I-Cell disease

Dr Leroy and Dr Sara Cathey from the Greenwood Genetics Centre have very kindly written a Medical Alert for families whose children may need an anaesthetic. This document can be viewed on the website or downloaded as a PDF . It is critically important to know that children with ML II have very small and stiff airways. Advanced intubation techniques are required. Removing the breathing tube (extubation) can be equally complicated in some individuals. Any elective surgery, even routine or simple procedures, should take place in a tertiary care center equipped to handle complicated patients with rare diseases.

A child with ML II is likely to have a protruding abdomen due to shortness of the chest, posture, or weakness of the muscles. Significant enlargement of liver and spleen is less common in ML II or III than in other lysosomal diseases. The liver and the spleen may be felt (palpated) by a doctor who examines your child because of this combination of factors.

Frequently, part of the abdominal contents will push out behind a weak spot in the wall of the abdomen. This is called a hernia. The hernia can come from behind the navel (umbilical hernia) or in the groin (inguinal hernia). Inguinal hernias should be repaired by an operation, but hernias sometimes recur. Umbilical hernias are not usually treated unless they cause entrapment of the intestine.

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Joint stiffness is common in both ML II and III and the maximum range of movement of all joints may become limited.

There is variation in the severity of problems that affect bones and joints, even between affected brothers and sisters. Those with ML II are affected early and skeletal problems may even be evident at birth. Anti-inflammatory drugs, such as ibuprofen, can help with joint pain, but their use should be monitored closely to make sure that irritation and ulcers in the stomach do not occur. Some individuals with ML II have decreased bone density leading to osteopenia and osteoporosis, also called secondary metabolic bone disease. Bisphosphonates have been trialled in a good number of ML II and ML III patients reducing pain, maintaining mobility and improving quality of life. Your orthopedist or endocrinologist can provide additional information about this treatment.

The bones of the spine (vertebrae) normally line up from the neck to the buttocks.

Individuals with ML II often have poorly formed vertebrae that may not stably support each other. One or two of the vertebrae in the middle of the back are sometimes slightly smaller than the rest and set back in line. This backward slippage of the vertebrae can cause an angular curve (kyphosis or gibbus) to develop, but it usually does not need treatment, unless severe.

Rarely, the bones that stabilize the connection between head and neck may be malformed (odontoid dysplasia) in people with ML II. If this occurs, fusion surgery may be required to connect all bones to each other so they do not slip further.

Parents of children with ML II should be cautious about how the area of the spine around the neck is handled. Activites that alter the stability of the neck (such as trampolining) should be avoided.

The shape of the hands is very noticeable in ML II; the hands are short and broad with stubby fingers. The fingers stiffen and gradually become curved, due to limited joint movement. The tips of the fingers can become permanently bent over.

Photo of Jonalin. Many affected individuals breathe very noisily even when there is no infection. At night they may be restless and snore. Sometimes the individual may stop breathing for short periods while asleep (sleep apnea). Pauses of up to 10-15 seconds may be considered normal. This noisy breathing, which stops and starts, can be very frightening for parents to hear. They may fear that their child is dying. If this is happening, the child’s oxygen level may be low when sleeping which can cause problems with the heart. If a parent notices significant choking or episodes of interrupted breathing, the child should be evaluated by a sleep specialist using a polysomnogram (sleep study). It is important to know that many individuals may breathe like this for years. Sleep apnea can be treated in some individuals by removing the tonsils and adenoids, opening up the airway with night-time CPAP treatment (continuous positive airway pressure), BiPAP (bi-level positive airway pressure), or tracheostomy, as discussed in the following paragraphs. There are reports of tonsils and adenoids growing back and continuing to cause airway problems.

The doctor may want the child to be admitted to the hospital overnight for a sleep study. Monitors are placed on the skin and connected to a computer to measure the levels of oxygen in the blood, breathing effort, brain waves during sleep and other monitors of the body’s function. From this study, the doctors can assess how much blockage to breathing is present, how much trouble your child is having moving air into the lungs during sleep, and how much effect this has on his body.

