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Special Article

Juvenile Batten disease

A diagnostic conundrum

Niederer, Kathryn PA-C

Author Information
Journal of the American Academy of Physician Assistants: June 2021 - Volume 34 - Issue 6 - p 44-47
doi: 10.1097/01.JAA.0000750980.85777.01
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Abstract

CASE

After years of infertility, two healthy parents conceived fraternal twins through in vitro fertilization. The pregnancy was without complication and two girls were delivered vaginally at 36 weeks 6 days gestation (Figure 1). All newborn screening in the hospital was normal.

FIGURE 1.
FIGURE 1.:
The twins in 2019, at age 8 years

During a routine well-visit examination with the pediatrician at age 9 months, Girl A was found to have a heart murmur and referred to a pediatric cardiologist; an echocardiogram revealed pulmonary valve stenosis and patent foramen ovale (PFO). The pediatric cardiologist recommended annual echocardiograms and physical examinations but no surgical intervention was required. The twins met all developmental milestones through age 12 months. When Girl A was about age 18 months, her parents noted that she had started to fall behind accomplishing her milestones. They were concerned about her speech delay, atypical gait, and hypersensitivity to sound and activities such as brushing her hair. They were referred to a pediatric developmental specialist and genetic testing returned negative for Fragile X syndrome and Rett syndrome. Additional testing and evaluations were performed during the following 6 months and resulted in a diagnosis of autism spectrum disorder for Girl A at age 2 years.

At age 2.5 years, the twins were enrolled in a reverse inclusion preschool, with Girl B considered a typical child. (Reverse inclusion is the practice of placing typically developing children into a class on a voluntary basis to serve as social-emotional and communication role models.) Girl A received speech therapy and applied behavior analysis therapy. Additional resources were brought into the home to provide support and reinforce the correction of behavioral concerns. The twins completed preschool and began mainstream kindergarten at age 5 years.

Girl A continued to struggle and exhibit behavioral difficulties, including violent tantrums with aggressive behavior (biting and kicking) toward family members. Her kindergarten teacher expressed concern about Girl A's close proximity of her face to the paper when she was writing. Academically, Girl A struggled to keep up with her peers. Vision testing was performed by an optometrist and the parents were told that she had 20/20 vision. Both girls graduated from kindergarten.

The first-grade teacher commented to the parents about Girl A's intermittent difficulty seeing the chalkboard in the classroom; she also expressed concern about Girl B's reading comprehension but had no concerns about her vision. Girl A's vision was tested by an ophthalmologist and reported as 20/20.

Box 1
Box 1

Despite multiple normal vision tests by optometry and ophthalmology, Girl A was referred to a children's hospital at the mother's request. An electroretinography was performed to determine retinal function (the test can show abnormal rod and cone responses even when the clinical picture is mild) and the results were abnormal. Girl A's visual acuity was retested and revealed as 20/200 in the right eye and 20/300 in the left eye. Legal blindness is 20/200. She was referred to a retinal specialist and fundoscopic examination revealed a round area of pigmented atrophy in the central macula, consistent with a bulls-eye lesion, diagnosing macular dystrophy (Figure 2). Repeat visual acuity testing by a retinal specialist was 20/400 in both eyes. Girl A was referred to a genetic counselor again, given the macular dystrophy, pulmonary valve stenosis, and autism diagnosis. The genetic counselor ordered a brain MRI on Girl A, which revealed diffuse loss of brain mass and an incidental 9-mm posterior thalamic lesion. Annual echocardiogram monitoring of her pulmonic valve stenosis remained stable and the PFO never closed.

FIGURE 2.
FIGURE 2.:
Bulls-eye maculopathy

While awaiting genetic testing results on Girl A, Girl B received a book as a present, which she successfully read until she encountered a red page with yellow writing, and could not see the words. Girl A's genetic testing results took months and concluded with diagnosis of a rare nervous system disorder: neuronal ceroid lipofuscinosis (NCL) or Batten disease.

