Systemic Disorders

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Metabolic & Systemic Disorders

Endocrine
Hematologic
Hepatic
Renal

RENAL FAILURE

Polyneuropathy

Epidemiology
- Frequency: 60% with at least subclinical neuropathy
- Male > Female
- Associated with glomerular filtration rate < 12 mL/min
- Possible pathogenesis
  - Deficiencies: Thiamine, Biotin, Zinc deficiencies
  - Uremic toxins: "Middle molecules" (β2-microglobulin)
- Associated medications: Colchicine; Nitrofurantoin; Alcohol
Clinical features
- General
  - Distribution: Symmetric; Distal; Legs > Arms
  - More severe with long term dialysis
- Sensory loss
  - Modalities: All (Large & Small fiber)
  - Distal > Proximal
  - Legs > Arms
- Spontaneous sensations
  - Paresthesias & Dysesthesias: > 40%
  - Pain & Burning (Feet): 10%
  - Itch
    - Especially frequent with hemodialysis
    - Associated with presence of polyneuropathy
- Motor: Weakness in patients with more severe neuropathy
  - Distal
  - Feet & Hands
- Spontaneous activity
  - Cramps: 66%
  - Restless legs
  - Myokymia
- Tendon reflexes: Reduced or Absent
  - Legs > Arms
  - Distal > Proximal
  - May be diffuse
- Autonomic dysfunction: Mild
  - Loss of R-R interval variation
  - Sympathetic skin response: Abnormal in 45%
- Course: Progression & resolution: Slow
Lab
- CSF: Unremarkable
- Electrophysiology
  - Mainly axonal loss: Low CMAP amplitudes
  - Mild slowing of NCVs
    - Not related to clinical signs
    - Correlates with creatinine clearance
    - Motor conduction velocity
      - May fall to 50% of mean control value
      - Peroneal correlates with creatinine clearance
    - Distal motor latencies: May be prolonged
    - SNAPs: Reduced amplitude
- Nerve pathology
  - Distal axonal degeneration & loss
  - Axon size: May be reduced
- Treatment
  - Renal transplantation
    - Improvement in most features
    - Little change in autonomic dysfunction
  - Dialysis: Stabilizes neuropathy
Rule out:
- Additional drug toxicity
- Amyloidosis

Mononeuropathy

Carpal tunnel syndrome
- Associations: Vascular shunts; Amyloid
- Often on side used in vascular access for dialysis
- Chronic dialysis: Some evidence of CTS in 90%
Ulnar neuropathy
Ischemic arm neuropathies: Related to fistulas

Neuromuscular junction

Aminoglycoside toxicity

Myopathy

Disorders
- Cachexia
  - Nephrotic syndrome
  - Inanition
- Electrolyte disturbances
  - Hypercalcemia
  - Hyperkalemia
    - Common in: Endstage renal disease ⁴
    - Pathology: Membrane depolarization
    - Symptoms: Fatigue; Reduced endurance
    - EMG: Non-diagnostic; No spontaneous activity
    - NCV: Some patients have co-existing neuropathy
  - Hypermagnesemia
- Disordered vitamin D metabolism: With bone disease
- Muscle infarction 2° arterial calcification: Calciphylaxis
  - Skin necrosis
  - Myopathy; Rhabdomyolysis
- Nephrogenic fibrosis
- Drug toxicity
- Aluminum
Laboratory
- Serum CK: Usually normal, except some drug toxicity
- Pathology: Type II muscle fiber atrophy

Nephrogenic Fibrosis (Nephrogenic fibrosing dermopathy) ²

Epidemiology
- Age: 4th to 6th decades
- Sex: Males & Females affected
Cutaneous fibrosing disorder
- Skin
  - Thickening & Hardening
    - Limbs: Usual
      - Legs: Most common; Distal > Proximal but sparing feet
      - Arms: Some patients; Distal or diffuse
    - Trunk: Occasional; Late
    - Face: Spared
  - Hyperpigmentation
  - Erythematous patches
  - Pain: Burning
- Course: Progressive
Clinical: Other
- Joints
  - Restriction of motion: Flexion contractures
  - Pain
- Muscles
  - Hardening: Distal > Proximal
  - Skin changes over affected muscles
  - Strength: Normal
- Neuropathy
  - Sensory: May be painful (Burning)
  - May be related to syndrome or renal disease
- Eyes: Scleral injection
Associated disease
- End-stage renal disease: Dialysis treatment; 2 to 7 years
Laboratory
- Serum CK: Low (< 50)
- Parathyroid hormone: Often high
- Calcium-phosphate products: High
- EMG: Myopathic changes
- NCV: Reduced SNAP & CMAP amplitudes in most
- Muscle MRI
  - High attenuation of fascial planes
  - Muscle signal: Patchy increase on T2 weighted image
  - Atrophy
Pathology: Skin
- Dermal fibroblasts, spindle-shaped: Proliferation
- Dendritic cells: Tissue accumulation
- Collagen bundles: Thickened
- Elastic fibers: Increased
- Mucin deposition
Pathology: Muscle
- Fibrosis: Perimysial (widening) > Endomysial
- Myopathy: Varied muscle fiber size
- Calcium deposition
- Inflammation: Perimysium

Nephrogenic fibrosis: MRI

Subcutaneous tissue: Thickened
Muscles
- Patchy high T2 signal
- MRI shows changes in: Vastus lateralis (Large arrow) & Gracilis (Small arrow) on right
Fascial planes: Increased signal

HEPATIC DISORDERS

Demyelinating neuropathy
Sensory neuropathy with 1° biliary cirrhosis
Vitamin E deficiency
- Childhood cholestatic disease
Hepatitis C
Navajo neuropathy with corneal ulceration
Hepatic myelopathy
Pruritis