Night time CPAP or BiPAP can open the airway at night using air pressure, which can help the child’s airway stay open. This treatment involves placing a mask on the face each night and having air pumped into the airway to keep it from collapsing. This may seem to be an extreme measure but many people are able to tolerate it because it can greatly improve the quality of sleep, as well as help prevent or reduce the risk of heart failure caused by low oxygen levels at night.

Individuals with ML II may experience pain and loss of feeling in the fingertips caused by carpal tunnel syndrome. The wrist or carpus consists of eight small bones known as the carpals, which are joined by fibrous bands of protein called ligaments. Nerves have to pass through the wrists in the space between the carpal bones and the ligaments. Thickening of the ligaments causes pressure on the nerves, and this can cause irreversible nerve damage. The nerve damage will cause the muscle at the base of the thumb to waste away and will make it hard for a child to oppose his thumb in a position for a normal grasp. Although your child may not complain of pain, carpal tunnel syndrome may be severe. If your child seems to have pain in the hands, particularly at night or upon waking, an electrical test called a nerve conduction or electromyograph study should be performed. This test will show whether carpal tunnel syndrome is the cause. If your child has any weakness at all in the hand or has decreased muscle mass at the base of the thumb, then ask for the test from your neurologist. Be persistent, as many physicians may not believe that carpal tunnel syndrome is present without the classic symptoms.

Any elective surgery, even routine or simple procedures, should take place in a tertiary care centre equipped to handle complicated patients with rare diseases.

Uncorrected carpal tunnel syndrome may result in the loss of sensation or the sensation of pins and needles in the hands and fingers. Carpal tunnel syndrome can be corrected through surgery.

A similar type of nerve compression can happen elsewhere in the body, such as the feet, and cause localized weakness or pain.

Children with ML II have significant developmental delays, in both motor skills and language. Few are ever able to walk independently, without support. Spoken language may be limited to few words or phrases but understanding is generally much better. Children with ML II are aware of and interact with their immediate environment. They show happiness and sadness, and have likes and dislikes, just as any child does.

There is no scientific evidence that a particular diet has any helpful effect on people with ML II. symptoms such as diarrhoea or constipation are as common in ML II as in the general population.

It is important to note that there is no diet that can prevent the storage of compounds normally degraded in lysosomes, because the compounds are actually created by the body. So reducing sugar intake or other dietary components cannot reduce storage.

Some children with ML II are not tolerant of hard food textures, preferring soft foods. This may be the result of the tongue thickening or swallowing complications. If this occurs, an evaluation by a pediatric nutritionist is recommended to ensure the child is receiving adequate nutrition. Many children with ML II have a limited number of foods in their diet, out of preference.

It is important that individuals with ML II and III have their hearing monitored regularly so that problems can be treated early. Frequent ear infections may contribute to conductive hearing loss.

Chronic middle ear effusion

Correct functioning of the middle ear depends on the pressure behind the eardrum being the same as that in the outer ear canal and the atmosphere. This pressure is equalized by the eustachian tube, which runs to the middle ear from the back of the throat. If the tube is blocked, the pressure behind the eardrum will drop and the drum will be drawn in. If this negative pressure persists, fluid from lining of the middle ear will build up and eventually become thick like glue. This is called middle ear effusion. An ENT physician may advise that grommets/ear tubes be placed if chronic middle ear effusion is causing pain, recurrent infection, or impaired hearing in your child. Remember, any surgical procedure, even simple ear tubes, should take place in a tertiary care centre equipped to handle complicated patients with rare diseases.

Children with ML II may benefit from having a mainstreamed education and enjoy the social interaction with peers. It is important to work with your school system and develop the best Individualized Education Program (IEP) for your child. The IEP should emphasize the child’s mobility limitations, adaptive physical education, and attention to fine motor modifications.

Photo of Sam Hudson. Children with ML II may be affected by mild corneal clouding. The circular window at the front of the eye (cornea) becomes cloudy which disrupts the clear layers of the cornea. Corneal clouding is rarely severe in ML II. Routine eye examinations by an ophthalmologist are recommended.

Birth weight and length may be smaller than expected in babies with ML II. Children with ML II stop growing around or before 2 years of age, and they remain small. Usually children with ML II take in the calories they need by mouth. Tube feedings might be needed in some circumstances, but it is important to recognize that extra calories cannot “make” a child with a disease that causes small stature grow taller.

