Batten Disease Finding Ends a Diagnostic Odyssey for California Family

January 24, 2013

By Allison Proffitt

January 24, 2013
| Three years after Jacob Allingham first began experiencing seizures that worsened into a bewildering and quickly progressing combination of symptoms, the exhausting (and exorbitant) diagnostic odyssey for Jacob and his similarly affected younger brother Dylan has come to an end.

Following countless genetic and neurological tests to diagnose the mystery disorder, the boys’ parents, Lisa and John Allingham of Sacramento, California, seized the opportunity to undergo exome sequencing. The offer came from Dietrich Stephan, the founder of a new clinical diagnostics company, SV Bio, who had been contacted by the children’s neurologist.

The discovery of the errant gene has left the Allinghams with the certainty of a confirmed diagnosis – a form of Batten Disease – and a host of unresolved implications. Some are unequivocally positive.

“We’re not able to do anything necessarily to change what [the boys] have,” Lisa says. But on the plus side, “We’re not doing MRIs every six months now, where they have to be sedated. We’re not doing all this blood work. We’re not doing EEGs. We’re not [doing this] because we don’t need to… We’re not doing all the labs and poking them and doing all kinds of stuff.”

Whether the diagnosis will aid the boys is unclear. Late Infantile Neuronal Ceroid Lipofuscinosis, to give the disease its formal name, is typically fatal between 8 and 12 years. But the Allinghams take a sliver of hope from the fact that trials are ongoing or about to start.

Jacob’s Saga 

Jacob Allingham poses in front of the
family Christmas tree last month.

John and Lisa Allingham had their hands full when Lisa gave birth to fraternal triplets in 2007. John, a manager at a local COSTCO, and Lisa, who worked at a Sacramento insurance company before the triplets were born, had tried for about two years to get pregnant with their first son, Jacob, before turning to in vitro fertilization (IVF). But the process is expensive and they knew their second pregnancy would probably be their last.

“We had talked with our fertility doctor about the odds,” Lisa says. “With three embryos they said it was a 6% chance that all three would take. We thought, gosh, 6% is really low… We decided to put three back, knowing that it was probably our last time that we were going to be able to do IVF.” The triplets were born in 2007. “We kind of beat the odds on that.”

The Allinghams’ fertility clinic offered preimplantation genetic screening, but with no red flags in the family histories, John and Lisa declined the offer. “When you don’t have a family history of anything, it just didn’t seem like something we needed to do,” she says. 

But as the Allingham family expanded from three to six, two-year-old Jacob started showing the first signs of delay. At an age when kids should normally be putting on their own shoes and washing their hands, Jacob was struggling, Lisa recalls. “But he’d not had any seizures. We had no reason to think he had anything medically going on.”

Busy looking after newborn triplets, Lisa reflects that “maybe we weren’t spending enough time” with Jacob. “We put a lot of that on ourselves. We’re not doing all that we could be doing because we’re exhausted all the time.”

It was in the summer of 2009 when Jacob, who had just turned four years old, began to experience seizures. Doctors initially diagnosed epilepsy, but curiously, Jacob’s MRI showed abnormal white matter. Though his seizures were managed with medication, Jacob continued to regress, suggesting more to the story than just epilepsy. Lisa remembers the next years as simply one test after another: an endless blur of MRIs, blood work, EEGs, spinal taps, and skin biopsies.

In preschool, Jacob’s verbal skills and cognitive abilities started to lag behind the other children. The school psychologist did an evaluation, as did a language therapist. Jacob’s language and speech difficulties had some characteristics in common with autism spectrum disorders, but autism didn’t explain all of his symptoms.

In July 2010, after seeing specialists in California, Jacob’s neurologist referred him to the Mayo Clinic in Minnesota, where the family met with a geneticist. “She went over all of our family history and she just really didn’t see any markers of concern,” says Lisa. “Both my husband and I know our families’ histories of everything, really. We didn’t really pursue the genetics. She thought there were a couple more things to do before that.”

Instead, Jacob underwent even more tests—two lumbar punctures, extensive EEG monitoring, and metabolic workups—but continued to decline as the inconclusive results—and bills—stacked up.

