Clinical Guidance

The six variants that have been reported in multiple unrelated individuals with stroke-like episodes and which may confer a higher risk for this phenotype are included in . Of note, approximately 20 additional variants have been reported in a single individual or family with stroke-like episodes. From a severity standpoint, most pathogenic variants cause a similar phenotype . Some data suggest that the relatively common pathogenic variant produces a more severe phenotype than other common pathogenic variants, while missense pathogenic variants in the intracellular domain of GJB1 cause a less severe phenotype .

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Diagnostic Criteria

Suggestive Findings

GJB1 Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) should be suspected in an individual with the following clinical findings, electrophysiologic findings, and family history.

Clinical findings

• Peripheral motor and sensory neuropathy with or without the following:

• Occasionally fixed CNS abnormalities

• Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria

• Stroke-like episodes. Acute fulminant episodes of reversible CNS dysfunction, usually with peripheral neuropathy or a family history of peripheral neuropathy

• Familial ataxia with peripheral neuropathy

Electrophysiologic findings. Nerve conduction velocities (NCVs):

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Differential Diagnosis

Neuropathy. See CMT Overview. Stroke-like episodes and peripheral neuropathy. Disorders to consider in the differential diagnosis include the following:

• MELAS (mitochondrial encephalopathy lactic acidosis and stroke) due mitochondrial DNA (mtDNA) variants

• POLG-related disorders

• CADASIL ; however, peripheral neuropathy has not been seen in all studies .

• Fabry disease manifesting with ischemic stroke and small fiber neuropathy

• Metabolic encephalopathy or ischemia due to complications of diabetes mellitus, kidney disease, or liver disease

• Neurosarcoidosis

• Lupus and other collagen vascular diseases

• Vasculitis

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Management Guidelines

Individuals with GJB1 Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical therapists, and occupational therapists.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CMT1X , the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • To determine extent of weakness atrophy, pes cavus, gait stability, sensory loss

• To evaluate for pain

• To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)

• To determine if affected person /or any family member has had episodes of acute transient neurologic dysfunction

Musculoskeletal

| Orthopedics / physical medicine rehab / PT/OT eval | To incl assessment of:

• Gross motor fine motor skills need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

• Feet for evidence of pes cavus, need for AFOs, specialized shoes

• Mobility, activities of daily living, need for adaptive devices

• Need for handicapped parking

Hearing

| Audiologic eval | Assessment for hearing loss if concerns

Miscellaneous/

Other

| Consultation w/clinical geneticist /or genetic counselor | To incl genet...

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Clinical Guidance

Obesity is to be avoided because it makes walking more difficult. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. Affected individuals should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger individuals with a family history or in individuals who have a variant previously associated with such events . The author recommends advising affected individuals that the avoidance of known precipitants such as hyperventilation or exertion [, , , ], re-acclimatization after return from high altitude , fever , head trauma , or minor infections may reduce the likelihood of such events. However, these recommendations must be balanced with quality-of-life considerations.

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"

Surveillance Guidelines

Table 3.

Recommended Surveillance for Individuals with CMT1X

System/Concern | Evaluation | Frequency

Neurologic

| • Screening neurologic exam focused on motor system cerebellar function

• Eval for pain

| Annually

Musculoskeletal

| • PT (gross motor skills) ADL

• OT (fine motor skills) ADL

Foot exam

| For pressure sores or poorly fitting footwear | Annually by physician; more often by affected person

ADL = activities of daily living; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes"