Vitamin syndromes

Home, Search, Index, Links, Pathology, Molecules, Syndromes,
Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

VITAMIN, MINERAL & NUTRITION RELATED SYNDROMES

Minerals
Copper deficiency
Iron
Selenium deficiency
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

CNS
- Cognition: B₁; Niacin; B₁₂; Lead; As; Hg
- Cerebellum: E; Hg
- Corticospinal: B₁₂; Cu
- Posterior column: B₁₂; Cu
Integument
- Skin: B₁; Lead; As; Thallium; Hexacarbon; Alcohol
- Nails: As; Thallium
Muscle: E
GI: E; Lead; As; Thallium
Cardiac: B₁
Renal: Hg
Hematologic
- Anemia: B₁₂; Cu; Lead
- Pancytopenia: As

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

Biochemistry

Sources: Yeast, Pork, Legumes, Cereal grains, Rice (Whole grain)
Metabolically active form: Thiamine pyrophosphate (TPP)
- Structure: Hydroxyl group is replaced by diphosphate ester group
- TPP is a coenzyme for two types of enzymes: Cleave a C-C bond adjacent to a carbonyl group
  - α-Ketoacid dehydrogenases
  - Transketolases
- TPP dependent enzymes also require a divalent cation, commonly Mg⁺⁺
Enzyme systems: Cofactor
- α-ketoglutarate dehydrogenase: Krebs cycle
- Pyruvate dehydrogenase: Pyruvate → Acetyl CoA
- Transketolase: Pentose monophosphate shunt
Transported into cells by thiamine carriers
- SLC19A2 (THTR1)
- SLC19A3 (THTR2)
Metabolism
- Half life: 1.5 to 24 hours
- Tissue storage: Limited time
  - Depletion with thiamine-deficient diet: 18 days; Range 1 to 4 weeks
Clinical features
- Peripheral neuropathy (Dry beri-beri) ¹⁰
  - Clinical
    - Onset
      - Progression: Variable
        
        Acute (< 1 month) 50%
        
        Chronic (> 1 year) 20%
      - Weakness (Legs): 50%
      - Sensory loss (Legs ± Hands): 50%
    - Distribution
      - Symmetric
      - Legs > Arms
    - Weakness
      - Distal > Proximal
      - Legs (Foot dorsiflexors) & Hands (Wrist extensors; 80%)
    - Sensory
      - Loss
        
        Modalities: Large & Small fiber
        
        Distribution: Distal; Feet & Hands
      - Pain
        
        Burning feet
        Lancinating pain
        Calf tenderness
        
        Paresthesias
        Frequency: Some patients
    - Autonomic neuropathy: With severe disease
      - Orthostatic hypotension
      - Bladder: Flaccid
      - GI: Gas retention
    - Tendon reflexes: Reduced or Absent, especially ankles
  - Laboratory
    - Nerve pathology
      - Axon loss: Especially large axons
      - Subperineurial edema: Some patients
      - No segmental demyelination
      - Other nerves involved (Distal regions): Vagus; Phrenic
      - Regeneration: May occur after treatment
      - Ultrastructure
        
