Batten Disease Diagnosis

It is difficult to diagnose Batten disease — a rare heritable disorder that affects around 1 in 100,000 births worldwide — and, as result, patients are often misdiagnosed or their diagnosis is delayed.

For a diagnosis of Batten, doctors need the patient’s medical and family history, and information from several laboratory tests.

Also called neuronal ceroid lipofuscinoses (NCL), Batten is caused by mutations in genes that encode proteins responsible for handling cellular wastes.

These mutations cause proteins to be made incorrectly, or not at all, so cellular wastes called lipofuscins build up inside lysosomes — the compartments within a cell that degrade substances that are no longer needed.

These cellular wastes cause neurodegeneration, or the death of nerve cells, and lead to many of the symptoms of Batten disease.

As many of these symptoms are subtle or not specific to the disease, Batten is often misdiagnosed, especially in the early stages. As such, patients often are tested for or diagnosed with a variety of diseases before a correct diagnosis of Batten is reached.

Complete patient medical information and lab testing — including tissue biopsies and blood, enzyme, and genetic tests — are used by clinicians in reaching a conclusive diagnosis.

Blood tests

The accumulation of lipofuscins leads to the formation of abnormal and distinctive vacuoles, or holes or cavities inside cells. The presence of these vacuoles can easily be detected with a simple blood test by analyzing a type of white blood cells, called lymphocytes, under a microscope.

Abnormally shaped lymphocytes are seen in several types of Batten disease, particularly in the juvenile type, also known as CLN3 disease.

Curvilinear bodies, or comma-shaped structures, have been reported in the cells of patients with late infantile Batten disease, or CLN2 disease, but no vacuoles are observed in lymphocytes of patients with this type of condition.

So-called granular osmiophilic deposits, which are abnormal material collections, are typically seen in the lymphocytes of people with CLN1 disease. 

Although a blood test is a reliable tool to detect certain types of Batten disease, abnormally shaped lymphocytes have not been reported for all forms. The results of blood tests should therefore be confirmed with a genetic test, which also will give certainty about the underlying genetic cause of the disease.

Genetic testing

The only sure way to diagnose Batten disease is through genetic testing.

To perform a genetic test for Batten disease (or any other genetic condition), the patient’s DNA is purified from a blood or tissue sample. The DNA is then sequenced — a process in which the exact DNA sequence of the gene is determined.

Next-generation sequencing is a large-scale DNA sequencing technology widely used to identify mutations in disease-associated genes.  To confirm the results and provide a definitive diagnosis of Batten disease, a conventional test called the Sanger method can be used.

Results usually become available within two to eight weeks (about two months) from the time the sample is submitted. The patient’s physician or genetic counselor can then discuss the results and advise patients and their families on treatment plans if necessary.

Enzyme tests

An enzyme assay is a biochemical test in which the activity of a particular enzyme is measured. A small blood or tissue sample (usually skin) from the patient is required to test enzyme activity.

First, a particular type of cells called fibroblasts is isolated from the sample and analyzed for the presence of enzymes including lysosomal exopeptidase (TPP1) and lipid hydrolase (PPT1). TPP1 enzymes are affected in patients with late infantile Batten, while PPT1 enzymes are involved in infantile Batten disease.

The results of this test give an estimate of how severe the disease is and how fast it may progress. For example, patients with no TPP1 or PPT1 enzyme activity seem to progress more rapidly, while those with mutations that do not completely inactivate the enzymes seem to progress more slowly.

Eye tests

Eye-related tests of Batten disease can be varied, and include electroretinograms, autofluorescence imaging, and optical coherence imaging.

An electroretinogram is used to measure electrical signals produced by the eye. In this way, the eye’s response to visual changes can be investigated. Children with Batten disease show key abnormalities on electroretinograms, and these differences may be of use in moving toward an early diagnosis before other symptoms, such as seizures and evidence of developmental regression, occur.

Autofluorescence imaging also can provide an indication of the health of the eye’s retina — a lining of tissue at the back of the eye that is sensitive to light. This imaging can be used to detect the accumulation of autofluorescent lipofuscin in retinal neurons and degeneration of the layers of the eye.

Optical coherence tomography or OCT uses light microscopy to create images of the different layers of the eye. OCT also can be used to identify degeneration, as it shows the thickness of eye layers that can help to detect the onset of atrophy.

Brain tests

Tests of changes in the brain can help, together with other diagnostic assessments, to diagnose Batten disease.

One of those tests is computed tomography or CT, an imaging technique that uses X-rays. In Batten, CT is used to detect atrophy in different brain areas. Ventricles or cavities in the brain also are seen on CT scans to be enlarged and dilated in these patients.

CT findings usually correlate with disease symptoms, and brain abnormalities are more pronounced with disease progression.

However, signs of juvenile Batten disease are usually not detected on CT scans in patients younger than 9. In patients who are ages 9 and older, atrophy is found mainly in outer brain regions. Neurological decline often correlates with the degree of atrophy evident.

Magnetic resonance imaging (MRI) is a technique that works without using potentially harmful radiation. It creates an image with the help of a magnetic field. Atrophy in different brain regions can be detected with MRI in patients with infantile, late infantile, and juvenile Batten disease. 

In juvenile Batten disease, cerebral atrophy is not usually detected by MRI in children under age 9. In those who are older, the atrophy detected by MRI is less pronounced in patients with one mutated gene, compared with those with mutations in both gene copies. As such, atrophy may be a less effective measure of disease duration and progression in these patients.

An electroencephalogram or EEG is another brain test used in the diagnosis of Batten. It measures the electrical activity in the brain. Seizures cause abnormal EEG patterns, evident in all forms of the disease.

Tissue biopsy

A tissue biopsy is a minor procedure to remove a small piece of tissue from the patient to be examined under a microscope.

In Batten disease, the most common type of biopsy is a punch biopsy of the skin, a method that obtains a small section of tissue through all the relevant skin layers.

This method can reveal accumulated lipofuscins, identified as greenish-yellow pigmented shapes that are present in cavities inside the cells. They appear as a distinctive fingerprint or half-moon shape.

These results can confirm if the patient has Batten disease, but if these structures are absent, it does not confirm a negative diagnosis. Other tests, such as genetic analyses or enzyme assays are required.

If the results from this biopsy are inconclusive, then a muscle or nerve biopsy may be conducted.

Urine tests

Although the disease can be confirmed only through genetic testing, a number of studies have suggested that testing urine for a substance known as dolichol may be useful in aiding the diagnosis of  Batten.

Dolichol normally exists between cell membranes. It also has been found in high concentrations in the brains of Batten patients.

Other substances, such as a subunit of an enzyme called ATP synthase, also were found to be elevated in the urine of patients with Batten disease. ATP synthase creates ATP, the energy-storing molecule that enables all cells to function.


Last updated: Sept. 29, 2021


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