Referring Physicians

INFORMATION:

At the present time, patients may be referred for evaluation of:

  1. Glut-1 DS (glucose transporter type-1 deficiency syndrome)
  2. MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes)
  3. MERRF (mitochondrial encephalomyopahy with ragged-red fibers)
  4. Pyruvate dehydrogenase deficiency
  5. Pyruvate carboxylase deficiency
  6. Ion channel disorders
  7. Genetic and metabolic encephalopathies of unknown origin
  8. Genetic and metabolic myopathies of unknown origin

There may be fees associated with the evaluation.

Upon review of this information, if warranted, further documentation and blood samples of the patient and immediate relatives may be requested. None of the items received will be returned. Therefore, only copies should be provided.

A. GENERAL REFERRALS (EXCLUDING Glut-1 DS)

All referrals must be made using the following forms and signed by patients and/or parents and the referring physician. They should be sent via regular mail to the address listed below. Please read the form instructions and conditions carefully.

Download Physician Referral form (do not use for Glut-1 DS) [MS Word File | PDF File]


B. Glut-1 DS REFERRALS

Prior contact with us is required. No documents or samples will be accepted without our prior approval. Please call either the lab or one of the coordinators listed below before sending any information. After contact has been made and approval acquired, referrals may be sent via regular mail or electronically to the address listed below. Please read the forms instructions and conditions carefully.

Download Physician Referral form (Glut-1 DS only) [MS Word File | PDF File]


Contact Information:

Colleen Giblin Laboratories
Columbia University Medical Center
College of Physicians and Surgeons (P&S), Room 5-443
630 W. 168 Street
New York, NY 10032

Laboratory phone:

212-305-8245

Laboratory fax:

212-305-0431

Clinical Coordinator:

Kristin Engelstad
Phone: 212-305-6834 || Fax: 212-342-2893
E-mail: ke4@columbia.edu

Current Studies

MELTIMI (MELAS Trial of Idebenone using MRS)

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS)

Study Purpose:
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) is a multi-system disorder that can cause exercise intolerance, migraines, gastrointestinal issues, memory loss, seizures and strokes. MELAS is caused by a mutation in mitochondrial DNA. The most common mitochondrial mutation causing MELAS is the A3243G mutation. The purpose of this clinical trial is to determine whether a medication called Idebenone has an effect on brain lactate as measured by magnetic resonance spectroscopy (MRS). MRS is done in an MRI scanner, and is safe and typically well tolerated. An additional goal is to study the safety and tolerability of Idebenone in people with MELAS.

Idebenone:
Idebenone is thought to improve energy production in mitochondria, the powerhouses of the cell. It is also thought to defend against free radicals that can cause damage in mitochondrial disease. It has improved neurological function in other mitochondrial diseases such as Friedreich’s ataxia. The study drug is an experimental medication, and it is hoped that this trial will be a first step towards approval by the Food and Drug Administration (FDA), a prerequisite for making it available to patients in this country.

Study Type: Clinical Trial

Official Title: MELTIMI Study (Idebenone and MELAS)

Estimated Enrollment: 21

Study Start Date: May 2009

Eligibility:

Inclusion Criteria

  • Ages: 8 to 64 years old
  • Gender: male and female
  • Genetic requirement: carrier of A3243G mitochondrial DNA mutation
  • Body Weight: at least 82 pounds

Exclusion Criteria (not eligible to participate)

  • Unable to have MRS (choclear implant, inability to lie still for 45 minutes, etc)
  • Patient is pregnant
  • Use of Idebenone at any dose, or CoQ10 at more than 100mg/day within a 1 month period prior to baseline
  • Clinically significant laboratory abnormalities (study doctor will determine)
  • Use of other clinical trial investigational drugs within a 1 month period prior to baseline

Study Medication:

  • Participants will be randomized to one of two doses of Idebenone or to placebo ( a pill that looks like Idebenone but contains no Idebenone)
  • Participants will take the study medication (Idebeonone or placebo) for 1 month.
  • In other disease, Idebenone has been safe and well tolerated.

