  • Onset: childhood


  • Clinical Presentation



    • Premature fatigue, weakness, stiffness induced by exercise


    • Myalgias


    • Cramps


    • Symptoms resolve with rest


  • Laboratory Findings



    • Positive ischemic exercise test


    • Creatine kinase elevated


    • Mild hemolysis


  • EMG: normal, myopathic, or irritative


  • Inheritance: AR


  • Path



    • Subsarcolemmal glycogen deposits (blebs)


    • Intermyofibrillar vacuoles


    • Immunohistochemical stains show absent phosphofructokinase staining.


IV. Glycogen Storage Disease Quick Reference Table























































Type

Eponym

Defect

Involved Tissue

Special Features


I

Von Gierke

Glucose-6-phosphatase

Liver, kidney

Hypoglycemic seizures


II

Pompe

Acid Maltase

Generalized

Floppy baby


III

Forbe

Debranching enzyme

Generalized


IV


Transglucosidase

Generalized


V

McArdle

Muscle phosphorylase

Muscle

Cramps, weakness


VI


Liver phosphorylase

Liver, WBC

Hypoglycemia


VII

Tarui

Phosphofructokinase

Muscle, RBC

Cramps, weakness


VIII

Phosphorylase kinase

Liver


WBC, white blood cell; RBC, red blood cell.



Amino Acid Metabolism


I. Amino Acidemias



  • Types



    • Proprionic acidemia


    • Methylmalonic acidemia


    • Multiple carboxylase deficiency



    • Isovaleric acidemia


    • 3-Oxothiolase deficiency


  • General Characteristics (common to all acidemias)



    • Onset: infancy


    • Clinical presentation



      • Vomiting


      • Anorexia


      • Lethargy


      • Ketoacidosis


      • Dehydration


      • Hyperammonemia


      • Neutropenia


      • Failure to thrive


      • Hypomyelination


      • Seizures


      • Mental retardation


      • Coma


      • Death


    • Inheritance: AR


    • Laboratory Findings



      • Hyperammonemia


      • Hyperglycinemia


      • Urine and serum organic acids


  • Specific Characteristics



    • Biotinidase deficiency—rash, ataxia, optic and auditory degeneration, paraplegia, seizures


    • Proprionic acidemia—hypotonia, infantile spasms, hypsarrhythmia, myoclonus


    • Methylmalonic acidemia—basal ganglia strokes, spasticity, dystonia, chorea


  • Treatment



    • Multiple carboxylase deficiency—biotin 10 mg/d


    • Methylmalonic acidemia—vitamin B12


    • Isovaleric acidemia—oral glycine supplements


II. Glutaric Aciduria Type I



  • Onset: infancy


  • Clinical Presentation



    • Spasticity


    • Dystonia


    • Choreoathetosis


    • Opisthotonos


    • Developmental delay


    • Macrocephaly


  • Laboratory Findings: urine and serum organic acids; enzyme assay


  • Imaging: atrophy. Gliosis in caudate and putamen. Caudate atrophy


  • Inheritance: AR


  • Treatment



    • Low-protein diet


    • Carnitine supplements


    • Riboflavin supplements



III. γ-Hydroxybutyric Aciduria



  • Onset: infancy (rare)


  • Clinical Presentation



    • Hypotonia


    • Seizures


    • Mental retardation


  • Inheritance: AR


  • Treatment: anticonvulsants


IV. Phenylketonuria (PKU)



  • Defect



    • PKU—decreased phenylalanine hydroxylase (conversion of phenylalanine to tyrosine)


    • Malignant PKU (stiff-baby variant)—dihydropterin reductase (biopterin) deficiency


  • Onset: infancy


  • Clinical Presentation



    • Normal at birth; symptoms appear after baby is exposed to phenylalanine in diet.


    • Mental retardation


    • Fair skin


    • Blue eyes


    • Blonde hair


    • Hyperreflexia


    • Hyperkinetic activity


    • Photosensitivity


    • Rash


    • Seizures


    • Musty body odor


  • Laboratory Findings



    • Phenylalanine screen positive if phenylalanine level >20 mg/dL



      • Check level at birth and at 2 weeks of age.


