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but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.
Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.
Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
Pathophysiology and phenotypes
In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.”
In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.
“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”
One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”
These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.
They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.
MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.
Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.
Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.
With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.
Another hypothesis purports that potential of elevated levels of toxic aldehydes/H2O2 similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
Treatment
Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.
One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.
Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.
Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.
Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”
Dr. Rodan has no relevant financial relationships to disclose.
but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.
Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.
Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
Pathophysiology and phenotypes
In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.”
In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.
“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”
One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”
These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.
They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.
MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.
Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.
Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.
With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.
Another hypothesis purports that potential of elevated levels of toxic aldehydes/H2O2 similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
Treatment
Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.
One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.
Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.
Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.
Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”
Dr. Rodan has no relevant financial relationships to disclose.
but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.
Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.
Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
Pathophysiology and phenotypes
In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.”
In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.
“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”
One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”
These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.
They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.
MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.
Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.
Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.
With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.
Another hypothesis purports that potential of elevated levels of toxic aldehydes/H2O2 similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
Treatment
Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.
One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.
Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.
Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.
Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”
Dr. Rodan has no relevant financial relationships to disclose.
FROM CNS-ICNA 2020