Comparing PMD, SPG2, and PMLD (PMDL)
PMD and SPG2 are both caused by a mutation (variant) of the Proteolipid Protein (PLP) gene. The PLP gene (sometimes referred to as PLP1) provides instructions for producing proteolipid protein and a modified version of the protein called DM20. The PLP gene is located on the long arm of the X Chromosome at position 22 (Xq22). PLP and DM20 are primarily located in the brain and spinal cord (central nervous system) and are the main proteins found in myelin. Myelin is the fatty covering that insulates nerve fibers and promotes the transmission of nerve impulses. DM20 is primarily involved in the formation of myelin before birth, PLP is the predominant protein after birth. Although these two disorders affect the same gene they are two different diagnoses, at opposite ends of the spectrum of severity, with PMD being the more severe and SPG2 the less severe.
Pelizaeus-Merzbacher Disease (PMD) is caused by a mutation of the Proteolipid Protein (PLP) gene, there are currently more than 100 identified mutations in the PLP gene that can cause PMD. Mutations are unique to families, once a mutation is identified all family members of the affected individual can be tested to determine if they are a carrier of the PMD mutation. Although PMD is hereditary all mutations must start somewhere, so it is possible that an affected individual is the first person in the family to have the PLP mutation. In this case the mother would not be a carrier, so it is unlikely that she would have another child (or children) with the same diagnosis. There seems to be no specific correlation between the mutation and the severity of PMD. The most common mutation is a duplication of the PLP gene. In many cases genes near the PLP gene can also be duplicated. A deletion of the entire PLP gene can also cause PMD. Mutations in the PLP gene that change one amino acid to another, in a critical area of the proteolipid protein (referred to as a point mutation) can also cause PMD. Because PMD is caused by the bodies inability to form proper myelin (dysmyelination) verses a destruction of already formed myelin (demyelination) it is technically not a progressive disease. The lack of proper myelin is the cause of the symptoms associated with PMD.
PMD is sometimes classified as classic or connatal based upon the severity and onset of symptoms. However, because PMD is present at birth, actually at conception, all PMD cases are technically connatal. All newborns are born with minimal myelin and myelination continues until approximately age two. For this reason many PMD males may appear "normal" at birth, or even up to a few months of age. But as a typical child continues to produce myelin and reach developmental milestones, the PMD child begins to lag behind. In families with a history of PMD the subtle symptoms like nystagmus and hypotonia are generally noticed earlier than in families with no known history. Medical texts generally describe Connatal and Classic PMD as follows;
Connatal PMD is the more severe of the two types. Symptoms can begin in infancy and include involuntary movements of the eyes (nystagmus), problems feeding, breathing issues (stridor), weak muscle tone (hypotonia), progressive spasticity leading to joint deformities (contractures) that restrict movement, ataxia, and seizures. Those affected with connatal PMD show little development of motor skills and intellectual function. Life expectancies are generally only a few months to a few years.
Classic PMD is the more common type. Within the first year of life, those affected with classic PMD typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), speech difficulties (dysarthria) and delayed development of motor skills such as crawling or walking. As the child gets older, nystagmus usually stops but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), and involuntary jerking movements (clonus). Life expectancies may reach into the third to fourth decade.
However, in reality PMD could be classified as severe and less severe. Nystagmus is present in both, though it does usually lessen with age. Both also have hypotonia as infants. In the more severe cases this low tone can contribute to breathing and feeding problems that may require medical intervention. Additionally, the more severely affected are generally more medically fragile. The degrees of movement disorders and developmental delays also varies with both, however all PMD males do make progress. The most severely affected individuals rarely develop any real self help skills, while the less severe may speak, self feed, combat crawl, maneuver their own manual, or power wheelchair and become toilet trained. It is very unlikely that even the least severely affected are able to walk independently. Motor skills are usually more severely affected than intellectual function. Both also experience spasticity and contractures as they mature. Seizures are not typical even in the most severely affected, but the males may have spells that appear as seizure type activity and may respond to anticonvulsant medications. Generally the more severely a male is affected the shorter their life expectancy is. Because life expectancies vary based upon the severity of the disease, some may only live a few years while others may live into their fifties or sixties.
