Primary Symptoms

Metabolic Crisis

• May include hypoglycemia, hyperlactacidemia, and mild hyperammonemia.
• Urine organic acids can show marked ketoacidosis and lactic acidosis.
• Acylcarnitine profiles may show elevated C14:1 in some individuals and elevated C10 in others.
• Metabolic abnormalities typically normalize after the metabolic crisis, although some individuals continue to have mildly elevated Creatine phosphokinase (CPK) levels.

Rhabdomyolysis

• Majority of individuals present with intermittent acute episodes of rhabdomyolysis.
• Dark urine due to myoglobinuria and profound lower-extremity weakness can develop.
• Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure.
• Creatine phosphokinase (CPK) can be significantly elevated in some individuals (>200,000 U/l).
• Elevated aldolase and transaminases can also occur
• For French-speaking families, visit No Myolyse to learn more about efforts underway in France to combat rhabdomyolysis

Variable Acute Presentation

• Acute presentation can vary from profound muscle weakness, ataxia, and/or disorientation to a comatose state

Cardiac Arrhythmias

• During acute illness, transient electrocardiogram (ECG) changes can be seen, most commonly QT prolongation and rarely Brugada type I pattern.
• Life-threatening recurrent ventricular tachycardia (VT) or torsade de pointes can occur primarily during times of acute illness and metabolic crises and can result in hemodynamic instability.

Other Important Symptoms Contributing to Diagnosis

Intellectual Disability

• Intellectual disability/developmental delay is present in almost all individuals with varying severity

Regression

• Loss of motor and cognitive skills

Poor Coordination and Unsteady Gait

• Poor coordination, unsteady gait, or clumsiness is frequently reported in individuals who are walking even prior to the first episode of metabolic crisis or rhabdomyolysis

Increased Tone

• Muscles are tight and tense even at rest with reduced capacity to stretch.
• Can lead to spasticity and rigidity

Episodic Muscle Weakness

• Unable to sit without falling
• Difficulty with grasping items/toys
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Benign Paroxysmal Torticollis (BPT)

• BPT typically manifests as a head tilt to one side for a few hours or days. It may not be affected by sleep. Spells can last as little as 10 minutes or as long as 2 months.
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Hyperreflexia

• Overactive reflexes

Clonus

• A series of involuntary, rhythmic, muscular contractions and relaxations
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Dysarthria

• A motor speech disorder characterized by poor articulation

Myopathic facies

• Facial appearance with bilateral ptosis (droopy eyes) and inability to elevate the corners of the mouth due to muscle weakness

Seizures

• Seizures are observed outside of crises in more than 75% of individuals including generalized myoclonic seizure and atonic seizures.
• Seizures are generally responsive to antiepileptic medications

Brain Imaging Abnormalities

• MRI may show cerebral volume loss.
• Some affected individuals had prominent lateral ventricles, with progressive brain atrophy.
• Some individuals have normal brain imaging studies.

Hypothyroidism

• Hypothyroidism has been reported in more than one third of individuals with TANGO2-related illness.
• Elevated serum thyroid stimulating hormone (TSH) and low free T4

Ophthalmology

• Intermittent exotropia (lazy eye) has been observed in most individuals.
• Rare individuals have been diagnosed with optic atrophy.

Other Episodic (non-seizure) Symptoms

• can include torticollis, instant onset fatigue, loss of muscle control, weakness, dizziness/balance issues, garbled speech, drooling, swallowing issues, dystonia, and/or clonus
• Presentation and duration can vary with each episode
• They can be instant onset and are sometimes alleviated by sleep.
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Hearing Loss

• Sensorineural hearing loss has been described in rare instances.