Hypoalphalipoproteinaemia

Hypoalphalipoproteinaemia is biochemically defined by reduced plasma HDL cholesterol. The conventional threshold is a sustained value below the fifth percentile for age and sex, corresponding to approximately 35 mg/dl. Extremely low HDL-C concentrations below 20 mg/dl mark the severe end of the biochemical spectrum.

In clinical practice the phenotypic spectrum encompasses severe forms, typically identified in childhood or early adulthood through characteristic biochemical or organ-specific findings on directed evaluation, and milder familial hypoalphalipoproteinaemia, most often detected as an incidental biochemical finding on adult lipid screening or routine cardiovascular risk assessment. Cardinal disease-specific features include corneal opacification (most marked in lecithin-cholesterol acyltransferase deficiency, less pronounced in apolipoprotein A-I deficiency and Tangier disease), hepatosplenomegaly with orange tonsils and peripheral neuropathy in , and renal involvement in familial lecithin-cholesterol acyltransferase deficiency.

Due to insufficient data, no reliable statement on prevalence can currently be made.

The genetic conditions associated with hypoalphalipoproteinaemia follow heterogeneous inheritance patterns. Severe biallelic disorders of HDL biogenesis or maturation (, familial lecithin-cholesterol acyltransferase deficiency, severe apolipoprotein A-I deficiency) follow autosomal recessive inheritance; heterozygous loss-of-function variants in the same genes contribute to autosomal dominantly transmitted familial hypoalphalipoproteinaemia with a milder phenotype.

A number of genes have been associated with hypoalphalipoproteinaemia. The genetic forms can be grouped into severe monogenic disorders and familial hypoalphalipoproteinaemia. Frequently identified causes include the following examples. Severe forms include (ABCA1, cellular cholesterol efflux defect) and apolipoprotein A-I deficiency (APOA1, primary HDL apolipoprotein deficiency). Familial hypoalphalipoproteinaemia reflects heterozygous variants in ABCA1, APOA1, or LCAT.

• Where hypoalphalipoproteinaemia is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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