Boucher-Neuhäuser syndrome

Alternate Names

Chorioretinal dystrophy, spinocerebellar ataxia and hypogonadotropic hypogonadism; Boucher-Neuhäuser syndrome; Ataxia-hypogonadism-choroidal dystrophy syndrome

Definition

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.

Epidemiology

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

Cause

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.

Genetics

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.

Gene mutation

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

Boucher-Neuhäuser syndrome is characterized by three specific features: ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy.

Ataxia

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.

Hypogonadotropic hypogonadism

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.

Eye abnormalities

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).

Onset

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.

Other medical problems

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).

Diagnosis

The diagnosis of a PNPLA6-related disorder is suspected on clinical and neuroimaging findings and confirmed by identification of biallelic pathogenic variants in PNPLA6.

Treatment

Management is symptomatic and individually tailored.

Ataxia: continuous training of speech and swallowing, fine-motor skills, gait, and balance Spasticity: interventions to improving strength and agility such as exercises, assistive walking devices and/or ankle-foot orthotics, drugs to reduce muscle spasticity Chorioretinal dystrophy: low vision aids when central acuity is reduced; involvement with agencies for the visually impaired re vocational training, mobility training, and skills for independent living Hypothyroidism: hormone replacement therapy as soon as identified Growth hormone deficiency: hormone replacement therapy during childhood and/or adolescence as indicated Hypogonadotropic hypogonadism: hormone replacement therapy at the expected time of puberty Prevention of secondary complications: A daily regimen of physical therapy to maintain and improve coordination, muscle strength, and gait; to reduce spasticity; and to prevent contractures.

NIH genetic and rare disease info

• NIH info on Boucher-Neuhäuser syndrome

Boucher-Neuhäuser syndrome is a rare disease.

Boucher-Neuhäuser syndrome Resources
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