Hereditary motor and sensory neuropathy with proximal dominance

Hereditary motor and sensory neuropathy with proximal dominance
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This condition is inherited in an autosomal dominant manner
Synonyms	Hereditary motor and sensory neuropathy, Okinawa type
Specialty	Neurology
Symptoms	Muscle weakness, involuntary contractions, asthenia, muscle atrophy, sensory loss, urinary incontinence, chronic cough
Complications	Progressive motor disability, severe sensory loss
Usual onset	Typically begins in the fourth decade of life (40s)
Duration	Chronic and progressive
Causes	Mutation in the TFG gene (chromosome 3q13.2)
Risk factors	Family history, genetic inheritance
Diagnosis	Electromyography, nerve conduction study, genetic testing, muscle biopsy
Differential diagnosis	Amyotrophic lateral sclerosis, other motor neuron diseases, Charcot–Marie–Tooth disease
Prevention	None known
Treatment	Supportive therapy, physical therapy, symptom management
Medication	Muscle relaxants, antispasmodics, pain management
Prognosis	Slowly progressive; variable severity
Frequency	Rare; mostly identified in families from Okinawa, Japan and Brazil
Deaths	Variable, typically due to complications in late-stage disease

Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P), also known as Hereditary motor and sensory neuropathy, Okinawa type, is a rare neurodegenerative disorder characterized by progressive muscle weakness, involuntary contractions, and loss of sensation. It is inherited in an autosomal dominant pattern and typically begins in the fourth decade of life.

Presentation

HMSN-P manifests with:

• Involuntary and spontaneous muscle contractions
• Asthenia (loss of strength)
• Proximal muscle atrophy followed by distal sensory loss
• Spasms and fasciculations, particularly in early stages
• Urinary incontinence and chronic dry cough in some cases

The disease has clinical overlap with amyotrophic lateral sclerosis (ALS), including similar neuropathological findings, such as TDP-43-positive cytoplasmic inclusions in motor neurons.

Genetics and Pathophysiology

HMSN-P is caused by mutations in the TFG (tropomyosin-receptor kinase fused gene) located on chromosome 3q13.2. The mutation affects intracellular protein trafficking and is believed to play a role in the degeneration of motor neurons through disruption of the ubiquitin-proteasome pathway.

Pathological findings include:

• TFG/ubiquitin and/or TDP-43-positive cytoplasmic inclusions in spinal motor neurons
• Cytosolic aggregation of TDP-43 in cultured cells expressing mutant TFG

Diagnosis

Diagnosis involves a combination of:

• Clinical evaluation
• Electromyography (EMG)
• Nerve conduction studies
• Muscle biopsy
• Confirmatory genetic testing for mutations in the TFG gene

Treatment

There is no known cure for HMSN-P. Management is supportive and may include:

• Physical therapy to maintain mobility
• Assistive devices for ambulation
• Medications to control spasticity or pain
• Monitoring for urinary dysfunction

Prognosis

HMSN-P is slowly progressive. Disease severity and rate of progression vary among individuals. Although it is disabling, life expectancy may not be significantly reduced in all patients.

Epidemiology

HMSN-P is extremely rare. It has been described primarily in two large families from Okinawa, Japan. Cases have also been reported in descendants in Brazil, indicating a founder effect in these regions.

See also

• Hereditary motor and sensory neuropathy
• Motor neuron disease
• Neurodegeneration
• Genetic disorders