Rare Diseases Are Not So Rare in Neurology

PHILADELPHIA—In neurology, rare diseases are not so rare. In fact, they are pretty common. “Essentially every patient who comes to see me in my office has a rare disease,” said Darryl C. De Vivo, MD, in his presidential plenary lecture on rare diseases and neurologic phenotypes at the 66th Annual Meeting of the American Academy of Neurology.

Dr. De Vivo is the Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director Emeritus of the Pediatric Neurology Service at the Columbia University Medical Center in New York City. He is also the Associate Chairman for Pediatric Neurosciences and Developmental Neurobiology, the Founding Director of the Colleen Giblin Research Laboratories for Pediatric Neurology at the Columbia University Medical Center, and the Codirector of the Center for Motor Neuron Biology and Disease.

Rare Diseases—The Basics
Dr. De Vivo outlined some basic facts and statistics regarding rare diseases. “Obviously, each rare disease is rare, by definition, but collectively, they are common.” Rare diseases are generally inherited as recessive traits, and most have a neurologic phenotype. A rare disease, as defined by the Orphan Drug Act of 1983, is a condition that affects fewer than 200,000 Americans. “That’s a considerable number,” Dr. De Vivo said, “when you consider that rare diseases range from affecting just one person to several thousand, but on average a rare disease affects about 4,000 people.” About 7,000 rare diseases are known and are listed on the NIH Office of Rare Diseases’ website.

Approximately two-thirds of rare diseases affect children but are “not limited to child neurology because these children often grow to adulthood, and some rare diseases do not become symptomatic until the adult period,” Dr. De Vivo said. About 80% of rare diseases are caused by genetic mutations. Approximately 25 to 30 million Americans have a rare disease, according to Dr. De Vivo, which equates to about 8% to 10% of the American population. He also noted that only 5% of the 7,000 known rare diseases have FDA-approved treatments.

A Brief History of a Rare Disease—Glut1 Deficiency
Dr. De Vivo chose Glut1 deficiency as the quintessential example of a rare disease. Glut1 deficiency was described 23 years ago in two infants who had a neurologic phenotype. Investigators assumed then that a fundamental defect existed in the transport of glucose from the blood into the brain. Knowing that ketones are the only alternative source of oxidizable fuel for brain metabolism, researchers recommended the ketogenic diet as the symptomatic treatment, and it remains the standard of care today.

Seven years after its first description, pathogenic mutations were identified in the Glut1 gene, or more specifically, the SLC2A1 gene. During the ensuing years the phenotypic variability of Glut1 deficiency has continued to expand and now includes various epileptic conditions, movement disorders, degrees of intellectual disability, and milder persistent paroxysmal variants. It is now estimated that in the United States, the prevalence of Glut1 deficiency is at least 3,150 cases, which is close to the average prevalence of 4,000 cases for the 7,000 known rare diseases.

In 2006, a mouse model was developed to further explore Glut1 deficiency and to investigate possible therapeutic interventions. It became clear that dystonia 18 was an allelic variant of Glut1 deficiency. In 2011, researchers noted that dystonia 9 was also an allelic variant.

Regarding the first two patients, Dr. De Vivo said “both infants presented with an epileptic phenotype in early infancy that contributed to their developmental delay and led to a disturbance in postnatal brain development, deceleration of head growth, and acquired microcephaly.” Both patients had evidence of low CSF glucose and low CSF lactate, which “has turned out to be a critically important diagnostic biomarker to identify this population of patients.” Because the red blood cell membrane is enriched with the Glut1 protein, transport of glucose into the patient’s red blood cells serves as an effective functional assay to identify patients with Glut1 deficiency.

“Since those first two patients, we’ve seen about 150 patients, and others have seen at least that number, if not more,” Dr. De Vivo said. “In every case, we have found that the CSF glucose and the CSF lactate values have been informative. The lumbar puncture is essentially diagnostic.” About two-thirds of patients with low CSF glucose and lactate have a definable disease-causing mutation in the SLC2A1 gene. “But more importantly, about 90% of the CSF glucose values fall below 40 mg/dL or 2.2 mmol/L. About two-thirds of the CSF lactate values fall below 1 mmol/L.”

Haploinsufficiency determines the pattern of inheritance in patients with Glut1 deficiency. The rate of glucose uptake by the patient’s red blood cell is a surrogate for the degree of haploinsufficiency. “More than 90% of the patients we’ve seen have one normal allele and one null allele, and the red blood cell uptake assay has a value of about 50% compared with controls. In a smaller percentage—well below 10% at this point in time—we have identified some patients who have recessive mutations in the Glut1 gene.”

An Evolving Phenotype
Glut1 deficiency also is instructive in the context of rare diseases because its clinical phenotype changes during development. “Developmental delay, to a greater or lesser degree, affects 100% of these patients, as does developmental clumsiness and ataxia,” Dr. De Vivo said.

“This is a lifelong disability that these patients have,” he added. “The epileptic phenotype is largely limited to infancy. You see it in about 90% of the patients with Glut1 deficiency, and then it gradually subsides through childhood, adolescence, and into early adulthood. In contrast, the movement disorder, dominated principally by dystonia, emerges from late infancy and early childhood, up through adolescence, so that about 100% of patients with Glut1 deficiency known to exist demonstrate persistent or paroxysmal dystonia.”

Gene Therapy
“We have now started investigating more effective disease-modifying therapies to treat this condition, starting with experiments involving patients’ cultured human fibroblasts,” Dr. De Vivo said. Using gene therapy strategies in a mouse model, Dr. De Vivo and colleagues have restored Glut1 activity and totally mitigate the motor defect. By restoring Glut1 activity to the mouse model, the researchers were also able to increase the brain expression of Glut1 RNA and Glut1 protein and increase the CSF glucose concentrations from abnormally low values to the normal values of wild-type mice. “We have gotten to the point where we can effectively treat or cure the mouse model of this disease, and now we have to position ourselves to conduct equivalent studies in the human setting,” Dr. De Vivo said.

Take-Home Messages
“It is quite obvious from your own experience and certainly from my experience that rare diseases are common in neurology,” Dr. De Vivo said. “We now have a number of tools with which we can mitigate many of the neurologic phenotypes. Preconception carrier testing is an effective way to prevent untreatable recessive diseases. We can test for more than 100 untreatable recessive diseases, like Tay-Sachs disease, by preconception carrier testing and prevent these diseases from occurring.”

Expanded newborn screening could also make a large impact, “since it would increase the opportunities for proactive treatment of the presymptomatic infant. Early diagnosis and treatment is probably the most important aspect to approaching these patients, as is the case with phenylketonuria, particularly if you can identify the patients from the genotypic point of view before they become phenotypically affected.”

Finally, Dr. De Vivo noted that molecular-based gene therapy is now entering the clinic. “We can now explore the wonderful opportunities that are emerging for gene therapy to rescue the phenotype in our patients who develop neurologic symptoms,” he concluded.

—Glenn S. Williams

PHILADELPHIA—In neurology, rare diseases are not so rare. In fact, they are pretty common. “Essentially every patient who comes to see me in my office has a rare disease,” said Darryl C. De Vivo, MD, in his presidential plenary lecture on rare diseases and neurologic phenotypes at the 66th Annual Meeting of the American Academy of Neurology.

Dr. De Vivo is the Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director Emeritus of the Pediatric Neurology Service at the Columbia University Medical Center in New York City. He is also the Associate Chairman for Pediatric Neurosciences and Developmental Neurobiology, the Founding Director of the Colleen Giblin Research Laboratories for Pediatric Neurology at the Columbia University Medical Center, and the Codirector of the Center for Motor Neuron Biology and Disease.

Rare Diseases—The Basics
Dr. De Vivo outlined some basic facts and statistics regarding rare diseases. “Obviously, each rare disease is rare, by definition, but collectively, they are common.” Rare diseases are generally inherited as recessive traits, and most have a neurologic phenotype. A rare disease, as defined by the Orphan Drug Act of 1983, is a condition that affects fewer than 200,000 Americans. “That’s a considerable number,” Dr. De Vivo said, “when you consider that rare diseases range from affecting just one person to several thousand, but on average a rare disease affects about 4,000 people.” About 7,000 rare diseases are known and are listed on the NIH Office of Rare Diseases’ website.