Spastic Paraparesis/Paraplegia type 2 (SPG2) is also caused by mutations in the PLP gene. Although SPG2 and PMD affect the same gene they are two different diagnoses, at opposite ends of the spectrum of severity, with SPG2 being the less severe and PMD being the more severe. There are currently more than 50 mutations that have been found to cause SPG. Some of these mutations disrupt the production of the proteolipid protein but do not interfere with the production of DM20. A deletion of the entire PLP gene can also cause SPG2. The changes to the proteolipid protein (mutations) that cause SPG seem to have a less detrimental effect on myelin production than those that cause PMD. PLP related mutations are generally inherited in an X-linked recessive manner so they mainly affect males, but the inheritance mode with SPG2 is a bit more complicated. SPG2 manifests with or without CNS (central nervous system) involvement and may also affect the peripheral nerves. Onset of SPG is usually during infancy or early childhood. The initial symptoms typically include stiffness, weakness and spasms of the leg muscles. Affected individuals may have difficulties with balance and an abnormal or spastic gait. Individuals with SPG do generally walk, but over time they may require assistive devices such as a walker or wheelchair. They are able to do most things their peers do, and some may even drive. Intelligence levels can range from mild delays to normal. SPG2 individuals usually have a normal life span. Individuals with SPG2 may experience progression of their symptoms and female carriers may also develop mild symptoms as they age. Furthermore, while males with PMD do not reproduce due to the severity of their disease, males with the SPG2 may reproduce.
Pelizaeus-Merzbacher-like disease (PMLD) is a vague diagnosis, describing the similarities of the symptoms to PMD. MRI findings and symptoms are similar in PMD and PMLD, but they differ in inheritance mode and the molecular diagnosis. PMD is X-linked recessive in inheritance, while the inheritance mode with PMLD is unclear. PMD is caused by mutations of the PLP gene, PMLD may be caused by multiple GJA12/GJC2 gene mutations, or other mutations that have yet to be identified. PMD affects the myelination of the CNS (central nervous system) without peripheral nerve involvement, while PMLD patients generally have CNS, as well as, peripheral nerve involvement. PMLD can affect males and females, while PMD tends to affect males. Also, because PMLD is not actually a diagnosis and is more of a description, it is not possible to make accurate predictions about abilities or life expectancies.
*This description is written by Patti Daviau and Amanda Thompson, lay people who have no formal medical training. We have a family history of PMD extending over eight generations, and Patti had three PMD sons of her own. Our family was involved with the doctors of Indiana University School of Medicine and Riley Children's Hospital in multiple research projects that lead to the first identified genetic mutation for PMD. Patti has spent over 30 years, and Amanda has 26 years of providing family support to other families with PMD children. They have personally seen over 300 individuals diagnosed with PMD.*
PMD and SPG2 are both caused by a mutation (variant) of the Proteolipid Protein (PLP) gene. The PLP gene (sometimes referred to as PLP1) provides instructions for producing proteolipid protein and a modified version of the protein called DM20. The PLP gene is located on the long arm of the X Chromosome at position 22 (Xq22). PLP and DM20 are primarily located in the brain and spinal cord (central nervous system) and are the main proteins found in myelin. Myelin is the fatty covering that insulates nerve fibers and promotes the transmission of nerve impulses. DM20 is primarily involved in the formation of myelin before birth, PLP is the predominant protein after birth. Although these two disorders affect the same gene they are two different diagnoses, at opposite ends of the spectrum of severity, with PMD being the more severe and SPG2 the less severe.
Pelizaeus-Merzbacher Disease (PMD) is caused by a mutation of the Proteolipid Protein (PLP) gene, there are currently more than 100 identified mutations in the PLP gene that can cause PMD. Mutations are unique to families, once a mutation is identified all family members of the affected individual can be tested to determine if they are a carrier of the PMD mutation. Although PMD is hereditary all mutations must start somewhere, so it is possible that an affected individual is the first person in the family to have the PLP mutation. In this case the mother would not be a carrier, so it is unlikely that she would have another child (or children) with the same diagnosis. There seems to be no specific correlation between the mutation and the severity of PMD. The most common mutation is a duplication of the PLP gene. In many cases genes near the PLP gene can also be duplicated. A deletion of the entire PLP gene can also cause PMD. Mutations in the PLP gene that change one amino acid to another, in a critical area of the proteolipid protein (referred to as a point mutation) can also cause PMD. Because PMD is caused by the bodies inability to form proper myelin (dysmyelination) verses a destruction of already formed myelin (demyelination) it is technically not a progressive disease. The lack of proper myelin is the cause of the symptoms associated with PMD.