Several times a year, Jacob was sedated for an MRI. His cerebellum (the part of the brain responsible for coordination and motor control, attention and language functions) was getting smaller. But the changes weren’t just visible in the imaging. As a four-year-old, Jacob ran and jumped. Now almost six, he was having trouble keeping his balance.

In May 2011, the family returned to the Mayo Clinic and a battery of genetic tests. A microarray test for Angelman Syndrome: negative. Skin and muscle biopsies and an eye exam for Batten Disease: negative. Mitochondrial genomic testing raised the possibility of Leber’s Hereditary Optic Neuropathy, but the disease didn’t match the clinical presentation. A genetic testing company screened the SETX gene revealing that Jacob and his father were carriers of a mutation linked with Spinocerebellar Ataxia autosomal recessive type 1. The company concluded that Jacob had SCAR1, and that his father had reduced penetrance, but the diagnosis didn’t match the clinical picture (SCAR1 patients don’t have seizures or language regression) or inheritance patterns.

It was as if everyone was grasping at diagnostic straws.

“It was a long three years of every single test and watching Jacob go through all these blood draws and all these things,” says Lisa. “Going to the Mayo Clinic twice and every turn was a dead end. It was a very interesting feeling, when you’re waiting for a test result to come back. Every time when it would come back negative, on the one hand you’re glad that it’s not some terrible thing that they’re testing for. But on the other hand, you don’t have an answer.”

Fresh Eyes 

Dylan Allingham 

In November 2011, more than two years after Jacob’s first seizure, one of the Allingham triplets, Dylan, had a high fever and seizure. At the emergency room, doctors reduced the fever and dismissed the seizure as febrile (simply resulting from the fever). A month later, he had a second one. He had just celebrated his fourth birthday.

This time around, as a second child began treading the path of his elder brother, the Allinghams knew what to look for. “We kind of noticed [some] language issues, a little bit of development [issues],” Lisa says. “It was exactly like Jacob.”

Cue a second battery of tests for a second son—more EEGs, more blood work, more MRIs. Dylan’s inconclusive results matched nothing—except Jacob’s. The Allinghams’ neurologist suggested a coincidence, but Lisa knew better.

“We figured it’s got to be something genetic,” she says. “For how similar the two were for it to just be a coincidence? As a mom, in your gut, you kind of know different. I knew that whatever this thing was, it was what they both had.”

Believing that they needed “a fresh set of eyes,” the family switched neurologists. Michael Chez, a pediatric neurologist and epileptologist, is Director of Pediatric Neurology at the Sutter Neuroscience Institute in Sacramento. By the time Chez met the family, Jacob was declining. “He was basically in a wheelchair, he wasn’t walking and he was down to five words, maybe,” remembers Lisa. Chez knew that something needed to be done quickly.

“They had been to Stanford and UCSF and Mayo and another local doctor in Sacramento and they had done a very extensive workup. Nothing could be faulted, it’s just they didn’t come up with any diagnosis,” says Chez. “We were chasing things hoping it would help because we didn’t have a clear answer.”

Within a few months of meeting the family, Chez turned to a former colleague. Before founding Navigenics and more recently SV Bio, Dietrich Stephan had previously worked on neurological disorders at the NIH and TGen (The Translational Genetics Research Institute in Phoenix) and had been a driving force behind the Autism Genome Project. Chez and Stephan had worked together on seizures in autistic children.

“[Doctors] had done everything humanly possible for this family, sent them to multiple centers of clinical excellence, sent away for different types of genetic tests, biochemical tests,” Stephan says. “And at the end of a $300,000 ordeal, [Chez] finally gave me a call and asked me if there was something we could do.”

Although Stephan’s new clinical diagnostics company, SV Bio, was still in its beta phase, he was anxious to help. SV Bio offered to run a standard exome sequencing analysis —“everything of everything,” as Lisa Allingham describes it—on the family members for free. When Chez proposed whole exome sequencing, Lisa and John did not hesitate. Lisa told him: “Anything you want to do, we are up for it.”