Approximately two-thirds of rare diseases affect children but are “not limited to child neurology because these children often grow to adulthood, and some rare diseases do not become symptomatic until the adult period,” Dr. De Vivo said. About 80% of rare diseases are caused by genetic mutations. Approximately 25 to 30 million Americans have a rare disease, according to Dr. De Vivo, which equates to about 8% to 10% of the American population. He also noted that only 5% of the 7,000 known rare diseases have FDA-approved treatments.

A Brief History of a Rare Disease—Glut1 Deficiency
Dr. De Vivo chose Glut1 deficiency as the quintessential example of a rare disease. Glut1 deficiency was described 23 years ago in two infants who had a neurologic phenotype. Investigators assumed then that a fundamental defect existed in the transport of glucose from the blood into the brain. Knowing that ketones are the only alternative source of oxidizable fuel for brain metabolism, researchers recommended the ketogenic diet as the symptomatic treatment, and it remains the standard of care today.

Seven years after its first description, pathogenic mutations were identified in the Glut1 gene, or more specifically, the SLC2A1 gene. During the ensuing years the phenotypic variability of Glut1 deficiency has continued to expand and now includes various epileptic conditions, movement disorders, degrees of intellectual disability, and milder persistent paroxysmal variants. It is now estimated that in the United States, the prevalence of Glut1 deficiency is at least 3,150 cases, which is close to the average prevalence of 4,000 cases for the 7,000 known rare diseases.

In 2006, a mouse model was developed to further explore Glut1 deficiency and to investigate possible therapeutic interventions. It became clear that dystonia 18 was an allelic variant of Glut1 deficiency. In 2011, researchers noted that dystonia 9 was also an allelic variant.

Regarding the first two patients, Dr. De Vivo said “both infants presented with an epileptic phenotype in early infancy that contributed to their developmental delay and led to a disturbance in postnatal brain development, deceleration of head growth, and acquired microcephaly.” Both patients had evidence of low CSF glucose and low CSF lactate, which “has turned out to be a critically important diagnostic biomarker to identify this population of patients.” Because the red blood cell membrane is enriched with the Glut1 protein, transport of glucose into the patient’s red blood cells serves as an effective functional assay to identify patients with Glut1 deficiency.

“Since those first two patients, we’ve seen about 150 patients, and others have seen at least that number, if not more,” Dr. De Vivo said. “In every case, we have found that the CSF glucose and the CSF lactate values have been informative. The lumbar puncture is essentially diagnostic.” About two-thirds of patients with low CSF glucose and lactate have a definable disease-causing mutation in the SLC2A1 gene. “But more importantly, about 90% of the CSF glucose values fall below 40 mg/dL or 2.2 mmol/L. About two-thirds of the CSF lactate values fall below 1 mmol/L.”

Haploinsufficiency determines the pattern of inheritance in patients with Glut1 deficiency. The rate of glucose uptake by the patient’s red blood cell is a surrogate for the degree of haploinsufficiency. “More than 90% of the patients we’ve seen have one normal allele and one null allele, and the red blood cell uptake assay has a value of about 50% compared with controls. In a smaller percentage—well below 10% at this point in time—we have identified some patients who have recessive mutations in the Glut1 gene.”

An Evolving Phenotype
Glut1 deficiency also is instructive in the context of rare diseases because its clinical phenotype changes during development. “Developmental delay, to a greater or lesser degree, affects 100% of these patients, as does developmental clumsiness and ataxia,” Dr. De Vivo said.

“This is a lifelong disability that these patients have,” he added. “The epileptic phenotype is largely limited to infancy. You see it in about 90% of the patients with Glut1 deficiency, and then it gradually subsides through childhood, adolescence, and into early adulthood. In contrast, the movement disorder, dominated principally by dystonia, emerges from late infancy and early childhood, up through adolescence, so that about 100% of patients with Glut1 deficiency known to exist demonstrate persistent or paroxysmal dystonia.”