Heart disease can occur in ML II.

During examinations, your doctor may hear a sound in your child’s heart, called a heart murmur. A murmur may be a normal finding or it may indicate a heart problem. A simple and painless test called an echocardiogram (similar to ultrasound screening of babies in the womb) is used to identify the problem. Heart valves are designed to close tightly to prevent blood from flowing in the wrong direction as blood passes from one chamber of the heart to another. If a valve becomes weakened or hardened, it may not shut firmly enough and a small amount of blood may leak through the valve. It is possible to have heart valve problems for years without any ill effects. If problems do occur, it may be possible to treat them with surgery.

Children with ML II can also develop the more serious problems of thickening and weakness of the heart muscle (cardiomyopathy) and congestive heart disease. Heart medications may be prescribed. Because of the unusual special problems that can occur in these diseases, you should select a cardiologist with some knowledge of Mucolipidosis. At a minimum, you should inform the doctor about the problems experienced by individuals with ML diseases.

Life expectancy in ML II is shortened, and survival beyond the first decade is not common.

Children with ML II generally have overgrown and swollen gums, which are characteristic of the disease. Their teeth may be late and troublesome in breaking through the gum. Teeth may appear just above or below the edge of the gum and are often widely spaced and poorly formed with fragile enamel. Sometimes the tongue may be enlarged, and the roof of the mouth may have a high arch.

It is important that the teeth are well cared for, as tooth decay can be a cause of pain. Teeth should be cleaned regularly. Cleaning inside the mouth with a small sponge on a stick soaked in mouthwash will help keep the mouth fresh and help avoid bad breath. Even with the best dental care, an abscess around a tooth can develop due to abnormal formation of the tooth.

Since individuals with ML may have thickening of the heart valves, you may be advised to give your child prescribed antibiotics before and after any dental treatment. This is because certain bacteria in the mouth may get into the bloodstream and cause an infection in an abnormal heart valve, potentially damaging it further. If teeth need to be removed while under an anaesthetic, it should be done in the hospital under the care of both an experienced anesthetist and a dentist – never in the dentist’s office.

Impaired cognitive development is characteristic of ML II. Other aspects of ML II can affect brain function, including inadequate oxygen levels, sleep deprivation due to sleep apnea, increased fluid pressure in and around the brain (hydrocephalus), and effects on the eyes and ears that affect the ability of the individual to see and hear normally.

The brain and the spinal cord are protected from jolting by the cerebrospinal fluid that circulates around them. Uncommonly, in individuals with ML II, the circulation of the fluid may become blocked over time so that it cannot be taken back into the bloodstream. The blockage (communicating hydrocephalus) causes increased pressure inside the head, which can press on the brain and cause headaches, incontinence, delayed development, expansion of the skull, and impaired vision. If hydrocephalus is suspected, an MRI should be performed. However, a lumbar puncture with pressure measurement (ideally pressure monitoring) is the best way to assess if increased intracranial pressure exists.. If your doctor confirms that the individual has elevated intracranial pressure, it can be treated by the insertion of a thin tube (shunt) that drains fluid from the brain into the abdomen (ventriculoperitoneal or VP shunt). The shunt has a pressure sensitive valve that allows spinal fluid to be drained to the abdomen when the pressure around the brain becomes too high. The lack of papilledema (swelling around the optic disk) or normal sized ventricles does not rule out hydrocephalus in individuals with ML II.

Runny nose

Typically, the bridge of the nose is flattened and the passage behind the nose may be smaller than usual due to poor growth of the bones in the mid-face and thickening of the mucosal lining. This combination of abnormal bones, with storage in the soft tissues in the nose and throat, leads to a narrow airway which can become easily blocked. Individuals with ML II can have chronic discharge of thick clear mucous from the nose (rhinorrhea), and chronic ear and sinus infections.

Throat

The tonsils and adenoids often become enlarged and can partly block the airway. The neck is usually short, which contributes to problems in breathing. The windpipe (trachea) becomes narrowed by storage material and may be stiff, due to abnormal cartilage rings in the trachea. Individuals with ML II may have hoarse sounding voices due to stiff vocal cords.