        Axonal accumulations: Tubular or Tubulovesicular structures
        
        Focal aggregates: Filaments, Microtubules, Glycogen, Mitochondria
    - Nerve conduction: Axon loss
      - Motor & Sensory
      - Length dependent
- Cranial nerve weakness (Occasional)
  - Laryngeal (Hoarseness)
  - Face
  - Tongue
- CNS
  - Extraocular movement paresis
  - Cerebellar degeneration: Ataxia
  - Encephalopathy
    - Acute: Wernicke's disease
      - Mental status change: Confusion; Memory loss; Agitation
      - Ataxia: Especially truncal; Gait disorder
      - Ocular: Paresis; Nystagmus; Retinal hemorrhages
    - Chronic: Korsakoff's psychosis
      - Memory disorders
      - Dementia
- Systemic
  - Cardiac failure (Wet beri-beri): Congestive; Tachycardia; Edema
  - Infantile beri-beri
    - Epidemiology
      - 3rd world
      - Malnutrition: Breast-feeding infants whose mothers are thiamine deficient
    - Onset age: 2 to 6 months
    - Cardiac failure: Acute; Cyanosis & Dyspnea
  - Anorexia: Weight loss
- Associated or causative disorders
  - Alcoholism
  - Malnutrition: Polished rice; HIV infection; Systemic malignancy; Anorexia nervosa
  - Dialysis
  - Malabsorption & repeated vomiting: Gastric resection; Pregnancy
  - Diet with thiaminases: Raw fish (carp)
  - Infantile beri-beri
- Treatment: Thiamine
  - Acute
    - Immediate: 100 mg/ml solution; Give 100 mg iv before glucose
    - Follow-up: 100 mg i.m. for 3 to 5 days
  - Chronic therapy: 50 mg i.m. for 2 weeks, then, Thiamine 50 mg p.o. per day
  - Prophylactic: Treat with thiamine before giving i.v. glucose
  - Response
    - Oculomotor change best
    - Dementia & Neuropathy less well
Laboratory
- Diagnosis
  - Serum thiamine levels (HPLC)
    - Normal range: 60 to 220 nM
    - Normal levels in Wernicke encephalopathy: Thiamine transporter gene mutations
  - Transketolase activity
    - Whole blood or Erythrocyte
    - Addition of thiamine diphosphate (TPP): Increased RBC Transketolase activity toward normal
  - Urine thiamine excretion: 24 hour measurement
- Other lab
  - Pyruvate, Serum: High
  - Brain MRI: Mammilary body & Medial thalamus T2 hyperintensity
Hereditary disorders of thiamine metabolism: Thiamine metabolism dysfunction syndromes (THMD)
- THMD1: SLC19A2 (THTR1)
  - Thiamine-responsive megaloblastic anemia syndrome (TRMA)
- THMD2: SLC19A3 (THTR2) : Leigh-like disorders
  - Biotin-responsive basal ganglia disease (BBGD)
  - Encephalopathy, Early-infantile, lethal
- THMD3: Microcephaly, Amish type; SLC25A19
- THMD4: Episodic flaccid paralysis & Encephalopathy; SLC25A19
- THMD5: Encephalopathy, Ataxia, Retardation & Dystonia, Progressive with Lactic acidosis, TPK1
Disorders treated by thiamine supplementation
- Pyruvate dehydrogenase deficiency
- Maple syrup urine disease

Riboflavin (B2)
Related syndromes

Riboflavin

Riboflavin Deficiency
- Test: Increased acylcarnitines
- ? Burning feet syndrome
- Hereditary : SLC52A1 ; Dominant; May be asymptomatic
Riboflavin Sensitive myopathies
- Multiple acyl–CoA dehydrogenase deficiency (Glutaricaciduria IIA)
- ACAD9
- ? Myopathic carnitine deficiency
- ? MELAS: With Idebenone
- Mitochondrial: tRNA Leu mutation (T3250C)
  - Genetics
    - Heteroplasmic
    - T3250C Mutation may also present with
      - Fatigue syndrome
      - Cardiomyopathy
  - Clinical
    - Onset: 1 year
    - Weakness: Proximal & Neck extensor
    - Lumbar lordosis
    - Normal EOM
  - Family history: Sibs with early death
  - Biochemistry: Complex I deficiency
Riboflavin transporter disorders
- Brown-Vialetto-van Laere 1: SLC52A3
- Brown-Vialetto-van Laere 2: SLC52A2 (RFVT2)
Treatment doses: 100 mg to 300 mg per day