Time and Travel Commitment:

  • Take study medication for 1 month
  • Participants will travel to NYC 2-3 times over a period of 14 weeks for research visit
  • Reimbursement for transportation and hotel will be provided

Contacts and Locations:

Kris Engelstad, Study Coordinator
Phone: 1-212-305-6834
E-mail: ke4@columbia.edu; melas@columbia.edu
Location: Columbia University Medical Center
Clinical Research Center for Mitochondrial Disorders
The Neurological Institute
710 W. 168th St, Box 68
New York, NY 10032

Publications: Our publications regarding MELAS are located in the “Publications” section of this website.

» download consent form. This consent form is solely for information to help you decide whether you want to participate in the MELTIMI study. Should you choose to participate, you will be requested to sign and date a current consent form, which may be slightly different than the consent shown here.


MELAS

Natural History Study – Mitochondrial Encephalomyopathies Associated with MtDNA Point Mutations

Status:

Open for Enrollment

Mitochondrial and Mental Retardation: Investigations of Clinical Syndromes Associated with MtDNA Point Mutations

The Natural History Study is an ongoing study that involves participants that have point mutations in mitochondrial DNA (mtDNA). These mutations affect the genetic material contained in the mitochondria of the cell. Mitochondria, often called the “powerhouse” of the cell, are small structures within cells that provide the energy necessary to power growth and change over time. The purpose of this study is to better characterize mitochondrial disorders as they present over time in participants. Through this study we hope to determine whether mtDNA point mutations produce any measurable disturbances of thinking, attention, intelligence, behavior, or neurological functioning. Eligible participants must have a proven mitochondrial point mutation. Some or all participants may represent members of a single family because mtDNA point mutations are inherited from one’s mother. Fathers and other paternal family members may also be invited to participate as control subjects.

Subjects are asked to return to our center, usually on a yearly basis, for ongoing evaluation and comprehensive care.

Study Team:

Contact Kris Engelstad (ke4@columbia.edu)


GLUT-1

Natural History Study – Neuroglycopenia: Glut-1 Deficiency Syndrome (GLUT-1 DS)

Status:

Open for Enrollment

Neuroglycopenia, also known as GLUT-1 Deficiency Syndrome (Glut-1 DS), is a disorder that interferes with the functioning of glucose transport proteins. These proteins are responsible for transporting glucose into the brain from the blood. When these transport proteins are not working properly, decreased amounts of glucose are available to the brain. Because glucose is the primary essential fuel for the developing brain, inadequate supplies of it can result in physical and cognitive difficulties. The purpose of this study is to examine the nature of these difficulties. Through this study we hope to determine the types of DNA mutations that cause this disease, how the glucose transporters are affected, and how the brain responds to these mutations. We plan to do this by studying the brain’s electrical activity, structure, and function. In this study we will evaluate language skills, attention, behavior, and neurological functioning. Eligible participants in this study are suspected of having neuroglycopenia.

Subjects are asked to return to our center, usually on a yearly basis, for ongoing evaluation and comprehensive care.

Study Team:

Contact Kris Engelstad (ke4@columbia.edu)

Mitochondrial Disorders

What are Mitochondrial Disorders?

Mitochondria, often called the “powerhouses” of cells, are small structures within cells that provide the energy for all cellular activity. When mitochondria do not function properly they are unable to provide the necessary energy for the cell and disease can develop. Some of the most well known mitochondrial disorders are:

  1. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes);
  2. MERRF (Myoclonic Epilepsy Ragged Red Fibers);
  3. NARP (Neuropathy; Ataxia; Retinitis Pigmentosa);
  4. MNGIE (Myoneurogenic Gastrointestinal Encephalopathy);
  5. LHON (Leber’s Hereditary Optic Neuropathy);
  6. KSS- Kearns Sayre Syndrome; and
  7. Leigh’s Syndrome.

The most common symptoms of mitochondrial disorders are:

  1. muscle weakness,
  2. exercise intolerance,
  3. fatigue,
  4. cognitive difficulties, and
  5. neurological problems.

