Approach Considerations
Whole exome sequencing (WES) is quickly becoming more clinically available, and, with next-generation sequencing, the rate of throughput has increased exponentially. Previously, WES was avoided owing to its high cost and slow timescale in the return of results. Now that the cost of WES testing is substantially lower and quicker to return results, it has been adopted as a powerful tool in the diagnostician’s arsenal. [22, 23]
Patients with GM1 gangliosidosis present with highly variable symptomology, sometimes complicating diagnosis based on clinical evaluation. Thus, WES should be considered as a primary method of diagnostic evaluation to identify for GLB1 gene mutation. A case report described a girl who presented with progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. Her clinicians suspected G M1 gangliosidosis, but enzymatic blood testing and β-galactosidase assay returned normal findings. Following a trio WES study, they identified a paternally inherited GLB1 mutation and diagnosed her with G M1 gangliosidosis. [24] Without WES, the complications of the traditional screening panels would have left this case undiagnosed.
Laboratory Studies
Acid β -galactosidase activity
Diagnosis of GM1 gangliosidosis can be confirmed by measurement of acid β -galactosidase activity in peripheral blood leukocytes. Patients with the infantile form have almost no enzyme activity, whereas patients with the adult form may have residual activity of 5-10% of reference values. Overlap is often present between homozygotes without GM1 gangliosidosis and heterozygote carriers; therefore, screening for heterozygote carriers using enzyme analysis is not reliable. [1]
Urine
Galactose-containing oligosaccharides are excreted in the urine. Their presence may be used as an ancillary diagnostic test, and the concentration of the metabolites is proportional to disease severity.
CBC count
Vacuolation of lymphocytes may be present in patients with GM1 gangliosidosis but is a nonspecific indicator seen in a variety of lysosomal storage disorders.
Dried blood spots
Diagnosis of GM1 gangliosidosis has been made based on dried blood spots from newborn screening filter paper, even after 15 months in storage. [25]
Molecular analysis
Molecular analysis of the β -1 galactosidase gene (GLB1) is clinically available. [21, 2]
Imaging Studies
Radiography
Skeletal radiographs may reveal changes characteristic of dysostosis multiplex (as observed in mucopolysaccharidosis), including thickened calvaria, J-shaped enlarged sella turcica, wide spatula-shaped ribs, flared ilia, acetabular dysplasia and flat femoral heads, wide wedge-shaped metacarpals, shortened long bones with diaphyseal widening, and hypoplastic and anteriorly beaked thoracolumbar vertebrae. Delayed bone age also may be demonstrated. In the adult form, only mild vertebral changes may be observed. [1]
CT and MRI
Neuroimaging using CT scan or MRI generally reveals diffuse atrophy and white matter demyelination with or without basal ganglia changes. Bilateral T2-weighted hyperintensities in the putamen are a frequently reported MRI finding in adult-onset disease. Mild cerebral atrophy may also be observed in the adult form. MR spectroscopy has demonstrated increased striatal myoinositol.
Ultrasound
An ultrasound of the abdomen may reveal organomegaly.
Echocardiography
Signs of cardiomyopathy or valvulopathy may be observed.
Other Tests
Electrocardiography
Signs of cardiomyopathy may be observed.
Electroencephalography
This test may reveal generalized dysrhythmia and epileptogenic foci.
Procedures
Acid β -galactosidase genotyping
Molecular diagnosis by direct sequencing can be useful for detecting heterozygous carriers and affected patients. [26, 21]
GM1 ganglioside levels can be increased in the cerebrospinal fluid (CSF) and may be useful for diagnosis and monitoring.
Bone marrow aspiration
Do not use this procedure as a diagnostic test. Nonspecific large foam cells, Gaucher cells, and ballooned cells have been reported in bone marrow but are typically reported in lower concentrations than in other lysosomal storage disorders. Sea-blue histiocytes have been reported. [1]
Skin biopsy
Obtaining a skin biopsy may be useful to establish acid β -galactosidase activity in cultured fibroblasts.
Prenatal diagnosis
Prenatal diagnosis has been performed successfully by assay of β -galactosidase activity in cultured amniocytes or amniotic chorionic villi. [1] Mutation identification allows prenatal or preimplantation genetic diagnosis.
Histologic Findings
Cytoplasmic distention is observed diffusely within neurons and glial cells (with numerous membranous cytoplasmic bodies) because of accumulated GM1 ganglioside.
Neuronal number is decreased, and cortical architecture is distorted.
Extraneural lipid-laden histiocytes are observed in the liver, spleen, lymph nodes, thymus, lung, intestine, interlobular septa of the pancreas, and bone marrow. Their distended cytoplasm leads to eccentrically placed small pyknotic nuclei. [1]
In dogs and cats, immunohistochemical methods have been shown to detect GM1 gangliosides before diagnosis could be made using molecular analysis techniques. This technique is useful for retrospective diagnosis of suspected cases of GM1 gangliosidosis postmortem. [27]