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

Nutritional & metabolic data
- Normal: With intake up to 200 mg/day
- Minimum daily requirement: 0.6 to 1.3 mg/day
- Active in phosphorylated form: Pyridoxal-5-phosphate
- Cofactor for enzymes involved in amino acid metabolism
- Absorption: Passive; Unsaturable
- Excretion: Urine
Sensory neuropathy/Neuronopathy
- Syndromes
  - High doses (180 g): Acute sensory neuronopathy
    - Paresthesias: Diffuse
    - Sensory loss
      - Proximal & Distal
      - Sensory ataxia
    - Autonomic dysfunction
    - Strength: Normal
    - Recovery: Poor on most
  - Lower doses (0.2 to 10 g/day): Chronic neuropathy
    - Sensory loss
      - Distal > Proximal
      - Panmodal
      - Sensory ataxia
    - Paresthesias & Pain: 50%
    - Course
      - Latency until symptoms: Shorter with higher doses
      - Progressive
      - Recovery with treatment: Good
    - Tendon reflexes: Reduced distally
    - Strength: Reduced with very high doses
    - Skin color: May be yellow
    - Nerve pathology: Distal axon loss
- Laboratory
  - B6 levels > 10x upper limit of normal (Normal 40–120 µg/l)
  - NCV
    - SNAP amplitudes: Decreased, not length dependent
  - CSF: Normal

Pyridoxine: Deficiency ¹⁵

Pyridoxine sources
- Grains (enriched)
- Chicken
- Fruit & Vegetables: Orange & Tomato juice, Banana, Avocado
- Normal GI microflora
At risk populations
- Malnutrition: Alcoholics, Prisoners, Refugees
- Infants of B₆ deficient mothers
- Increasing age
- Patients using Isoniazid, Penicillamine & Hydralazine
  - Slow acetylation of isoniazid
  - Isoniazid & hydralazine cause increased excretion of pyridoxine in urine
Clinical
- Many patients have other, additional nutritional deficiencies
- Polyneuropathy
  - Distal
  - Symmetric
  - Sensory > Motor
  - Pain & Paresthesias
  - Axonopathy
- CNS
  - Infantile seizures
    - Pyridoxine responsive: Normal pyridoxine levels
    - Deficient diet: Breast milk feeding from undernourished mothers
  - Adults: Depression; Irritability; Confusion
- Skin: Pellagra-like rash
Diagnosis
- Erythrocyte glutamic pyruvate transaminase ± pyridoxine
- Measure tryptophan metabolites (xanthenuric acid) after tryptophan loading
- High serum & CSF pyruvate
Treatment
- Dose: ≤ 50 mg/day
- Prophylaxis in Isoniazid treatment & Pregnancy: 30 to 50 mg/day

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
    - Postural hypotension
    - Incontinence
    - Impotence
- 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
        
        Thyroiditis
        
        Diabetes
        
        Addison's
        
        Ovarian failure
        
        1° Hypoparathyroidism
        
        Graves
        
        Vitiligo
        
        Myasthenia gravis
        
        Lambert-Eaton syndrome
        
        Common variable immunodeficiency with low Ig or IgA (younger patients)
      - 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
  - 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)

Vitamin E
- Mixture of tocopherols
- α-tocopherol most potent
- Antioxidant
  - Prevents peroxidation of polyunsaturated membrane fatty acids
  - ? Relationship with vitamin E
- Recommended daily allowance: Males 10 mg; Females 8 mg
- Absorbed & incorporated into chylomicrons in small intestine
Causes of deficiency
- Transfer protein disorders
  - A-β-lipoproteinemia
  - Vitamin E transporter deficiency
- Malabsorption
  - Chronic cholestasis
  - Cystic fibrosis
  - Chronic bowel disease: Celiac; Whipple's; Inflammatory; Tropical sprue; Chronic pancreatitis
  - Surgical: Post gastrectomy; Short bowel syndromes
  - Chylomicron retention disease
- Reduced intake
  - Malnutrition
  - Total parenteral nutrition: May be associated with selenium deficiency
Clinical
- Polyneuropathy
  - Sensory loss
    - Large fiber modalities
    - Sensory ataxia
  - Tendon reflexes: Absent
  - Electrodiagnostic
    - Sensory potentials: Usually small; May be normal
    - Abnormal somatosensory evoked potentials
- Myopathy: 1 patient
  - Related to high dose cholestyramine treatment
  - Weakness: Generalized
  - Serum CK: High
  - Muscle pathology: Small ovoid inclusions (H&E purple; GT pink; Acid phos +)
- CNS
  - Ophthalmoplegia
  - Spinal
    - Posterior column sensory loss
    - Extensor plantar responses
- Systemic: A-β-lipoproteinemia
  - Retinitis pigmentosa
  - Acanthocytosis
Pathology
- Dorsal root neurons: Early loss of distal region of central projection
- Spinal cord: Loss of fibers in posterior & Clarke column
- Axonal dystrophy (swellings) in cuneate & gracile nuclei
Diagnosis
- Vitamin E levels: Undetectable or very low levels in serum
- Other: Fat malabsorption → Fatty stools; Low serum carotene
Treatment: Vitamin E supplementation
- A-β-lipoproteinemia
  - 50 to 200 IU/day
  - 100 to 200 mg/kg/day in childhood
  - ? + Vitamins A & K
- Malabsorption: 1 to 4 g/day

