Palmer et al. 2023 – A Summary for Families

What was done before

In 2018, Dr. Emma Palmer, Dr. Vera Kalscheuer and colleagues provided a description of the genetic and clinical characteristics of 52 individuals with CLCN4-NDC. Their findings are summarised below:

Overall, in the new publication, the authors aimed to expand on their previous work but looking at a larger cohort of individuals with CLCN4 gene changes. Through a collaborative and international effort with clinicians from all over the world they provided clinical data on 56 new families, and through a review of new and previously published cases they summarized features on 122 individuals with CLCN4 gene changes, the largest cohort to date. Finally, they looked at the effects of 59 different CLCN4 gene variants on ClC-4 function.

What they found

1. Summary of clinical features (*percentages given for total number reported cases; 56 new individuals + previously reported individuals)  

Learning difficulties – are the most common clinical feature in males (most often males have a moderate to severe intellectual disability but sometimes learning difficulties are borderline or mild). In females, prediction of cognitive function is much harder. Individuals with de novo variants often have more significant learning difficulties, but that is not always the case.

Speech and language difficulties – 100% of males have delayed speech and language. Delayed speech and language affects the majority (95%) of females with de novo variants but less than 15% of females with inherited variants or variants where we do not yet know if they are inherited or de novo.

Behavioural and mental health conditions – the most common conditions are

• attention deficit hyperactivity disorder (ADHD/hyperactivity/impulsivity/restlessness (30% of all males; 35% females with a de novo variant);
• autism spectrum disorder. This was diagnosed in 25% of all males and 30% females with de novo variants;
• challenging behaviors/angry outbursts (28% males, 30% females with de novo variants);
• anxiety (17% of males; 45% females with de novo variants; 8.1% females with inherited variants/unknown inheritance).

Less frequent but also observed are obsessive compulsive behavior (10% males, 10% females with de novo variants), depression/bipolar disorder (8.6% males, 5% females with de novo variants).

Epilepsy – affects 60% of all males, 25% of females with de novo variants. The onset of epileptic seizures is  typically within first 3 years of life (but there are a couple of individuals who developed in early teenage years). The most common type of seizures are generalized absence and tonic-clonic seizures and focal onset seizures. Epilepsy is often easy to treat with anti-seizure medications, but in some individuals can be harder and require multiple treatments. So far there is not a clear relationship between the severity of epilepsy and the severity of learning difficulties.

No specific anti-seizure medications have been so far shown to be more helpful in controlling seizures in individuals with CLCN4-NDC.

Brain differences – neuroimaging (MRI or CT scan of the brain) showed differences in the structure of the brain in just under 70% of males and 60% of females with de novo variants. The most common findings were changes to the brain white matter (57% males; 30% females with de novo variants) and abnormalities of the corpus callosum which is a white matter tract connecting the two halves of the brain (40% males; 23.5% females with de novo variants). None of these brain differences needed specific surgery or treatments.

Other neurological symptoms – infantile hypotonia (weak muscle tone) was reported in about 40% of males and 55% of females with de novo variants. Later onset neurological symptoms included tremor, ataxia (an unsteady gait), hyperkinesis (very rapid movements) or stereotypical (repetitive, unusual) movements, other changes in gait such as walking with a stooped posture, or progressive spasticity (increased tone), was observed in 26% of males and 40% of females with de novo variants.

Gastrointestinal issues – these affected many individuals. Symptoms included gastrointestinal reflux (15% males, 25% females with de novo variants); constipation (15% males, 35% females with de novo variants); feeding difficulties (17% males, 55% females with de novo variants).

Growth issues – Slow weight gain affected about 15 % males and 30% of females with de novo variants. Some individuals had short stature (15% males, 30% females with de novo variants). Progressive microcephaly (a smaller head circumference than typical) was more common in females with de novo variants (~70%) compared to males (~20%)

Other findings – other less commonly noted clinical features included scoliosis (a sway in the spine), pes planus (flat feet) and/or lax joints, sleep disorders, otitis media with effusions (middle ear infections), and strabismus (squints).

However, other organs, such as the heart, kidney and liver, do not seem to be affected in individuals with CLCN4-NDC. There was no evidence for an increased risk of cancers.

2. Summary of analysis of CLCN4 gene variants and their effect on ClC-4 protein function

The potential effects of the CLCN4 gene variants on the function of the ClC-4 protein were investigated using a technique that allows scientists to compare the function of the ‘changed’ ClC-4 found in patients with a normally functioning ClC-4. This method allows researchers not only to determine whether the changed ClC-4 protein is functioning differently, and also in what way (e.g. not working at all, working less, working in a different way). This is very critical knowledge for efforts to develop effective therapies for CLCN4-NDC.

The figure below, obtained from the new publication, shows a schematic of the ClC-4 protein (in grey), with each dot representing a variant in the ClC-4 protein found in 59 of the patients included in the study, and with the different colors indicating how that specific change has affected the function of the protein. Overall, the results revealed a wider variety of impacts on the function of ClC-4 than previously described, highlighting the complexity of CLCN4-NDC and providing key insights to guide further research efforts.

What’s next? 

More research! While this new publication has significantly increased our knowledge of CLCN4-NDC, further work is needed to continue learning about the spectrum of CLCN4 gene variants and their implications on protein function and clinical symptoms. The more we understand about the function of ClC-4 and CLCN4-NDC the more chances of finding effective therapeutic options. 

Can I help? 

Yes, you can! If you or a close family member have a diagnosis of CLCN4-NDC you can help us learn more about the condition by participating in the CLCN4 patient registry, hosted by Simons Searchlight. You can learn more about the registry and how to sign up here!

You can also help by donating or helping us fundraise so that we can keep supporting the much needed scientific research on CLCN4-related condition.

Thank you to the authors

On behalf of the CLCN4 community we would like to thank the authors of the paper, with a special mention to Dr. Emma Palmer, Dr. Vera Kalscheuer and Dr. Michael Pusch, who led the efforts and work that resulted in this publication and helped prepare this summary.  A big thank you to Natalie Grainger (UNSW) for her fantastic work in producing the snapshot summary.