Genetic Polyneuropathy
Definition
Genetic polyneuropathy refers to a group of inherited disorders characterized by dysfunction of peripheral nerves. These nerves transmit signals between the central nervous system and the rest of the body, and their impairment leads to sensory, motor, or autonomic symptoms. Genetic mutations affecting the structure or function of peripheral nerves underlie these conditions, often resulting in progressive disability.
Classification
Genetic mutation: Mutations in genes encoding myelin proteins (e.g., PMP22, MPZ). Mutations in genes affecting axonal transport or cytoskeletal structure (e.g., MFN2, GJB1).
Pattern of inheritance: Autosomal dominant (e.g., Charcot-Marie-Tooth disease type 1A). Autosomal recessive (e.g., hereditary sensory and autonomic neuropathies). X-linked (e.g., X-linked Charcot-Marie-Tooth disease).
Pathophysiological mechanism: Demyelinating neuropathies characterized by slowed nerve conduction velocity due to myelin sheath abnormalities. Axonal neuropathies primarily involve axonal degeneration, leading to reduced nerve conduction amplitude.
Hereditary Motor and Sensory Neuropathy (HMSN) HMSN, also known as Charcot-Marie-Tooth (CMT) disease, is the most common form of genetic polyneuropathy. It is a heterogeneous group of disorders with distinct genetic subtypes.
HMSN type I (demyelinating): Caused by mutations affecting myelin structure or function (e.g., PMP22 duplication in CMT1A). Marked slowing of nerve conduction velocity, distal muscle weakness, areflexia, and sensory loss.
HMSN type II (axonal): Associated with axonal degeneration (e.g., mutations in MFN2). Normal or mildly reduced nerve conduction velocity with reduced amplitudes; less severe sensory involvement.
HMSN type III (Dejerine-Sottas disease): A severe, early-onset demyelinating neuropathy. Profound motor delay, weakness, and sensory loss.
HMSN type IV (Refsum disease): Rare autosomal recessive neuropathy linked to metabolic defects. Retinitis pigmentosa, ichthyosis, ataxia, and neuropathy.
HMSN type V: This is a rare axonal form of hereditary motor and sensory neuropathy characterized by a gradually progressive distal muscle weakness and atrophy, which may occur with or without sensory deficits. Clinical manifestations often include gait disturbances, foot drop, and pes cavus. These features may be accompanied by pyramidal signs, such as extensor plantar responses, mild hypertonus, and brisk tendon reflexes, as well as muscle cramps, pain, and spasticity.
HMSN type VI: This condition represents a rare axonal hereditary motor and sensory neuropathy characterized by a progressive, peripheral, axonal sensorimotor neuropathy of variable severity, primarily affecting the distal lower limbs. It is commonly associated with progressive optic atrophy of varying severity, often culminating in visual impairment. Clinical presentations typically include distal limb muscle weakness and atrophy, hypo- or areflexia, foot deformities, diminished visual acuity (frequently accompanied by central scotoma), nystagmus, and impaired peripheral and nocturnal vision. Additional reported features include sensorineural hearing loss, significant joint contractures, anosmia, scoliosis or lumbar hyperlordosis, cognitive impairment, and vocal cord paresis.
HMSN type VII:
Hereditary sensory and autonomic neuropathy type VII (HSAN7) is a rare genetic disorder characterized by an impaired ability to feel pain, excessive sweating (hyperhidrosis), and significant gastrointestinal complications. The inability to sense pain increases the risk of unnoticed injuries, infections, and joint damage over time, potentially leading to severe consequences if left unmanaged. Gastrointestinal issues associated with HSAN7 can vary in severity but often include painful constipation, diarrhea, and other digestive disturbances that may result in malnutrition or failure to thrive, especially in children.
HMSN type X: X-linked form associated with mutations in GJB1 (connexin 32). Features: Mixed demyelinating and axonal neuropathy with additional CNS involvement in some cases.
HNPP: Hereditary neuropathy with pressure palsies (HNPP) is a genetic condition that causes episodes of numbness, tingling, and muscle weakness, often triggered by minor pressure or repetitive movements. It affects the peripheral nerves, which connect the brain and spinal cord to muscles and sensory organs. Symptoms commonly appear in the teenage years or early adulthood but can develop at any age, affecting areas like the legs, feet, wrists, elbows, or hands. Individuals with HNPP may experience pain, loss of sensation, or difficulty moving specific parts of the body, such as foot drop or wrist drop, due to nerve dysfunction.
Clinical Manifestations
Symptoms of genetic polyneuropathy vary depending on the specific condition and its severity and including muscle weakness and atrophy, typically beginning in distal part of extremities (e.g., foot drop), difficulty with fine motor tasks and walking. Det sensory symtoms include loss of sensation, particularly in a "stocking-and-glove" distribution, paresthesia and pain. Orthostatic hypotension and dyfunction of bladder, bowel, or sexuality are considered autonomic symptoms. Skeletal deformities (e.g., pes cavus, scoliosis) and gait abnormalities are another features.
Diagnosis
Clinical evaluation: Detailed history of symptom onset and progression. Family history of similar conditions.
Electrophysiological studies: Nerve conduction studies to differentiate between demyelinating and axonal neuropathies. EMG is used to differentiate between neuropathies and myopathies/denervating disorders (SMA).
Genetic testing: Identifying specific mutations through targeted panels, whole exome sequencing, or whole genome sequencing.
Additional tests: Nerve biopsy (rarely used) to confirm histopathological changes. Blood tests to rule out acquired causes of neuropathy.
Treatment
Symptomatic treatment: Physical therapy to maintain muscle strength and mobility. Orthotic devices are used for foot drops or gait abnormalities. Pain management with medications such as gabapentin, pregabalin, or tricyclic antidepressants.
Supportive care: Occupational therapy and psychological support for fine motor skill challenges and coping with chronic illness.
Emerging therapies: Gene therapy and RNA-based approaches are under investigation.
Multidisciplinary approach: Collaboration among neurologists, physiatrists, geneticists, and other specialists.
Prognosis
The prognosis of genetic polyneuropathy varies widely depending on the specific disorder and its progression rate, In slowly progressive disorders the symptoms may progress over decades, and most individuals maintain some degree of independence. In rapidly progressive or severe forms the early onset and aggressive progression may lead to significant disability in the childhood or adolescence.
Early diagnosis and supportive interventions improve quality of life. Ongoing research may offer new therapeutic options in the future.
