Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

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

Summary: Background:
  - Spinal and bulbar muscular atrophy (SBMA) is an inherited disease. It causes weakness in muscles used for swallowing, breathing, and speaking. SBMA mainly affects men, but women can carry the gene for it. Researchers think there may be a link between SBMA and excess fat in the liver.
  Objective:
  - To look for fatty liver and liver injury in people with SBMA, people with motor neuron disease, and people who carry the gene for SBMA.
  Eligibility:
  -  Adults 18 years and older who have SBMA, have motor neuron disease, or are carriers of SBMA.
  -  Healthy adult volunteers.
  Design:
  -  Participants will be screened with medical history, physical exam, and blood tests.
  -  Participants will have 1 outpatient visit of 1-2 days. Women will have a urine pregnancy test. All participants will have:
  -  Blood tests.
  -  Liver ultrasound. A probe is placed on the abdomen at certain locations and angles and takes pictures. The painless procedure takes 20-30 minutes.
  -  Liver magnetic resonance imaging (MRI) scan. The MRI scanner is a metal cylinder with a magnetic field. Participants will lie on a table that slides in and out of it. They will be in the scanner for about 30 minutes. They will get earplugs for loud noises.
  -  Some participants with abnormal liver testing will have a biopsy (small piece) of the liver taken. The biopsy site will be located with ultrasound, then cleaned and numbed. The physician will quickly pass a needle in and out of the liver while the participants holds their breath. Afterward, participants will be monitored in bed for 6 hours.
  -  Participants may return for follow-up and another 1-2 day outpatient visit yearly for up to 2 years.

Detailed description: 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.

Eligibility: -  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.

Relevance to patient case: not relevant