Hypervitaminosis E

Weakness: Proximal
Myalgia
Serum CK: High
Muscle
- Necrosis
- GT stain: Paranuclear accumulation of red granular material
  - Inclusion staining pattern: NADH-TR, Acid phosphatase, Esterase

Vitamin D deficiency ⁵

1,25-Dihydroxy Vitamin D₃

Function
- Steroid hormone
- Active form: 1,25-dihydroxy vitamin D₃ (Calcitriol)
- Action via intracellular receptor
- Regulates Ca⁺⁺ & Phosphorus homeostasis
Clinical: Similar to 1° hyperparathyroidism
- Epidemiology
  - Dietary deficiency more common in
    - Northern Europe & US
    - Elderly patients
    - Immigrant populations
    - Infants: Vitamin D deficiency rickets
  - Other predisposition to vitamin D deficiency
    - Pigmented skin
    - Reproductive age females
      - High parity
      - Breast feeding, prolonged
    - Clothing: Wearing long sleeved dresses & veils (Females)
- Myopathy (50%)
  - Weakness
    - Distribution: Proximal; Symmetric; Arms > Legs
    - Severity: Mild to Moderate (4 of 5)
    - Gait disorder: Common
  - Muscle wasting
  - Myalgia
  - Muscle physiology
    - Reduced Force generation
    - Delayed relaxation
  - Course: Slow progression over months
- Tendon reflexes: Normal
- Carpopedal spasm
- Bone
  - Pain: Back, Hips or Lower limbs
  - Osteomalacia or Rickets (See Spinal disorders)
- Treatment
  - Vitamin D
    - Ergocalciferol: Oral (50,000 U 1x/week x6) or IM
    - Vitamin D: Oral 2000 to 3000 IU/Day for 6 weeks
  - Ca⁺⁺ supplementation: > 1 g/day
  - Disease course after treatment
    - Improvement in strength & reduced pain over weeks to months
Laboratory
- 25-Hydroxyvitamin D reduced (< 20 nmol/l)
- Parathyroid hormone: Increased
- Alkaline phosphatase: Often increased
- Serum CK: Normal
- Serum Phosphate: Low
- Serum Ca⁺⁺: Normal or Low (≤2.1 mmol/l)
- Radiographic: Osteomalacia; Pseudofractures (28%)
- EMG
  - Normal or Myopathic (Small polyphasic action potentials)
  - No spontaneous activity
- Muscle biopsy
  - Normal or Non-specific changes
  - Muscle fiber atrophy
Vitamin D deficiency: Other causes
- Vitamin D malabsorption
  - Dietary deficiency
  - Reduced Sun exposure
  - Malabsorption: Post-surgical; Bowel disease
  - Renal: Tubular acidosis; Chronic failure
  - Anticonvulsants
- Osteogenic osteomalacia
  - Onset: Mean 4th decade; Range 5 to 63 years
  - Clinical: Bone pain; Muscle weakness
  - Neoplasm: Mesenchymal; Bone & Soft tissue; Limbs, Head & Neck
  - Lab: Hyperphosphaturia, Hypophosphatemia, Normal serum Ca⁺⁺, Decreased serum 1,25-dihydroxyvitamin D₃

