NORD gratefully acknowledges Xenia Chepa-Lotrea, National Institutes of Health, National Human Genome Research Institute, MD candidate at Georgetown University School of Medicine, and Robert B Hufnagel, MD, PhD, National Institutes of Health, National Eye Institute, Ophthalmic Genetics and Visual Function Branch, for assistance in the preparation of this report.
Laurence-Moon syndrome (LNMS) is a genetic condition that results in a complex association of problems that affect several different body parts. People with LNMS may have difficulties with functions of the brain, eyes, ears, stomach, kidneys, hands and feet. They often also demonstrate a tendency to short stature and obesity. Because of the many complications seen in this condition, it is important that the patient has a strong, comprehensive health care team.
LNMS was later termed Laurence-Moon-Bardet-Biedl syndrome because of similarities with Bardet-Biedl syndrome (BBS). It is often considered, but still debated, whether BBS is a distinct condition. Arguments are based on differences in the underlying genetic causes of these the disorders (see Related Disorders). These two disorders also share similarity to Oliver-McFarlane syndrome (OMS). All three conditions are characterized by progressive blindness, obesity, and learning disabilities.
Differences in the clinical presentation include subtle but important hints as offered in the following examples. LNMS is associated with difficulty in controlling body movements, which is also seen in adolescent and adult patients with OMS and less frequently in BBS. LNMS and OMS are associated with abnormal pituitary gland function. BBS is associated with extra fingers and toes, and kidney and liver dysfunction. OMS is associated with abnormal growth of eyelashes and eyebrows. Neither LNMS nor BBS are generally associated with such difficulty.
Of important note to patients and physicians, the practical management of these conditions is similar. These conditions are all managed with close attention to each individual patient’s symptoms. This contributes to the ability to group LNMS, BBS, and OMS together in clinical settings. For the purposes of the description of these entities by what is known of their genetic cause, we have drawn stricter differentiating lines between them and offer distinct articles on each related disorder.
The major signs that people present with which raise the suspicion that they may have LNMS are summarized below. The individual components of this condition can notably vary greatly in severity however.
Physicians may begin to investigate the diagnosis of a genetic condition when they identify structural abnormalities of the hands and feet. Abnormalities commonly include both too many and too few fingers or toes. Between LMS and BBS, it is the people with BBS that are born with an extra digit near the pinky or an extra toe near the fifth “little” toe. In medical terminology, this is described as a ‘postaxial polydactyly’. Interestingly, the presence of an extra toe is more common than that of an extra finger. In patients with LNMS, fingers and toes may however have some degree of webbing, which is referred to as “syndactyly”. Syndactyly is especially common between the second and third toes. Less often, fingers and toes may be abnormally short in length. This finding is called a “brachydactyly” and can be especially expected to affect the thumb. The thumb may additionally be placed subtly closer to the wrist than expected. Finally, the feet may also be overall short in length, of wide width, and carry a flat arch.
In regard to additional skeletal changes, patients with LNMS may notice or be told that they have some slight changes in the basic shape of their teeth. Teeth are made up of two major segments, the body and roots. Patients with LNMS may experience taurodontism, in which the development of tooth’s body is enlarged relative to the roots. Most commonly, it is the flat, molar teeth at the back of the mouth that are affected. Most commonly, this condition is noted at the time of first dental x-rays, where the teeth will appear more rectangular than expected.
People with LNMS are also often burdened by problems with the coordination of their body’s movements. Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult. Such impairment is specifically the result of problems with the cerebellum, the sub-section of the brain responsible for coordination. The dysfunction of the cerebellum can lead to dysfunction of the spinal nerve conduction pathways that communicate signals between the brain and muscles. This results in a complex constellation of movement irregularities. The term ataxia is used to describe this loss of control over coordinated bodily movements, and can make it difficult to speak, eat, walk, and maintain balance. Ataxia is accompanied by spasticity, a continuous contraction of muscles in an involuntary manner. The term contracture is used to describe a hardening and shortening of muscles and surrounding connective tissue.
People with LNMS also often experience other problems related to functions controlled by the brain.
Most patients with LNMS will experience a gradual loss of vision. The term “retinitis pigmentosa” is used to describe the particular, gradual-onset, vision loss that progresses according to a particular pattern. Retinitis pigmentosa begins with a night blindness that worsens with a loss of the ability to distinguish colors from one another, finally deteriorating into “tunnel vision”. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database).
Mild-to-moderate learning difficulties are common in individuals with LNMS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with LNMS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (such as delayed speech or reading skills) are not due to underlying visual impairment. If the learning disability is rooted in neurological impairments, they are often associated with symptoms of poor coordination, gross and fine motor skills, and social milestones in childhood such as inability to play complicated games with other children.
