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VITAMIN, MINERAL & NUTRITION RELATED SYNDROMES

• 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, Selenium
• GI: E; Lead; As; Thallium
• Cardiac: B₁
• Renal: Hg
• Hematologic
  • Anemia: B₁₂; Cu; Lead
  • Pancytopenia: As

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
  • Peripheral neuropathy (Dry beri-beri) ¹⁰
    • Clinical
      • Onset
        • Progression: Variable
          • Acute (< 1 month): 50%; ANAN ¹⁷
          • 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
      • Cranial nerves (Occasional)
        • Laryngeal (Hoarseness)
        • Face
        • Tongue
      • Tendon reflexes: Reduced or Absent, especially ankles
      • Systemic
        • Vomiting
        • Weight loss
        • Alcohol abuse
    • 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
      • CSF: Protein & Cells Normal
  • 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)
    • ETFDH
    • FLAD1
  • 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 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

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 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 Oxidizes cobalt in cobolamin: Methylcobalamin inactivated Inhibits conversion of homocysteine to methionine: 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 (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

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

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 Cofactor required in carboxylation enzymes Acetyl-CoA carboxylase Pyruvate carboxylase Deficiency: Causes Prolonged antibiotic therapies: Deplete intestinal fauna High consumption of raw eggs: Eggwhite protein avidin Binds biotin Prevents absorption Biotinidase deficiency Neurodegeneration, infantile-onset, Biotin-responsive (NERIB) : SLC5A6 Clinical Onset Encephalopathy & Confusion: Subacute onset Dysarthria & Dysphagia ± Facial nerve palsy: Supranuclear ± External Ophthalmoplegia Late features Spastic paraparesis Mental retardation Dystonia Treatment: Biotin (5-10 mg/kg/day) MRI: Central necrosis of the head of the caudate ± Putamen

Biotin

• Epidemiology: 2 families, 3 patients
• Genetics
  • Mutations: Frameshift; stop; Missense
• SLC5A6 protein
• Clinical
  • Onset age: Early infancy to 1 year
  • Development: Delayed intellectual & Motor
  • Spasticity
  • Microcephaly
  • Bone: Osteopenia & Fractures
  • Treatment: Biotin; Pantothenic acid; α-Lipoic acid
• Laboratory
  • Polyneuropathy: Mixed demyelinating & axonal; Sensorimotor
  • Blood: Ca⁺⁺ ↓, Phosphate ↑, Alkaline phosphatase ↑
  • Hypogammaglobulinemia
  • Brain MRI: Corpus callosum thin; Pons hypoplasia
  • Brain pathology: Cerebrum & Cerebellum small; Axonal spheroids

• 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

• 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

• 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%
  • Bilateral: 55%
  • 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
  • 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 or Kashin-Beck disease)
    • ? Associated with Coxsackie B infection
  • Deficiency
    • Low-selenium areas: China, North Korea, Siberian region of Russia
    • Associated disorders: Cardiovascular, Cancer, Liver, Arthropathy, Covid-19 mortality
  • Selenoprotein disorders
    • Congenital muscular dystrophy with rigid spine: SEPN1
    • Multisystem disorder: SECISBP2
    • 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

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 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

• 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)
  • MPCD: SLC25A3
• Copper chaperone
  • SPG42: SLC33A1
• Enzymes: Copper-containing
  • Ubiquitous
    • Superoxide dismutase: ALS1
    • Mitochondrial Complex IV: Cytochrome c oxidase
  • Tissue specific
    • Lysyl oxidase: Secreted by fibroblasts
    • Tyrosinase: Skin melanocytes
    • Ceruloplasmin: Plasma protein
    • Haephestin: Intestinal
• Diabetes, Type I: Copper & Ceruloplasm levels mildly higher

• 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 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

• 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

• 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