Biotin deficiency

Biotin

Biotin
- Cofactor required in carboxylation enzymes
  - Acetyl-CoA carboxylase
  - Pyruvate carboxylase
Deficiency: Causes
- Prolonged antibiotic therapies: Deplete intestinal fauna
- Excessive consumption of raw eggs
  - Eggwhite protein avidin binds biotin & prevents absorption
Onset
- Subacute encephalopathy & confusion
- Dysarthria & Dysphagia
- ± Facial nerve palsy: Supranuclear
- ± External ophthalmoplegia
Late features
- Spastic paraparesis
- Mental retardation
- Dystonia
MRI: Central necrosis of the head of the caudate ± Putamen
Treatment: Biotin (5-10 mg/kg/day)

Retinoid (Vitamin A derivatives) toxicity

Drugs: Etretinate; Isoretinoin
Discomfort
- Hyperesthesias & paresthesias
- Muscle cramps
- Myalgias & arthralgias
- Fatigue
Weakness
- Proximal
- Mild; Occasional
CNS: Pseudotumor
Systemic: Hepatitis
Serum CK: Normal or High
Muscle: Minor change
- Variation in fiber size
- Occasional necrotic fiber
- EM
  - Elliptical bodies between muscle fibers
  - Simplified neuromuscular junctions

Cuban epidemic neuropathy ¹

Nomenclature: Similar to Strachan's syndrome in prisoners of war
Epidemiology
- Age: 25 to 64
- Male slightly > Female
- Risk factors
  - Tobacco use (Especially cigars)
  - Nutrition reduced
  - Cassava consumption
- Protective
  - Lycopena non-vitamin A antioxidant in tomato, guava, watermelon & red fruit
  - Riboflavin
- Causes: ? Reduced B-group vitamins, carotenoids & sulfur-containing amino acids
Clinical
- Optic neuropathy: Cecocentral scotoma (Bilateral); Photophobia; Color vision reduced
- Sensory-neural hearing loss: High tone
- Polyneuropathy
  - Symmetric
  - Sensory
  - Painful dysesthesias in hands & feet
  - ± Foot drop
- Gait disorder
- Autonomic: Urinary incontinence
- Myelopathy: Dorsolateral; Spasticity in legs
Laboratory
- Neuropathy: Axonal loss, Large > small fiber loss; Axonal regeneration
- CNS: Reduced Myelinated axons in Posterior column
Treatment: B-group vitamins
Prognosis
- Recovery in most with early treatment
- Visual field defects may persist

