Differential Clinical case Organic Clues Diagnostic Overshadowing Clinical Reasoning Unconfirmed Diagnosis

When a Genetic Neurological Disorder Was Considered Functional: The FLVCR1 Case

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A 31-year-old woman experienced progressive weakness, sensory disturbances, coordination problems, muscle spasms, seizure-like episodes and urinary incontinence. She also had severe inherited retinal disease, two brothers with the same retinal condition, and genetic findings associated with disorders affecting both the eyes and nervous system. Despite this, her neurological symptoms were repeatedly considered functional.

That is not speculation. It is what the authors of a July 2026 case report published in Case Reports in Ophthalmology documented. Their paper, FLVCR1 Variant as a Cause of Retinal and Neurologic Dysfunction in Retinitis Pigmentosa with Coats-Like Vasculopathy, describes a patient whose neurological symptoms were not connected to her existing genetic findings during earlier clinical evaluations. The authors argue that recognising the neurological manifestations associated with FLVCR1 variants sooner might have prompted more targeted investigation and management.

The troubling part is not simply that functional neurological disorder (FND) appeared in the differential diagnosis. It is that a potentially relevant genetic explanation was already available, yet the connection was apparently missed. The patient was left without a definitive neurological diagnosis while her symptoms continued to progress.

The patient had been diagnosed with retinitis pigmentosa during her teenage years. This is a group of inherited retinal disorders characterised by progressive degeneration of the light-sensitive cells responsible for vision. Symptoms commonly begin with night blindness and can progress to loss of peripheral and central vision. Some forms affect the retina alone, while others form part of broader genetic syndromes involving the nervous system.

Her retinal disease was severe. She had longstanding night blindness and progressive photophobia, eventually losing all light perception in her left eye. Her right eye also deteriorated substantially, with retinal imaging revealing cystoid macular oedema, abnormal blood vessels and extensive lipid exudation associated with a Coats-like vascular response. These abnormalities were objectively documented through ophthalmological examination and imaging.

In October 2021, genetic testing identified two FLVCR1 variants: c.1092+5G>A, classified as pathogenic, and c.1058C>T (p.Thr353Met), classified as likely pathogenic. FLVCR1 is involved in haem transport and has established associations with inherited retinal and neurological disorders. These include posterior column ataxia with retinitis pigmentosa (PCARP) and hereditary sensory and autonomic neuropathies (HSANs), conditions that can involve impaired coordination, sensory abnormalities and autonomic dysfunction.

The family history strengthened the genetic picture. Both of the patient's brothers had retinitis pigmentosa. Although parental genetic testing was not performed, the authors considered the pattern consistent with autosomal recessive inheritance, with the two FLVCR1 variants likely occurring on opposite copies of the gene. Genetic consultation subsequently concluded that the variants were the likely cause of her retinal disease and neuropathy.

By then, however, the neurological history had already become extensive.

Coordination difficulties and migraine headaches reportedly began in 2019. In September 2023, the patient developed progressive weakness in all four limbs, accompanied by abnormal sensations spreading from the right to the left side of her body. Brain and spinal MRI investigations and a lumbar puncture were unremarkable. An autoimmune panel detected elevated GAD65 antibodies at 0.12 nmol/L, above the laboratory reference limit of 0.02 nmol/L, although the significance of this finding was not established. Guillain-Barré syndrome was considered, and she received four days of intravenous immunoglobulin with some reported improvement. No definitive explanation emerged.

In October 2023, the patient experienced further episodes of lower-limb weakness alongside events involving brief unresponsiveness, upward deviation of the eyes, confusion afterwards and occasional urinary incontinence. Nerve conduction studies were normal. Guillain-Barré syndrome was considered again, but this time clinicians also suspected FND.

Here is the problem. The patient had a progressive neurological presentation, a known inherited retinal disorder, a family history of similar disease and genetic findings associated with neurological dysfunction. Yet the functional interpretation entered the clinical picture while the relationship between those findings remained unexplored. Normal MRI, lumbar puncture and nerve conduction studies did not eliminate the possibility of genetic neurological disease. They merely failed to identify abnormalities detectable by those particular investigations.

The authors state:

Despite confirmed diagnosis of FLVCR1-related retinopathy, the patient’s neurological symptoms were never formally connected to her diagnosis in prior clinical evaluations.

They go further, reporting that her neurological symptoms were considered functional on multiple occasions. That observation is central to the case. A recognised genetic disorder was present, its possible neurological manifestations were relevant to the patient's presentation, and the connection had not been made during previous assessments.

