Boucher-Neuhäuser syndrome is a rare disorder that affects movement, vision, and sexual development. It is part of a continuous spectrum of neurological conditions, known as PNPLA6-related disorders, that share a genetic cause and have a combination of overlapping features. Boucher-Neuhäuser syndrome is characterized by three specific features: ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy.

Ataxia describes difficulty with coordination and balance. In Boucher-Neuhäuser syndrome, it arises from a loss of cells (atrophy) in the part of the brain involved in coordinating movements (the cerebellum). Affected individuals have an unsteady walking style (gait) and frequent falls.

Another key feature of Boucher-Neuhäuser syndrome is hypogonadotropic hypogonadism, which is a condition affecting the production of hormones that direct sexual development. Affected individuals have a delay in development of the typical signs of puberty, such as the growth of facial hair and deepening of the voice in males, and the start of monthly periods (menstruation) and breast development in females. Other hormone abnormalities lead to short stature in some affected individuals.

The third characteristic feature of Boucher-Neuhäuser syndrome is eye abnormalities, most commonly chorioretinal dystrophy. Chorioretinal dystrophy refers to problems with the light-sensitive tissue that lines the back of the eye (the retina) and a nearby tissue layer called the choroid. These eye abnormalities lead to impaired vision. People with Boucher-Neuhäuser syndrome can also have abnormal eye movements, including involuntary side-to-side movements of the eyes (nystagmus).

The key features of Boucher-Neuhäuser syndrome can begin anytime from infancy to adulthood, although at least one feature usually occurs by adolescence. Ataxia is often the initial symptom of the disorder, but vision problems or delayed puberty can be the earliest finding. Vision and movement problems worsen slowly throughout life and can result in blindness or the need for a wheelchair for mobility in the most severely affected individuals.

People with Boucher-Neuhäuser syndrome can have additional medical problems, including muscle stiffness (spasticity); impaired speech (dysarthria); and difficulty processing, learning, or remembering information (cognitive impairment).

Most cases of Boucher-Neuhäuser syndrome are caused by mutations in the PNPLA6 gene. Such mutations are the only known cause of the condition. Researchers speculate that as-yet-unidentified mutations in the PNPLA6 gene or changes in other genes are involved in the remainder of cases.

The PNPLA6 gene provides instructions for making a protein called neuropathy target esterase (NTE), which helps regulate the amount of certain fats (lipids) that make up the outer membrane surrounding cells. The correct levels of these lipids are critical to the stability and function of cell membranes. In particular, the NTE protein breaks down (metabolizes) a lipid called lysophosphatidylcholine, which in high amounts can damage cells. NTE is found most abundantly in the nervous system and is thought to help maintain the stability of membranes surrounding nerve cells (neurons). NTE is also thought to play a role in the release of hormones from the pituitary gland, a process that requires particular changes in the cell membrane. The pituitary gland is located at the base of the brain and produces several hormones, including those that help direct sexual development and growth.

PNPLA6 gene mutations are thought to impair NTE's function. However, it is unclear how these mutations cause Boucher-Neuhäuser syndrome. Researchers speculate that impairment of lysophosphatidylcholine metabolism alters the balance of lipids in the cell membrane. This imbalance may damage neurons, leading to the movement and vision problems that characterize Boucher-Neuhäuser syndrome. The imbalance may also impair the release of hormones involved in sexual development, accounting for the delayed puberty in affected individuals.

Researchers are unsure how mutations in the PNPLA6 gene lead to different combinations of features, resulting in the spectrum of PNPLA6-related disorders.

Normal Function

The PNPLA6 gene provides instructions for making a protein called neuropathy target esterase (NTE). The NTE protein is involved in the breakdown of certain fats (lipids). Specifically, NTE breaks down a lipid called lysophosphatidylcholine, which is one of several compounds found in the outer membranes surrounding cells. The correct levels of these compounds are critical to the stability of the cell membranes.

The NTE protein is found most abundantly in the nervous system. It plays an important role in maintaining the stability of the membranes surrounding nerve cells (neurons) and of these cells' specialized extensions, called axons, that transmit nerve impulses. NTE may also play a role in the release of hormones from the pituitary gland, a process that requires particular changes in the cell membrane and appears to involve the lipids found there. The pituitary gland is located at the base of the brain and produces several hormones, including those that help direct sexual development and growth.

Health Conditions Related to Genetic Changes

Boucher-Neuhäuser syndrome

More than a dozen mutations in the PNPLA6 gene have been found to cause Boucher-Neuhäuser syndrome, a disorder characterized by coordination and balance problems (ataxia), vision impairment, and delayed puberty. The mutations are thought to impair the function of the NTE protein. Researchers are unsure how such a reduction in function leads to the signs and symptoms of the condition. They speculate that impairment of lysophosphatidylcholine metabolism alters the balance of compounds in the cell membrane. This imbalance may damage axons, leading to the movement and vision problems that characterize Boucher-Neuhäuser syndrome. The imbalance is also thought to impair the release of hormones involved in sexual development, accounting for the delayed puberty in affected individuals.

Gordon Holmes syndrome

At least six mutations in the PNPLA6 gene cause Gordon Holmes syndrome, a rare condition characterized by ataxia and reduced production of hormones that direct sexual development (hypogonadotropic hypogonadism), which leads to delayed or absent puberty or other reproductive problems. As in Boucher-Neuhäuser syndrome (described above), the mutations that cause Gordon Holmes syndrome impair the function of the NTE protein, which researchers suspect disrupts the levels of lysophosphatidylcholine in cell membranes. The resulting imbalance of compounds in cell membranes is thought to damage neurons in the brain, causing ataxia, and impair the pituitary gland's release of hormones involved in sexual development, leading to hypogonadotropic hypogonadism. It is unclear how mutations in the same gene cause different combinations of features.

Other disorders

Mutations in the PNPLA6 gene cause a continuous spectrum of neurological conditions called PNPLA6-related disorders. Conditions in this group include Boucher-Neuhäuser syndrome (described above), Gordon Holmes syndrome (described above), Oliver-McFarlane syndrome, Laurence-Moon syndrome, and spastic paraplegia type 39. PNPLA6-related disorders feature combinations of overlapping signs and symptoms, including ataxia, muscle stiffness (spasticity), abnormally fast (brisk) reflexes, reduced sensation in the extremities (peripheral neuropathy), intellectual disability or other cognitive problems, eye abnormalities, impaired vision, hair abnormalities, hypogonadotropic hypogonadism, and reduced function of the pituitary gland (hypopituitarism). It is unknown how mutations in a single gene cause such a wide range of disorders.

Other Names for This Gene

• BNHS
• iPLA2delta
• LNMS
• NTE
• NTEMND
• OMCS
• patatin-like phospholipase domain-containing protein 6
• SPG39
• sws

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Boucher-Neuhäuser syndrome is a rare condition. Its prevalence is unknown.