Paramyotonia Congenita
Introduction
Paramyotonia congenita (PMC) is a rare, autosomal dominant, non-dystrophic myotonic disorder characterized by paradoxical myotonia, which worsens with continued activity and exposure to cold. Unlike other myotonias, PMC does not improve with exercise. It is classified as a sodium channelopathy caused by mutations in the SCN4A gene, which encodes the voltage-gated sodium channel Nav1.4, essential for skeletal muscle excitability.
Epidemiology
PMC is a rare condition with an estimated prevalence of approximately 1 in 100,000 to 1 in 500,000. It affects both sexes equally and typically manifests in early childhood or adolescence. Due to its autosomal dominant inheritance, familial cases are common, but sporadic cases due to de novo mutations can also occur.
Pathophysiology
PMC is primarily caused by missense mutations in the SCN4A gene, which lead to altered function of the Nav1.4 sodium channels. These mutations typically impair channel inactivation, resulting in persistent sodium influx, prolonged depolarization, and muscle membrane hyperexcitability. Cold temperatures exacerbate this dysfunction by further delaying channel inactivation, which explains the patients' cold sensitivity.
Clinical Manifestations
Paramyotonia congenita typically presents in infancy or early childhood with muscle stiffness (myotonia) that paradoxically worsens with repeated activity and is aggravated by cold, especially in facial and hand muscles. Episodes may be accompanied by transient muscle weakness or even flaccid paralysis. The condition primarily affects facial, neck, hand, and forearm muscles, while leg involvement is less common.
Diagnosis
Treatment
Prognosis
PMC is typically a benign condition without progressive muscle weakness or atrophy. While symptoms can be bothersome and affect quality of life, life expectancy is normal. Symptom severity often stabilizes or slightly improves with age, although cold sensitivity usually persists.
Hyperkalemic Periodic Paralysis
Introduction
Hyperkalemic periodic paralysis (HyperPP) is a rare, autosomal dominant, non-dystrophic muscle disorder classified among the sodium channelopathies. It is characterized by recurrent episodes of muscle weakness or paralysis, often triggered by rest after exercise, fasting, cold exposure, or ingesting potassium-rich foods. The condition is most commonly caused by mutations in the SCN4A gene, which encodes the voltage-gated sodium channel Nav1.4 in skeletal muscle.
Epidemiology
HyperPP is a very rare disorder, with an estimated prevalence of approximately 1 in 200,000 individuals. It is inherited in an autosomal dominant manner and affects both sexes equally. Symptom onset typically occurs in childhood or early adolescence.
Pathophysiology
Most cases are caused by mutations in the SCN4A gene, leading to dysfunction of the Nav1.4 sodium channels. These mutations impair channel inactivation, increasing sodium influx and disrupting the muscle membrane potential. Elevated extracellular potassium levels worsen this effect, explaining the sensitivity to potassium and other triggering factors.
Clinical Manifestations
HyperPP presents with episodic, often symmetrical muscle weakness lasting from minutes to several hours and occasionally up to 24 hours. Episodes typically affect proximal muscles, particularly in the limbs, and are triggered by fasting, rest after physical activity, cold exposure, or potassium intake. Myotonia (muscle stiffness) may be present but is not always observed. Muscle function is usually normal between attacks, although some individuals develop mild to moderate persistent weakness over time.
Diagnosis
Treatment
Prognosis
Hyperkalemic periodic paralysis is generally a benign disorder with normal life expectancy. Some individuals may develop permanent muscle weakness over time, particularly if attacks are frequent and left untreated. With appropriate treatment and lifestyle adjustments, most patients can achieve good symptom control and maintain a normal quality of life.
Severe Neonatal Episodic Laryngospasm (SNEL)
Introduction
Severe neonatal episodic laryngospasm (SNEL) is a sporadic, potentially life-threatening form of sodium channel myopathy presenting in the neonatal period. It is characterized by recurrent, sudden episodes of apnea and cyanosis due to involuntary laryngeal closure (laryngospasm), leading to respiratory distress. SNEL is associated with mutations in the SCN4A gene, which encodes the skeletal muscle sodium channel Nav1.4, also expressed in laryngeal muscles.
Epidemiology
SNEL is very rare, and the true prevalence is unknown. It typically presents within the first days or weeks of life. Most reported cases are sporadic, but familial autosomal dominant inheritance has also been observed. Due to its rarity and severity, the condition may be underdiagnosed or misattributed to other causes of neonatal apnea.
Pathophysiology
Mutations in the SCN4A gene cause the function of Nav1.4 sodium channels to be altered, leading to impaired inactivation and persistent depolarization of muscle membranes. In SNEL, this dysfunction particularly affects the laryngeal muscles, causing hyperexcitability and spontaneous closure of the vocal cords. The resulting laryngospasm obstructs the airway and causes life-threatening apnea. The condition may co-occur with other manifestations of sodium channelopathy, such as myotonia or periodic paralysis.
Clinical manifestations
Neonates with severe neonatal episodic laryngospasm experience sudden, recurrent episodes of apnea and cyanosis, often without warning. These episodes are caused by transient, involuntary laryngospasm that obstructs the airway. Additional symptoms may include stridor, feeding difficulties, generalized hypotonia, and occasionally myotonia or muscle stiffness. Triggers can include crying, feeding, or handling.
Diagnosis
Treatment
Prognosis
The prognosis varies depending on the severity and frequency of laryngospasm episodes. With early diagnosis and appropriate management, some infants improve over time and experience resolution of symptoms. However, severe and prolonged apneic events can lead to hypoxic injury or death if untreated. Long-term outcomes depend on the extent of respiratory compromise and associated neuromuscular symptoms.
