Clinical Guidance

Neonatal-Onset Form

(formerly c.261-10TG or -10TG intron 2). Homozygosity for this pathogenic splice site variant is associated with the severe neonatal-onset form .

• Affected individuals who have one pathogenic c.199-10TG allele and another pathogenic variant on the other allele tend to have severe clinical features, with no apparent correlation to survival .

• The c.199-10TG pathogenic variant is the most common pathogenic variant described to date, and the most common pathogenic variant observed in individuals of East Asian and Southeast Asian descent, suggesting a possible founder effect .

(p.Phe91fs). Homozygosity for this pathogenic deletion of Turkish origin has been correlated with the severe neonatal-onset form of CACT deficiency .

Source: GeneReviews — "Carnitine-Acylcarnitine Translocase Deficiency"

Diagnostic Criteria

Carnitine acylcarnitine translocase (CACT) is a part of the carnitine shuttle that is localized to the inner mitochondrial membrane. It transfers long-chain acylcarnitines formed by the action of carnitine palmitoyl-transferase I (CPT1) in the outer mitochondrial membrane into the mitochondrial matrix in exchange for free carnitine. These acylcarnitines are then converted into acyl-CoA by carnitine palmitoyl-transferase 2 (CPT2) to enter -oxidation . No consensus clinical diagnostic criteria for carnitine-acylcarnitine translocase (CACT) deficiency have been published.

Suggestive Findings

Scenario 1: Abnormal newborn screening (NBS) result. NBS for CACT deficiency is primarily based on quantification of the acylcarnitine analytes on dried blood spots by tandem mass spectrometry. See also ACM...

Source: GeneReviews — "Carnitine-Acylcarnitine Translocase Deficiency"

Differential Diagnosis

Table 3. Genes of Interest in the Differential Diagnosis of Carnitine-Acylcarnitine Translocase Deficiency

Management Guidelines

No consensus clinical practice guidelines for carnitine-acylcarnitine translocase (CACT) deficiency have been published. When CACT deficiency is suspected during the diagnostic evaluation (i.e., due to elevated C16 and C18:1 on acylcarnitine profile), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure, obesity) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Evaluations Following Initial Diagnosis

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

Table 4.

Recommended Evaluations Following Initial Diagnosis of Carnitine-Acylcarnitine Translocase (CACT) Deficiency

Evaluation | Comment

Consultation w/metabolic physician / biochemical geneticist specialist metabolic dietitian1 | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)

• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance emergency treatment, prognosis, risks for acute encephalopathic crises).

Source: GeneReviews — "Carnitine-Acylcarnitine Translocase Deficiency"

Clinical Guidance

Avoid the following:

• Prolonged fasting

• Catabolic illness (fever, intercurrent infection)

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

• Strenuous physical activity

• Anesthetics that contain high doses of long-chain fatty acids, such as propofol, although use for short procedures is likely to be tolerated

Source: GeneReviews — "Carnitine-Acylcarnitine Translocase 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 — "Carnitine-Acylcarnitine Translocase Deficiency"

Surveillance Guidelines

In addition to regular evaluations by a metabolic specialist and metabolic dietitian, the following are recommended. Table 9. Recommended Surveillance for Individuals with Carnitine-Acylcarnitine Translocase (CACT) Deficiency

Source: GeneReviews — "Carnitine-Acylcarnitine Translocase Deficiency"