STAC3 Disorder

Alternate names

Congenital myopathy cleft palate and malignant hyperthermia; Congenital myopathy - cleft palate - malignant hyperthermia; Congenital myopathy-cleft palate-malignant hyperthermia syndrome; Congenital myopathy with myopathic facies, scoliosis, and malignant hyperthermia; Bailey-Bloch congenital myopathy; Native American myopathy

Definiton

STAC3 Disorder is a genetic condition that affects the muscles and skeleton. The main features are muscle weakness present at birth, club foot, fixed joints (joint contractures), and curvature of the spine.

Epidemiology

STAC3 disorder was first found in individuals from the Lumbee Native American Tribe in North Carolina. The condition affects an estimated 1 in 5,000 people in this population. STAC3 disorder has since been found in other populations worldwide, though its prevalence is not known.

Cause

• STAC3 disorder is caused by mutations in the STAC3 gene.
• This gene provides instructions for making a protein that plays a role in the tensing (contraction) of skeletal muscles.
• Muscle contractions are triggered by changes in the concentration of certain charged atoms (ions) in muscle cells.
• The STAC3 protein aids in the process that triggers the release of calcium ions within muscle cells to start (initiate) muscle contraction.
• The STAC3 protein interacts with two structures in muscle cells that are critical for calcium ion flow, dihydropyridine receptor (DHPR) and ryanodine receptor 1 (RYR1).
• However, STAC3's role in this formation is unclear.
• RYR1 forms a channel (the RYR1 channel) through which calcium ions can flow.
• In response to certain signals, DHPR turns on (activates) the RYR1 channel, and the activated RYR1 channel releases calcium ions stored in structures inside muscle cells.
• The resulting increase in the calcium ion concentration within muscle cells stimulates muscles to contract, allowing the body to move.

Gene mutation

• STAC3 gene mutations reduce the amount or impair the function of the STAC3 protein.
• Although the mechanism is unclear, studies show that a shortage of functioning STAC3 protein prevents the release of stored calcium ions by RYR1 channels.
• A disruption in calcium ion release prevents muscles from contracting normally, leading to the muscle weakness characteristic of STAC3 disorder.
• It is unclear how these STAC3 gene mutations lead to malignant hyperthermia in susceptible individuals.
• Mutations in other genes related to malignant hyperthermia activate the RYR1 channel improperly in response to certain drugs.
• As a result, large amounts of calcium ions are released from storage within muscle cells, causing skeletal muscles to contract abnormally.
• An increase in calcium ion concentration also activates processes that generate heat (leading to hyperthermia) and produce excess acid (leading to acidosis). It is unknown if STAC3 gene mutations have a similar effect on RYR1 channel activity.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

The following list includes the most common signs and symptoms in people with STAC3 disorder. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

• Muscle weakness present at birth (congenital myopathy)
• Low muscle tone (hypotonia)
• Facial weakness
• Down turned corners of the mouth
• Drooping eyelids (ptosis)
• Clubfoot (talipes)
• Fixed joints (joint contractures)
• Cleft palate
• Increased risk for complications from general anesthesia (malignant hyperthermia)
• Curvature of the spine (scoliosis)

STAC3 disorder is very rare and how the symptoms change over time has not been well described.

• The muscle weakness and curvature of the spine tend to slowly get worse, although some people with STAC3 disorder have mild symptoms that don't change.
• Most adults with STAC3 disorder are shorter than average and may have delayed motor skills (like walking and running).
• Intelligence is usually normal.
• A few have severe symptoms that result in very serious respiratory and feeding difficulties.

Diagnosis

STAC3 disorder (also known as Native American myopathy) should be suspected in individuals with the following clinical and laboratory findings.[1].

Clinical findings

• Congenital myopathy
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.

Musculoskeletal anomalies

• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth)
• Scoliosis, kyphosis, or kyphoscoliosis
• Palatal anomalies including cleft palate
• Micrognathia

Characteristic facial features.

• Myopathic facies, micrognathia, and palatal anomalies can be seen in a number of neuromuscular disorders of varying etiologies; the characteristics that best distinguish STAC3 disorder from other conditions include low-set and/or posteriorly rotated ears, short and/or downslanting palpebral fissures, and telecanthus.
• Short stature
• Susceptibility to malignant hyperthermia

Laboratory findings. Creatine kinase baseline levels are most often normal .

Establishing the Diagnosis The diagnosis of STAC3 disorder is established in a proband with clinical findings consistent with Suggestive Findings and biallelic pathogenic variants in STAC3 identified by molecular genetic testing.

Treatment

At present, no treatment halts or reverses the manifestations of STAC3 disorder. Treatment of musculoskeletal involvement is symptomatic and ideally provided by a multidisciplinary neuromuscular team to address the following:[2].

• Occupational and physical therapy needs regarding range of motion and mobility
• Use of adaptive devices for mobility and activities of daily living
• Feeding difficulties
• Speech delays
• Scoliosis
• Respiratory insufficiency
• Due to the medical comorbidities in STAC3 disorder, decisions regarding type and timing of cleft palate surgery should be determined by a multidisciplinary craniofacial team.
• Depending on the structure of the managing craniofacial team, interventions for ptosis may be undertaken by an ophthalmologist as part of team care, or as an insertion intervention.

NIH genetic and rare disease info

• NIH info on STAC3 Disorder

STAC3 Disorder is a rare disease.

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