Lipid Storage Disorders Workup

Updated: Jun 10, 2020
  • Author: Rubia Khalak, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Laboratory Studies

Diagnosis of lipid storage disorders depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

Prenatal diagnosis

If an index case has been identified, an attempt at prenatal diagnosis is warranted. Amniotic fluid can be evaluated by assaying cultured cells from the amniotic fluid or from chorionic villus for the targeted enzymatic activity. For some disorders, molecular genetic testing can be used to detect enzyme mutation detection or linkage analysis. [24]

Newborn screening

The first large-scale pilot was conducted in Taiwan for Pompe disease (glycogen-storage disease type II). Pseudodeficiencies for Pompe disease are common in Asian populations. [25] A fluorescence assay was used to measure alpha glucosidase activity at three different pH levels.

In another large pilot study conducted in New York State and Washington State, tandem mass spectrometry (MS/MS) was used in newborn screening to assess enzyme activity for Pompe disease, mucopolysaccharidosis type I, and Fabry disease, finding a lower number of screen positives. [26]


Imaging Studies

Brain imaging

Brain imaging studies are frequently obtained during evaluation of infants and children with developmental delay or retrogression. However, they are not essential to diagnosis, which depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

For many of the lipid storage disorders, MRI findings are either normal or not specific enough to be diagnostic. However, T2 hypointensity with T1 hyperintensity has been noted in patients with Tay-Sachs disease. In contrast, with infantile Krabbe, T1 hypointensity can be seen with T2 hyperintensity. In Niemann-Pick disease type C, frontal lobe and/or brainstem/cerebellar atrophy may be seen. [27]

Findings vary with different disorders.

Skeletal radiography

In GM1 gangliosidosis, skeletal abnormalities are similar to those associated with mucopolysaccharidoses. They include anterior beaking of vertebrae, enlargement of sella-turcica and thickening of calvaria.

In Gaucher disease type 1, more than half of patients have radiological evidence of skeletal involvement including an Erlenmeyer flask deformity of the distal femur.

In patients with symptomatic bone disease, lytic lesions can develop in long bones like the femur, ribs, and pelvis. Osteosclerosis may be evident at an early age.

Chest radiography

Patients with sphingomyelinase deficiency (NPD types A and B) typically have fine reticular-nodular infiltrates.

Findings are not associated with clinical pulmonary disease in young patients but can be accompanied by pulmonary dysfunction later in life.

Abdominal radiography

Patients with Wolman disease typically have calcification of the adrenal noted on abdominal radiograph.


Other Tests

Genetic testing

For most disorders, carrier identification and prenatal diagnosis are available. Making a specific diagnosis in an affected child is important in order to provide genetic counseling.

More recently, investigators have focused efforts on determining molecular basis. These studies have resulted in identification of specific disease-causing mutations, allowing for improved diagnosis, prenatal diagnosis and carrier identification.

For some disorders (eg, Gaucher disease), it is possible to make genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling. Thus, determination of genotype is recommended when possible. [28]

Disease-specific molecular analysis

Fabry disease

Most pathogenic GLA mutations are “private” and nonrecurrent; more than 300 mutations have been described. In general, mutations that result in prematurely truncated α-gal A, which are approximately 45% of those reported, result in a classic Fabry phenotype in a hemizygote. [29] Missense mutations that result in very low leukocyte α-gal A levels also result in a classic phenotype.

Gaucher disease

Sequencing of the GBA gene is the definitive method in the diagnosis of Gaucher disease. Within the Ashkenazi Jewish population, four common mutations (p.N370S, p.L444P, c.84insG, and c.IVS2 1) account for 90% of the disease-causing alleles; these same mutations account for 50%-60% of disease-causing alleles in non-Jewish patients. [30]

Krabbe disease

The diagnosis can be confirmed via molecular analysis of the GALC gene. [31] Genotype-phenotype correlation is limited and may be possible only if the clinical impact of a particular genotype is known in a larger set of patients with Krabbe disease.

Metachromatic leukodystrophy

The diagnosis of MLD can also be confirmed with molecular genetic analysis of the ARSA gene. To date, more than 140 disease-relevant mutations have been identified. Several recurrent mutations account for up to 60% of disease-relevant alleles in certain populations. [32, 33] ARSA mutations characterized in more detail have been divided into two groups: (1) “null alleles” such as c.459 1g>a (25% of disease alleles) and c.1204 1g>a, which result in complete loss of enzymatic activity, and (2) “R alleles” such as p.P426L (25% of disease alleles) and p.I179S (12.5% of disease alleles), which allow the synthesis of ARSA enzyme with residual catalytic activity of up to 5% of normal. [34]

Niemann-Pick disease, types A and B

Sequencing of the SMPD1 gene is the most reliable method to confirm a diagnosis of NPD. In the Ashkenazi Jewish population, three founder mutations, p.R496L, p.L302P, and fsP330, account for more than 95% of mutant alleles and are associated with the NPA phenotype. [35] Biomarkers may play a role in confirming a diagnosis of Niemann-Pick disease type C1 (isolation of abundant N-palmitoyl-O-phosphocholineserine [PPCS] levels urine). [36]

Tay-Sachs disease

HEXA gene DNA analysis or enzymatic assay of leukocyte beta-hexosaminidase A are approaches for diagnosis of Tay-Sachs disease. [6]


Histologic Findings

Examination of tissues reveals pathologic storage of substrate in many tissues including liver, bone marrow and, for some disorders, the brain.

Gaucher disease has a pathologic hallmark, which is the Gaucher cell in the reticuloendothelial system, particularly in bone marrow. Cells, which are 20-100 µm in diameter, have a wrinkled-paper appearance resulting from presence of intracytoplasmic inclusions of substrate. Cytoplasm reacts strongly positive with periodic acid-Schiff stain. Presence in bone marrow and organ tissue specimens is highly suggestive of Gaucher disease, although it can be found in patients with granulocytic leukemia and myeloma.

Sphingomyelinase deficiency (NPD types A and B) and NPD type C have a pathological hallmark, which is histochemically lipid-laden foam cells, often called Niemann-Pick cells. [5] These cells can be readily distinguished from Gaucher cells by their histologic and histochemical characteristics. They are not pathognomonic for NPD because histologically similar cells are found in patients with Wolman disease, cholesterol ester storage disease, lipoprotein lipase deficiency, and GM1 gangliosidosis type 2.