Rare Neurodegenerative Disorder May Share Similar Genetic Mutation With Parkinson’s

A rare neurodegenerative disorder called neuronal intranuclear inclusion body disease (NIID) may share a similar genetic mutation with Parkinson’s disease (PD), a study suggests.

Patients who present with typical Parkinson’s disease may carry this mutation, respond to parkinsonian medications and not develop clinical features of NIID.

The study, “Association of NOTCH2NLC Repeat Expansions With Parkinson Disease,” was published in the journal JAMA Neurology.

Trinucleotide repeat disorders consist of a group of human diseases that primarily affect the nervous system. These disorders are a result of genetic mutations characterized by abnormal expansion of repetitive DNA sequences.

The presence of a GGC nucleotide — the building blocks of DNA — expansion in the Notch homolog 2 N-terminal-like C (NOTCH2NLC) gene causes NIID, a rare neurodegenerative condition characterized by varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor.

While large GGC repeats, ranging from 66 to 517 units, have been reported in NIID patients, it is unclear if NOTCH2NLC GGC expansions are associated with typical Parkinson’s disease.

To fill this knowledge gap, a team of researchers at the National Neuroscience Institute (NNI) and Singapore General Hospital genetically screened a large group of Parkinson’s patients for GGC repeats using DNA sequencing techniques. Biochemical and neuroimaging tests also were performed.

Among 2,076 participants, from Chinese or other Asian ethnicities, 1,000 participants were diagnosed with sporadic Parkinson’s (mean age at onset 62.6 years) and 1,076 were healthy participants serving as controls (mean age 54.9 years).

All participants were genetically screened for NOTCH2NCL GGC repeats using repeat-primed polymerase chain reaction (PCR) — a type of DNA amplification technique.

A total of 13 Parkinson’s patients carried NOTCH2NLC GGC repeat expansions greater than 40 units, while all healthy controls had fewer than 40 repeats.

Ten Parkinson’s patients carried a GGC expansion of between 41 and 64 GGC repeats (1% of those with sporadic Parkinson’s). The other three patients carried GGC repeats of 79 or more units, two with 122 and 79 repeats, respectively, who exhibited typical parkinsonism and responded well to small dosages of levodopa medication, with no clinical or imaging features of NIID.

A third Parkinson’s patient, carrying 130 GGC repeats, had no family history of Parkinson’s disease and only developed cognitive impairment more than 10 years after diagnosis.

No patient with Parkinson’s was a carrier of known Parkinson’s-associated genes.

“To our knowledge, this is the first study reporting PD patients with NOTCH2NLC gene mutations as seen in NIID patients. Thankfully, they responded to PD medications better than most PD patients do. This suggests that there must be factors that can influence why some develop PD while many others develop the more severe form of NIID,” Ma Dongrui, MD, PhD, senior medical laboratory scientist and first author of the study, said in a press release.

In addition to GGC repeats, there are two forms of sequence interruptions, GGA and AGC, within the repeat expansions, in Parkinson’s and NIID patients. These sequence interruptions may be protective against the formation of abnormal disease-causing gene expansions and affect disease manifestations.

In NIID patients, the reported frequency of GGA interruptions is 12%. In this study, all three Parkinson’s patients with long GGC expansions, carried no GGA sequence interruptions. However, the frequency of AGC sequence interruption within the GGC expansion in these patients was higher than in NIID patients (25% vs 8%).

This study shows that, while the condition is uncommon, patients with sporadic Parkinson’s carrying NOTCH2NLC GGC repeats (more than 79 units) can present with typical parkinsonism, requiring low levodopa dosages, with no other clinical or imaging features of NIID even after several years of follow-up.

“Our findings suggest that many neurodegenerative diseases overlap and may share a common etiology. Finding a common link and uncovering the reason why a similar gene mutation leads to both mild PD and a severe form of NIID can help identify new drugs for these conditions,” said Tan Eng King, MD, senior author of the study and senior consultant at NNI’s Department of Neurology.

Among limitations to the study findings, the team reported, was that the absence of GGA sequence interruptions in the three Parkinson’s patients may either affect the stability of the GGC expansion or influence gene expression through unknown factors.

Thus, “the functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated,” the researchers wrote.

“It might be beneficial for clinicians to be watchful of early cognitive impairment or imaging evidence that may suggest NIID in patients diagnosed with PD. As NIID is caused by a genetic mutation, it also may be worth looking out for family members of PD patients who may show signs of NIID,” Tan said.