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VITAMIN, MINERAL & NUTRITION RELATED SYNDROMES

Minerals
  Copper
  Iron
  Selenium
Vitamins
  A: Retinoids
  B1: Thiamine
  B2: Riboflavin
  B12 deficiency
  Biotin
  D
  E
    Deficiency
    Intoxication
  Niacin
  Folate
  Pyridoxine
    Deficiency
    Intoxication
MULTIFACTORIAL
Alcoholism
Celiac disease
Critical illness polyneuropathy
Cuban neuropathy
Postgastroplasty (Bariatric surgery)
Strachan's

Also see
  GI disorders
  Toxic disorders
    Muscle
    Nerve


Vitamin & Toxic Disorders: Symptom features

Thiamine (B1) deficiency (beri-beri)
B1 Biochemistry
Deficiency
  Clinical
  Laboratory
Thiamine disorders
Thiamine
"A certain very troublesome affliction, which attacks men,
is called by the inhabitants Beri-beri (which means sheep).
I believe those, whom this same disease attacks,
with their knees shaking and legs raised up, walk like sheep.
It is a kind of paralysis, or rather Tremor:
for it penetrates the motion and sensation
of the hands and feet, indeed sometimes the whole body..."

Jacobus Bonitus, Java, 1630

Riboflavin (B2)
  Related syndromes
Riboflavin

Niacin
  (Nicotinic acid; Vitamin B3)
    Deficiency

Nicotinamide
  • Biochemistry
    • Niacin: Includes Nicotinic acid & Nicotinamide
    • Metabolically active forms
      • Nicotinamide adenine dinucleotide (NAD)
      • NAD phosphate (NADP)
    • Functions: Oxidation–reduction reactions
    • Associated enzymes carry out oxidation & reduction reactions
    • Sources: Meat, Liver, Fish, Legumes, Coffee & tea
  • Diet
    • Sources: Meat, Liver, Fish, Legumes, Coffee & Tea
    • Inhibitor: Leucine excess (Millet) blocks conversion of tryptophan to niacin
  • Pellagra
    • Causes
      • Reduced diet intake of niacin or tryptophan
      • Niacin deficiency: Isoniazid; Alcoholism
      • Associations
        • Hartnup's disease: Defective intestinal absorption of amino acids
        • Carcinoid syndrome: Conversion of tryptophan to serotonin by tumor
        • HIV infection
    • Clinical: DDD
      • Diarrhea
      • Dermatitis: Areas exposed to sunlight
      • CNS: Dementia; Hyperreflexia; Startle myoclonus; Insomnia; Fatigue
      • Tongue: Glossitis; Burning sensations
      • Neuropathy
        • Similar to Beri-Beri
        • ? Related to other associated vitamin deficiencies
        • Treatment: No response to niacin alone
    • Treatment
      • Niacin: 40 to 250 mg qd; Causes flushing
      • Nicotinamide: 100 mg po qid; Then 50 mg tid until skin lesions resolve
      • Children: Nicotinamide 10–50 mg orally every 6 hours

