Can you give an overview of primary carnitine deficiency in adults, including its genetics, clinical presentation, diagnosis, and management?

Primary Carnitine Deficiency in Adults

Overview

Primary carnitine deficiency (PCD) is an autosomal recessive disorder caused by mutations in the SLC22A5 gene that can present in adulthood with cardiomyopathy, cardiac arrhythmias, skeletal myopathy, or fatigue, and requires lifelong oral L-carnitine supplementation at 50-400 mg/kg/day to prevent life-threatening cardiac complications. 1, 2

Genetics and Pathophysiology

• PCD is inherited as an autosomal recessive trait with a recurrence risk of 25% in each pregnancy when both parents are carriers 3, 2
• The disorder results from mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter, with over 100 mutations identified 2, 4
• The c.136C>T (p.P46S) mutation is the most frequently identified mutation 2
• Nonsense mutations are significantly more common in symptomatic patients compared to asymptomatic individuals (P < 0.001), while missense mutations often retain residual carnitine transport activity 4
• The estimated incidence in the United States is approximately 1 in 50,000 individuals based on newborn screening data 2

Clinical Presentation in Adults

Adults with PCD typically present with cardiac manifestations rather than the metabolic crises seen in children:

• Cardiomyopathy with progressive heart failure is the most common adult presentation 5, 2
• Cardiac arrhythmias including atrial fibrillation, ventricular tachycardia, and long QT syndrome have been documented 2, 6
• Skeletal myopathy with elevated creatine kinase and fatigability 2
• Persistent unexplained fatigue, sometimes misattributed to hypothyroidism 7
• Many adults remain asymptomatic and are only identified through newborn screening of their offspring 2, 7, 4

Critical Clinical Pitfall

A substantial proportion of adult cases (35.7% in published series) are symptomatic, with cardiac arrhythmias present in 12% of cases 6. The disorder can remain undiagnosed until life-threatening cardiac events occur, particularly during periods of metabolic stress such as pregnancy 5, 6.

Diagnosis

The diagnostic workup requires multiple complementary tests, not just serum carnitine alone:

Laboratory Evaluation

• Plasma free carnitine concentration <5 μM (normal 25-50 μM) is diagnostic 2
• Calculate the acyl-to-free carnitine ratio: normal ≤0.25, deficiency >0.4 1
• Measure total carnitine and acylcarnitine esters simultaneously 1
• Obtain blood triglycerides, liver function tests, glucose, lactate, and ammonia to establish baseline and assess metabolic status 1
• Urine ketones should be checked 1

Confirmatory Testing

• Fibroblast carnitine transport activity <10% of controls confirms the diagnosis 2
• Molecular genetic testing of the SLC22A5 gene identifies causative mutations 2
• Plasma or serum is the preferred sample type for symptomatic patients 3

Baseline Cardiac Assessment

Once PCD is diagnosed, perform:

• Echocardiogram to assess for cardiomyopathy 2
• Electrocardiogram to evaluate for arrhythmias and QT prolongation 2, 6
• Creatine kinase measurement 2
• Pre-prandial blood glucose levels 2

Management

Treatment Protocol

Oral L-carnitine supplementation at 50-400 mg/kg/day divided into three doses is the primary treatment 1, 2. This represents approximately 3-6 grams daily for most adults, which is 10-fold higher than doses used for secondary carnitine deficiency 1.

• Clinical improvement occurs rapidly within days to weeks of initiating therapy 1
• Continue treatment until carnitine levels and acyl-to-free carnitine ratio normalize 1
• Cardiomyopathy is reversible even in adults with severe heart failure when treatment is reinitiated 5

Critical Management Pitfall

This is a lifelong genetic transporter defect requiring continuous replacement therapy—never discontinue treatment once symptoms resolve 1. A documented case showed recurrent severe heart failure at age 29 after discontinuing medication at age 13, which fully reversed with reinitiation of carnitine supplementation 5.

Side Effects and Tolerability

• Common side effects at 3 g/day include nausea, vomiting, abdominal cramps, diarrhea, and fishy body odor 8, 1
• Gastrointestinal side effects are the primary limiting factor for therapy 9
• Rare but serious side effects include muscle weakness in uremic patients and seizures in those with pre-existing seizure disorders 8, 1

Monitoring and Surveillance

No formal surveillance guidelines exist, but the following approach is recommended:

• Annual echocardiogram and electrocardiogram to monitor cardiac function 2
• Frequent plasma carnitine levels to ensure adequate supplementation 2
• Creatine kinase and liver transaminases during acute illness 2
• Monitor for normalization of the acyl-to-free carnitine ratio 1

Special Considerations for Women

Adult women with PCD who are pregnant or planning pregnancy require specialized management:

• Meet with a metabolic or genetic specialist ideally before conception 2
• Carnitine levels are typically lower during pregnancy, requiring dose adjustments 2
• Syncopal episodes and cardiac symptoms can escalate during pregnancy in untreated or inadequately treated patients 6

Transition of Care

The period of transition from pediatric to adult care represents a high-risk time for non-compliance 5. Young adults may desire to be "healthy" and discontinue treatment, leading to potentially fatal cardiac complications. Adequate disease education and promotion of self-management should occur before patients reach this vulnerable age 5.

Differential Diagnosis

PCD must be differentiated from secondary causes of carnitine deficiency:

• Various organic acidemias 2
• Fatty acid oxidation defects 2
• Prolonged parenteral nutrition 8
• Chronic hemodialysis 8

Carrier screening requires targeted mutation analysis of the SLC22A5 gene, as plasma carnitine analysis alone is insufficient for determining carrier status 2.