The primary reason for poorly functioning mitochondria is the presence of mitochondrial DNA (mtDNA) mutations. All cells, except for egg and sperm cells, have two copies of DNA, one inherited from the mother and one from the father. Mitochondria, however, have their own DNA, all inherited from the mother. When each mitochondrion divides to make two new mitochondria, the copies of DNA are divided randomly between the new mitochondria. If the DNA inherited from the mother is defective (i.e. carries a mutation), all or some of the DNA in the newly formed mitochondria may be defective, leading to mitochondria that may eventually function improperly.

Sometimes mutations in mitochondrial DNA (mtDNA) also occur spontaneously without anyone in the family having had one before, however most mutations begin with someone in a family and are commonly transmitted through the maternal lineage (maternal inheritance), as described above. As a result, these mutations can be found in several different individuals from many generations in one family. The child’s mother may or may not have symptoms, but if she carries a mitochondrial mutation it will be transmitted to all of her offspring. A father of a child can carry a mutation and also be affected by a disease but he will not carry the mutation to his children. It is difficult to estimate the population frequency of mitochondrial disorders, but reports have estimated the prevalence to be as high as 5.7 per 100,000 in the population over 14 years of age.

Types of Mitochondrial Disorders

Currently there are several known and established mitochondrial disorders. Scientists continue to discover new mutations in the mitochondrial DNA with the goal of characterizing unique disorders resulting from these mutations.

A description of the most well known mitochondrial disorders is below:

  1. MELAS- Mitochondrial Encephalopathy Lactic Acidosis and Stroke Like Episodes:

    MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a disorder that affects several body systems and usually has its onset in childhood. It is characterized by a progressive encephalopathy and stroke-like episodes leading to disability. MELAS is caused by a genetic mutation and has been associated with at least 6 different point mutations on mitochondrial DNA (mt DNA). The most common mutation for MELAS is an A-to-G switch at nucleotide 3243 in the strand of mitochondrial DNA. Clinical symptoms are determined by various factors including the amount (percentage) of point mutations in each organ (including the brain).

    In individuals affected by MELAS, early psychomotor development, involving physical and mental processes, is usually normal, but short stature is common. The first onset of symptoms is frequently between the ages of two and ten years. Common initial symptoms include seizures, recurrent headaches, lack of appetite (anorexia), and recurrent vomiting. Inability to exercise and limb weakness can also be early signs of MELAS. Seizures are often associated with stroke-like episodes of weakness on one side of the body that may come and go over time or cortical blindness. These stroke-like episodes may be associated with altered consciousness and may be recurrent. The combined effects of the stroke-like episodes may gradually impair motor abilities, vision, and mental functioning, often by adolescence or young adulthood. Sensorineural hearing loss is common. People affected by MELAS typically also show elevated levels of lactic acid (lactic acidosis) in the blood.

  2. MERRF- (Myoclonic Epilepsy Ragged Red Fibers):

    MERFF is characterized by myoclonus (twitching or spasms of muscle); epilepsy (seizure disorder); cerebellar dysfunction displayed as ataxia (defective muscle coordination) and gait (walking) disorder; dementia (memory problems); and optic atrophy (the loss of some or most of the fibers of the optic nerve). Also common is polyneuropathy (disorder of the peripheral nerves) causing distal sensory loss; hearing loss; and myopathy (muscle problems). Weakness is usually proximal (closest to the center of the body) and affected people may experience muscle pain either while resting or during exercise, cramps, and fatigue. Short stature and lipomata (fatty tumors) also occur in about 10% of people with MERRF.

  3. NARP (Neuropathy; Ataxia; Retinitis Pigmentosa):

    NARP is a disorder characterized by proximal and distal weakness (closest and farthest from the center of the body); sensory neuropathy (nerve disease) resulting in reduced vibration; reduced tendon reflexes, particularly at the ankle; and retinitis pigmentosa (a condition characterized by widespread pigmentary changes in the retina) resulting in reduced night vision. Other features of NARP include dementia (memory problems), seizures (common in early onset, tonic-clonic later), developmental delay, and dystonia (impaired muscle tone).