Bariatric surgery (Postgastroplasty) syndromes: Polyneuropathy +

Epidemiology
- Surgery: For morbid obesity
- Frequency of neuropathy: 5% to 10% of Gastric bypass surgeries
Associated with
- Malnutrition
- Surgical procedures
  - Gastrojejunectomy
  - Gastric stapling
  - Gastroplasty
  - Gastrectomy
  - Jejunoileal bypass: Higher risk
- Vomiting
  - Severe protracted
  - May be chronic after gastrectomy (68%)
- Weight loss
  - Degree: Mean 28%; Range 11% to 48%
  - Rapid
- B12 deficiency
- Copper deficiency
- Selenium deficiency
- Vitamin E deficiency
Neuropathy types ⁹
- Polyneuropathy: Sensory-predominant
- Mononeuropathy
- Radiculoplexus neuropathy
Polyneuropathy ± Myelopathy
- Clinical
  - Onset
    - Course
      - Chronic: 75%
      - Acute or Subacute: 25%
    - Numbness & paresthesias: Distal then proximal in legs
  - Sensory loss
    - Distal ± Proximal
    - Modalities
      - Large fiber: Joint position & Vibration
      - Small fiber
    - Myelopathic pattern
      - Sacral loss
      - Level on trunk
      - Some patients
  - Pain: 60%
    - Feet or Lower back
    - Less prominent than in nutritional (Cuban) neuropathy
  - Weakness: Some patients
    - Distal or Proximal
    - Legs > Arms
  - Hyporeflexia (66%)
  - Autonomic: Uncommon
    - Hypotension: Syncope
  - Progression: May develop quadriparesis
  - CNS association: Optic neuropathy, central scotoma
- Laboratory
  - Nerve conduction studies: Axonal loss
  - Pathology
    - Nerve
      - Axonal loss
      - Inflammation: Perivascular; Endoneurial & Perineurial
    - Muscle
      - Type 2 muscle fiber atrophy
      - Denervation: Angular muscle fibers
  - Serum albumin: Reduced
  - Serum transferrin: Reduced
Sensory polyneuropathy
- Onset: Years after surgery
- Distal
- Symmetric
- Paresthesias
- Slowly progressive
Mononeuropathy
- Median nerve at wrist: 75%
- Onset course
  - Rapid: 50%; More often in nerves other than median
  - Slow: 50%
Radiculoplexus neuropathy
- Frequency: 5%
- Locations: Cervical & Lumbosacral
- Onset course: Rapid
- Pain: All
- Electrodiagnostic: Axonal loss
Myelopathy: Postero-lateral spinal cord
- Weakness: Paraparesis
- Sensory loss
  - Spinal sensory level
  - Posterior column involvement: Prominent
CNS
- Encephalopathy: Wernicke-Korsakoff like disorder
  - Confusion
  - Memory loss
  - Eye movement disorders
- Affective disorders
- Optic neuropathy
  - Acute onset
  - 1 to 3 years after surgery
  - Visual loss pattern: Central or Cecocentral scotoma
- D-lactate disorder: Bacterial overgrowth
Dumping syndrome
- Clinical features: "Neurohormonally mediated symptoms"
  - Facial flushing
  - Lightheadedness
  - Palpitations
  - Fatigue
  - Diarrhea
- Associations
  - Frequency: Up to 70% of patients after Roux-en-Y gastric bypass
  - Typically triggered by ingestion of concentrated sugar
Electrophysiology
- EMG: Denervation
- Nerve conduction studies
  - Axonal loss
  - Sensory + Motor involvement
Prevention: Nutrition counseling
Treatment
- Parenteral nutrition
- Vitamins: Thiamine +
- ? Reversal of surgery
Prognosis
- Death 8%
- Good resolution of signs 35%

Selenium Deficiency ^3, ⁴

Selenium
- Trace essential element
- Sources: Meat; Fish; Cereals
- Component of selenoproteins: Glutathione peroxidases; Iodothyronine 5'-deiodinases
- Deficiency produces
  - Glutathione peroxidase activity: Reduced
  - Oxidative damage
  - Reduced levels of selenoproteins
  - Increased toxicity of drugs & toxins: Nitrofurantoin; Paraquat
Deficiency & other syndromes
- Myopathy
- Cardiomyopathy, Epidemic
  - 2° Reduced dietary selenium in pregnant women & children in Keshan, China (Keshan disease)
  - ? Associated with Coxsackie B infection
- Selenoprotein disorders
  - Congenital muscular dystrophy with rigid spine: SEPN1
  - Hyperthyroxinemia: DIO1
- Selenium toxicity: Nail & Hair loss; Gastroenteritis; Dermatitis
- Animal disorders
  - "White muscle" or "Yellow fat" disease: Horses (Especially < 30 days), Cattle (offspring) & Guinea pigs
  - Probably related to concurrent selenium & vitamin E deficiency
  - Geography: More precipitation; Black or gray soils
Myopathy
- Frequency: Occurs only in minority of selenium deficient patients
- Causes of deficiency
  - Malabsorption: Chronic bowel disease
  - Dietary deficiency
    - Especially in regions with low selenium in soil: New Zealand; China; Central Africa
    - Parenteral nutrition: Long term; Critical illness
  - Chronic disorders with oxidative stress: HIV infection; Alcohol abuse
- Clinical
  - Muscle pain: Proximal
  - Weakness: Proximal, Symmetric
- Laboratory
  - Serum CK: High or Normal
  - Serum Selenium: Low
  - Vitamin E levels: Commonly low
  - Muscle biopsy
    - Muscle fiber atrophy
    - Vacuoles
    - Thinned myofibrils
    - Mitochondria: Enlargement; Reduced Number
- Treatment: Selenium supplementation
  - Most helpful with malabsorption & parenteral nutrition
  - Latency to improvement: 4 weeks
Cardiac disease: Arrhythmia; Cardiac failure

