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Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis
H Mierzewska1, E Jamroz, T Mazurczak
1Hanna Mierzewska, MD, PhD, Clinic of Child and Adolescence Neurology, Institute of Mother and Child, 17A Kasprzaka St., 01-211 Warsaw, Poland,
Abstract:
Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination - hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy.
Insights
Pelizaeus-Merzbacher disease (PMD), a genetic disorder affecting myelination, is caused by PLP1 gene mutations. Diagnosis is often delayed, with cerebral palsy being a common misdiagnosis for this hypomyelinating leukodystrophy.
Area of Science:
- Neurogenetics
- Molecular Neurology
- Pediatric Neurology
Background:
- Pelizaeus-Merzbacher disease (PMD) is an X-linked hypomyelinating leukodystrophy.
- It results from mutations in the PLP1 gene, crucial for proteolipid protein 1 synthesis and proper central nervous system myelination.
- Abnormal myelination leads to neurological deficits, including hypomyelination and dysmyelination of cerebral white matter, and sometimes peripheral neuropathy.
Purpose of the Study:
- To investigate the genetic basis of Pelizaeus-Merzbacher disease in suspected cases.
- To analyze the clinical phenotypes and genetic mutations in a cohort of patients with suspected PMD.
- To evaluate diagnostic delays and common misdiagnoses associated with PMD.
Main Methods:
- Genetic analysis of the PLP1 gene in DNA samples from 68 patients with suspected PMD.
- Clinical evaluation and review of medical histories of affected individuals.
- Magnetic resonance imaging (MRI) findings of hypomyelination were used for patient selection.
Main Results:
- PLP1 gene mutations were identified in 14 boys from 11 families, representing approximately 20% of the suspected cases.
- Thirteen patients presented with classical PMD forms, exhibiting variable severity even among siblings.
- One patient had a severe congenital form, and one carrier mother showed symptoms of spastic paraplegia (SPG2). No clear phenotype-genotype correlation was observed.
- Diagnostic delays were common, with misdiagnosis as cerebral palsy occurring frequently.
Conclusions:
- Genetic confirmation of Pelizaeus-Merzbacher disease (PMD) through PLP1 gene mutation analysis is crucial.
- The clinical spectrum of PMD is broad, and diagnostic delays highlight the need for increased awareness.
- Distinguishing PMD from other neurological conditions like cerebral palsy is essential for timely and accurate diagnosis and management.
