Familial clustering in NMOSD may be more common than thought

Study findings highlight potential for genetic predisposition to NMOSD

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by Andrea Lobo |

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An illustration shows three bottles, two containing strands of DNA and one half-filled with liquid.

Familial clustering of neuromyelitis optica spectrum disorders (NMOSD) — having more cases within families than what would be expected — is more common than originally thought.

That’s according to a new study whose findings highlight a complex genetic predisposition to the progressive autoimmune disease.

Certain DNA variants were shared between affected family members, either all with NMOSD or some with multiple sclerosis (MS), another autoimmune disease affecting the nervous system. However, “the demographic, clinical, and outcome profiles of familial cases were not different from sporadic cases,” or those seemingly occurring at random, the researchers noted.

The scientists, from Bangkok, called for future research to clarify the genetic basis of familial NMOSD.

The study, “Familial neuromyelitis optica spectrum disorders: Case series and systematic review,” was published in the journal Multiple Sclerosis and Related Disorders.

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Familial clustering in NMOSD initially thought to be rare

NMOSD is an autoimmune disease that affects the nervous system, leading primarily to the inflammation of the optic nerve — which sends and receives signals from the eye — and the spinal cord. It results in vision and muscle control problems.

The abnormal immune attacks against nervous system cells is driven by self-reactive antibodies that, in most cases, target a protein called aquaporin-4 channel (AQP4).

Most NMOSD cases are sporadic, and “familial NMOSD is assumed as a rare occurrence,” the researchers wrote.

However, NMOSD has been reported across one or two generations of the same family in some cases. Moreover, a previous multinational study showed that familial cases accounted for 3% of total cases — a number “greater than expected based on the prevalence of NMOSD in the general population of 1/100,000,” the team noted.

In addition, increasing research suggests that about half of NMOSD patients have a family member with other autoimmune disorder, pointing to a potential role of genetics in the disease’s development.

Now, a team of researchers from several institutions in Thailand described — reportedly for the first time — familial cases of NMOSD in that country. Typically, familial clustering in a given disease is defined as its occurrence among relatives in a family at a greater rate than would be expected in a population at large.

To identify NMOSD patients with a history of this disease or MS in their family, the team retrospectively analyzed data from the electronic medical database at Mahidol University’s Faculty of Medicine Siriraj Hospital.

Six familial cases were identified from among 165 NMOSD patients followed at the hospital, corresponding to 3.6% of the cases. These patients came from three different families — two siblings from each family — and all were positive for anti-AQP4-antibodies, also called AQP4-IgG.

In the first family, both the older brother and the younger sister developed NMOSD symptoms at age 43. However, their first signs differed: the man showed leg muscle weakness and numbness, while his sister experienced speech difficulties, followed by vision problems.

In the other two families, the siblings also developed their first symptoms at similar ages, either around their 40s or their 50s. These initial symptoms ranged from leg weakness to leg partial paralysis in the second family, and from neck numbness to uncontrollable nausea and vomiting in the third family.

Persistent episodes of nausea, vomiting, and/or hiccups comprise the signs of a condition referred to as area postrema syndrome, which is considered a diagnostic criterion of NMOSD.

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History of MS found in some cases of familial NMOSD clustering

The team then systematically reviewed studies published up to December 2022 describing familial NMOSD cases. They found 27 studies including 93 cases from 45 families, which when combined with their six familial cases, gave a total of 99 cases from 48 families.

A total of 40 of these families were affected only by NMOSD (concordant families), while eight families also had cases of MS (discordant families).

Among concordant families, most patients (86.7%) were women and more than half (53%) were Asian. About one-quarter (25.3%) were Caucasian, while 12% were African, and 9.6% were Latino.

AQP4-IgG were detected in all affected members from 19 families, while the remaining 21 families had affected members who were either negative for these antibodies or had unknown status.

Most concordant families (92.5%) had two people with NMOSD, while the other three families had three or more affected members. The disease usually affected one or two generations of the same family, most commonly siblings (52.5%), followed by parents and children (32.5%). More rare patterns involved aunts/uncle-nephews, or cousins.

In non-sibling cases, maternal transmission was more common — occurring in 16 families, or 84.2% — while paternal transmission occurred in three families.

Based on available data from 75 patients of concordant families, the mean age at disease onset was 37.2 years, with a mean age difference at onset between family members of 16 years.

Available information from 48 patients showed that the most common initial symptoms were inflammation of the spinal cord (68.8%) and of the optic nerve (45.8%). In 22 cases (45.8%), the presenting symptom was the same between family members.

“Other autoimmune diseases were documented in 11 cases,” the team wrote.

Familial clustering of NMOSD is more common than would be expected in the general population.

Among 37 cases of concordant families with available information on treatment, most patients (94.6%) received into-the-vein (intravenous) methylprednisolone for acute treatment. To prevent relapse, they were mainly treated with azathioprine (29.7%) and rituximab (24.3%).

Among discordant families, most patients were also women (87.5%) and most families were either Caucasian or Asian (37.5% each). The disease frequently affected one generation, usually siblings (62.5%).

The mean age at disease onset was 28.7 years, with a mean age difference at onset between family members of five years. Most NMOSD cases were positive for AQP4-IgG, but “there was no predominant initial presentation,” the team wrote.

These findings highlighted that “familial clustering of NMOSD is more common than would be expected in the general population,” the researchers wrote.

Importantly, “epidemiology, clinical characteristics, and disease outcome of familial cases are indistinguishable from sporadic NMOSD,” they added.

Genetic testing was performed in 10 cases from five concordant families, and eight cases from four discordant families. Some specific DNA variants in genes involved in immunity were shared among familial cases, indicating genetic susceptibility.

However, “further studies are needed to illustrate our understanding of the genetic basis of familial NMOSD,” the researchers concluded.