  4. MNGIE (Myoneurogenic Gastrointestinal Encephalopathy):

    MNGIE typically appears during the second through fifth decades of life and is a multisystem disorder causing visceral neuropathy characterized by diarrhea, constipation, and/or gastroparesis resulting in nausea, vomiting, weight loss, and malabsorption (inadequate absorption of nutrients from the intestinal tract). Many people also experience Borborygmi (rumbling in the stomach), feel full quickly when eating, and may have diverticulitis (pain caused by pouches formed in the colon). Ocular symptoms include ophthalmoplegia (paralysis of eye muscles), ptosis (drooping eyelids) and degeneration of the retina. Thin appearance and ongoing weight loss are clinical features of MNGIE, as is short stature and neuropathy (disease of the nerve). Pain may be experienced, along with progressive weakness and lack of reflexes. Hearing loss is also common, as is leukoencephalopathy (destruction of nerve fiber covering). Normal intelligence is common with MNGIE; dementia (memory problems) does not occur.

  5. LHON (Leber’s Hereditary Optic Neuropathy):

    Leber’s hereditary optic neuropathy (LHON) is a condition that affects predominantly young adult males and involves the degeneration of retinal ganglion cells (RGCs) and their axons within the retina of the eye that leads to an acute loss of central vision. LHON is usually due to one of three disease causing mitochondrial DNA (mtDNA) point mutations.

    People with LHON experience an acute onset of visual loss, generally first in one eye and then a few weeks later in the other. This eventually evolves to very severe optic atrophy (the loss of some or most of the fibers of the opticnerve) and permanent decrease of visual acuity. In the acute stage, which may last a few weeks, the affected eye demonstrates an edematous (swollen) appearance of the nerve fiber layer, which can be seen on an eye examination, just before or after the onset of visual loss. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma (area of visual loss surrounded by area of well preserved vision).

  6. KSS- Kearns Sayre Syndrome:

    Kearns-Sayre syndrome (KSS) is a rare neuromuscular disorder with onset usually before the age of 20. It is the result of abnormalities in the DNA of mitochondria – small rod-like structures found in every cell of the body that produce the energy that drives cellular functions. The mitochondrial diseases correlate with specific DNA mutations that cause problems with many of the organs and tissues in the body. KSS is characterized by progressive limitation of eye movements until there is complete immobility, accompanied by eyelid droop (ptosis). It is also associated with abnormal accumulation of pigmented material on the membrane lining the eyes. Additional symptoms may include mild skeletal muscle weakness, heart block (a cardiac conduction defect), short stature, hearing loss, an inability to coordinate voluntary movements (ataxia), impaired cognitive function, and diabetes. Seizures are infrequent. Several endocrine disorders can also be associated with KSS.

  7. Leigh’s Syndrome

    Leigh’s syndrome usually has its onset during the first year of life, but can occur later. It is characterized by hypotonia (low tone) and episodes of vomiting, ataxia, choreoarthetosis, hyperventilations, encephalopathy associated with loss of verbal milestones, spasticity, abnormal breathing rhythm, and hearing loss, ataxia, systagmus, dystonia, visual loss, peripheral neuropathy. Signs and symptoms may manifest with stress such as an intercurrent infection and carbohydrate intolerance. Motor and intellectual regression occurs.

Diagnosis:

The evaluation of a patient for mitochondrial disease can encompass several tests. The standard set of examinations used in most cases include the following:

  1. Neurological History and Examination
  2. Medical and family history – including pedigree analysis
  3. Tissue sample for mitochondrial DNA analysis
  4. Muscle biopsy
  5. General and specialized blood tests
  6. Other diagnostic tests, as indicated

Tissue samples can be sent to Columbia University for mitochondrial DNA analysis.

Please Contact

The Houston Merritt Clinical Research Laboratory [http://www.columbiamitodiagnostics.org]
Tel: 1-212-305-3947
Fax: 212-305-3986

Current Clinical Studies: