Finding the Hidden Components in Genetic Conditions: Glutaric Acidemia Type II

Genes are the building blocks of heredity. Passed from parent to child, they hold DNA, the instructions for making proteins which do most of the work in cells. They move molecules from one place to another, build structures, and break down toxins.¹

Sometimes there is a mutation, a change in a gene or genes. The mutation changes the gene’s instructions for making a protein, so the protein does not work properly or is missing entirely. This can cause a medical condition called a genetic disorder.¹

Glutaric Acidemia Type II: Defined and Diagnosed

Glutaric acidemia type II is an inherited disorder that interferes with the body’s ability to break down proteins and fats to use for energy. The buildup of the proteins and fats can cause the patient to go into metabolic acidosis. Severe cases begin in infancy and childhood, with sudden metabolic crises that are triggered by common childhood illnesses. Severe cases in infancy almost always result in death. Less severe cases begin to show symptoms between childhood and early adulthood.²

Patients with this disorder are instructed to eat often to avoid low blood sugars which would cause the body to try and break down protein and fat for energy, triggering a metabolic crisis. The patient is put on a diet of mostly carbohydrates to give the body readily available sugars to use for energy. Patients eat small amounts of protein and fat to avoid buildup in the bloodstream. Patients born with a severe gene mutation will have difficulty breathing, weak muscle tone, severe metabolic crisis, or heart or liver problems. These patients commonly die in infancy, even with treatment. Those with a less severe gene mutation develop symptoms later in childhood or early adulthood. Symptoms vary from muscle weakness, nausea and vomiting, and hypoglycemia. There may also be a characteristic odor from the patient described as sweaty feet. The patient may then develop frequent sudden metabolic crisis.²

Glutaric acidemia type II is a very rare disorder that can be caused by mutations in any of three genes (ETFA, ETFB, ETFDH). It is inherited in an autosomal recessive pattern; therefore, each parent carries one copy of the mutated gene with no signs or symptoms of the disease. The disease appears when both copies of the gene in each cell have the mutation. Adults usually become symptomatic when the body is stressed by common illnesses, which quickly turns into metabolic crisis. These unexplained medical conditions lead to detailed diagnostic testing. An organic acid panel of urine and blood tests will demonstrate suspicion of the disease, but final confirmation is by gene mutation analysis.²

Our Experience

A 32-year-old female with a history of glutaric acidemia presented with nausea and emesis that began earlier in the morning. She denied abdominal pain, diarrhea, fever, back pain, dysuria, and hematuria. The patient took Zofran 8 mg that morning without relief.

With the patient’s history of glutaric acidemia and inability to metabolize protein and amino acids, she checks her urine ketone level daily; normal tests should be negative. If “trace,” she rechecks her urine hourly at home. If “moderate” or high, the patient is to report to an emergency room for further evaluation and a specific protocol treatment (levocarnitine intravenous drip). The patient is well educated about this disorder. This morning, her ketone level was “high.” Concurrent symptoms are consistent with prior episodes.

History: 

• Severe metabolic acidosis with coma in 2011, diagnosed with glutaric acidemia.
• Recurrent hospitalizations with acidemia, seizures, and renal dysfunction.
• Cardiac arrest in 2014, precipitated by severe hyperkalemia.
• The above was all caused by primary disorder.

Family: 

• Parents are positive for carriers of glutaric acidemia type II.
• No family history of cardiac disease, no prolonged QT or sudden cardiac arrest.

Home medications include: 

Riboflavin 100 mg three times per day, co-enzyme Q10 capsule two times per day, sodium citrate 500 mg three times per day, levocarnitine 10 ml three times per day, and sodium bicarbonate 650 mg two times per day. 

Diagnostics:

Initial workup in the emergency room included the following:

• A pH of 7.29 with a pCO₂ of 30, pO₂ 46, Serum bicarbonate 14.6.
• Hemoglobin 13.3, WBC 7.7.
• Sodium 135, Potassium 4.5, Chloride 92, Bicarbonate 13, Glucose 54, BUN 19, Creatinine 0.9, Magnesium 2.0.
• Calcium 8.2, Anion gap is about 20, Albumin 4.8, Lactic acid 1.5.  Serum acetone is moderate; Urine pH is 5.5, 4+ ketones.

Cardiac markers: BNP, Troponins - normal.

Vital Signs: 

Blood pressure 119/72, pulse 130 beats per minute, respirations 22 breaths per minute, oxygen saturation 100%, temperature 98.1 ºF.

Electrocardiogram: 

• Sinus rhythm with a short PR interval and prolonged QT interval of 475 ms.
• Cardiac telemetry showing a short episode of five beats of nonsustained ventricular tachycardia, during which the patient experienced palpitations upon admission to the intensive care unit.

Diagnostic impression:

1. Lab findings consistent with metabolic acidosis and ketosis.
2. Severe high anion gap metabolic acidosis secondary to glutaric acidemia type II.
3. Nonsustained ventricular tachycardia in addition to prolonged QTC.

Cardiology consultation/plan:

1. Avoid medications that prolong QT interval (patient was using Zofran).
2. With history of cardiac arrest, ICD was previously discussed, but deferred since severe hypokalemia was the questionable cause.
3. Two-dimensional echocardiogram to assess left ventricular function and ejection fraction to rule out any structural heart disease.
4. Nuclear stress testing to rule out any potential ischemia.
5. EP evaluation for her prior history of arrest and her prolonged QT at this time.

EKG: 

Sinus rhythm, short PR 100 ms, QT 419, QTc 475 ms.

Echo: 

Systolic function was normal. Ejection fraction was 60%. There were no regional wall motion abnormalities.

Nuclear Stress: 

Perfusion imaging: a small, mildly severe, fixed myocardial perfusion defect of the apical anterior wall likely due to attenuation from breast tissue. Gated spect: the calculated left ventricular ejection fraction was 63%.

Electrophysiology consultation/plan:

1. Nonsustained ventricular tachycardia.
2. History of electrolyte imbalance.
3. History of seizures, due to glutaric acidemia type II.
4. Survivor of cardiac arrest.
5. Incomplete penetrance of QT gene.
6. Electrophysiology study, no current Class I indications for ICD placement.

Electrophysiology study: 

Programmed stimulation from right atrium, right ventricular apex and right ventricular outflow tract, baseline and Isuprel 3 mcg.

Patient arrives in sinus rhythm with abnormal BCI 1175 ms, PR 125 ms, QRS 80 ms, QT 450 ms, AH 60 ms, HV 35 ms. After Isuprel BCI 515 ms, PR 120 ms, QRS 80 ms, QT 300 ms, AH 40 ms, HV 35 ms. Carotid sinus massage – normal. 

• SA node function: Corrected sinus node recovery time 1940 ms at right atrial pacing 600 ms. 
• AV node function: Wenckebach 530 ms, AVNERP 700/530.
• VA conduction: Normal decremental and concentric.
• SVTs: No dual AVN/accessory pathways.
• VT study: Not inducible despite aggressive stimulation protocol 400/200/190/180 ms.

Conclusions: 

• Prolong QT interval.
• Severely abnormal corrected sinus node recovery time (2 sec).
• Abnormal AVN function.

Plan: Discuss with Patient

Although the patient met criteria for a pacemaker, due to her prior history of cardiac arrest, baseline long QT (incomplete penetrance of long QT gene), and tendency for abnormal serum electrolytes, we believed she would benefit from an ICD.

The patient’s genetic metabolic disorder, along with long QT and perhaps incomplete penetrance, clearly place her at higher risk of recurrent ventricular tachycardia events and sudden cardiac arrest. 

Regarding incomplete penetrance of long QT gene, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. Clinical symptoms are not always present in individuals who have genetic mutations.^3-5

It is currently thought that most patients affected by long QT syndrome show QT interval prolongation or clinical symptoms. Long QT syndrome may appear with very low penetrance; the individual does not always have clinical symptoms of the disease.⁶

Subpectoral implantation of a dual-chamber ICD was performed. Device-based testing was performed during implant. The device was programmed to detect ventricular tachycardia at 185, antitachycardia pacing x 3, shocks x 3. Ventricular fibrillation detection was set at 210 followed by full energy shocks x 4.

Review and Management 

Diagnostic impression:

• Nonsustained ventricular tachycardia, glutaric acidemia type II, metabolic acidosis, history of cardiopulmonary arrest (2014), electrocardiogram with prolonged QT.
• Normal left ventricular function, nuclear stress test negative for ischemia, stable cardiovascular status, post-operative ICD placement.

The patient discharged from the hospital with full knowledge of her condition and device therapy. The patient has not yet been seen in follow-up.

Our physicians and staff found this case unique and challenging. We feel we provided the best options for this young woman, since genetic components do not always “fit” required criteria. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein.  

References

1. Genetic Disorders. MedlinePlus. Published Dec 9, 2014. Available online at https://www.nlm.nih.gov/medlineplus/geneticdisorders.html. Accessed February 3, 2015. 
2. Glutaric acidemia type II. Genetics Home Reference. Published February 2014. Available online at https://ghr.nlm.nih.gov/condition/glutaric-acidemia-type-ii. Accessed February 3, 2015.
3. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99(4):529-533.
4. Giudicessi JR, Ackerman MJ. Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res. 2013;161(1):1-14.
5. Handbook: Help Me Understand Genetics. Genetics Home Reference. Available online at https://ghr.nlm.nih.gov/handbook/inheritance/penetranceexpressitivy. Accessed February 3, 2015.
6. Long QT Genetic Testing. GeneDx. Available online at https://www.genedx.com/test-catalog/cardiology/long-qt-syndrome-and-its-genetics/. Accessed February 3, 2015.