Genetic mimics of neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) are neuroinflammatory conditions characterised by acute or subacute involvement of the optic nerves, spinal cord, and brain or brainstem. However, a range of genetic disorders affecting these same structures may mimic their core clinical features, posing important diagnostic challenges for neurologists.

In contrast to NMOSD and MOGAD, most genetic conditions typically follow a progressive course but can at times have relapsing presentations. Nevertheless, acute or subacute presentations are increasingly recognised, sometimes occurring on a background of subtle neurological dysfunction, thereby resembling an inflammatory aetiology. Subacute bilateral visual loss, for example, has been described in a genetically confirmed case of classical Ehlers–Danlos syndrome (TNXB variant), with orbital magnetic resonance imaging (MRI) demonstrating optic nerve thickening and enhancement consistent with optic neuritis. ¹ Hemophagocytic lymphohistiocytosis (HLH) presenting with isolated central nervous system (CNS) involvement or with systemic features is a well-recognised mimic of demyelination in the paediatric patients. ²

Mitochondrial disorders are another key group. Optic neuropathy is a hallmark manifestation, either in isolation, as in Leber hereditary optic neuropathy (LHON), or as part of broader syndromic phenotypes, including ‘plus’ forms and dominant optic atrophy. Visual loss in LHON typically evolves over 3–6 months before stabilisation, and associations with multiple sclerosis have been reported.^3,4

Genetic myelopathies may also mimic NMOSD. Adrenomyeloneuropathy, due to ABCD1 variants, can present with spastic paraparesis, bladder dysfunction and, in some cases, inflammatory-appearing longitudinally extensive spinal cord lesions. ⁵

In this issue of Multiple Sclerosis Journal, area postrema syndrome (APS), a core feature of NMOSD, has been described as a manifestation of a genetic condition. Charcot–Marie–Tooth disease type 1X (CMT1X), caused by GJB1 variants, has been reported in a 43-year-old woman presenting with intractable hiccups, nausea, and a dorsal medullary lesion. The presence of a peripheral neuropathy prompted genetic testing, which confirmed a pathogenic GJB1 variant. The patient received corticosteroids, and the lesion resolved without further relapses. ⁶ Although the co-existence of a seronegative NMOSD with CMT1X cannot be completely ruled out, the absence of the antibody, with no further relapses off immunosuppressant, suggests a possible CNS involvement on the background of the genetic, classically peripheral nervous system condition.

For neurologists, red flags suggesting a genetic aetiology include a more insidious or progressive course, atypical imaging features or poor treatment response and the presence of systemic or extra-CNS features such as neuropathy or other organ involvement (i.e. adrenocortical insufficiency, systemic inflammatory response). In seronegative or uncertain cases, repeat antibody testing (possibly with live cell based assay) and consideration of alternative diagnoses, including genetic causes, are essential to avoid misdiagnosis, inappropriate long-term immunotherapy and delay in accessing specific therapies that are available for some genetic disorders.