Copper Deficiency & Disorders

MRI: Copper Deficiency
Posterior column T2 signal

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
  - Loss: Vibration; Joint position
  - Paresthesias
  - Gait: Sensory ataxia
- 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 loss¹¹
- 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

Copper smelting

Arsenic toxicity

Copper-associated: Disorders & Enzymes

¹⁶

Transporters, ATP-Copper
- Menkes syndrome : ATP7A
- Occipital horn syndrome : ATP7A
- Distal spinal muscular atrophy, X-linked 3 (SMAX3): ATP7A
- Wilson's disease : ATP7B
  - Copper toxicity
  - Mechanism: Mitochondrial enzyme toxicity ⁸
    - Facilitates formation of oxygen radicals (ROS)
    - Inhibition of pyruvate dehydrogenase (PDH) & α-ketoglutarate dehydrogenase (KGDH)
Enzymes: Copper-containing
- Ubiquitous
  - Superoxide dismutase: ALS1
  - Mitochondrial Complex IV: Cytochrome c oxidase
- Tissue specific
  - Lysyl oxidase: Secreted by fibroblasts
  - Tyrosinase: Skin melanocytes
  - Ceruloplasmin: Pasma protein
  - Haephestin: Intestinal
Diabetes, Type I: Copper & Ceruloplasm levels mildly higher

Copper: Animal disorders

Ataxic myelopathy
- Swayback: in utero
- Enzootic ataxia: Neonatal
- Pathology: Cavitation of cerebral white matter
- Pathogenesis: ? Cytochrome oxidase dysfunction
Animal types
- Ruminants: Lamb
- Goats: Cerebellar syndrome
- Moose (Sweden)
External link: Copper Development Association

Iron Disorders

Iron deposition & metabolism disorders
- Neurodegeneration with brain iron accumulation (NBIA)
  - 1: Pantothenate kinase–associated neurodegeneration (NBIA1); PKAN2
  - 2: NBIA2; PLA2G6
    - Neuroaxonal Dystrophy (NBIA2A) : Onset in 1st 2 years
    - Karak syndrome (NBIA2B) : Childhood onset
  - 3: Neuroferritinopathy (NBIA3) : FTL1
  - 4: MPAN (NBIA4); c19orf12
  - 5: NBIA5 (SENDA) : WDR45 ; Xp11.23
    - WDR45 protein: Autophagy & Lysosomal function
    - Clinical
      - Psychomotor retardation, Childhood, Static
      - Dystonia-parkinsonism & Dementia: 3rd & 4th decade; Sudden onset, Progressive
      - Spastic paraparesis
  - 6: NBIA6; COASY; 17q21
  - 7 : REPS1 ; 6q23
  - 8 : CRAT ; 9q34
  - Aceruloplasminemia : Ceruloplasmin
  - ATP13A2
    - Kufor-Rakeb syndrome (PARK9) :
    - Spastic ataxia, Hereditary
  - Fatty acid hydroxylase-associated neurodegeneration (FAHN) : FA2H
  - SCP2
  - DDHD1
- Friedreich ataxia : Frataxin
- SPG35 & Leukodystrophy with Spasticity & Dystonia: FA2H
- Hemochromatosis
- Superficial siderosis
- Hemosiderin: After hemorrhage
- Huntington's disease
Iron-Sulfur Cluster disorders
- Myopathy + Exercise intolerance: ISCU
- Myopathy + Rhabdomyolysis: FDX1L
- Friedreich ataxia: Frataxin
- Glutaredoxin 5 : Sideroblastic anemia
- Infantile encephalopathy with multiple mitochondrial dysfunctions 1: NFU1
- Infantile encephalopathy with multiple mitochondrial dysfunctions 2: BOLA3
- Biosynthesis of mitochondrial iron-sulfur [4Fe-4S] proteins
  - IBA57: Encephalopathy
Heme transporter
- Posterior column ataxia & Retinitis pigmentosa (PCARP): FLVCR1

