And it had a history. My grandmother had died at 29 of what we believed was something similar, my mother had been symptomatic before I was old enough to form the question, my older sister would be told at 26 that she had it, too. What the disease had in our house was a pronoun. “It.” As in, “it got worse over the winter.” As in, “your sister might get it.” As in, “we don’t know much about it.”
The author, far right, with her sister and mother in 1990.
That last sentence was repeated so many times, by so many doctors, that it stopped feeling like an update and started feeling like a fact about the world. Some things were known. This wasn’t one of them. We filed it alongside questions that were genuinely unanswerable, not worth revisiting.
We were wrong about that. I just didn’t know it yet.
I grew up as the primary caregiver for my mother from roughly age 8‚ managing the household, bridging the gap between what was happening inside our walls and what we presented to the world outside them. By the time I was old enough to understand what I was doing, I had already been doing it for years, not because anyone assigned it to me explicitly but because someone had to and I was there and I was capable, and it turned out that capability was its own kind of assignment.
The disease organized my childhood the way weather organizes a farming life. You don’t fight it, you work around it, you learn its seasons. And somewhere in the years of working around it, you stop asking what it is and start managing what it does.
Three generations of women in my family — my grandmother, my mother, my sister — carried the same condition through the same blood before any of us had a clinical word for it. Fifty years of documented family history. Fifty years of doctors who shrugged with genuine sympathy and said, rare. Poorly understood. Difficult to characterize.
I believed them for a long time.
Here is something worth knowing about the category called rare disease. Rare does not mean unknown. It usually means underresearched, underfunded, and underconnected to the people living inside it. There are approximately 7,000 to 10,000 identified rare diseases, depending on what definition you use. Many of them have names, and many have researchers who have dedicated careers to a single mutation, a single protein, a single entry point into the vast underlit territory of conditions that affect small numbers of people and therefore attract small amounts of attention and money.
The work on these diseases gets done‚ slowly, in small labs, by scientists who chose a difficult corner of medicine because something drew them there. The work gets published. The knowledge accumulates.
And then, in too many cases, it stays there. There is no architecture reliably connecting what medicine knows about a rare condition to the families living inside it. Research participants from earlier decades have no right to follow-up notification. Families whose cases contributed to literature that eventually named their disease may never know the paper was written.
The loop, opened when the family first came to medical attention, can stay open indefinitely on their end. On the other end, in a database they don’t know to search, the loop may have closed years ago. This is not malice, it’s infrastructure, but the cost is real regardless.
The cost is my mother going through nearly 40 years of illness without being told that someone had looked at what she had and given it a name. The cost is my sister and her 15 years of deterioration and her death at 41, in a world where a researcher somewhere had been asking the same questions we asked in our living room, except the researcher was getting answers and we were not getting calls.
I am a research methodologist. For 23 years I have worked at an academic medical center building systematic reviews‚ assembling bodies of medical literature to answer clinical questions, following citation chains, evaluating sources, asking the next question without assuming the answer. I had the skills and the access and I had stopped looking, and that is the sentence I keep coming back to. I had stopped asking the question that mattered most to me personally‚ not because I forgot, not because I stopped caring, but because somewhere in the decades of shrugged answers, I had accepted the not-knowing as the settled state. The doctors had said rare, poorly understood, difficult to characterize for so long that I had internalized their uncertainty as my own. A research methodologist’s skill set and a grieving daughter’s resignation, and the resignation had won.
That last sentence was repeated so many times, by so many doctors, that it stopped feeling like an update and started feeling like a fact about the world. Some things were known. This wasn’t one of them. We filed it alongside questions that were genuinely unanswerable, not worth revisiting.
We were wrong about that. I just didn’t know it yet.
I grew up as the primary caregiver for my mother from roughly age 8‚ managing the household, bridging the gap between what was happening inside our walls and what we presented to the world outside them. By the time I was old enough to understand what I was doing, I had already been doing it for years, not because anyone assigned it to me explicitly but because someone had to and I was there and I was capable, and it turned out that capability was its own kind of assignment.
The disease organized my childhood the way weather organizes a farming life. You don’t fight it, you work around it, you learn its seasons. And somewhere in the years of working around it, you stop asking what it is and start managing what it does.
Three generations of women in my family — my grandmother, my mother, my sister — carried the same condition through the same blood before any of us had a clinical word for it. Fifty years of documented family history. Fifty years of doctors who shrugged with genuine sympathy and said, rare. Poorly understood. Difficult to characterize.
I believed them for a long time.
Here is something worth knowing about the category called rare disease. Rare does not mean unknown. It usually means underresearched, underfunded, and underconnected to the people living inside it. There are approximately 7,000 to 10,000 identified rare diseases, depending on what definition you use. Many of them have names, and many have researchers who have dedicated careers to a single mutation, a single protein, a single entry point into the vast underlit territory of conditions that affect small numbers of people and therefore attract small amounts of attention and money.
The work on these diseases gets done‚ slowly, in small labs, by scientists who chose a difficult corner of medicine because something drew them there. The work gets published. The knowledge accumulates.
And then, in too many cases, it stays there. There is no architecture reliably connecting what medicine knows about a rare condition to the families living inside it. Research participants from earlier decades have no right to follow-up notification. Families whose cases contributed to literature that eventually named their disease may never know the paper was written.
The loop, opened when the family first came to medical attention, can stay open indefinitely on their end. On the other end, in a database they don’t know to search, the loop may have closed years ago. This is not malice, it’s infrastructure, but the cost is real regardless.
