What are the disorders of neurons?

Disorders of Neurons

Neuronal disorders encompass developmental malformations, autoimmune conditions targeting neuronal surface antigens, and neurodegenerative diseases characterized by progressive neuronal loss and protein aggregation.

Developmental Disorders of Neurons

Disorders of Neuronal Migration

• Periventricular nodular heterotopia occurs when neurons fail to migrate from the ventricular zone due to disruption of the neuroependyma or abnormal vesicular trafficking, resulting in clusters of neurons remaining at the ventricular border 1
• Lissencephaly results from interrupted neuronal migration caused by disruption of the molecular apparatus needed for moving neurons, including mutations in genes regulating tubulins and microtubule-associated proteins (LIS1, DCX) 1
• Polymicrogyria and cobblestone malformations arise from cortical over-migration into the leptomeninges due to defects in the pial surface, with the size of membrane defects determining whether the cortex appears polymicrogyric (small gaps) or cobblestone (large gaps) 1

Disorders of Post-Migrational Development

• Focal cortical dysplasia (FCD) Type I represents isolated post-migrational developmental abnormalities affecting cortical organization 1
• FCD Type II (subtypes a and b) involves marked disruption of cortical lamination with dysmorphic neurons and balloon cells, forming a spectrum with dysplastic megalencephaly through germline or somatic mutations in mTOR pathway genes 1
• Secondary microcephaly and certain forms of dysgyria result from disturbances in axonogenesis, dendritogenesis, and synapse formation 1

Autoimmune Neuronal Disorders

Neuronal Surface Antibody-Associated Syndromes

• NMDAR-antibody encephalitis is antibody-mediated, commonly affects children and young women, often without associated tumors, and responds to immunomodulatory therapy 1
• Voltage-gated potassium channel (VGKC) complex antibody syndromes (targeting LGI1 or CASPR2) cause limbic encephalitis and Morvan's syndrome, are generally effective with immunotherapy 1
• AMPAR, GABA-BR, GlyR, and mGluR antibody syndromes represent additional neuronal surface antibody disorders that benefit from immunomodulatory treatment 1

Paraneoplastic Neuronal Disorders

• Classical paraneoplastic syndromes (with Hu, Yo, Ri, Ma2, CV2/CRMP5 antibodies) are T cell-mediated rather than antibody-mediated, typically affect adults aged 40-70 years, and show poor response to immunotherapy 1
• These disorders cause neuronal cell loss through T cell cytotoxicity, with antibodies serving as biomarkers for underlying tumors (SCLC, breast, ovary, testicular) rather than pathogenic agents 1

Neurodegenerative Disorders

Motor Neuron Diseases (Anterior Horn Cell Disorders)

• Amyotrophic lateral sclerosis (ALS) affects anterior horn cells in the spinal cord, representing a central nervous system disorder with peripheral manifestations, characterized by denervation with fibrillation potentials and fasciculations on EMG 2
• Spinal muscular atrophy and poliomyelitis are additional anterior horn cell disorders causing progressive motor neuron loss 2
• Post-polio syndrome develops 30-40 years after acute poliomyelitis in 25-40% of survivors, presenting with new muscle weakness and pain 2

Parkinsonian Syndromes

• Parkinson's disease presents with resting tremor, bradykinesia, and rigidity after approximately 40-50% of dopaminergic neurons in the substantia nigra are lost, typically with peak onset at 60-70 years 3
• Progressive supranuclear palsy (PSP) is the most common atypical parkinsonism (prevalence 5/100,000), presenting with lurching gait, early falls, axial dystonia, and later vertical supranuclear gaze palsy 3
• Multiple system atrophy (MSA) has typical onset at 55-65 years, with MSA-P subtype showing parkinsonian features and MSA-C showing cerebellar ataxia, distinguished by prominent autonomic dysfunction 3

Cerebellar Disorders

• Dysmetria is a cardinal sign of cerebellar dysfunction characterized by impaired ability to measure distance in muscular movements, assessed through finger-to-nose and heel-to-shin tests 4
• Causes include cerebellar lesions, spinocerebellar ataxias, paraneoplastic cerebellar degeneration, and congenital cerebellar malformations 4

Common Neurodegenerative Proteinopathies

• Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis represent the most common neurodegenerative disorders, characterized by progressive loss of selectively vulnerable neuronal populations 5, 6
• These disorders are classified as amyloidoses, tauopathies, α-synucleinopathies, and TDP-43 proteinopathies based on their principal molecular abnormality 6
• Mixed pathologies (combinations of multiple proteinopathies with or without cerebrovascular disease) are increasingly recognized, particularly in individuals over 65 years, and lower the threshold for developing cognitive impairment 7

Common Pathogenic Mechanisms

Shared Biological Processes

• Aging, genetic factors, progressive neuronal dysfunction, neuronal death and apoptosis, protein misfolding and aggregation, neuroinflammation, mitochondrial dysfunction, axonal transport defects, and gut microbiota dysbiosis are involved across multiple neurodegenerative diseases 8
• Abnormal protein conformers may spread cell-to-cell along anatomically connected pathways, explaining specific anatomical patterns of neurodegeneration 6
• These biological processes form complex pathogenic networks rather than isolated mechanisms, explaining why interventions targeting single pathways have proven insufficient 9, 8

Critical Clinical Pearls

• Distinguish developmental from acquired disorders: Malformations of cortical development result from in utero disruptions, while autoimmune and neurodegenerative disorders typically present postnatally 1
• Recognize treatable autoimmune conditions: Neuronal surface antibody syndromes respond to immunotherapy, unlike classical paraneoplastic syndromes or neurodegenerative diseases 1
• Differentiate anterior horn cell disease from peripheral neuropathy: Anterior horn cell disorders show pure motor involvement without sensory symptoms, while peripheral neuropathies typically affect both 2
• Identify atypical parkinsonism early: Early prominent falls, rapid progression, poor levodopa response, and early autonomic dysfunction distinguish PSP and MSA from Parkinson's disease 3