Folate deficiency: Neuropathy ¹⁴

Epidemiology
- No causative relationship to neuropathy established
- May occur in setting of multiple vitamin deficiencies
- Rare in countries with folate supplemented foods
- Folate deficiency caused by
  - Reduced intake or absorption
  - Increased requirements: Pregnancy; Lactation
  - Drugs: Antineoplastic, Antiepileptic, Oral contraceptive
  - Alcoholism
Clinical
- Systemic: Immunologic, Hematologic, Dermatologic, Cardiovascular
- Neurologic: Spina bifida, Depression, Dementia, Optic neuropathy, Myelopathy
- Polyneuropathy
  - Onset
    - Age: 5th to 9th decase
    - Leg numbness
  - Sensory loss
    - Pan-modal
    - Distal
    - Legs (100%) > Arms (44%)
    - Romberg sign: Positive
  - Pain (40%)
  - Tendon reflexes: Reduced, sparing biceps
  - Strength: Normal or Mildly reduced
  - Course: Slow progression
  - Treatment: Folate supplementation
Laboratory
- Folate levels: Measure RBC folate
- RBCs
  - Low in 20%
  - Macrocytosis 40%
- Serum Homosysteine: High
- Nerve pathology: Axons loss, large > small; Regeneration
- Electrodiagnostic: Axon loss, Legs > Arms

Critical Illness Neuropathy

Controversial syndrome
Very ill patients in intensive care (ICU) often develop mild polyneuropathy
- Distal
- Symmetric
- Sensory > Motor
Severe weakness in ICU is rarely 2° to "Critical illness polyneuropathy": Most have Myosin-loss myopathy
- Clinical features of myosin-loss myopathy
  - Sub-Acute onset
  - Respiratory failure
  - Weakness: Severe; Proximal > Distal
- Electrodiagnostic studies
  - NCV may mimic an axonal neuropathy with small CMAPs
  - Small CMAPs are 2° to inexcitability of muscle, not axonal loss
  - Sural sensory potentials may be reduced or absent
    - 2° to sensory neuropathy
    - Does not indicate severe loss of motor axons
  - EMG of proximal muscles rarely shows clear evidence of denervation
- Biopsy of a proximal muscle is required for diagnosis of myosin-loss myopathy
  - Small, sometimes angular muscle fibers: Usually type 2 muscle fiber atrophy, not denervation
  - ATPase stain at pH 9.4: Muscle fibers with reduced or absent staining

Return to Neuromuscular Home Page

1. Curr Opin Neurol 1998;11:539-544
2. Textbook of Clinical Neurology 1998 pp 798-809
3. JNNP 1999;67:829-830
4. Muscle Nerve 1998;21:637-639, 2003;Online January
5. Arch Int Med 2000;160:1199-1203, Can J Neurol Sci 2009;36:336-339
6. Immunology Today 2000;21:348-354
7. Neurology Today 2003;61:273-274, Arch Neurol 2003;60:1303-1306; Arch Neurol 2003;60:1782-1785
8. Ann Neurol 2004; Online March
9. Neurology 2004;63:1462–1470
10. Ann Neurol 2003;54:19-29
11. Muscle Nerve 2006;34:789-793
12. Neurobiol Dis 2006;23:725-730
13. NEJM 2013;368:149-160
14. Neurology 2015;84: Online Feb
15. J Clin Neuromuscul Dis 2014;16:25-31
16. J Trace Elem Med Biol 2019;56:156-161

Some illustrations from MW King

2/11/2020