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Neurology Research Runs Through Three Generations of Women

Article In Brief

Anne Louise Oaklander, MD, PhD, FAAN, and her daughter Madeleine C. Klein are collaborating on research on small-fiber polyneuropathy. The collaboration represents the second- and third-generation of women involved in research; Dr. Oaklander's mother, Isabelle Rapin, MD, was recognized as a pioneer in the field of child neurology.


Dr. Anne Louise Oaklander (left) and her daughter Madeleine C. Klein presented a poster together at this year's ANA annual meeting.

While Madeleine C. Klein was growing up in Boston, dinner-table conversation often focused on her mother's medical work and her father's engineering challenges at their joint lab.

“The dinner talk was pretty science-y,” Klein said, joking that she added the “Kardashian” pop culture moments. “My dad worked in the lab with my mom, so he was familiar with what was going on. We heard a lot about my mother's cases. There were a lot of “teachable” moments.”

Klein's mother, Anne Louise Oaklander, MD, PhD, FAAN, tells a similar story about growing up with her father, an academic professor who studied unemployment prevention, and her mother, Isabelle Rapin, MD, professor of neurology and pediatrics at Albert Einstein College of Medicine in New York City. Dr. Rapin, who died in 2017, was credited as a pioneer in establishing pediatric neurology as a field, and for her research on autism, developmental language disorders, and inherited metabolic brain disorders.

“I grew up in a remarkable household where everyone was doing something they were passionate about. They'd have dinner parties and invite their like-minded friends and all talk about their plans,” said Dr. Oaklander, an associate professor of neurology at Harvard Medical School and director of the Nerve Unit and the Neurodiagnostic skin biopsy laboratory.

“Among my mother's close friends were Robert Katzman, Leon Thal, and Oliver Sacks, all luminaries in neurology, and they made it sound so interesting.”

Just as Dr. Rapin passed on her passion for medicine and science to her daughter, so too has Dr. Oaklander done that for her daughter. Klein graduated from the University of Massachusetts at Amherst with a degree in biology and a focus on genetics. After graduation, she began working in a Massachusetts General Hospital neurogenetics lab studying mouse models of neuronal ceroid lipofuscinosis (Batten's disease), and enjoyed discussing lysosomal storage disorders, a focus of her grandmother's earlier work. Then while applying to medical schools for fall 2020, Klein began working temporarily in her mother's lab.

“Madeleine was taking time off to study for the MCATS and I realized I had several genetics projects going on and said, ‘Why don't you slide into the lab while you're applying to medical school and see if we can work together on some for a while?” Dr. Oaklander said. “I accomplish more when I'm surrounded by smart people with particular expertise, who know more than I do.”

Indeed, the whole family has an expertise in science. Klein's father, Max Klein, PhD, an engineer, also works in Dr. Oaklander's lab. Her older brother, Daniel Klein, holds a PhD in particle physics, and works for Amazon.

The mother-daughter collaboration led to the presentation of a paper at this year's American Neurological Association (ANA) annual meeting in October, describing the lab's work on small-fiber polyneuropathy. In 2013 Dr. Oaklander and her husband, Dr. Max Klein, with Dr. Rapin's encouragement, published the first characterization of a new pediatric neurology condition—early-onset small fiber neuropathy.

“Many patients are seemingly healthy kids or teens who develop unexplained chronic pain or other sensory disturbances, often starting in their feet,” Dr. Oaklander explained.

“Some recover on their own, but in some it gets worse well before it becomes chronic. It often affects the internal organs, which depend as well on small-fiber control so some present with exertional intolerance or GI problems, such as nausea after eating.”

The ANA Abstract

The abstract Klein submitted to the 2019 ANA meeting from her collaboration with her mother, “Normalizing Sodium-channel Firing in Small-fiber Neuropathy from SCN9A-variant May Improve Axonopathy Along with Symptoms,” was selected as a works-in-progress publication and profiled in an ANA press release. Her poster featured the Soares family. José and Sarah Soares first brought their 9-year-old Sebastian to Dr. Oaklander in 2015.