      • Obtain biopterin screen if phenylalanine levels are high.


    • Tyrosine is low.


  • Electroencephalogram (EEG)



    • Untreated: paroxysmal; hypsarrhythmia


    • Treated: normal


  • Imaging: decreased metabolism in the caudate and putamen; atrophy


  • Inheritance



    • PKU: AR chromosome 12


    • Malignant PKU: AR chromosome 4


  • Treatment



    • Low phenylalanine diet


    • Biopterin for malignant PKU (poor prognosis)


V. Nonketotic Hyperglycinemia



  • Onset: Neonate


  • Clinical Presentation



    • Hiccups


    • Respiratory arrest


    • Coma


    • Seizures


    • Microcephaly



    • Hypotonia leading to hypertonia


    • Death is common in the neonatal period.


  • Laboratory Findings—cerebrospinal fluid (CSF glycine: serum glycine) 0.10


  • EEG: burst suppression; hypsarrhythmia; focal epileptiform discharges


  • Imaging: atrophy; hypomyelination


  • Treatment: anticonvulsants


VI. Urea Cycle Defects



  • Specific Defects



    • Ornithine transcarbamylase deficiency



      • Most common


      • X-linked recessive


    • Carbamoyl phosphate synthetase deficiency



      • Most severe


      • AR


    • Arginosuccinic acid synthase deficiency (citrullinemia)



      • AR


    • Arginosuccinase deficiency



      • AR, chromosome 9


  • General Characteristics (common to all urea cycle defects)



    • Onset: neonate


    • Clinical presentation



      • Coma


      • Seizures


      • Hypotonia


      • Respiratory arrest


      • Occasional hemorrhages


      • Vomiting


      • Death without treatment


      • Normal with early treatment


    • Laboratory Findings



      • Serum ammonia >500 µg/dL


      • Serum amino acids (increased glutamine)


      • Elevated AST and ALT


    • Imaging: cerebral edema; occasional hemorrhage


    • Path



      • Cerebral edema


      • Alzheimer type II cells


      • Decreased myelination


      • Neuronal loss


    • Treatment



      • Hemodialysis to decrease ammonia


      • Dietary restriction of nitrogen (low-protein diet)


      • Avoid valproate for seizures as this drug increases ammonia


VII. Hartnup Disease—Amino Acid Transport Defect



  • Onset: infancy


  • Clinical Presentation



    • Variable


    • Failure to thrive



    • Photosensitive rash


    • Intermittent ataxia


    • Nystagmus


    • Tremor


  • Laboratory Findings: neutral amino acids with low serum tryptophan


  • Defect: defective sodium-dependent neutral amino acid transport in the small intestine and renal tubules leading to increased fecal and urinary amino acid excretion


  • Treatment



    • High-protein diet


    • Nicotinic acid supplements (niacin)


    • General improvement with age


VIII. Lowe Syndrome (Oculocerebrorenal Syndrome)



  • Onset: neonate


  • Clinical Presentation



    • Mental retardation and developmental delay


    • Glaucoma


    • Cataracts


    • Myopathy


    • Pendular nystagmus


    • Punctate cortical lens opacities may be only sign in heterozygote female carriers


    • Death from renal failure


  • Inheritance: X-linked recessive


  • Path: loss of central and peripheral myelinated fibers


  • Defect: thought to be caused by a membrane transport defect


IX. Maple Syrup Urine Disease



  • Onset: neonate


  • Clinical Presentation



    • Hypertonic


    • Opisthotonos


    • Fluctuating ophthalmoplegia, which correlates with serum leucine levels


    • Clonus


    • Generalized seizures


    • Developmental delay


    • Patient eventually becomes flaccid and areflexic.