Waiting to Exome 

SV Bio took blood samples from Jacob, Dylan, and their parents, and sequenced the four exomes on an Illumina HiSeq instrument. The sequencing took a few weeks; alignment, variant calling, and pathogenicity assessment took about 24 hours, Stephan says.

About a month from submitting the blood samples, a diagnostic report was generated automatically.

Lisa Allingham was right. After more than three years, a fortune in medical bills, and innumerable diagnostic dead ends, the exome sequencing revealed that both boys do indeed have the same genetic disease: late infantile Neuronal Ceroid Lipofuscinosis (NCL), a recessive lysosomal storage disorder caused by damage to the TPP1 gene, tripeptidyl peptidase I, on chromosome 11.

John and Lisa each carry a different mutation in the gene—one a missense mutation, the other a splicing mutation. Jacob and Dylan inherited both damaged copies. The incidence of late infantile NCL is estimated at less than one in 200,000.

“When [Dr. Chez] told us what it was—he gave me ‘Late Infantile Neuronal Ceroid Lipofuscinosis’—I was like, ‘What did you say? You need to write that down!’” says Lisa. It wasn’t until she’d performed some late-night Internet research that she realized that the diagnosis was a form of Batten Disease, one of the diseases that doctors had ruled out a year earlier.

“Oh my gosh, this has come up before! We have heard this before!” Lisa thought.

The name “Batten Disease” has typically been applied to the juvenile form of NCL, characterized by onset between 5 and 7 years old, although now the label is applied to all forms of NCL. Early signs of juvenile NCL include clumsiness and seizures—symptoms both boys had—but also blindness, which has not affected the Allingham boys. An infantile version presents before age 2, whereas late infantile NCL, the form of the disease that affects Jacob and Dylan, is characterized by onset between ages 2 and 4.

All forms of the disease have the same prognosis, though the timing is different: mental impairment, worsening seizures, and progressive loss of sight and motor skills. And all forms of the disease are fatal. 


The Allingham boys join a small but select group of publicly-revealed children whose diagnostic odysseys have been solved by exome sequencing.

In 2008, Hugh Rienhoff launched a personal crusade to find a diagnosis for his daughter, Beatrice, and launched an effort called My Daughter’s DNA to help others in a similar predicament. After years gathering and analyzing sequence and transcriptome data, late last year Rienhoff announced that he believes he has finally found the elusive causative gene.

In 2010, as Jacob was preparing to go to the Mayo Clinic for the first time, the story of Nicholas Volker was capturing attention following a successful diagnosis and bone marrow transplant by doctors at the Children's Hospital of Wisconsin and Medical College of Wisconsin, led by Howard Jacob and colleagues. For the past 18 months, Nic has been out of hospital and back at school. Since the Volker case, Jacob and colleagues have sequenced the exomes or genomes of more than 20 children. 

Another case that has received national attention is that of teenage twins Noah and Alexis Beery, the children of Joe and Retta Beery, who have Dopa-responsive dystonia. Exome sequencing performed at Baylor College of Medicine (BCM) using sequencing technology from Life Technologies (where Joe is chief information officer) pinpointed the faulty gene and led to a shift in medication that has had a profound benefit on the children’s health. Some call it a cure.

Last October, Stephen Kingsmore and coworkers at Children’s Mercy Hospital in Kansas City, Missouri, reported a collaboration with Illumina to use whole genome sequencing to rapidly diagnose genetic diseases in acutely ill newborns. (Kingsmore previously collaborated with Craig Benson and the Beyond Batten Disease Foundation to develop a screening panel of 600 genes for severe childhood genetic disorders.)

A month later, Boston Children’s Hospital announced the winners of the first CLARITY Challenge to identify and present the putative mutations underlying the disorders of three patients at the hospital who had had their full genomes sequenced. For one boy, Adam Foye, the competition closed an 11-year diagnostic odyssey as teams identified the genetic mutation for his muscular disorder.

Several other organizations performing clinical exome sequencing, such as BCM and Ambry Genetics, have reported numerous successful diagnoses over the past 12 months. As sequencing costs fall and options for interpretation become more sophisticated, reliable and abundant, the number of cases like Nic Volker and Adam Foye and the Allingham boys will assuredly increase.