Gene Therapy
“We have now started investigating more effective disease-modifying therapies to treat this condition, starting with experiments involving patients’ cultured human fibroblasts,” Dr. De Vivo said. Using gene therapy strategies in a mouse model, Dr. De Vivo and colleagues have restored Glut1 activity and totally mitigate the motor defect. By restoring Glut1 activity to the mouse model, the researchers were also able to increase the brain expression of Glut1 RNA and Glut1 protein and increase the CSF glucose concentrations from abnormally low values to the normal values of wild-type mice. “We have gotten to the point where we can effectively treat or cure the mouse model of this disease, and now we have to position ourselves to conduct equivalent studies in the human setting,” Dr. De Vivo said.

Take-Home Messages
“It is quite obvious from your own experience and certainly from my experience that rare diseases are common in neurology,” Dr. De Vivo said. “We now have a number of tools with which we can mitigate many of the neurologic phenotypes. Preconception carrier testing is an effective way to prevent untreatable recessive diseases. We can test for more than 100 untreatable recessive diseases, like Tay-Sachs disease, by preconception carrier testing and prevent these diseases from occurring.”

Expanded newborn screening could also make a large impact, “since it would increase the opportunities for proactive treatment of the presymptomatic infant. Early diagnosis and treatment is probably the most important aspect to approaching these patients, as is the case with phenylketonuria, particularly if you can identify the patients from the genotypic point of view before they become phenotypically affected.”

Finally, Dr. De Vivo noted that molecular-based gene therapy is now entering the clinic. “We can now explore the wonderful opportunities that are emerging for gene therapy to rescue the phenotype in our patients who develop neurologic symptoms,” he concluded.

—Glenn S. Williams

PHILADELPHIA—In neurology, rare diseases are not so rare. In fact, they are pretty common. “Essentially every patient who comes to see me in my office has a rare disease,” said Darryl C. De Vivo, MD, in his presidential plenary lecture on rare diseases and neurologic phenotypes at the 66th Annual Meeting of the American Academy of Neurology.

Dr. De Vivo is the Sidney Carter Professor of Neurology, Professor of Pediatrics, and Director Emeritus of the Pediatric Neurology Service at the Columbia University Medical Center in New York City. He is also the Associate Chairman for Pediatric Neurosciences and Developmental Neurobiology, the Founding Director of the Colleen Giblin Research Laboratories for Pediatric Neurology at the Columbia University Medical Center, and the Codirector of the Center for Motor Neuron Biology and Disease.

Rare Diseases—The Basics
Dr. De Vivo outlined some basic facts and statistics regarding rare diseases. “Obviously, each rare disease is rare, by definition, but collectively, they are common.” Rare diseases are generally inherited as recessive traits, and most have a neurologic phenotype. A rare disease, as defined by the Orphan Drug Act of 1983, is a condition that affects fewer than 200,000 Americans. “That’s a considerable number,” Dr. De Vivo said, “when you consider that rare diseases range from affecting just one person to several thousand, but on average a rare disease affects about 4,000 people.” About 7,000 rare diseases are known and are listed on the NIH Office of Rare Diseases’ website.

Approximately two-thirds of rare diseases affect children but are “not limited to child neurology because these children often grow to adulthood, and some rare diseases do not become symptomatic until the adult period,” Dr. De Vivo said. About 80% of rare diseases are caused by genetic mutations. Approximately 25 to 30 million Americans have a rare disease, according to Dr. De Vivo, which equates to about 8% to 10% of the American population. He also noted that only 5% of the 7,000 known rare diseases have FDA-approved treatments.

A Brief History of a Rare Disease—Glut1 Deficiency
Dr. De Vivo chose Glut1 deficiency as the quintessential example of a rare disease. Glut1 deficiency was described 23 years ago in two infants who had a neurologic phenotype. Investigators assumed then that a fundamental defect existed in the transport of glucose from the blood into the brain. Knowing that ketones are the only alternative source of oxidizable fuel for brain metabolism, researchers recommended the ketogenic diet as the symptomatic treatment, and it remains the standard of care today.

Seven years after its first description, pathogenic mutations were identified in the Glut1 gene, or more specifically, the SLC2A1 gene. During the ensuing years the phenotypic variability of Glut1 deficiency has continued to expand and now includes various epileptic conditions, movement disorders, degrees of intellectual disability, and milder persistent paroxysmal variants. It is now estimated that in the United States, the prevalence of Glut1 deficiency is at least 3,150 cases, which is close to the average prevalence of 4,000 cases for the 7,000 known rare diseases.

