Conquering a rare metabolic condition: A family, a pediatrician, and two labs join forces

Sam and his family pose at a formal event about SSADH deficiency.
Sam (center), flanked by his parents and siblings, is helping scientists better define SSADH deficiency and has donated his cells to research. Since his diagnosis with SSADH deficiency at the age of 18 months, scientists at Boston Children’s have been making strides toward developing a gene therapy.

As a newborn, Sam Hoffman never cried or made a sound. His mother, Carolyn, often had to wake him up to feed him. He missed many of his infant milestones. At one visit, his pediatrician tapped his leg and couldn’t get a reflex. A urine test found extremely high levels of 4-hydrobutyric acid or GHB — weirdly, the key ingredient in the party drug “ecstasy.”

“No one knew what this meant for Sam,” says Carolyn. “He was sent to a lot of places for evaluation.”

Sam, who lives in Wisconsin, was eventually diagnosed with a rare metabolic condition called succinic semialdehyde dehydrogenase (SSADH) deficiency, marking the 81st known case in the world. Carolyn and her husband Brad were told Sam might never walk or talk. They were advised to start raising money for research.

Twenty-five years later, Carolyn and Brad head the SSADH Association. The association is supporting an international natural history study of SSADH, led by Phillip Pearl, MD, at Boston Children’s Hospital and of which Sam is a part. It’s also funding two laboratory research projects at Boston Children’s — including work that could lead to a gene therapy.

A missing enzyme

SSADH deficiency is a recessive disorder caused by loss of one of the two enzymes that break down GABA, the brain’s major inhibitory neurotransmitter. Without SSADH, the brain cannot properly regulate its GABA levels. GABA and GHB (a GABA byproduct) accumulate, throwing off the brain’s normal balance of excitation and inhibition.

People with SSADH deficiency typically have severe language defects and mild to moderate intellectual disability. Many have disordered sleep, low muscle tone, and impaired balance and coordination, confining some children to wheelchairs. Roughly half have epilepsy — with an increased risk of sudden death. Some have autism-like features, anxiety, and inattention, and many, like Sam, have obsessive-compulsive symptoms.

Pearl outside wearing a lab coat.
Phillip Pearl, MD (Photo: Michael Goderre, Boston Children’s)

In 1997, Pearl evaluated a boy with severe seizure episodes and a speech disorder of unknown cause. “He had been to multiple specialists,” Pearl recounts. “I was very junior and didn’t have any answers, but the family kept coming back because I would talk to them.”

Pearl had never heard of SSADH deficiency, but a urine test showed elevated GHB. Pearl forged a connection with Michael Gibson, PhD, who had originally described the condition in 1983.

“He had the animal model and I was the clinical investigator,” says Pearl. “Before long, I had a database of every patient with this disease in the world. It spawned a new career direction.”

Sam first met Pearl when he was 5 or 6 years old. “It was such a comfort and relief to talk to someone who knew what SSADH deficiency was and could explain it,” Carolyn says.

Defining SSADH deficiency

In 2014, Pearl brought his research to Boston Children’s and set up a biorepository. The natural history study is revealing more details about SSADH deficiency and its wide range of manifestations. Researchers have collected data about Sam and others over the years through lab testing, brain imaging, and neurological, cognitive, and neuropsychological testing.

One thing the study is helping define is who is at most risk for seizures, which typically start at roughly 10 years of age. “You have no idea what that means for families,” says Carolyn. “I have worried about seizures for 26 years. The science is changing people’s lives.”

Photos of Sam in a chair having TMS and having leads placed on his head in preparation for an MRI.
Sam undergoes transcranial magnetic stimulation (TMS, left) and is prepped for a brain MRI (right) as part of the natural history study on SSADH deficiency. TMS is used to measure cortical excitability and as a potential biomarker to track the disease’s natural history and the effects of treatments such as gene therapy.

Toward a platform for drug screening: Modeling SSADH deficiency in human neurons

In 2016, Pearl received funding from the SSADH Association to model the disease in neurons made from patients’ skin cells. These were created through stem cell technology in Boston Children’s Human Neuron Core. The work, now centered in the lab of Mustafa Sahin, MD, PhD, could lead to a platform for drug testing.

Afshar-Saber in the Human Neuron Core where she conduct research on SSADH deficiency.
Wardiya Afshar Saber, PhD

Wardiya Afshar Saber, PhD, in the Sahin Lab is investigating the role of GABA-producing inhibitory neurons as well as excitatory neurons derived from a handful of patients, including one with severe seizures. Using advanced tools, she can capture the firing patterns of individual cells, comparing those with and without SSADH deficiency.

“It had been assumed that the disease mainly affected inhibitory neurons, but we’re finding that in patients with epilepsy, excitatory neurons may also be different,” she says.

Since accumulation of GABA and GHB would normally be expected to increase inhibition, she and her colleagues speculate that a brain deficient in SSADH may try to correct itself by becoming hyper-excitable, leading to seizures.

Developing a gene therapy treatment

In 2020, the association began funding therapeutic development. This work, led by Henry Lee, PhD in the lab of Alexander Rotenberg, MD, PhD, at first focused on replacing the missing SSADH enzyme with a drug. But they’ve since pivoted to exploring replacement of SSADH with gene therapy. In a mouse model created by the team, the SSADH gene, injected inside a viral vector, traveled to the brain. In some cases, it improved movement and strength and suppressed seizures. There’s more work to come to translate the treatment to humans; precise dosing and timing may be critical.

Lee at a lab bench in the Human Neuron Core.
Henry Lee, PhD

“We want to understand the criteria and parameters that will make gene therapy work safely,” says Lee. “We have a clear path, and we know what needs to be done before testing in patients.” The researchers are also considering using an antisense oligonucleotide approach, using drugs consisting of short bits of genetic code that would mirror the SSADH gene mutation and compensate for its effects.

Pearl is excited by the progress, which he sees as forging a path for other inherited metabolic epilepsies. “To see a program that could bring a clinical treatment for a disease I’ve been working on for 25 years is remarkable to me,” he says. “Families are exhilarated about this.”

‘Research is hope’

Sam, an AC/DC fan, now works for Goodwill Industries and volunteers stocking shelves at a food pantry. He can read, text, get things done on his iPad, and ride a bike. The Hoffmans are working on having him live independently, though he struggles with executive functioning, money management, social interactions, and his obsessive-compulsive disorder.

Today more than 200 patients are known to have SSADH deficiency, now readily diagnosed through whole exome sequencing. And more is being learned about it all the time.

“I tell families about all the research when they get diagnosed,” says Carolyn. “Even ten years ago, we weren’t in a position to do that. Research is hope.”

More about the SSADH natural history study, care in the Epilepsy Center, and research in the Rosamund Stone Zander Translational Neuroscience Center and F.M. Kirby Neurobiology Center.

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