Chez and Stephan think the moment can’t come soon enough. 

“If you have a sporadic disease that is early onset and severe… the chances are it’s genetic,” says Stephan. “If the physician is not sure what test to order, [I suggest] reflex immediately to an exome. We want to make it very simple for a physician to order the right test and one way to do that is to cast a very wide net.”

The earlier, erroneous SCAR1 prediction for Jacob is indicative of genetic testing today, says Stephan. “The SETX mutation doesn't make sense in the context of inheritance,” he says. “This is a perfect example of how genetic testing is done today—there are assumptions made about which gene is causative and then it is tested.”

The “everything of everything” approach is more cost effective and quicker, Chez says, than standard genetic tests. “This will give you the answer much more quickly and efficiently than all the other biopsy and spinal fluid tests and MRIs repeatedly,” he says.

Action Plan 

The Allingham family at Thanksgiving, 2012. 

Even if the results of the testing don’t offer the immediate therapeutic benefits that Nic Volker or the Beery twins enjoyed, there is still great value to the Allinghams in knowing.

“When I first reviewed this report and I saw the diagnosis, I was quite devastated,” says Stephan, candidly. “This is a death sentence. Generally between eight and 12 years old, these kids die. And that’s terrible in terms of communicating that information to the ordering physician. [But] I think the value of having this answer gives them options they could have never had access to before in terms of [clinical] trials, if they decided to go down that route. It also offers that family reproductive opportunities.”

The Batten Disease diagnosis didn’t present the Allinghams with a certain cure, but it does offer new options.

A group at Weill Cornell Medical Center has invited the boys to be a part of an ongoing gene therapy clinical trial that would be valuable for research but is not offering much likelihood of improvement for the boys. The Allinghams are unsure. “It’s a time commitment [and significant surgery],” says Lisa. “It’s an 18-month process and we would need to be [in New York]—especially with both boys—for weeks if not months at a time. We have two other children who need us just as much.”

BioMarin, a pharmaceutical company based in California, is launching a clinical trial in Europe for an enzyme study that may eventually be accessible to the Allingham boys.

Without the genetic testing, Chez says these possibilities would have never arisen. “It gives us some grounding and some targets and some hope for these people. Knowledge is power.”

The diagnosis has provided answers for the rest of the family as well. After Jacob’s and Dylan’s diagnoses were confirmed with an enzyme test, the two unaffected Allingham triplets, now five, were tested and found to be asymptomatic carriers. Someday John and Lisa will tell them their carrier status, and, Lisa says, “they will need to make the choices that they’ll be faced with as adults and having their own children.” The couple has also offered to help their own siblings undergo carrier testing, but no one has taken the plunge yet.

Now the Allinghams are getting used to their new normal. Both boys’ seizures are fairly well-controlled, although they do have breakthrough seizures a few times a month. Jacob had a feeding tube inserted in September and has been able to gain some much-needed weight. “The happiest kid ever” with a winning smile, Jacob spends most of his time in his wheelchair or assisted walker, but loves to play on the floor at home and at school.

“He does kind of a skooch-crawling thing,” Lisa says. “You can tell it’s work for him, for sure. His body is constantly working… But the thing about Jacob that I just totally love is that he doesn’t even realize that he can’t do stuff… that desire to play as much as he can is definitely still there.” His vocabulary is very limited, but he can communicate and understands and answers simple questions.

Two year earlier in disease progression, Dylan is a funny kid who likes, “to kind of be a pest to his siblings,” Lisa laughs. He runs and enjoys playing soccer, although his coordination is deteriorating slightly. He’s in a mainstream kindergarten class with the help of a full time aide and receives speech therapy.

“They don’t even know they have this horrible disease,” Lisa says. “They don’t feel different; they don’t feel like they can’t do something. They just do what they do and they’re happy.”

For the boys, ignorance may be a blessing, but for John and Lisa, knowing is still better than not. “It’s not quite the result we were hoping for, but at the same time I’m very grateful that we do know,” she says. “I don’t know how much longer we would have been searching… The not knowing was harder than knowing.”