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Pelizaeus-Merzbacher disease

ICD-10 Codes

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Description

Pelizaeus-Merzbacher disease (PMD) is an inherited condition involving the brain and spinal cord (central nervous system) that primarily affects males [1]. It is a rare genetic disorder that affects the central nervous system and is linked to problems with the white matter of the brain and spinal cord [2].

PMD is a demyelinating disorder of the CNS belonging to the group of hypomyelinating leukodystrophies [3]. The disease was named in honor of Friederich Pelizaeus, a German physician, and Ludwig Merzbacher, a German pathologist. Pelizaeus discovered PMD in 1885 when he came across a family that had several male individuals with nystagmus, spastic paresis, ataxia, and other symptoms [3].

PMD is an X-linked leukodystrophy, which means that the mutated gene is on the X chromosome, one of the two sex chromosomes [8]. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin [4].

The symptoms of PMD typically present with muscle tone weakness (hypertonia), involuntary eye movements (nystagmus), and developmental delays [7]. Classic Pelizaeus-Merzbacher Disease (PMD) usually presents with abnormal eye movements (nystagmus) or noisy breathing (stridor) in the first month of life, followed by developmental delay, abnormal motor development, and stiffness [9].

The disease is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by a decrease in the amount of insulating myelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as leukodystrophies [10].

Additional Characteristics

  • nystagmus
  • stridor
  • Pelizaeus-Merzbacher disease
  • hypertonia
  • developmental delays
  • demyelinating disorder
  • hypomyelinating leukodystrophy
  • X-linked leukodystrophy
  • leukodystrophy
  • classic Pelizaeus-Merzbacher Disease

Signs and Symptoms

Diagnostic Tests

Pelizaeus-Merzbacher disease (PMD) can be diagnosed through various diagnostic tests, which are essential for confirming the condition and ruling out other potential causes.

Imaging Tests

  • Magnetic Resonance Imaging (MRI): MRI is a crucial diagnostic tool for PMD. It reveals symmetric and widespread abnormality of the white matter of the cerebrum, brain stem, and cerebellum [6]. This imaging test helps identify the characteristic changes in the brain's white matter associated with PMD.

Genetic Tests

  • Molecular genetic testing: This test is used to confirm the diagnosis by detecting mutations in the PLP1 gene, which codes for proteolipid protein 1 (PLP1) [3]. The PLP1 gene is responsible for producing a myelin protein essential for proper brain function.
  • Genetic screening techniques: Since the gene responsible for PMD is known, genetic screening can be used to confirm a diagnosis [8].
  • Fluorescence in-situ hybridization (FISH): FISH is another genetic test that can help diagnose PMD by detecting abnormalities in the PLP1 gene [12].

Other Diagnostic Tests

  • Electrophysiologic tests: These tests may also be performed to assess the condition of the nervous system and confirm the diagnosis.
  • Quantitative multiplex PCR: This test determines the copy number of the PLP1 gene, which is essential for diagnosing PMD [5].
  • Deletion/duplication analysis: This genetic test can help identify deletions or duplications in the PLP1 gene associated with PMD [7].

Clinical Evaluation

In addition to these diagnostic tests, a comprehensive clinical evaluation is necessary to confirm the diagnosis of PMD. This includes assessing symptoms such as nystagmus, motor developmental delays, and spasticity.

It's essential to note that a definitive diagnosis can only be made through molecular genetic testing or other specific genetic tests that detect mutations in the PLP1 gene.

Treatment

Current Status of Drug Treatment for Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease (PMD) is a rare and fatal genetic disorder that affects the central nervous system. While there is no specific treatment available, researchers have been exploring various therapeutic options to manage the symptoms and slow down the progression of the disease.

Supportive Care

According to search result [3], medical therapy for PMD is limited to supportive care, which includes physical therapy, orthotics, and antispasticity agents such as intrathecal baclofen. These treatments aim to alleviate symptoms like spasticity, ataxia, and nystagmus.

Emerging Therapies

Recent studies have shown promise in developing new treatments for PMD. For instance, a team of researchers from Case Western Reserve University has developed a potential treatment method using antisense oligonucleotides drugs to suppress levels of PLP1 RNA [5]. This approach has been shown to reduce symptoms and extend lifespan in animal models.

Additionally, Ionis-developed antisense oligonucleotides have been reported to reduce PMD's hallmark symptoms and extend lifespan in humans [7]. Furthermore, a study on stem cell-based treatment of Pelizaeus Merzbacher disease suggests that differentiated pluripotent stem cells can be used as replacement therapy for treating the disease [8].

Orphan Medication Designation

The European Union has designated a medicine as an orphan medication for the treatment of Pelizaeus-Merzbacher disease on August 16, 2023 [9]. This designation indicates that the medicine is intended to treat a rare disease and may be eligible for incentives and support.

Genetic Basis and Future Directions

PMD is caused by mutations in the PLP1 gene, which encodes the proteolipid protein of myelinating oligodendroglia [11]. Understanding the genetic basis of PMD can lead to the development of targeted therapies. Researchers are also exploring other potential treatments, such as attenuation of endoplasmic reticulum stress using chloroquine [12].

Conclusion

While there is no specific treatment available for Pelizaeus-Merzbacher disease, researchers are actively exploring various therapeutic options to manage symptoms and slow down the progression of the disease. Emerging therapies, including antisense oligonucleotides and stem cell-based treatments, show promise in improving outcomes for individuals with PMD.

Recommended Medications

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Differential Diagnosis

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy that can be challenging to diagnose due to its similarities with other neurological disorders. The differential diagnosis for PMD includes:

  • Metachromatic Leukodystrophy: This is another type of leukodystrophy that affects the myelin sheath, similar to PMD. However, Metachromatic Leukodystrophy is caused by a deficiency of the enzyme arylsulfatase A, whereas PMD is caused by mutations in the PLP1 gene.
  • Adrenoleukodystrophy: This is a genetic disorder that affects the adrenal glands and the myelin sheath. It can cause similar symptoms to PMD, such as nystagmus, spasticity, and developmental delays.
  • Pelizaeus-Merzbacher-like disease (PMLD): This is a rare condition that shares similarities with PMD, but has distinct genetic and clinical features.

Other conditions that may be considered in the differential diagnosis of PMD include:

  • Krabbe disease: A rare genetic disorder that affects the myelin sheath and causes symptoms such as nystagmus, spasticity, and developmental delays.
  • Canavan disease: A genetic disorder that affects the brain's white matter and can cause symptoms similar to PMD.
  • Alexander disease: A rare genetic disorder that affects the brain's white matter and can cause symptoms such as nystagmus, spasticity, and developmental delays.

It is essential to note that a definitive diagnosis of PMD requires genetic testing, which involves analyzing the PLP1 gene for mutations. The differential diagnosis for PMD should be considered in conjunction with clinical features, radiologic findings, and laboratory results to ensure accurate diagnosis and treatment planning.

References:

  • Hudson, L. D. (2003). Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene.
  • Hudson, L. D., & Shy, M. E. (2011). Pelizaeus-Merzbacher disease: a review of the literature and a case report.
  • Pelizaeus-Merzbacher disease. (2022). In GeneReviews [Internet].

Additional Information

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