Pyridoxine:
  Intoxication
Pyridoxine

Pyridoxine: Deficiency 15

Vitamin B12 (Cobalamin) deficiency
Causes
Clinical features
Testing

Vitamin B12
  • Vitamin B12
    • Cofactor for: Methionine synthase & l-Methylmalonyl–coenzyme A mutase
    • Necessary for development & initial myelination of CNS
    • Daily requirement: 2.4 μg
  • Clinical features
    • Polyneuropathy
      • Symmetric
      • Sensory change: 2° spinal or peripheral nerve lesions
        • Early: Paresthesias
        • Loss: Especially of large fiber modalities
        • Distal
      • Motor
        • Distal weakness
        • Later in disease course
      • Reflexes
        • Tendon: Reduced or absent at ankles
        • Plantar: Upgoing
      • Autonomic
    • CNS
      • Spinal cord: Earliest locus of involvement
        • Major cause of sensory & motor disability
        • Posterior column fiber loss
        • Spasticity in legs
        • Similar clinical features to N2O toxicity
      • Other CNS
        • Adults: Cognitive impairment
          • Megaloblastic madness
          • MRI: Leukoencephalopathy
        • Childhood syndromes: Mental retardation or Encephalopathy
        • Sensory
          • Smell & Taste reduced
          • Optic atrophy
        • Gait ataxia
    • Anemia: Due to reduced DNA synthesis
      • Megaloblastic
      • Hypersegmented neutrophils
      • Leukopenia
      • Thrombocytopenia
      • LDH: High
      • Haptoglobin level: Reduced
    • Gastrointestinal: Glossitis; Diarrhea
    • Fingernails: Hyperpigmented
    • Infants
      • Development: Delay or Regression
      • Hypotonia, Lethargy & Feeding difficulties
      • Seizures
      • Movements: Myoclonus; Choreoathetosis; Tremors
      • Microcephaly
  • Testing 13
    • Serum: Presence of B12 deficiency
      • B12 Low
        • < 200 pg/ml
          • 65–95% sensitive for proven clinical B12 deficiency
          • 50% to 60% predictive of clinical response to B12 treatment
          • Assay often unreliable: In presence of anti-intrinsic factor antibodies
        • < 350 pg/ml
          • Sensitivity: 90%
          • Specificity: 25% for detecting high level of methylmalonic acid
      • Homocysteine, Serum or Plasma, High (Normal < 14)
        • > 21 μmol/liter: 96% sensitive for clinical B12 deficiency
        • Homocysteine also elevated in folate deficiency & renal insufficiency
        • Hyperhomocysteinemia in countries with folate-fortified food: Suggests B12 deficiency
        • B12 treatment: High levels fall
      • Methymalonic acid, Serum High (Normal < 400)
        • > 400 nmol/liter: 98% sensitive for clinical B12 deficiency
        • 300–1000 nmol/liter: Poor specificity for clinical response
        • Megaloblastic anemia or Myelopathy: Levels of methylmalonic acid
          • > 500 nmol per liter: Nearly all patients
          • > 1000 nmol per liter: 86%
        • False positive elevation of 300–700 nmol/liter: Renal failure & Volume depletion
        • B12 treatment: High levels fall
    • Specific causes of B12 deficiency
      • Pernicious anemia
        • Intrinsic factor antibodies
          • Sensitivity: 50%
          • Specificity: 100%
          • Must be tested > 7 days after vitamin B12 injection: Prevents false positive result
        • Parietal cell antibodies
          • Sensitivity: 80%
          • Specificity: 50% to 100%
        • Rule out: Gastric cancer
      • Atrophic body gastritis (Antral sparing; Autoimmune gastritis)
        • Fasting high serum gastrin level (> 100 pmol/liter): Sensitivity 85%
      • Pepsinogen I low in serum (< 30 μg/liter): Sensitivity 90%
      • B12 malabsorption
        • ? Increase serum holotranscobalamin level after oral loading: Not available in US
        • Proven B12 deficiency in patient who eats meat or receives multivitamin therapy
    • MRI: Hyperintense T2 spinal lesions
      • Location: Posterior columns (50%)
      • Lesions resolve after 8 to 12 months of therapy