The cost is my mother going through nearly 40 years of illness without being told that someone had looked at what she had and given it a name. The cost is my sister and her 15 years of deterioration and her death at 41, in a world where a researcher somewhere had been asking the same questions we asked in our living room, except the researcher was getting answers and we were not getting calls.
I am a research methodologist. For 23 years I have worked at an academic medical center building systematic reviews‚ assembling bodies of medical literature to answer clinical questions, following citation chains, evaluating sources, asking the next question without assuming the answer. I had the skills and the access and I had stopped looking, and that is the sentence I keep coming back to. I had stopped asking the question that mattered most to me personally‚ not because I forgot, not because I stopped caring, but because somewhere in the decades of shrugged answers, I had accepted the not-knowing as the settled state. The doctors had said rare, poorly understood, difficult to characterize for so long that I had internalized their uncertainty as my own. A research methodologist’s skill set and a grieving daughter’s resignation, and the resignation had won.
The author, her baby son, and her mother.
There is a specific exhaustion that comes from caring for people with unnamed conditions across many years. You ask the questions when they feel fresh. You push when pushing feels possible. And then the decades accumulate and the people you were asking on behalf of are gone, and you are left with your own life to build from whatever remains, and the unanswered questions stop feeling like questions and start feeling like the way of things.
I’ve written a memoir about all of this called “Naming It.” After finishing the memoir, I sat down with the oldest document I had, my grandmother’s death certificate, which my aunt mailed me 20 years ago. I looked at it many times without understanding it, because I had not yet learned how to read it. Going through it to check a fact I stopped on cause of death: acute coronary thrombosis. A catch all. It was not an answer. It was a placeholder. It still is. In 1954, though, differential diagnosis capabilities were limited and no one looked further.
Using Claude I typed in everything I knew about what came after my grandmother’s death and my family’s history, along with the research from the ’80s and ’90s. Within seconds it answered what decades of shrugs had not. The research had worked, comparisons were made, and “it” had a name: FENIB, an ultra-rare genetic neurodegenerative disorder with progressive dementia and seizures, found in less than 1 in 1 million people. It had been named and studied for years. My family was in the literature. We had seen doctors for years. Still, no one told us.
Learning the name did not only answer a question. It reorganized everything behind it, the way a random set of details rearranges the moment you learn the one thing connecting them. I spent my life managing what the disease did. Now I understood what it was.
My grandmother handed my mother an inheritance that nobody named. My mother did the same. I can hand my children an inheritance with a name.
So I told them. Not in front of a fireplace the way I had pictured it growing up, when I was telling children who did not yet exist how I survived. This time it was at our favorite restaurant on an ordinary Wednesday. I told them everything I discovered over the previous 72 hours. The death certificate, the research, the name: FENIB.
For decades the disease in our family had only a pronoun. My children are the first generation to grow up with its name.
Miranda Pappas is a research methodologist with more than two decades of experience evaluating clinical and scientific evidence. She holds a master’s degree in counseling psychology and is the author of the forthcoming memoir “Naming It.”
https://www.statnews.com/2026/10/22/rare-disease-family-name-fenib-personal-essay/
Roussel BD, Lomas DA, Crowther DC. Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis). Epileptic Disord. 2016 Sep 1;18(S2):103-110. doi: 10.1684/epd.2016.0847. PMID: 27618835.
Abstract
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.
Yang X, Fang Z, Yan L, He X, Luo H, Han Z, Gui J, Cheng M, Jiang L. Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. Seizure. 2022 Dec;103:137-147. doi: 10.1016/j.seizure.2022.11.008. Epub 2022 Nov 13. PMID: 36417830.
Abstract
Background: Familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare neurogenetic disease, is characterized by progressive cognitive decline and myoclonus and caused by pathogenic variants of the SERPINI1 gene that lead to the formation of neuroserpin inclusion bodies.
Methods: We described the case of an Asian patient with FENIB associated with a pathogenic variant of SERPINI1 and summarized and analyzed the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with this disease.
Results: The patient, a 16-year-old Chinese girl, presented with progressive cognitive decline and myoclonus that had started at the age of 11 years. The girl was found to carry a de novo heterozygous c.1175G>A (p.G392E) variant of the SERPINI1 gene, which is a pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics. She had responded poorly to antiseizure medications (ASMs). At the last follow-up, her myoclonus was still out of control, and her self-care ability was poor. Our literature review revealed that 13 similar cases (including 9 cases in male patients) have been reported so far, in which six pathogenetic variations in SERPINI1, including G392E, were responsible for FENIB. All the patients presented with myoclonus, and 12 patients had experienced at least one other type of seizure. Further, as observed in our case, 9 out of 12 patients did not respond to ASMs. Progressive cognitive decline was observed in all the patients, and 10 out of 13 patients had dyskinesia. The median age of disease onset was 21 years, and the median age at the time of death was 33 years. Further, 9 out of 13 patients showed signs of cerebral and/or cerebellar atrophy. Finally, neuroserpin inclusion bodies were identified in six patients who underwent brain biopsy or autopsy.
Conclusions: Pathogenic variants of SERPINI1 should be suspected in children with progressive cognitive decline and myoclonus, especially in those with progressive myoclonus epilepsy. Further, gene detection and brain biopsy are important means for the diagnosis of FEN.
Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, Todd R, Bradshaw C, Kent P, Feiglin D, Rosenbaum A, Yerby MS, Shaw CM, Lacbawan F, Lawrence DA. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 1999 Dec;155(6):1901-13. doi: 10.1016/S0002-9440(10)65510-1. PMID: 10595921; PMCID: PMC3277299.
Abstract
We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.
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