PMD is sometimes classified as classic or connatal based upon the severity and onset of symptoms. However, because PMD is present at birth, actually at conception, all PMD cases are technically connatal. All newborns are born with minimal myelin and myelination continues until approximately age two. For this reason many PMD males may appear "normal" at birth, or even up to a few months of age. But as a typical child continues to produce myelin and reach developmental milestones, the PMD child begins to lag behind. In families with a history of PMD the subtle symptoms like nystagmus and hypotonia are generally noticed earlier than in families with no known history. Medical texts generally describe Connatal and Classic PMD as follows;
Connatal PMD is the more severe of the two types. Symptoms can begin in infancy and include involuntary movements of the eyes (nystagmus), problems feeding, breathing issues (stridor), weak muscle tone (hypotonia), progressive spasticity leading to joint deformities (contractures) that restrict movement, ataxia, and seizures. Those affected with connatal PMD show little development of motor skills and intellectual function. Life expectancies are generally only a few months to a few years.
Classic PMD is the more common type. Within the first year of life, those affected with classic PMD typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), speech difficulties (dysarthria) and delayed development of motor skills such as crawling or walking. As the child gets older, nystagmus usually stops but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), and involuntary jerking movements (clonus). Life expectancies may reach into the third to fourth decade.
However, in reality PMD could be classified as severe and less severe. Nystagmus is present in both, though it does usually lessen with age. Both also have hypotonia as infants. In the more severe cases this low tone can contribute to breathing and feeding problems that may require medical intervention. Additionally, the more severely affected are generally more medically fragile. The degrees of movement disorders and developmental delays also varies with both, however all PMD males do make progress. The most severely affected individuals rarely develop any real self help skills, while the less severe may speak, self feed, combat crawl, maneuver their own manual, or power wheelchair and become toilet trained. It is very unlikely that even the least severely affected are able to walk independently. Motor skills are usually more severely affected than intellectual function. Both also experience spasticity and contractures as they mature. Seizures are not typical even in the most severely affected, but the males may have spells that appear as seizure type activity and may respond to anticonvulsant medications. Generally the more severely a male is affected the shorter their life expectancy is. Because life expectancies vary based upon the severity of the disease, some may only live a few years while others may live into their fifties or sixties.
Spastic Paraparesis/Paraplegia type 2 (SPG2) is also caused by mutations in the PLP gene. Although SPG2 and PMD affect the same gene they are two different diagnoses, at opposite ends of the spectrum of severity, with SPG2 being the less severe and PMD being the more severe. There are currently more than 50 mutations that have been found to cause SPG. Some of these mutations disrupt the production of the proteolipid protein but do not interfere with the production of DM20. A deletion of the entire PLP gene can also cause SPG2. The changes to the proteolipid protein (mutations) that cause SPG seem to have a less detrimental effect on myelin production than those that cause PMD. PLP related mutations are generally inherited in an X-linked recessive manner so they mainly affect males, but the inheritance mode with SPG2 is a bit more complicated. SPG2 manifests with or without CNS (central nervous system) involvement and may also affect the peripheral nerves. Onset of SPG is usually during infancy or early childhood. The initial symptoms typically include stiffness, weakness and spasms of the leg muscles. Affected individuals may have difficulties with balance and an abnormal or spastic gait. Individuals with SPG do generally walk, but over time they may require assistive devices such as a walker or wheelchair. They are able to do most things their peers do, and some may even drive. Intelligence levels can range from mild delays to normal. SPG2 individuals usually have a normal life span. Individuals with SPG2 may experience progression of their symptoms and female carriers may also develop mild symptoms as they age. Furthermore, while males with PMD do not reproduce due to the severity of their disease, males with the SPG2 may reproduce.
Pelizaeus-Merzbacher-like disease (PMLD) is a vague diagnosis, describing the similarities of the symptoms to PMD. MRI findings and symptoms are similar in PMD and PMLD, but they differ in inheritance mode and the molecular diagnosis. PMD is X-linked recessive in inheritance, while the inheritance mode with PMLD is unclear. PMD is caused by mutations of the PLP gene, PMLD may be caused by multiple GJA12/GJC2 gene mutations, or other mutations that have yet to be identified. PMD affects the myelination of the CNS (central nervous system) without peripheral nerve involvement, while PMLD patients generally have CNS, as well as, peripheral nerve involvement. PMLD can affect males and females, while PMD tends to affect males. Also, because PMLD is not actually a diagnosis and is more of a description, it is not possible to make accurate predictions about abilities or life expectancies.
*This description is written by Patti Daviau and Amanda Thompson, lay people who have no formal medical training. We have a family history of PMD extending over eight generations, and Patti had three PMD sons of her own. Our family was involved with the doctors of Indiana University School of Medicine and Riley Children's Hospital in multiple research projects that lead to the first identified genetic mutation for PMD. Patti has spent over 30 years, and Amanda has 26 years of providing family support to other families with PMD children. They have personally seen over 300 individuals diagnosed with PMD.*