    • Evoked potentials
      • Somatosensory: Abnormal tibial & median
      • Motor: Normal in most
  • Pathology
    • Spinal cord
      • Multifocal axonal loss & demyelination
      • Localization
        • Cervical & thoracic
        • Posterior column > Anterolateral & Anterior
    • Peripheral nerve: Axonal loss; Occasional ± demyelination
  • Treatment
    • Pernicious anemia: 1000 μg daily IM over 1 week; Then oral 1000 to 2000 μg daily for life
    • Other malabsorption: Oral cyanocobalamin 500 to 1000 μg daily for 1 week; Taper to 1000 μg monthly
    • Dietary deficiency: > 2 μg daily
    • Infants: IM cyanocobalamin 250 to 1000 μg daily for 1 week; Then oral supplementation
  • Prognosis: Stabilization, or Some improvement
    • Paresthesias
      • Resolve within weeks
      • Rarely transient exacerbation after treatment
    • Myelopathy changes slowly if at all
  • Causes of B12 deficiency: Normal body stores last 3 to 4 years
    • Gastrointestinal malabsorption
      • Deficient intrinsic factor production
        • Post-gastrectomy
        • Antibody vs parietal cells 6: Pernicious anemia
          • Onset: Median = 60 years; Female slightly > Male
          • Antibody targets: Gastric H+/K+-ATPase
            • Catalytic α subunit, and
            • Glycoprotein β subunit
          • Regions of stomach affected: Fundus & body; Not antrum
          • Mechanisms of B12 deficiency
            • Reduced intrinsic factor production 2° parietal cell loss
            • Antibodies to B12 binding site on intrinsic factor
              • Prevent formation of complex normally carried to terminal ileum & absorbed
          • Associated immune disorders
          • Associated neoplasia: Gastric carcinoma (1% to 3%)
          • Family history
            • 20% of relatives also have pernicious anemia;
            • Especially 1st degree females
          • Gastritis treatment: Corticosteroids; Azathioprine
      • No digestion of cobalamin-R-binder complex
        • Pancreatic insufficiency
      • Consumption of cobalamin in GI tract
        • Intestinal bacterial overgrowth
      • Poor absorption by distal ileum
        • Sprue-related disorders
        • Autosomal recessive disorders
            Anemia; Proteinuria; Juvenile onset
      • Parasitic infection: Diphyllobothrium latum
    • Dietary inadequacy in vegetarians
      • Sources: Meat & dairy products
    • Congenital disorders of B12 binding proteins
      • Transcobolamin I (Vitamin B12 R-binding protein) deficiency
        • Neurological B12 deficiency syndromes in adults
      • Gastric intrinsic factor deficiency (IFD)
        • Gene: GIF
        • Congenital anemia & jaundice
      • Transcobalamin II deficiency
        • Gene: TCN2
        • Megaloblastic anemia; Diarrhea; Immunodeficiency; Mental retardation
    • Abnormalities of synthesis of active forms of B12
      • Methylcobalamin deficiency
        • Type E : Methionine synthase reductase (MTRR)
        • Type G : Methionine synthase (MTR)
        • Neurological (CNS) & Hematological B12 deficiency syndromes
        • Age: Children
      • Methylmalonic aciduria, cblA type (Adenosylcobalamin deficiency)
        • Gene: MMAA
        • Episodic ketoacidosis; Encephalopathy; Neutropenia; Osteoporosis
      • Combined methylcobalamin & adenosylcobalamin deficiency
        • Methylmalonic aciduria & Homocystinuria, cblC type : MMACHC
        • Methylmalonic aciduria & Homocystinuria, cblD type : MMADHC (C2orf25)
        • Mental retardation; Anemia ± Myelopathy in slowly progressive cases
      • Nitrous oxide exposure
        1. Oxidizes cobalt in cobolamin: Methylcobalamin inactivated
        2. Inhibits conversion of homocysteine to methionine:
        3. Reduced supply of S-adenosylmethionine
    • Abnormal release of B12 from lysosomes
      • Methylmalonic aciduria & Homocystinuria, cblF type : LMBRD1
      • Methylmalonic aciduria & Homocystinuria, cblJ type: ABCD4

Putnam

Vitamin E deficiency
Vitamin E (α-tocopherol)

Hypervitaminosis E
Vitamin D deficiency 5
1,25-Dihydroxy Vitamin D3

Biotin deficiency
  • Biotin
  • Deficiency: Causes
  • Clinical
    • Onset
      • Encephalopathy & Confusion: Subacute onset
      • Dysarthria & Dysphagia
      • ± Facial nerve palsy: Supranuclear
      • ± External Ophthalmoplegia
    • Late features
    • Treatment: Biotin (5-10 mg/kg/day)
  • MRI: Central necrosis of the head of the caudate ± Putamen
Biotin

Neurodegeneration, infantile-onset, Biotin-responsive (NERIB)
  Solute carrier family 5 (Sodium-dependent vitamin transporter), Member 6 (SLC5A6) ; Chromosome 2p23.3; Recessive
Retinoid (Vitamin A derivatives) toxicity
Cuban epidemic neuropathy 1

Bariatric surgery (Postgastroplasty) syndromes: Polyneuropathy +
Selenium 3, 4

Copper Deficiency & Disorders


Copper deficiency: Acquired
  • Predisposition
    • Zinc: High levels
      • Increased intake
        • Chronic over years
        • Sources
          • Zinc supplements
          • Coins
          • Denture creams
      • Idiopathic
    • Molybdenum excess
    • Gastric bypass surgery
    • Chemotherapy: Tetrathiomolybdate
    • Copper chelating agents: Penicillamine; Clioquinol
    • Hyperhomocysteinemia 12
    • Deficient copper intake
      • Total parenteral nutrition
      • Infancy
    • Nephrotic syndrome
  • Clinical syndrome: Myelopathy 7
    • Sensory
    • Motor: May be normal other than gait
      • Spasticity
      • Leg dysfunction: Upper motor neuron pattern
      • Gait: Spastic-Ataxic
    • Reflexes
      • Tendon reflexes: Increased
      • Plantar responses: Extensor
    • Course: Progression over years
    • Laboratory
      • MRI: T2 signal increased
      • Early pathology: Axonal swelling
    • Treatment: Stabilization; Little improvement
  • Clinical syndrome: Lower motor neuron syndrome + Sensory loss 11
    • Clinical
      • Weakness
        • Asymmetric
        • Proximal & Distal
        • Gait disorder
      • Sensory loss: Large fiber modalities
      • Reflexes
        • Tendon: Brisk; May be reduced distally
        • Plantar: Upgoing
    • Electrodiagnostic
      • EMG: Diffuse denervation
      • NCV
        • CMAP: Small; Asymmetric
        • SNAPs: Normal
    • Muscle biopsy
      • Acute denervation: Angular muscle fibers; Targets
      • ? Mitochondrial complex IV reduced activity
  • Clinical syndrome: Neuropathy
    • Sensory-Motor
    • NCV: Axonal loss
  • Clinical syndrome: Optic neuropathy
  • Laboratory
    • Hematologic features
      • Sideroblastic anemia
      • Neutropenia
      • Myelodysplastic syndrome
    • EKG
      • QRS complex: Increased amplitude
      • T waves: Inverted
      • Increased ST segments
  • Differential Diagnosis
    • B12 deficiency
    • Methylmalonic Acid
    • Hereditary
      • Menkes : Urine & Hepatic copper low; Ceruloplasmin low
      • Wilson: Urine & Hepatic copper high; Ceruloplasmin low
  • Treatment
    • Copper supplementation: Cupric sulfate
      • IV: 2 mg IV for 5 days
      • Oral: 8 mg daily Cu x 1 week, 6 mg for 2nd week,
                  4 mg 3rd week, 2 mg thereafter
    • Stop zinc intake
    • Paresthesias often improve




MRI: Copper Deficiency
Posterior column T2 signal

Copper smelting: Associated with Arsenic toxicity


Copper-associated: Disorders & Enzymes 16
Copper: Animal disorders
Iron Disorders

Folate deficiency: Neuropathy 14

Critical Illness Neuropathy
Return to Neuromuscular Home Page

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3. JNNP 1999;67:829-830
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15. J Clin Neuromuscul Dis 2014;16:25-31
16. J Trace Elem Med Biol 2019;56:156-161
17. Muscle Nerve 2018;57:33–39

Some illustrations from MW King

9/1/2020