Given the autosomal recessive pattern of Batten disease inheritance and the one episode of color blindness, Girl B also underwent genetic testing. While awaiting the results, Girl B saw a retinal specialist and had the same abnormal findings on fundoscopic examination as her sister. Genetic testing results were later received and confirmed that both girls are affected with juvenile Batten disease, the focus of this article.

DISCUSSION

Batten disease is only one of about 5,000 rare diseases, most which have a genetic basis. A rough estimate would be that one out of 10 persons worldwide could be affected by a rare disease and one of two patients with a rare disease is a child.1 Approved treatments are available for only 5% of rare diseases; 95% have no treatment and no cure.2 Based on prevalence, the combination of all rare diseases are not that rare as an estimated 300 million people worldwide are affected by a rare disease.2

Batten disease is a rare and fatal neurodegenerative disease caused by an autosomal recessive genetic mutation that impairs lysosomal function, resulting in waste accumulation within cells. In autosomal recessive diseases, a child inherits two copies of an abnormal gene--one from each parent. Unaffected parents are called carriers because each carries one copy of the gene mutation.

The 13 forms of Batten disease, referred to CLN 1 through 8 and CLN 10 through 14, which are broken into four groups: infantile, late infantile, juvenile, and adult (Table 1). At least 20 genes have been identified with Batten disease.3 As a group, Batten disease is the most frequent neurodegenerative disease of childhood, with juvenile Batten disease being the most prevalent form.4 The exact number of cases worldwide is unknown, but it is estimated that 2 to 4 per 100,000 children in the United States are affected.4 Newborn screening is not available for any form of Batten disease.

TABLE 1. - Overview of the subclassifications of Batten disease
CLN5-14 are variants of the classic gene defects and each fall into one of the four subclassifications
Subclassification Classic gene defect Age of onset Initial presenting symptoms Life expectancy
Infantile CLN1 6 months to 2 years Microcephaly, muscle contractions Less than 5 years old
Late infantile CLN2 2 to 4 years Seizures, ataxia, myoclonus 8 to 10 years old
Juvenile CLN3 5 to 10 years Vision loss Late teens to early 20s
Adult CLN4 25 to 43 years Epilepsy, tics, tremors, ataxia, dysarthria Normal lifespan

Symptoms of Batten disease may vary significantly for each patient and include vision loss (initially central vision loss followed by peripheral vision loss), color blindness, cognitive impairment, seizures, language difficulty progressing to inability to speak, and motor dysfunction progressing to inability to ambulate and eat (Table 1).

Juvenile Batten disease typically presents between ages 5 and 10 years with vision difficulties and is fatal by the patient's late teens or twenties. In patients with juvenile Batten disease, the most common initial symptom is vision loss, and initial testing early in the disease process typically fails to find any indication of Batten disease. Children start to struggle in school and experience developmental regression, the loss of previously acquired skills, typically beginning with the loss of ability to speak in complete sentences. Seizures typically begin about age 10 years and can present as absent or grand mal (Figure 3). Seizures are extremely difficult to control and require a regimen of multiple anticonvulsants. As the disease progresses, fine and gross motor functions decline to the point of ataxia. Children with juvenile Batten disease also develop severe dementia, sleeplessness, and may exhibit psychotic behaviors such as hysterical sobbing and hallucinations. Muscle rigidity and spasticity develop, leading to contractures and eventual wheelchair dependence and loss of speech. Difficulty swallowing and resultant aspiration results in the need for percutaneous endoscopic gastrostomy tube placement for nutrition.

FIGURE 3.
FIGURE 3.:
Girl B undergoing an EEG at age 7 years

Some adolescents with Batten disease also experience progressive cardiac involvement including dysrhythmias and ventricular hypertrophy (Table 1).5 Their growth is the same as a typical child, although they may experience precocious puberty.

The gold standard for diagnosis of Batten disease is genetic testing to detect and confirm the mutated gene; however, this testing is extremely expensive and analysis and results take months. New gene mutations resulting in Batten disease continue to be discovered. Many other tests can support a diagnosis of Batten disease, including bloodwork with vacuolated lymphocytes, elevated chemical level of dolichol on urinalysis, lipofuscin accumulation on skin biopsy, seizure patterns on EEG, and brain atrophy on CT or MRI.