Sebastian cried constantly and couldn't attend school because of his red, painful, and itchy feet with ulcers, tachycardia, his growth retardation, and secondary depression/anxiety.

Genetic sequencing confirmed Dr. Oaklander's immediate impression that there might be a sodium-channel mutation; the testing revealed that Sarah, her father, one of Sebastian's brothers, and later, her fourth child also carry the same SCN9A gene variant. Dr. Oaklander treated Sebastian, and then others in the family with sodium-channel blocking drugs. Unexpectedly, these not only virtually abolished their symptoms, but repeated skin biopsies confirmed that the patients' degenerated nerve endings regrew, the abstract reported.

“The way we treat neuropathy depends entirely on the cause,” said Dr. Oaklander. “It's like an infection—you have to know exactly what's causing it. Often the symptoms of small-fiber are vague, so it's important to use diagnostic testing—a skin biopsy—to confirm or refute this potential diagnosis.”

A Professional Relationship

Forming a professional relationship with a parent can take time. Dr. Oaklander said Dr. Rapin was an inspiration to her while she was growing up, and then became a mentor once she entered science and medicine, but it took a while to establish their professional relationship. For a long time, Dr. Oaklander just wanted to get away from her parents, and thought it was annoying to have a famous parent. But over time, she came to appreciate her mother's help, and how she read and critiqued some of her manuscripts and proposals.

It's a little different working with her daughter, she said. “She's much nicer to me than I was to my mother. Seriously, people who knew me in medical school say I was really trying to keep away.”

As for Klein's interest in research, the 25-year-old said she knew in high school that she was interested in genetics, particularly the molecular side of things. The complexity of genetics is fascinating, she said.

“You're looking at the interplay of all the things going on in the cell and realizing that it's not as easy as just the dominant gene and the recessive gene, it's not just straight-up DNA,” she said. “You realize that with genetics, DNA may not be the end-all and be-all of how things are going to be.”

The mother-daughter team continues to work together—Klein focuses on genetics while her mother focuses on neuropathy. They have a new research award to develop a mouse knock-in model of the Soares' mutation. They hope to study how the mice develop, and if some problems—like slow growth—occur because of the mutation or are a secondary symptom, of chronic pain, for example.

The two first started working together on an editorial published in eLife in November 2018. It concerned Fabry disease, a lysosomal storage disorder that often causes early-onset small-fiber neuropathy. Affected children often develop episodes of burning pain and digestive difficulties. This pain can flare up when their temperature rises as a result of exercise, fever, or hot weather. Their editorial discussed Fabry mouse-model research, explaining how the accumulation of abnormal fat molecules in lysosomes disrupts sodium channels in small fiber neurons.

“That was a turning point for us,” said Klein. “We learned that we can work together, bounce ideas off each other. There's an advantage to being a mother and daughter—it gives us a comfortable working relationship. She's not afraid to let me know if something I suggest doesn't sound right or doesn't make sense. Plus these collaborations truly require both our expertise.”

The encouragement from parent to child continues on to another generation. Dr. Rapin strongly encouraged Dr. Oaklander to get her PhD, and while Oaklander said it's been very helpful in her research, she didn't push the PhD to her daughter. Right now, Klein is opting for medical school, focusing on pediatric genetics, not neurology.

“I thought about this for a long time,” Klein said. “I want my primary focus to be helping people, but I [also] plan to be involved in research and developing new ideas.”

Klein is hoping to take a break from the family dinner table. “I would love to leave Boston and go somewhere I haven't been before,” she said. “As much as I love my family, I look forward to stepping out from Boston and moving away a little bit, but not too far away.”

Link Up for More Information

• Klein MC, Oaklander AL. Ion channels and neuropathic pain Elife 2018;7:pii:e42849.
    • Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes Pediatrics 2013;131(4):e1091–1100.
      • Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia Pain 2013;154(11):2310–2316.