The paper does not describe the clinical signs used to justify the suspicion of FND. There is no documented account of Hoover's sign, entrainment, distractibility or another positive functional sign being used to establish that interpretation. The available record therefore gives no way to evaluate the evidentiary basis for the functional suspicion. This is particularly important when the patient's symptoms included progressive weakness, impaired ambulation, sensory disturbances and possible autonomic manifestations, all of which required careful neurological investigation.

Genetic consultation eventually provided a more coherent explanation for at least part of the presentation. FLVCR1-related disease can affect structures beyond the retina, including pathways involved in sensation and coordination. PCARP is associated with retinal degeneration and posterior column dysfunction, while FLVCR1-related hereditary sensory and autonomic neuropathies can involve abnormalities of sensation and autonomic regulation. The patient's neurological presentation was not identical to the classical descriptions of either condition, but that did not make the genetic findings irrelevant. It made the case unusual enough to warrant publication.

This distinction matters. A rare genetic disorder does not have to reproduce every feature of its original description before clinicians investigate whether it explains an evolving neurological presentation. Disease phenotypes expand precisely because patients do not always conform to established descriptions. If atypical manifestations are dismissed before their relationship to known pathology is investigated, those manifestations may never become part of the recognised clinical spectrum.

The authors also discuss the patient's seizure-like episodes, noting that their reported features were more consistent with focal impaired-awareness seizures than generalised tonic-clonic seizures. That interpretation was not confirmed through documented electroencephalographic testing, and the report does not establish that FLVCR1 caused the episodes. The significance is that these events remained part of an unresolved neurological presentation requiring investigation, rather than evidence that a functional explanation had been established.

There are limitations to what the case proves. The report does not document a definitive FND diagnosis subsequently overturned, and the genetic findings do not conclusively explain every reported symptom. Historical medical records were incomplete, parental genetic testing was unavailable, and the patient was eventually lost to follow-up. These limitations are sufficient reason to classify the case as an unconfirmed diagnostic reversal, not a proven misdiagnosis. They do not change the documented fact that functional attribution occurred while a potentially relevant genetic neurological explanation remained unrecognised.

The broader concern is diagnostic overshadowing. Once symptoms are interpreted through a functional framework, subsequent findings may be assessed as additional manifestations of that framework rather than evidence requiring reconsideration. The danger is not theoretical when a patient already has a genetic disorder capable of affecting the nervous system. A failure to investigate that connection can leave a potentially important disease process insufficiently characterised.

This case also raises questions about the common phenotype hypothesis, discussed in The Diagnosis of the Gaps: FND and the Problem of Phenotype Overlap. The hypothesis proposes that some clinical features interpreted as functional may be shared across different neurological disorders rather than necessarily representing a separate disease process. The FLVCR1 report does not provide the positive-sign examination data needed to test that proposition directly. It does, however, document a situation in which symptoms considered functional overlapped with a neurological presentation that the authors subsequently connected, at least in part, to genetic disease.

The distinction between diagnostic overlap and independent comorbidity was also examined in POTS Found After FND: Comorbidity, or a Common Phenotype?. Merely identifying two diagnostic labels does not establish that two independent disease processes exist. In this case, the available evidence leaves the original functional suspicion unresolved while identifying a genetic explanation that deserved greater attention. The appropriate response to that uncertainty is further investigation, not an assumption that the functional interpretation must remain intact.

There is a related problem with the gap between how FND is supposed to be diagnosed and how functional attribution occurs in actual clinical practice. When Defending FND Means Missing the Point addresses the tendency to respond to documented concerns about diagnostic practice by repeating what the diagnostic standards require. The relevant question here is not what an ideal assessment would have involved. It is what evidence supported the suspicion of FND in this patient's actual clinical history, and why the neurological implications of the FLVCR1 findings were not recognised earlier.

The authors suggest that earlier recognition of the possible neurological manifestations of FLVCR1-related disease might have prompted targeted neurological evaluation and subsequent management. They cannot establish what the patient's outcome would have been under a different diagnostic approach. Nevertheless, their conclusion identifies a missed opportunity to investigate an existing biological explanation for a progressive clinical presentation.

That missed opportunity deserves scrutiny. Genetic testing had already identified abnormalities associated with neurological disease. The patient's symptoms progressed. Conventional investigations did not provide a definitive answer. Functional attribution nevertheless became part of the clinical history, and the potential relationship between the genetic findings and neurological manifestations was not formally established during earlier assessments.

The central question is therefore simple: What evidence justified considering this patient's neurological symptoms functional, and why was the existing genetic explanation not investigated more thoroughly?

The case report cannot answer the first part because the relevant clinical reasoning was not documented. It provides a substantial reason to ask the second. That is enough to make this case important, without pretending that the authors proved more than they actually did.

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