Chest

The chest is short and the shape of the chest is frequently abnormal as the junction between the ribs and the breastbone (sternum) is not as flexible as it should be. The chest is therefore rigid and cannot move freely to allow the lungs to take in a large volume of air. The muscle at the base of the chest (diaphragm) is pushed upwards if the liver and spleen are enlarged, further reducing the space for the lungs. When the lungs are not fully cleared, there is an increased risk of infection (pneumonia).

Treatment of respiratory infections

It is essential to consult your doctor before using over-the-counter medications. Drugs for controlling mucous production may not help. Drugs, such as antihistamines, may dry out the mucous, making it thicker and harder to dislodge. Decongestants usually contain stimulants that can raise blood pressure and narrow blood vessels, both undesirable for people with ML II. Cough suppressants or drugs that are too sedating may cause more problems with sleep apnea by depressing muscle tone and respiration.

Although most children with colds do not require antibiotics, individuals with Mucolipidosis frequently contract secondary bacterial infections of the sinuses or middle ear. Bacterial infections should be treated with antibiotics. Poor drainage of the sinuses and middle ear makes overcoming infections difficult. Therefore, it is common to have infections improve on antibiotics and then promptly recur after the antibiotic course is over. Chronic antibiotic therapy might be used to help some individuals with recurring ear infections. While overusing antibiotics is dangerous because of the risk of antibiotic-resistant infections, appropriate use of antibiotics is important in people with ML. You will need a doctor with whom you can develop a good working relationship to manage the frequent infections. Ventilation tubes can be used to improve drainage from the ear and speed resolution of infections. It is important to consult with an Ears, Nose and Throat (ENT) specialist experienced with ML diseases to determine which type of tube is best. Any elective surgery (even simple ear tubes) should take place in a tertiary care center equipped to handle complicated patients with rare diseases.

It is very hard when a child cannot express him or herself to know whether the crying is from pain or frustration. Children may have ear infections, toothache, aches and pains in their joints or feel discomfort from a full stomach. Do not hesitate to ask your doctor to check whether there is a physical reason for your child’s distress.

Palliative care is any form of medical care or treatment that concentrates on reducing the severity of disease symptoms. The goal is to prevent and relieve suffering and to improve quality of life for people facing serious, complex illness. This support encompasses aspects such as respite care, symptom management and bereavement support and many extend over a period of time. An assessment of medical need and a care plan can lead to support provided to the child and family so both can experience a better quality of life.

In ML II birth weight and length are often below normal. Clinical features of the disease are apparent at birth or in the first few months of life, including multiple joint contractures and kyphosis or scoliosis. In children with ML II, the neck is short, cheeks are often rosy, and the nose may be broad with a flattened bridge and upturned nostrils. The mouth may be wide, and children with ML II have very thickened gums. Eyebrows may be bushy and meet in the middle, and the eye sockets are usually shallow making the eyes appear prominent. Infants with ML II may have an unusual head shape, with prominence of the forehead. Some children with ML II may have fair skin, blonde hair and blue eyes, despite the colouring of their parents.

Photo of Zack. Joint stiffness is a common feature of ML II. Limitation of motion and joint stiffness can cause significant loss of function. Range-of-motion exercises (passive stretching and bending of the limbs) may offer some benefits in preserving joint function, and should be started early. Passive hydrotherapy is beneficial for the joints while minimizing painful impact. Exercises that cause pain should be avoided. Once significant limitation has occurred, increased range-of-motion may not be achieved, although further limitation may be minimized.

Individuals with ML II tend to have thickened and tough skin, sometimes making it difficult to draw blood or place intravenous catheters. Excess hair on the face and back occasionally occurs. Sweating and cold hands and feet are also occasional problems, and are possibly related to the heart, circulation, or other mechanisms that control temperature regulation. Periodic blue or cold hands or feet should be evaluated by a cardiologist to determine if a heart problem might be present. Skin sensitivity and increased sweating may cause decreased tolerance of heavy clothing or specific fabrics. Irritated areas or rashes should be monitored.

Caring for a severely affected child is hard work. Parents need a break to rest and enjoy activities, which may not be possible when their affected child is with them. Brothers and sisters also need their share of attention and need to be taken on outings that may not be feasible for their affected child. Many parents use some form of respite care or have someone come in regularly to help at busy times.