In 2006, a mouse model was developed to further explore Glut1 deficiency and to investigate possible therapeutic interventions. It became clear that dystonia 18 was an allelic variant of Glut1 deficiency. In 2011, researchers noted that dystonia 9 was also an allelic variant.

Regarding the first two patients, Dr. De Vivo said “both infants presented with an epileptic phenotype in early infancy that contributed to their developmental delay and led to a disturbance in postnatal brain development, deceleration of head growth, and acquired microcephaly.” Both patients had evidence of low CSF glucose and low CSF lactate, which “has turned out to be a critically important diagnostic biomarker to identify this population of patients.” Because the red blood cell membrane is enriched with the Glut1 protein, transport of glucose into the patient’s red blood cells serves as an effective functional assay to identify patients with Glut1 deficiency.

“Since those first two patients, we’ve seen about 150 patients, and others have seen at least that number, if not more,” Dr. De Vivo said. “In every case, we have found that the CSF glucose and the CSF lactate values have been informative. The lumbar puncture is essentially diagnostic.” About two-thirds of patients with low CSF glucose and lactate have a definable disease-causing mutation in the SLC2A1 gene. “But more importantly, about 90% of the CSF glucose values fall below 40 mg/dL or 2.2 mmol/L. About two-thirds of the CSF lactate values fall below 1 mmol/L.”

Haploinsufficiency determines the pattern of inheritance in patients with Glut1 deficiency. The rate of glucose uptake by the patient’s red blood cell is a surrogate for the degree of haploinsufficiency. “More than 90% of the patients we’ve seen have one normal allele and one null allele, and the red blood cell uptake assay has a value of about 50% compared with controls. In a smaller percentage—well below 10% at this point in time—we have identified some patients who have recessive mutations in the Glut1 gene.”

An Evolving Phenotype
Glut1 deficiency also is instructive in the context of rare diseases because its clinical phenotype changes during development. “Developmental delay, to a greater or lesser degree, affects 100% of these patients, as does developmental clumsiness and ataxia,” Dr. De Vivo said.

“This is a lifelong disability that these patients have,” he added. “The epileptic phenotype is largely limited to infancy. You see it in about 90% of the patients with Glut1 deficiency, and then it gradually subsides through childhood, adolescence, and into early adulthood. In contrast, the movement disorder, dominated principally by dystonia, emerges from late infancy and early childhood, up through adolescence, so that about 100% of patients with Glut1 deficiency known to exist demonstrate persistent or paroxysmal dystonia.”

Gene Therapy
“We have now started investigating more effective disease-modifying therapies to treat this condition, starting with experiments involving patients’ cultured human fibroblasts,” Dr. De Vivo said. Using gene therapy strategies in a mouse model, Dr. De Vivo and colleagues have restored Glut1 activity and totally mitigate the motor defect. By restoring Glut1 activity to the mouse model, the researchers were also able to increase the brain expression of Glut1 RNA and Glut1 protein and increase the CSF glucose concentrations from abnormally low values to the normal values of wild-type mice. “We have gotten to the point where we can effectively treat or cure the mouse model of this disease, and now we have to position ourselves to conduct equivalent studies in the human setting,” Dr. De Vivo said.

Take-Home Messages
“It is quite obvious from your own experience and certainly from my experience that rare diseases are common in neurology,” Dr. De Vivo said. “We now have a number of tools with which we can mitigate many of the neurologic phenotypes. Preconception carrier testing is an effective way to prevent untreatable recessive diseases. We can test for more than 100 untreatable recessive diseases, like Tay-Sachs disease, by preconception carrier testing and prevent these diseases from occurring.”

Expanded newborn screening could also make a large impact, “since it would increase the opportunities for proactive treatment of the presymptomatic infant. Early diagnosis and treatment is probably the most important aspect to approaching these patients, as is the case with phenylketonuria, particularly if you can identify the patients from the genotypic point of view before they become phenotypically affected.”

Finally, Dr. De Vivo noted that molecular-based gene therapy is now entering the clinic. “We can now explore the wonderful opportunities that are emerging for gene therapy to rescue the phenotype in our patients who develop neurologic symptoms,” he concluded.

—Glenn S. Williams