No specific treatment is available to slow the progression or cure infantile or juvenile Batten disease. In 2017, the FDA approved cerliponase alfa to treat the CLN2 subtype of late infantile Batten disease. This drug is delivered as an infusion via intrathecal shunt to slow the symptoms of the disease but is not a cure. A gene therapy trial for the CLN6 variant form of late infantile Batten disease was recently concluded but study results have not been released. An active gene therapy clinical trial for juvenile Batten disease also is underway.

Treatment options for all forms of Batten disease are palliative to manage the myriad symptoms, and include medications (antiseizure, antipsychotic, antidepressants, sedatives, GABA analogues, pain relievers), herbal supplements (curcumin, N-acetylcysteine, turmeric, elderberry syrup, essential oils), and speech and occupational therapy. Support groups for the family are also extremely important; the many organizations include Batten Disease Support and Research Association (www.bdsra.org), National Organization for Rare Disorders (www.raredisease.org), and Global Genes (www.globalgenes.org).

Research is focused on treatment options and cures including gene therapy, stem cell therapy, antisense oligonucleotides therapy, and small-molecule drugs. Funding is limited because Batten disease is a rare disease, but research may have applications for other types of rare diseases.

The financial cost of the disease is high, and delay in diagnosis can lead to increased medical testing and expenses, family stress, and the possibility of incorrect treatment. Common early misdiagnoses include retinitis pigmentosa, macular degeneration, autism, seizure disorder, epilepsy, and pervasive developmental disorders. Prompt early diagnosis leads to more time with family, less time searching for diagnoses, addressing future family planning decisions, improved eligibility requirements for clinical trials when available, and the ability to connect with other affected families.

CASE OUTCOME

The twins are now age 11 years and attend public school with the assistance of an aide. Both girls are legally blind with minimal to no light perception, ambulate with canes, suffer with mild to moderate dementia, and have seizures and extreme insomnia. Girl A also experiences delusions and severe obsessive-compulsive behavior. Girl B's cognitive function has slowed significantly. She still can learn and retain new information but is forgetful and repetitive. She has severe pain, anxiety, and recognizes her decline.

The girls are followed by multiple medical specialists including neurologists, retinal specialists, psychiatrists, a palliative care team, a chronic pain team, gastroenterologists, endocrinologists, cardiologists, social workers, physical therapy, occupational therapy, and low vision specialists. Their medication regimen administered four times daily varies but includes: aripiprazole, fluoxetine, sertraline, clobazam, pregabalin, misoprostol, hydroxyzine, clonidine, trazodone, methadone, meclizine, ibuprofen, and morphine and clonazepam as needed.

Their parents attend weekly grief counseling therapy sessions. They continue to fight for their girls by working with medical researchers around the world to fund studies to develop a treatment or cure for Batten disease.

CONCLUSION

Children with Batten disease typically appear normal at birth but then fail to reach their developmental milestones on schedule or show regression during childhood. Initial symptoms do not occur simultaneously but manifest over a period of time. Diagnosis can be extremely difficult early in the disease but referral should be made to specialists when the clinical picture does not correlate with the history or when multiple diagnoses are given with suspicion that all the signs and symptoms are part of underlying and undiagnosed syndrome.

REFERENCES

1. Global Genes Allies in Rare Disease. www.globalgenes.org. Accessed March 23, 2021.
2. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165–173.
3. Schulz A, Kohlschütter A. NCL disorders: frequent causes of childhood dementia. Iran J Child Neurol. 2013;7(1):1–8.
4. von Tetzchner S, Elmerskog B, Tøssebro AG, Rokne S. Juvenile neuronal ceroid lipofuscinosis, childhood dementia and education. Snøfugl Forlag. Oslo, Trondheim, and Asker, Norway, 2019.
5. Ostergaard JR. Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights. Degener Neurol Neuromuscul Dis. 2016;6:73–83.
Keywords:

Batten disease; neuronal ceroid lipofuscinosis; genetic; bulls-eye maculopathy; vision loss; dementia

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