Isadora Souza Rocha
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Paola Nabhan Leonel dos Santos
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João Guilherme Bochnia Küster
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Maria Angélica Vieira Lizama
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Vinícius Riegel Giugno
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Context: Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, associated with myelin sheath development and stability. The result is a broad spectrum of clinical phenotypes. Diagnosis is confirmed by genetic testing. Clinical features include hypotonia followed by progressive spasticity, nystagmus, ataxia and cognitive impairment. Males are more affected. Females are asymptomatic or present milder symptoms. Most cases arise from duplications, point and null mutations. Null mutations are associated with milder phenotypes. Brain Magnetic Resonance Imaging (MRI) may reveal hypomyelination. There is no disease modifying treatment for PMD. We aim to present the case of a woman with a novel variant of the PLP1 gene. Case report: A 38-year-old female presented with 23 years of progression of upper limb tremor, speech impairment, lower limb rigidity and urinary incontinence. She reported abnormal development of reading and writing skills. She had a brother with cognitive impairment, delayed motor development, gait disorder and generalized tonic-clonic seizures; and a sister with upper limb tremor, dysarthria and behavioral disorder. Hypomyelination was detected on brain MRI. Complete exome sequencing detected a novel likely pathogenic variant of PLP1 gene: ChrX(GRCh37):NC_000023.10:g.103041651del:NM _000533.3:c449del, p.Asp150AlafsTer10, heterozygous. Conclusions: The patient’s case resembles a milder form of PMD. This is supported by literature linking deletions and female sex to milder phenotypes. In 20 to 40% of cases with suggestive clinical findings, no PLP1 mutation is found. New studies are needed to identify other variants associated with PMD.
The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.