Clinical Guidance

No genotype-phenotype correlations have been identified. Nonsense and frameshift variants in SLC22A5 are more prevalent in symptomatic individuals. Missense variants are more prevalent in asymptomatic individuals .

Source: GeneReviews — "Primary Carnitine Deficiency"

Diagnostic Criteria

Suggestive Findings A diagnosis of primary carnitine deficiency (PCD) may be suspected due to an abnormal newborn screening result prior to onset of suggestive findings or may be considered because of symptoms of PCD . Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for PCD is primarily based on use of dried blood spots collected between 24 hours and 72 hours after birth to quantify free carnitine (C0) concentration by tandem mass spectrometry. (For information on NBS by state in the United States, see www.newbornscreening.hrsa.gov.) Low concentration of free carnitine can identify (1) an infant with PCD, (2) a mother with PCD, or (3) both. NBS can identify a mother with PCD because transfer of carnitine across the placenta from an affected mother to her fetus results in a low plasma carnitine concentration in her newborn. Thus, an infant who does not have PCD but is born to a mother who has PCD can have low plasma carnitine concentrations shortly after birth, resulting in a false positive NBS result . Note: (1) NBS for PCD has low positive predictive value (e.g., 4.7% in California ). There are many factors that may affect NBS for PCD, including maternal carnitine deficiency, prematurity, pivalic acid-containing antibiotics, and some other inborn errors of metabolism. At least one country (New Zealand) has discontinued NBS for this disorder because of its very low sensitivity and positive predictive value . (2) In the US, most NBS laboratories determine their own cutoff levels for test results that are considered to be out of range and require further laboratory testing because out-of-range NBS results individually are not entirely specific to PCD. Positive NBS results (i.e., low blood concentrations of free carnitine) require evaluation of the newborn and mother as soon as possible and no later than three days after birth. • See and on how to make an analyte diagnosis or confirm a diagnosis molecularly. • For recommendations on presumptive treatment of affected newborns while awaiting diagnosis confirmation to prevent irreversible neurocognitive impairment, consult a metabolic specialist to discuss immediate treatment for PCD with oral levocarnitine supplementation and other recommended care. • If a metabolic specialist is not available, begin treatment for PCD with oral levocarnitine supplementation (typically 100-200 mg/kg/day, divided in three doses; see ) to prevent metabolic decompensation. Table 1. Primary Carnitine Deficiency: Testing Recommended at the Time of Diagnosis of Low Carnitine Blood Levels via NBS

Source: GeneReviews — "Primary Carnitine Deficiency"

Differential Diagnosis

Primary carnitine deficiency (PCD) needs to be differentiated from secondary carnitine deficiency associated with other inherited metabolic disorders, including organic acidemias and fatty acid oxidation defects , and acquired conditions . Genetic disorders. Free and total carnitines, a plasma acylcarnitine profile, and urine organic acid analysis can be useful in differentiating fatty acid oxidation disorders and organic acidemias from PCD.

Table 4.

Selected Autosomal Recessive Disorders Associated with Secondary Carnitine Deficiency in the Differential Diagnosis of Primary Carnitine Deficiency

Gene(s) | Disorder | Biochemical Phenotype

ACADM

| Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency | Elevated C8, C10, C10:1; increased excretion of dicarboxylic acids

ACADS

| Short-chain acyl-CoA d...

Source: GeneReviews — "Primary Carnitine Deficiency"

Management Guidelines

No clinical practice guidelines for primary carnitine deficiency (PCD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PCD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Primary Carnitine Deficiency: Recommended Evaluations Following Initial Diagnosis

Evaluation | Comment

Consultation w/metabolic physician/ biochemical geneticist

| Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)

Cardiology

| Echocardiogram electrocardiogram

Laboratory tests

| • CK liver transaminases

• Post-prandial blood glucose concentration

• Plasma free/total carnitine concentration following initiation of treatment

Consultation w/psychologist /or social worker

| To ensure understanding of diagnosis assess parental/ affected person's coping skills as needed

Clinical Guidance

Avoid the following:

• Prolonged fasting beyond age-appropriate periods

• Catabolic illness (using measures to avoid intercurrent infection, such as being up to date on vaccinations with anticipation of likelihood of febrile illness post vaccination, wearing a mask in crowded environments, considering alternatives to daycare, recognizing symptoms early)

• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

Source: GeneReviews — "Primary Carnitine Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Primary Carnitine Deficiency"

Surveillance Guidelines

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Table 10. Primary Carnitine Deficiency: Recommended Surveillance

Source: GeneReviews — "Primary Carnitine Deficiency"