    • Coma


  • Laboratory Findings: elevated branched amino acids (leucine, isoleucine, and valine) on serum amino acid screen. Positive 2,4-dinitrophenylhydrazine urine test. Characteristic urine odor


  • Imaging: cerebral edema greatest in cerebellar deep white matter and brainstem


  • Path: white matter cystic degeneration; gliosis


  • Defect: α-ketoacid dehydrogenase deficiency resulting in abnormal oxidative decarboxylation and accumulation of branched-chain amino acids


  • Prognosis: may have normal IQ if treated within 5 days


  • Inheritance: AR


  • Treatment



    • Thiamine supplementation


    • Dietary restriction of branched-chain amino acids



X. Homocystinuria



  • Onset: variable


  • Clinical Presentation



    • Marfanoid habitus


    • Cod fish vertebra (biconcave)


    • Eye anomalies



      • 90% have ectopia lentis (lens displaced downward)


      • Myopia


      • Glaucoma


      • Optic atrophy


    • CNS



      • Mental retardation


      • Seizures


      • Behavioral disorders


      • Stroke (beginning at age 5 to 9 months)


  • Laboratory Findings



    • Increased homocysteine on serum and urine amino acids


    • Positive methionine challenge test


  • Path: intimal thickening and fibrosis of blood vessels leading to arterial and venous thrombosis


  • Defect: cystathionine β-synthase deficiency resulting in accumulation of homocysteine and methionine. There is also impaired methylation of homocysteine to methionine from enzyme deficiency or cofactor B12 deficiency.


  • Inheritance: AR, chromosome 21


  • Treatment



    • Restrict dietary methionine.


    • Pyridoxine supplements


    • Vitamin B12 supplements


    • Cysteine supplements


Purine Metabolism


I. Lesch-Nyhan Syndrome



  • Onset: age 6 months


  • Clinical Presentation



    • Crystalluria


    • Developmental delay


    • Choreoathetosis


    • Dystonia


    • Opisthotonos


    • Hyperreflexia


    • Mental retardation


    • Self-mutilating behavior


  • Laboratory Findings: hyperuricemia


  • Defect: hypoxanthine-guanine phosphoribosyl transferase deficiency


  • Inheritance: X-linked recessive



  • Treatment



    • Allopurinol 20 mg/kg per day (blocks uric acid synthesis)


    • Physical restraint


    • L-5-hydroxytryptophan + L-dopa


    • Fluphenazine (may help decrease self-mutilating behavior)


Lipoprotein Metabolism


I. Abetalipoproteinemia (Bassen-Kornzweig Disease)



  • Clinical Presentation



    • Neurologic symptoms begin by age 12 years.


    • Fat malabsorption with diarrhea and steatorrhea


    • Acanthocytosis


    • Retinopathy


    • Vitamin A, D, E, and K deficiency


    • Neuropathy with decreased reflexes, proprioception, and sensation


    • Progressive ataxia


    • Positive Romberg


    • Decreased night vision (retinitis pigmentosa)


    • Weakness


  • Laboratory Findings



    • Acanthocytosis


    • Absent β-lipoproteins (chylomicrons, low-density lipoprotein (LDL), very LDL)


    • Decreased triglycerides and cholesterol


    • Low Vitamin A, D, E, and K levels (fat-soluble vitamins)


    • Increased prothrombin time


  • Nerve Conduction Velocity (NCV): slowed conduction


  • Path



    • Loss of large myelinated fibers


    • Spinocerebellar and posterior column degeneration


  • Defect: decreased posttranslational processing of apolipoprotein B


  • Inheritance: AR


  • Treatment



    • Dietary restriction of triglycerides


    • Vitamin E supplements


II. Tangier Disease



  • Clinical Presentation



    • Large orange tonsils


    • Lymphadenopathy


    • Splenomegaly


    • Corneal infiltrates


    • Relapsing multiple mononeuropathies


    • Loss of pain and temperature sensation


    • Peripheral neuropathy in 50% with demyelinating sensory, sensorimotor, or motor neuropathy


  • Laboratory Findings



    • Decreased total cholesterol and LDL


    • Triglycerides normal or increased


    • Very low HDL



  • Path



    • Lipid droplets in Schwann cells and in reticular endothelial system of other cells


    • Neuropathy: demyelination/remyelination


    • Syringomyelia: like syndrome with axonal degeneration


  • Defect: α-lipoprotein deficiency


  • Inheritance: AR


  • Treatment: None

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Sep 8, 2016 | Posted by in NEUROLOGY | Comments Off on Metabolic Disorders

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