Study of Hepatic Function in Patients With Spinal and Bulbar Muscular Atrophy

Objectives:

Spinal and bulbar muscular atrophy (SBMA), or Kennedy s disease, is a slowly progressive
hereditary motor neuron disease for which there is currently no effective treatment. Whether
the liver is affected in SBMA is unclear. Preliminary analysis in SBMA patients has shown
changes including increased hepatic fat, which requires additional investigation. Female
carriers and patients with motor neuron disease will also participate in the study to
evaluate for liver fat and function via imaging and laboratory tests.

Study Population:

We plan to enroll 15 men with genetically confirmed SBMA, 15 age-matched healthy control men,
15 SBMA carrier women, 15 age-matched healthy control women and 15 males with other motor
neuron disease patients as disease controls. As of September 2017, recruitment is complete
for men with genetically confirmed SBMA (n=15 recruited), age-matched healthy control men
(n=15 recruited), SBMA carrier women (n=14 recruited), and 15 age-matched healthy control
women (n=14 recruited). Recruitment of motor neuron disease subjects as disease controls for
the study began in April 2018 and is ongoing. Our goal is to recruit 12 more disease control
subjects.

Design:

Subjects will complete liver evaluations at the NIH that may include blood work, liver MRI
imaging with spectroscopy (MRS), ultrasound, and biopsy. Liver biopsy will be performed on a
subset of subjects with SBMA only, who have a clinical indication for biopsy analysis. Liver
tissue will be analyzed by the NIH Clinical Center Pathology Department, and additional
studies will be done in the research laboratory at NIH. Patients may undergo repeated
non-invasive testing to determine if the liver findings are changing over time. An evaluation
of muscle fat by MRI spectroscopy will be done with a subset of up to 10 subjects receiving
the liver studies.

Outcome measures:

Subjects will be assessed using several different types of measurements including blood work
for fatty metabolism, muscle function, and hepatic function. Liver biopsies will be used to
determine the pattern and degree of fatty infiltration in SBMA patients. Liver and muscle
imaging will be used to detect fat. Ultrasound elastography will be used to assess the extent
of fibrosis and loss of elasticity in the liver.

- INCLUSION CRITERIA:

The study population will consist of several subgroups of patients. An individual must meet
one of the following subgroup inclusion criteria to participate in this study.

SBMA subgroup:

1. Male

2. Genetically confirmed SBMA

3. Able to travel to the NIH

4. Greater than 18 years old

SBMA carriers:

1. Female

2. Genetically confirmed SBMA heterozygote

3. Able to travel to the NIH

4. Greater than 18 years old

Other motor neuron disease patients:

1. Diagnosis of motor neuron disease other than SBMA (e.g.. amyotrophic lateral sclerosis
(ALS), spinal muscular atrophy)

2. Able to travel to the NIH

3. Greater than 18 years old

4. . Male

Healthy male control:

1. Male

2. No history or diagnosis of liver disease

3. No history of SBMA or other motor neuron disease

4. Greater than 18 years old

5. No diagnosis of diabetes or insulin resistance

6. No history of alcohol abuse within the last 1 year

7. No history of hyperlipidemia (LDL < 195) or hypertriglyceridemia (TAG < 225)

Healthy female control:

1. Female

2. No history or diagnosis of liver disease

3. No history of SBMA or other motor neuron disease

4. Greater than 18 years old

5. No diagnosis of diabetes or insulin resistance

6. No history of alcohol abuse within the last 1 year

7. No history of hyperlipidemia (LDL < 195) or hypertriglyceridemia (TAG < 225)

EXCLUSION CRITERIA:

- Diagnosed with an acquired or inherited liver disease eg., hepatitis B, hepatitis C,
HIV, autoimmune hepatitis, cholestatic liver disease, Wilson s disease, iron overload
disease, alpha-1 antitrypsin deficiency, hepatocellular carcinoma, (hepatic neoplasm
or metastasis, etc.) or injury except for fatty liver disease.

- Contraindications to MRI such as a contraindicated non-removable metal device (i.e.
pacemaker, defibrillator, insulin pump, metal clips, non-removable jewelry) or
claustrophobia.

- Currently pregnant or pregnant within the past 6 months. Pregnant women are excluded
from the study because of the known associated abnormalities in liver function that
can occur in this population. The long term effects of MRI on the developing fetus are
unknown and would present a risk with participation.

In addition to the above criteria, the patients receiving a liver biopsy will need to meet
the additional exclusion criteria below:

- Coagulopathy (PT/PTT values that are prolonged >= 3 seconds from the upper limit of
normal, including treatment with oral and parenteral anticoagulants), thrombocytopenia
(< 70,000), abnormal bleeding time or platelet dysfunction.

- Taking anti-platelet agents for cardiovascular protection that cannot be safely
stopped for the performance of the liver biopsy.

- Obesity, which is defined as a BMI>30 at the screenig visit.