Hepatic Demyelinating Neuropathy

Frequency: 50% to 70%
Usually subclinical
Distal; sensory
Autonomic: Usually parasympathetic, mild

Hepatic myelopathy ¹

Associated with
- Chronic liver disease
- Acquired hepatocerebral degeneration: White matter enhancement on T2 MRI
Myelopathy
- Spasticity: Legs > Arms
- Tendon Reflexes: Brisk
- Sensory: Normal
- Bladder: Normal
Other CNS: Ataxia; Encephalopathy
Pathology: Pyramidal tract loss of myelinated axons

Hematologic Disorders

Myopathies + ⁵

Hemolytic Anemia
- PFK deficiency (GSD VII/Tarui): PFKM
- GSD XII: ALDOA
- TPI deficiency: TPI1
- PGK deficiency: PGK1
- IPEX: FOXP3
- Immune: LHIM; Jo-1
Sideroblastic anemia
- Mitochondrial
  - MLASA1: PUS1
  - MLASA2: YARS2
  - MLASA3: MT-ATP6
  - MC1DN30: NDUFB11
  - Perrault 4 (HLASA): LARS2
  - Pearson Marrow-Pancreas syndrome
- Also see
  - Mitochondrial disease + Anemia
  - Copper deficiency
  - Childhood-onset spasticity with hyperglycinemia (SPAHGC): GLRX5
  - Sideroblastic anemia & Spinocerebellar ataxia: ABCB7
Macrocytic anemia
- COXPD 18: SFXN4
- ODOAD: OPA1
Neutropenia
- Barth: TAZ
- CNM1: Dynamin 2
Eosinophilia
- LGMD 2A: CAPN3
Jordan anomaly
- NLSD-M: PNPLA2
- NLSD-I: ABHD5
Thrombocytopenia
- Tubular Aggregate Myopathy 1: STIM1
- Tubular Aggregate Myopathy 2: ORAI1
- HIBM2: GNE
- Shwachman–Diamond
Pancytopenia
- ATXPC: SAM9DL
Acanthocytes
- A-β-lipoproteinemia: MTP
- Neuroacanthocytosis: VPS13A
- PKAN: PANK2

Hemochromatosis ³

General
- Disorder of iron storage
  - Inappropriate increase in intestinal iron absorption
  - Deposition of iron in parenchymal cells
- Several hereditary causes
  - Common adult form: HFE with C282Y mutation; Recessive
Clinical
- Onset
  - Age: Midlife
  - Symptoms: Fatigue, Abdominal Pain
- Organ damage
  - Liver: Cirrhosis; Hepatomas
  - Pancreas (Diabetes)
  - Joints: Arthritis
  - Pituitary: Hypogonadotropic hypogonadism
  - Cardiac: Cardiomyopathy
  - Skin: Pigmentation
- Polyneuropathies
  - Frequency (26%)
  - Sensory loss
  - Type
    - Large or Small fiber
    - Axon loss
  - May be associated with diabetes
- Myopathy
  - Objective features: Rare
  - Associated with hemodialysis
  - Proximal weakness
  - Discomfort: Cramps, Fatigue & Pain
  - Hemosiderin deposits
- Laboratory
  - Serum ferretin: High
- Treatment: Removal of iron by phlebotomy or erythrocytapheresis

Retinitis Pigmentosa + Myopathy ⁶

● Retinol dehydrogenase 11 (RDH11)

; Chromosome 14q24.1; Recessive

Epidemiology: 1 Chinese patient
Genetics
- Mutations: Leu313Pro; Splice site (c.75-3C>A)
- Allelic disorder: Retinal dystrophy, Juvenile cataracts, Short stature (RDJCSS)
RDH11 protein
- 11-cis-retinol dehydrogenase
- Role in retinoid cycle
Clinical
- Onset: 1 year; Delayed walking
- Intellectual delay
- Eye
  - Cataracts: Binocular
  - Retinitis pigmentosa: Visual loss
- Weakness: Limbs
Laboratory
- Serum CK: 441 to 618
- Muscle pathology
  - Fiber sizes: Varied
  - Internal architcture: Linearization
  - Ultrastructure: Focal myofilament pathology
  - RDH11: Present on sarcolemma, not cytoplasm

Dyserythropoietic Anemia + Centronuclear Myopathy, Canine (DAMS) ⁷

● EH Domain-binding protein-like 1 (EHPB1L1)

; Chromosome 11q13.1; Recessive

Epidemiology: Labrador Retrievers & English Springer Spaniels
Genetics
- Mutations: Stop; c.388C>T, c.3120delC; Homozygous
- Allelic disorder: Recurrent fetal death in humans
EHPB1L1 protein
- Actin cytoskeletal organization
- Apical-directed transport in polarized epithelial cells
- Membrane vesicles in endocytic recycling compartment
  - Through connections with Rab8 & BIN1-Dynamin complex
Clinical
- Weakness
  - Temporal
  - Pelvic
  - Dysphagia
  - Megaesopagus
- Trismus
- Exercise intolerance
Laboratory
- Anemia: Microcytic, Hypochromic; Metarubricytosis; Target cells; Acanthocytes
- Muscle
  - Central nuclei
  - Fiber sizes: Varied
  - COX & SDH: Dark central staining of muscle fibers
  - Lipid & Connective tissue increased
- Serum CK: Normal

Return to Neuromuscular Home Page

References
1. Neurology 2000;54:1011
2. Muscle Nerve 2004;30:569–577
3. J Neurol 2010; Online April
4. Clin Neurophysiol 2021;132:3125-3135
5. Muscle Nerve 2022 Jan 5
6. Clin Genet 2022 Jan 6
7. Genes 2022;13:1533, Genes 2022;13:1427

9/24/2022