People living with LNMS have been found to have smaller than average size anterior pituitary glands and can suffer from a series of different complications as a result. The anterior portion of the pituitary gland is responsible for regulating many functions including the body’s metabolism, emotional responses to stressors, physical bodily growth, and reproductive capacity. The body’s metabolism is controlled by thyroid stimulating hormone. With low levels of thyroid stimulating hormone, people will experience many different symptoms: fatigue, sensitivity to cold, poor ability to concentrate, weight gain, constipation, shortness of breath. The body will potentially change its common behaviors. For example, skin will become dry and course, hair will fall out, reflexes will slow.
People with LNMS often have decreased levels of the sex hormones estrogen and testosterone. This is also due to the small size of the pituitary gland, a small gland located in the brain that is responsible for producing the chemical signals that orchestrate the production of sex hormones. As a result of a weak signal to produce estrogen and testosterone, the reproductive organs of both men and women living with LNMS may be underdeveloped, resulting in reduced fertility or even infertility. Males with LNMS may have an underdeveloped set of testicles that may be undescended. In females, the uterus, fallopian tubes, and ovaries are often underdeveloped. Menstruation cycles can be delayed from the average first age of onset and when they do begin, may follow an irregular cycle.
Other less common features that have been reported in patients living with LNMS include a skull shape shorter than average, termed “brachycephaly” and electrical abnormalities of the heart. (For more information, choose “congenital heart block” as your search term in the Rare Disease Database). People may also experience a loss of hearing, increased incidence of diabetes, liver fibrosis, and urinary and genital structural malformations.
LNMS is most commonly attributed to changes (mutations) in the PNPLA6 gene. Genes are specific sequences in DNA that provide instructions for the production of proteins. Proteins serve as the body’s cellular machinery and building blocks. The PNPLA6 gene is responsible for the production of proteins that drive the breakdown of cell membranes. The PNPLA6 protein is an enzyme that is thought to drive the growth of nerve and non-nerve cells as they grow and mature. This gene is notably associated not only with LNMS but also Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, and spastic paraplegia type 39. These conditions are described in brief under the Related Disorders section.
LNMS follows an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Males and females are affected equally. In North America, it is estimated that 1 in 100,000 people is affected by LNMS. Kuwait and Newfoundland are two places where the number of people affects with LNMS are comparatively high.
Due to its highly variable clinical presentation of the condition, no formal diagnostic criteria have been established for LMS or, for that matter, any PNPLA6-related disorders. LMS is definitively diagnosed with molecular testing for mutations in the PNPLA6 gene.
The treatments available for LNMS are oriented towards managing the manifestations of the illness.
People with LNMS often experience ataxia, spasticity, and contracture that compromise their ability to move comfortably. Physical therapy aimed towards improving strength and agility is key. Often walking can be assisted by tools such as ankle-foot orthotic braces, weight-bearing walkers, etc. Physical exercise can reduce the symptoms of ataxia, spasticity, and prevent contracture. A dedicated regimen of nutritious, well-balanced meals and regular exercise is recommended to avoid some of the less common but equally severe aspects that have been noted to affect patients with LNMS. There is most notably, an increased incidence of diabetes and abnormal cholesterol levels in patients with LNMS.
The poor functional capacity of the anterior pituitary gland that results in slowed metabolism, poor growth, and impaired fertility can be managed with hormone replacement therapies. Levothyroxine is a medication that mimics the functions of the thyroid hormone and can aid in speeding up the metabolism of the body, resulting in reduced symptoms of lethargy, hair loss, and obesity. Growth hormone supplementation can be offered to reduce the burden of short stature in patients identified as children.
It is important for patients with LNMS to be under the care of an ophthalmologist. There is no cure for the vision problems that accompanies LNMS, but ophthalmologists can help create corrective lenses against developing problems. Individuals with LNMS should undergo regular ophthalmologic examinations and keep up with their changing prescriptions. Since visual impairment is a major hurdle to learning in the classroom, special services might be organized on an individual basis between a child’s physician and their school.
For patients living with LNMS, it is important to recognize that the many difficulties described above are associated with the brain’s neurological function. It is thus important to protect baseline function capacity of the brain. Inactivity and obesity exacerbate neuropathy. Alcohol and recreational drugs should be avoided.
Generally, very little information exists to guide women living with rare diseases who are interested in becoming pregnant. Pregnancy is well known to take many physical demands on a woman’s body and women who are living with LNMS are generally warned that symptoms of ataxia may worsen or even develop for the first time during pregnancy. Pregnant women with LNMS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.
Patients living with LNMS experience alterations to the shape of their teeth. Taurodontism is generally noted at the dental office at the time of first x-rays. Extra care may be needed in brushing and cleaning all aspects of the affected teeth, and dentists may need special tools to examine all aspects of the affected teeth.
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