Is one of the NBIA disorders caused by a mutation in the DCAF17 gene and characterized by both neurologic and endocrine symptoms.
The first symptoms of Woodhouse-Sakati syndrome are typically found in individuals ranging from age 10 to the early 20s.
It has been described in patients from Middle East, Europe, North Africa, India and Pakistan. A founder mutation accounts for the cases in the Middle Eastern population.
SYMPTOMS
The first symptoms appears typically at age 10 to the early 20s.
Common symptoms
- Dystonia with extrapyramidal signs (involuntary muscle contraction and spasms, unusual and sometimes painful movements positions), may be generalized or focal (located in one location)
- Choreoathetosis, involuntary, rapid, jerky movements) occurring in association with athetosis (relatively slow, sinuous, writhing motions)
- Impaired gait (difficulty with walking)
- Scoliosis (curvature of the spine to the side)
- Dysarthria (speech problems), Difficulty using or controlling the muscles of the mouth, tongue, larynx or vocal cords which are used to make speech. This can make a person’s speech difficult to understand in several different ways, including stuttering, poor articulation and slurring, or soft or raspy speech
- Dysphagia (difficulty swallowing)
- Hypogonadism (underdeveloped testes or ovaries), often results in delayed puberty, causes low estradiol or testosterone levels
- Alopecia (hair loss)
- Diabetes mellitus, causes individuals to have a high level of sugar in their blood, blood tests show low serum insulin levels
- Sensorineural deafness, hearing loss caused by a problem with cranial (brain) nerve VIII, the inner ear or the central processing centers of the brain
- Cognitive decline (mental and intellectual deficit)
Diagnosis
It is a multisystemic disorder.
There may be various craniofacial abnormalities such as a high forehead, flat occiput, triangular face, prominent nasal root, hypertelorism which is an abnormally increased distance between the eyes, and down-slanting palpebral fissures.
Hyperreflexia (overactive or over responsive reflexes), and camptodactyly which involves the fixed flexion deformity of the interphalangeal joints of the little finger are also seen.
Also seen are flattened T waves on an ECG, seizures, sensory polyneuropathy,
MRI findings for Woodhouse-Sakati
- Hypointensity (darkness) in T2 MRI in the globus pallidus and substantia nigra, The dark patches indicate iron accumulation are seen only seen in some cases
- Confluent hyperintensities (bright patches that run together) in the white matter
- Blood test low insulin growth factor-1level
Diagnosis of Woodhouse-Sakati syndrome is confirmed through genetic testing of the DCAF17 gene to find two gene changes. Genetic testing begins with sequence analysis, and if no gene changes are found, then it continues on to deletion/duplication analysis.
Very rarely, an individual with the signs and symptoms of Woodhouse-Sakati syndrome will have only one or even no DCAF17 gene changes identified. In these cases it becomes very important to have doctors experienced with Woodhouse-Sakati syndrome review the MRI and the person’s symptoms very carefully to be as sure as possible of the diagnosis.
TREATMENT
There is no standard treatment for Woodhouse-Sakati. A team of medical professionals can recommends treatments based on current symptoms.
The extent of their disease can be determined by
- Blood work to check for signs of diabetes, levels of insulin and HbA1c
- Neurologic evaluation of ambulation (walking) and speech
- Assessment for physical therapy, occupational therapy, and/or speech therapy
- Developmental assessment
- Medical genetics consultation
Therapies to manage dystonia
- Botulinum toxin or Botox is injected intramuscularly in spastic, dystonic muscles to help them relax for a period of time
- Artane (trihexyphenidyl), taken orally, usually divided into multiple doses each day
- Baclofen (oral or intrathecal) usually first taken orally and divided into several doses each day. In the intrathecal method, an implanted baclofen pump delivers medication directly into the spinal fluid
- Deep brain stimulation, a stimulator sends electrical impulses to the affected brain region to help muscles relax. It involves surgical implantation of a lead, extension and battery pack (IPG). The lead contains 4 electrodes and is implanted in the globus pallidus region of the brain. The extension connects the lead to the battery pack (IPG). The IPG is a battery-powered neurostimulator that is placed in the abdomen (or in some cases below the clavicle)
- Physical and occupational therapy, may or may not be indicated for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful
Long-term surveillance for Woodhouse-Sakati
- Annual glucose tolerance test to check for signs of diabetes
- Nutrition, monitoring of height and weight in children. Evaluation of swallowing difficulties due to head and neck dystonia. Nutritional supplements and gastric (tube) feeding (if needed)
- Regular assessments of ambulation and speech abilities
PROGRESSION
In most individuals, the first symptoms of Woodhouse-Sakati syndrome appear in adolescence.
The average lifespan varies for individuals with Woodhouse-Sakati syndrome, but due to improvements in medical care, more affected individuals are now living well into adulthood.
Cause
The altered DCAF17 gene inherited in an autosomal recessive manner is the cause Woodhouse-Sakati. “Autosomal” refers to the fact that the DCAF17 gene is located on chromosome 2, which is one of the autosomes (chromosome pairs 1-22). “Recessive” refers to the fact that a mutation must be present in both copies of the DCAF17 gene for a person to have Woodhouse-Sakati syndrome.
When both parents are carriers (having a copy of an altered gene),there is a 25% chance to have a child having Woodhouse-Sakati and 50% chance that the child will be a carrier like his/her parents and a 25% chance that the child will not have Woodhouse-Sakati or be a carrier.
Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.
Prenatal Test
If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.
Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.