Clinical characteristics: Chylomicron retention disease (CMRD), characterized by the inability to secrete chylomicrons from the enterocytes following the ingestion of fat, typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat. This leads to steatorrhea – the severity of which relates to the fat content of the diet – and in some cases, hepatomegaly. Organ systems outside of the gastrointestinal tract may also be affected (often due to malnutrition and deficiencies of fat-soluble vitamins), including neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency, poor bone mineralization and delayed bone maturation due to vitamin D deficiency, prolonged international normalized ratio (INR) due to vitamin K deficiency, mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms), and (in a small proportion of adults) cardiomyopathy with decreased ejection fraction. Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels, and low serum concentrations of fat-soluble vitamins (A, D, E, and K). Endoscopy typically demonstrates a gelée blanche ("white hoar frosting") appearance of the duodenal mucosa.

Diagnosis/testing: The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in SAR1B identified by molecular genetic testing.

Management: Treatment of manifestations: Ensure adequate caloric intake with a low-fat diet (<30% of total calories from fat) enriched in essential fatty acids with or without medium-chain triglycerides; high-dose oral fat-soluble vitamins, including vitamin E (hydrosoluble form) 50 IU/kg/d, vitamin A 15,000 IU/d, vitamin K 15 mg/week, and vitamin D 800-1200 IU/d; consider adding IV vitamin supplementation if an individual is late to be diagnosed with neurologic complications, although benefit is not proven in this situation; standard treatment for deficits in night vision and/or color vision, ataxia, and cardiomyopathy.

Surveillance: Annually: measurement of growth parameters; evaluation of digestive and neurologic symptoms; assessment of dietary fat content/compliance; and measurement of lipid profile, liver function tests, complete blood count, INR, and vitamins A, D, and E. Every three years after age ten: liver ultrasound, neurologic exam with serum creatine kinase and electromyography, ophthalmologic evaluation, and DXA scan. Every three to five years in adults: echocardiogram with assessment of ejection fraction.

Agents/circumstances to avoid: Avoidance of fatty foods, particularly those rich in long-chain fatty acids.

Pregnancy management: Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended.

Genetic counseling: CMRD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SAR1B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the SAR1B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.