Pathogenic variants

Pathogenic variants

Clinical signs

Nexmif pathogenic variants are usually due to stop-gain, frame-shift errors, or to other larger structural variants. However, all of them involve a protein expression decrease in the structure of the genetic material.

This X-linked loss of function disorder shows a broad phenotypic spectrum in females, in contrast to a more severe picture in males.

It was initially thought that females with this syndrome were all asymptomatic, as this tipically happens with X chromosome linked disorders. Not the case with Nexmif: females can have as many symptoms as males. Usually these show a wider variation of the developmental and cognitive profile. However, a severe form of epilepsy is more common in females, very difficult to treat. Hypothyroidism, precocious puberty, primary amenorrhea and delayed bone age have also been reported.

However, it is impossible to predict in advance what symptoms and problems a child will develop. Each person is unique, therefore, even if in the same formal condition or in the presence of the same identical type of mutation, each of us can have very different clinical manifestations.
Signs and symptoms

Signs and symptoms

how the syndrome shows up

Neurological Area

Nexmif kids develop slower. They roll, sit and stand later than their peers. Some will learn to walk, some will not. The walking of a child with this condition is often stiff and awkward.

Many children with this condition suffer from epilepsy. Typically these are early crisis, within the first year of life. The NEXMIF epilepsy syndrome is an overlap of MAE (myoclonus-astatic epilepsy) and EMA (epilepsy with eyelid myoclonia and absences).

Some develop the so-called West’s syndrome which is another type of epilepsy, difficult to treat, with after awakening seizures in which arms and legs move towards each other. Different types of seizures can occur, such as those with stiffening (tonic), jerking (clonic), or seizures in which arms legs fall or also the head falls forward (atonic), myoclonus, limbs stiffening (focal seizures) or crises with staring and numbness (focal seizures with reduced state of consciousness), crises with fixed and blinking gaze (absences with eyelid myoclonias). Most children experience different types of seizures that are often difficult to control, with a phasic pattern, which is clearly leading to drug-resistant epilepsy.

Nexmif children show extraordinary difficulties in falling asleep, mostly after frequent and long awakenings. In some of these children problems are caused by epileptic seizures during sleep, not detected by adults. Surely the preparation at bedtime with a relaxing ritual, following a fixed pattern, can help the timing and quality of the first fall asleep. The use of delayed-release melatonin, always under medical advice, can be useful in falling asleep after awakening at night.

Children with the syndrome often have difficulty in understanding, processing and cataloging all the stimuli that they get. They can easily get over-stimulated without finalization. They may also suffer from unexpected stimuli such as loud sounds, other people’s crying, or noises.

Young children with this syndrome often have low muscle tone, which makes them feel weaker and tired. Lower muscle capacity makes it difficult for babies to lift their heads. This is one of the reasons why these children usually develop more slowly and with higher difficulty.

In some cases, on the other hand, excessive muscle tension is recorded with consequent spasticity, crossed or tiotoe walking.


It is often more difficult for Nexmif children to be coordinated and maintain balance. They have an awkward gait and fall more easily. Even the balance in the hands grip is poor. This makes it more difficult for them to write, bring a cup to their mouth or practice fine motor skills in general.

Cognitive-behavioral Area

Learning to speak is very difficult for our children. Most can make sounds but not words. A small percentage are able to compose single words or short sentences, but they are generally better able to understand than to speak for themselves.

Children with Nexmif syndrome are more likely to exhibit autistic features. They are focused on themselves and do not have a great productive need for contact with other people. They often have difficulty getting and maintaining eye contact. They have oversized temper tantrums or can become aggressive. It is much more comfortable for them to return to fixed and predictable life patterns during the day: unexpected changes or events can be problematic.

Many children like to make nervous, repetitive movements with their arms and hands. Such movements are called stereotypies. Some of them wave their hands and fingers, others make twisting or rubbing movements on the chest, especially in moments of excitement or emotion.

These children mostly have learning difficulties. It is also difficult to try to teach them something since they are also often hyperactive. Most of them have an intelligence quotient below 70, which we rate as intellectual disability.

It is clear from the outset that these children have difficulty in maintaining visual engagement and attention on a game or even on a cartoon. They pass from one activity to another without consciousness or intention, they get very easily distracted. They have impulsive behaviors, i.e. they tend to act first and then think. In addition, they have problems staying still even during lunch or at school, having great difficulties in managing very small tasks.


Some children with Nexmif syndrome have problems with breastfeeding. These babies have slow, difficult, and erratic sucking on the breast or teat. Feedings are often very long and sometimes it is necessary to temporarily administer tube feeding to babies, because otherwise they will not receive enough nourishment. Usually, with growth, the ability to feed and drink improves in most cases.

Children with this syndrome often suffer from reflux of food and liquids from the stomach to the esophagus. Since the stomach contains acid, this also ends up in the esophagus and sometimes goes up to the mouth. This acid can cause pain, making babies cry and sometimes making them inappetent or calling up regurgitation or vomiting.

Nexmif babies can produce a lot of saliva. This is due to the the face and mouth muscle relaxation, which often facilitates the involuntary outflow of saliva from the mouth itself. The other option would be the spontaneous / automated swallowing: it is not taken for granted, as it requires the patient to be able to feel his own body. It is advisable to insist on trying to teach the child how to do it.

Constipation is very common. Often stools are hard and dry, with difficult evacuation. This can also cause abdominal pain, bloated stomach or reduce appetite.

Most of these children are unable to develop a complete sphincter control and need to use diapers beyond the typical age.

Strabismus is quite common in children with this syndrome. In addition, the so-called cerebral visual impairment can occur. It means that the brain has difficulty perceiving the stimuli that the eyes transmit and this makes it difficult for children to see, even if they do not have a real eye problem. One case of a rare maculopathy (Torpedo) associated with this mutation is reported in the literature. Since it is unclear whether this gene may play a role in ocular development, it is recommended that ophthalmologic and orthoptic checks are performed after diagnosis.

Although children may experience growth difficulties at an early stage, as they grow older, people with this syndrome have a greater chance of becoming overweight.

In some cases, Nexmif children are shorter than their peers.

Even the head, in some of these children, does not grow according to the typical development curve. Some cases of microcephaly are reported.

In many syndromes, children often have a visibly typical appearance. This means that children with the same syndrome often look more alike than their own brothers and sisters, even if they are not related to each other. Instead, Nexmif kids mostly have few noticeable external features. In some cases, a round face shape is noted, with the upper part of the head often narrower than the lower part, the nose often small or a reduced distance between nose and mouth.