Clinical Guidance

In general, pathogenic null variants with no residual enzyme function result in infantile-onset LAL-D and pathogenic variants that allow for residual lysosomal acid lipase (LAL) enzyme activity result in childhood/adult-onset LAL-D.

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"

Diagnostic Criteria

Consensus diagnostic and treatment guidelines for lysosomal acid lipase deficiency (LAL-D) are available . Rapid diagnosis by biochemical and genetic testing is available. Although newborn screening is possible, it has not yet been implemented in the United States. Once a diagnosis of infantile-onset LAL-D is made, it should be considered a clinical emergency and treatment should be initiated without delay with dietary modification and enzyme replacement therapy .

Suggestive Findings

Infantile-Onset LAL-D

Infantile-onset LAL-D should be suspected in infants with the following clinical, supportive laboratory, and imaging findings.

Clinical findings

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"

Differential Diagnosis

Genetic disorders in the differential diagnosis of lysosomal acid lipase deficiency (LAL-D) are listed (infantile-onset LAL-D) and (childhood/adult-onset LAL-D). Table 4. Infantile-Onset Lysosomal Acid Lipase Deficiency: Differential Diagnosis

Management Guidelines

Recommendations for the diagnosis and management of infantile-onset lysosomal acid lipase deficiency (LAL-D) have been published . Practice and dosing regimens vary between countries/regions. Multinational consensus clinical practice guidelines do not exist.

Evaluations Following Initial Diagnosis

Initial management of infantile-onset LAL-D should be considered a medical emergency . To establish the extent of disease and needs in an individual diagnosed with infantile-onset LAL-D, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 6.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Recommended Evaluations at Initial Diagnosis

System/Concern | Evaluation | Comment

Biochemical

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

• Initiation of treatment is required as soon as diagnosis is made.

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

Gastroenterology/

Hepatology

| • Liver enzymes (AST/ALT)

• Albumin, GGT, alkaline phosphatase

• Total conjugated bilirubin levels

• LDH level

• Nutritional baseline profile including fat-soluble vitamins, essential fatty acids, magnesium, selenium

• Electrolytes

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"

Clinical Guidance

Those with thrombocytopenia should avoid use of nonsteroidal anti-inflammatory drugs.

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"

Therapies Under Investigation

It is clear that early treatment results in better outcome . A clinical trial is currently recruiting affected individuals to study the safety and efficacy of in utero ERT in lysosomal storage diseases, including LAL-D (NCT04532047). Preclinical trials of gene therapy are also promising . See for information about an international LAL-D registry. 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.

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to targeted therapy, and the emergence of new manifestations, the evaluations (infantile-onset LAL-D) and (childhood/adult-onset LAL-D) are recommended. Table 12. Infantile-Onset Lysosomal Acid Lipase Deficiency: Recommended Surveillance

Source: GeneReviews — "Lysosomal Acid Lipase Deficiency"